[
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A new family with a bleeding diathesis and FVIII deficiency secondary to abnormal binding of von Willebrand factor (vWF) to factor VIII (FVIII) is described. Two propositi of this family, an 18-year-old male and a 33-year-old female, both with a history of epistaxis, bruising, bleeding from the gums, epistaxis, hemarthrosis, and hematoma, were analyzed. Also additional members of the same family with no bleeding history were also studied. The propositi showed normal vWF activities, low FVIII activity; one of them had been diagnosed as having hemophilia A and the other was a hemophilia A carrier. Both showed a very poor response to treatment with FVIII concentrates and desmopressin (DDAVP) but a good clinical response to cryoprecipitate. APTT was prolonged and no inhibitory activity was noticeable in their plasmas. Thirty-five units per kilogram body weight of Hemofil M was infused to both propositi and FVIII reached basal level within 60 minutes of the infusion. No FVIII response at all was observed in the female after intravenous DDAVP administration. However, the male who received the infusion of 35 U/kg body weight of Humate-P achieved a normal FVIII level that was maintained for 12 hours. Multimeric analysis of vWF was normal in all the members studied. Von Willebrand factor domain for FVIII binding was assayed in the two propositi and in six other members of the same family by using a non-isotopic and sensitive method, a modification of the one previously described, using the Hemofil M concentrate as exogenous FVIII. The data obtained showed that both propositi had similar binding to that observed by using plasma of a patient with severe von Willebrand disease. Furthermore, five siblings had a decreased binding of vWF to FVIII, when compared with plasma from normal individuals or patients with hemophilia A. We also observed that, for screening purpose, the ratio of bound FVIII/immobilized vWF (at saturation of the anti-vWF and offering of 1 U/ml of exogenous FVIII) distinguished two levels of abnormality (normal range 0.70-1.15, propositi 0.004-0.007, and remaining members affected 0.25-0.42). The most probable explanation is that the propositi are homozygous or double heterozygous, the other five siblings affected being heterozygous for a recessive vWF defect. This more accessible assay presented here may be of help in routine analysis for diagnosing this type of von Willebrand disease, which has important implications for therapy and genetic counseling. To assess the frequency and characteristics of children with inherited bleeding disorders that were initially misdiagnosed, leading to inappropriate disease management. This study was conducted at the Haematology/Pathology Department of Fauji Foundation Hospital, Rawalpindi, Pakistan, from August 2014 to August 2018. Children who were diagnosed with an inherited bleeding disorder but did not respond to initial therapy were reevaluated. In total, 62 children were diagnosed with a bleeding disorder. Of these, 27 were diagnosed with an inherited bleeding disorder and 35 with an acquired bleeding disorder. Of the 27 children with inherited bleeding disorders, 18% (n = 5) were misdiagnosed and treated inappropriately. The median age of the misdiagnosed patients was 9 years (range, 5-13 years). Three patients with Bernard-Soulier syndrome had been misdiagnosed as having immune thrombocytopenic purpura, 1 patient with von Willebrand disease had been misdiagnosed as having hemophilia A, and 1 patient with haemophilia B had been misdiagnosed as having hemophilia A. There are chances of misdiagnosis and improper or invasive management if comprehensive laboratory evaluation and a thorough clinical evaluation are not performed in children with congenital bleeding disorders. Congenital bleeding disorders account for approximately one in 10,000 births. Dentists are often anxious about delivering treatment to this special group of patients. In the Irish Republic, patients with inherited bleeding disorders have their dental care co-ordinated centrally at the National Centre for Hereditary Coagulation Disorders (NCHCD), St James's Hospital, Dublin. Dental care is normally integrated with routine outpatient haematological appointments. This ensures regular monitoring of oral health and the early treatment of any hard/soft tissue pathology. This article describes, in simple diagrammatic form, the normal coagulation mechanism (Figures 1 and 2), explains common coagulation terms (Appendix 1), and examines the three most common congenital bleeding disorders: haemophilia A, haemophilia B, and von Willebrand disease. General recommendations based on the current literature are provided with respect to procedures that are appropriate to perform in a general dental practice setting. Although not discussed in this article, it is important to note that non-coagulation bleeding disorders also exist. These include: hereditary haemorrhagic telangiectasia; blood vessel wall defects resulting from connective tissue disorders such as Marfan syndrome and Ehlers-Danlos syndrome; and, platelet disorders such as Bernard-Soulier syndrome, resulting in defective platelet adhesion. Chronic menorrhagia causes anemia and impairment of life quality. In this study the aim was the screening of bleeding disorders in adolescents and young women with menorrhagia. The study was performed prospectively by pediatric hematologists. A form including demographic characteristics of the patients, bleedings other than menorrhagia, familial bleeding history, characteristics of the menorrhagia, and impairment of life quality due to menorrhagia was filled out by the researcher during a face-to-face interview with the patient. A pictorial blood assessment chart was also used for evaluation of blood loss. All patients underwent pelvic ultrasound sonography testing and women also received pelvic examination by gynecologists. Whole blood count, peripheral blood smear, blood group, serum transaminases, urea, creatinine, ferritin, PFA-100, PT, aPTT, INR, TT, fibrinogen, VWF:Ag, VWF:RCo, FVIII, and platelet aggregation assays were performed. Platelet aggregations were studied by lumiaggregometer. Out of 75 patients enrolled, 60 patients completed the study. The mean age was 20.68±10.34 (range: 10-48) years and 65% (n=39) of the patients were younger than 18 years. In 18 (46%) of the adolescents, menorrhagia subsided spontaneously. In 20% (n=12) of the patients, a bleeding disorder was detected (1 case of type 3 von Willebrand disease, 2 patients with low VWF:Ag, 1 case of probable von Willebrand disease, 3 cases of Bernard-Soulier syndrome, 2 cases of Glanzmann thrombasthenia, 2 cases of immune thrombocytopenic purpura, 1 case of congenital factor VII deficiency). In patients with menorrhagia, at least complete blood count, peripheral smear, aPTT, PT, VWF:Ag, VWF:RCo, FVIII, and fibrinogen assays must be performed. When there is history of nose and gum bleeding, platelet function assay by lumiaggregometer must also be performed. In nearly 50% of adolescents, menorrhagia is dysfunctional and transient. Detailed coagulation assays can be postponed in adolescents if bleeding history other than menorrhagia and/or family history of bleeding and/or parental consanguinity is absent. All subjects with menorrhagia must consult with gynecologists and hematologists. None declared. Ehlers-Danlos syndrome includes 11 distinct entities. The diversity of this collagen dysplasia and its combination with other abnormalities make it difficult to understand physiopathologically. A case of Ehlers-Danlos syndrome is reported, which is novel owing to its combination with clotting abnormalities and especially with muscular dystrophy. To our knowledge this has not previously been reported. The patient was a young man aged 16 years who presented with Ehlers-Danlos syndrome satisfying Perelman's diagnostic criteria. His father and two brothers had comparable clinical symptoms, but his mother and sister were healthy. The four male subjects had an increased cephalin-kaolin time, reduced levels of factor VIII and Willebrand's factor (but without haemophilia A or Willebrand's disease), and, especially, an abnormal platelet ATP secretion. The proband alone had muscular disease with bilateral quadriceps fatigability and amyotrophy. The muscle enzyme levels were greatly increased, the electromyographic trace was myogenic, and the biopsy showed severe muscular dystrophy. This new observation poses the problem of the relation between clotting abnormalities and collagen abnormalities in the Ehlers-Danlos syndrome. It is difficult to classify this case within any of the 11 known types because of its muscular manifestations. It may perhaps be a fortuitous combination or an extension of the nosological framework of this syndrome. Differential diagnosis The differential diagnosis for Bernard–Soulier syndrome includes both Glanzmann thrombasthenia and pediatric Von Willebrand disease. BSS platelets do not aggregate to ristocetin, and this defect is not corrected by the addition of normal plasma, distinguishing it from von Willebrand disease. Following is a table comparing its result with other platelet aggregation disorders: Treatment Bleeding events can be controlled by platelet transfusion. Most heterozygotes, with few exceptions, do not have a bleeding diathesis. BSS presents as a bleeding disorder due to the inability of platelets to bind and aggregate at sites of vascular endothelial injury. In the event of an individual with mucosal bleeding tranexamic acid can be given. The affected individual may need to avoid contact sports and medications such as aspirin, which can increase the possibility of bleeding. A potential complication is the possibility of the individual producing anti-platelet antibodies. He published a Swedish-language article in 1926 about the disease, titled Hereditär pseudohemofili (\"Hereditary pseudohemophilia\"). He referenced six previous publications from the years of 1876 to 1922, totalling 19 cases on families with bleeding diatheses. The earlier authors attributed the condition to hemophilia (even in the cases of females) or to thrombopathy, which was discovered shortly before as the cause of what had previously been known as purpura hemorrhagica or Werlhof's disease. Von Willebrand also conducted hematological examinations on Hjördis and some of her family members. He recorded a normal or slightly reduced number of platelets and an undisturbed clot retraction, unlike Glanzmann's thrombasthenia. The bleeding time (Duke) was greatly prolonged, extending to more than 2 hours in some cases, while the clotting time was within the normal range. He concluded that the disease was either a new form of thrombopathy or a condition of the capillary endothelium. – hemorrhagic disorders – afibrinogenemia – bernard-soulier syndrome – disseminated intravascular coagulation – factor v deficiency – factor vii deficiency – factor x deficiency – factor xi deficiency – factor xii deficiency – factor xiii deficiency – hemophilia a – hemophilia b – hypoprothrombinemias – platelet storage pool deficiency – hermanski-pudlak syndrome – purpura, thrombocytopenic, idiopathic – thrombasthenia – thrombocythemia, hemorrhagic – vascular hemostatic disorders – cryoglobulinemia – ehlers-danlos syndrome – hemangioma, cavernous – hemangioma, cavernous, central nervous system – multiple myeloma – pseudoxanthoma elasticum – purpura, hyperglobulinemic – purpura, schoenlein-henoch – scurvy – shwartzman phenomenon – telangiectasia, hereditary hemorrhagic – waldenstrom macroglobulinemia – vitamin k deficiency – hemorrhagic disease of newborn – von willebrand disease – waterhouse-friderichsen syndrome Epistaxis, superficial and deep hematomas, hemarthrosis, gastrointestinal bleeding, hematuria represent the most frequent hemorrhagic events in congenital coagulation disorders. Occasionally, bleeding manifestations occur in unusual sites or are peculiar. A clotting defect may alter the clinical aspect of skin conditions or infections (hemorrhagic scabies or varicella). Hemobilia may occur as a complication of transjugular liver biopsy in hemophilia or Bernard-Soulier syndrome. Hemarthrosis of small joints of feet and hands occur in patients with hemophilia treated with protease inhibitors. Intramedullary hematomas of long bones have been described in α2-plasmin inhibitor or fibrinogen deficiencies. Spleen fracture with consequent hemoperitoneum has been reported in patients with fibrinogen deficiency. Rectus muscle sheath hematoma may occur in patients with factor VII (FVII)or FX deficiency. Acute or subacute intestinal obstruction may be caused by intramural wall hematomas in hemophilia and von Willebrand (vW)-disease. Physicians should always keep in mind that a congenital hemorrhagic disorder may cause bleeding in any tissue of the body and therefore alter the normal clinical features of a given disease. Factor X deficiency Factor XI deficiency Hemophilia A Hemophilia B Bernard-Soulier syndrome Platelet function defects Antiplatelet drug ingestion Fibrinolytic defects The objective of the present study was to determine the pattern of inherited bleeding disorders in southern Iran and evaluate the effect of a comprehensive coagulation laboratory and related efforts. A total of 545 patients with inherited bleeding disorders were evaluated during 1992-2007 by a cross-sectional study. Data were collected by a data-gathering form. Statistical analysis was done using Statistical Package for the Social Sciences version 15. A P value less than 0.05 was considered statistically significant. Overall 411 patients had common bleeding disorders including 326 hemophilia A, 46 hemophilia B, and 39 von Willebrand disease. Seventy-nine patients had rare coagulation disorders including deficiency of factor VII (n = 26), factor X (n = 18), factor XIII (n = 9), factor I (n = 9), factor XI (n = 7), factor V (n = 4), combined factor VIII and factor V (n = 4), and combined factor X and factor VII (n = 2). Fifty-five patients had platelet disorders including 23 with Glanzmann's thrombasthenia, 15 with Bernard-Soulier syndrome, and 17 with other platelet disorders, most of which (45) were diagnosed after the establishment of the comprehensive coagulation laboratory. Annual mean number of new diagnosed patients with common and rare bleeding disorders increased from 29 +/- 4 to 38 +/- 17. The ratio of the patients diagnosed with rare bleeding disorders to common bleeding disorders significantly increased after the establishment of the comprehensive diagnosis laboratory (P < 0.001).It seems that implementation of collaborative projects by the Shiraz Hemophilia Society and the establishment of the comprehensive coagulation laboratory and treatment centers have been successful in increasing diagnosis of the inherited bleeding disorders and consequently better management of the patients. – blood coagulation disorders – coagulation protein disorders – activated protein c resistance – afibrinogenemia – factor v deficiency – factor vii deficiency – factor x deficiency – factor xi deficiency – factor xii deficiency – factor xiii deficiency – hemophilia a – hemophilia b – hypoprothrombinemias – von willebrand disease – disseminated intravascular coagulation – blood coagulation disorders, inherited – activated protein c resistance – afibrinogenemia – antithrombin iii deficiency – bernard-soulier syndrome – factor v deficiency – factor vii deficiency – factor x deficiency – factor xi deficiency – factor xii deficiency – factor xiii deficiency – hemophilia a – hemophilia b – hermanski-pudlak syndrome – hypoprothrombinemias – protein c deficiency – thrombasthenia – von willebrand disease – wiskott-aldrich syndrome – platelet storage pool deficiency – hermanski-pudlak syndrome – protein s deficiency Diagnosis Basic tests performed in any patient with bleeding problems are a complete blood count-CBC (especially platelet counts), activated partial thromboplastin time-APTT, prothrombin time with International Normalized Ratio-PTINR, thrombin time-TT, and fibrinogen level. Patients with abnormal tests typically undergo further testing for hemophilias. Other coagulation factor assays may be performed depending on the results of a coagulation screen. Patients with von Willebrand disease typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time. To determine the frequency of inherited bleeding disorders, its complications, and treatment modalities available for its treatment. Cross-sectional study. Patients with a history of bleeding tendency were tested for confirmation of the diagnosis. History and clinical findings were recorded. Laboratory analysis included prothrombin time (PT), activated partial thromboplastin time (APTT), bleeding time (BT), and fibrinogen assay. Patients with prolonged APTT were tested for factors VIII (FVIII) and IX (FIX). If FVIII was low, von Willebrand factor: antigen (vWF:Ag) and von Willebrand factor:ristocetin cofactor (vWF:RCo) were performed. When PT and APTT both were prolonged, FV, FX, and FII were tested. Platelet aggregation studies were done when there was isolated prolonged BT. Urea clot solubility test was done when all coagulation tests were normal. All patients with hemophilia A and B were evaluated for inhibitors. Of the 376 patients, inherited bleeding disorder was diagnosed in 318 (85%) cases. Median age of patients was 16.4 years. Hemophilia A was the commonest inherited bleeding disorder that was observed in 140 (37.2%) followed by vWD 68 (18.0%), platelet function disorders 48 (12.8%), and hemophilia B in 33 (8.8%) cases. We also found rare congenital factor deficiencies in 13 (3.4%), low VWF in 11 (3.0%) participants and 5 (1.3%) in female hemophilia carriers. Hemarthrosis was the most frequent symptom in hemophilia A and B (79.7%) involving knee joint. Inhibitor was detected in 21 (15%) cases. Fresh frozen plasma/cryoprecipitate were the most common modality of treatment. In 58 patients, no abnormality was detected in coagulation profile. Hemophilia A and vWD are the most common congenital bleeding disorders in this study. Hemarthrosis involving knee joint was the most common complication. Inhibitor was detected in a significant number of patients. Plasma is still the most common modality of treatment. Hemophilia is widely distributed all over the world, but little is known about its clinical profile in resource-limited regions. An insight into its clinical spectrum will help in the formulation of policies to improve the situation in these areas. To study the clinical profile of hemophiliacs (age <18 years) in Jodhpur region and screen them for transfusion-transmitted infections. A cross-sectional study conducted in the Department of Pediatrics, Umaid Hospital, Dr. S. N. Medical College, Jodhpur, over a period of 12 months. Out of a total of 56 cases enrolled, 51 (91%) cases were diagnosed as hemophilia A while 5 (9%) were diagnosed as hemophilia B. Positive family history was found in 26 (46%) cases. According to their factor levels, 25 (44%) cases had severe disease, 20 (36%) had moderate disease, and 11 (20%) had mild disease. The mean age of onset of symptoms and diagnosis was 1.73 ± 1.43 and 3.87 ± 3.84 years, respectively. First clinical presentation was posttraumatic bleed in 20 (36%), gum bleeds in 17 (30%), epistaxis in 4 (7%), joint bleeds in 4 (7%), skin bleeds in 4 (7%), and circumcision bleed in 3 (5%) cases. Knee joint was the predominant joint affected by hemarthrosis in 38 (68%), followed by ankle in 29 (52%), elbow in 20 (36%), and hip joint in 7 (13%) cases. All patients had a negative screening test for transfusion-transmitted infections. Occurrence of posttraumatic bleeds and gum bleeds in an otherwise normal child should warn the clinician for evaluation of hemophilia. Acquired hemophilia Ehlers-Danlos syndrome Factor XI deficiency Glanzmann thrombasthenia Haemophilia C Haemophilia type B Physical child abuse Platelet disorders Von Willebrand disease Normal values fall between 3 – 10 minutes depending on the method used. A disadvantage of Ivy's method is closure of puncture wound before stoppage of bleeding. Duke's method With the Duke;s method, the patient is pricked with a special needle or lancet, preferably on the earlobe or fingertip, after having been swabbed with alcohol. The prick is about 3–4 mm deep. The patient then wipes the blood every 30 seconds with a filter paper. The test ceases when bleeding ceases. The usual time is about 2–5 minutes. This method is not recommended and cannot be standardized because it can cause a large local hematoma. Interpretation Bleeding time is affected by platelet function, certain vascular disorders and von Willebrand Disease—not by other coagulation factors such as haemophilia. Diseases that cause prolonged bleeding time include thrombocytopenia, disseminated intravascular coagulation (DIC), Bernard-Soulier disease, and Glanzmann's thrombasthenia. Keeping an updated registry of bleeding disorders is crucial for planning care and documenting prevalence. We aimed to assess the prevalence of various bleeding disorders including rare inherited coagulation and platelet disorders concerning their clinico-epidemiological, diagnostic data and bleeding manifestations severity. Patients suffering from manifestations of bleeding or coagulation disorders presented to Hematology Clinic during 16 years were included and prospectively followed up. Demographics, clinical characteristics, complete blood count, bleeding, prothrombin and activated partial thromboplastin times, platelet aggregation tests and bone marrow aspiration were recorded. Overall 687 patients with bleeding disorders from total 2949 patients were identified. Inherited coagulation defects were found in 27.2%; hemophilia A (70.6%), hemophilia B (13.9%), factor I deficiency (2.3%), factor V deficiency (1.6%), factor X deficiency (4.2%), factor VII deficiency (2.6%), factor XIII deficiency (1.1%), combined factor deficiency (2.1%) and unclassified coagulation disorders in 1.6% of studied patients. Overall 72.7% had diagnosed with platelet disorders; immune thrombocytopenia was the commonest (74.8%), and inherited conditions represent (25.2%) in the following order: Glanzman's thrombasthenia (11.2%), von Willebrand disease (6.6%), Bernard-Soulier syndrome (1%) and Chediak Higashi in 0.4% and unclassified in 6%. Median age of diagnosis of coagulation and platelet disorders were 33 and 72 months. Presenting symptoms of coagulation disorders were: 25.1% post circumcision bleeding, 22.5% ecchymosis, 20.9% hemoarthrosis and 15% epistaxis. Symptoms of rare coagulation disorders were postcircumcision bleeding (20%), bleeding umbilical stump (20%), epistaxis (12%), hemoarthrosis (8%) and hematomas (4%). Presenting symptoms in rare inherited platelet disorders were purpura, ecchymosis, epistaxis and bleeding gums, respectively. Analysis of the clinico-epidemiological data of patients with bleeding disorders is a useful tool for monitoring and improving their quality of care. Causes other than coagulation Bleeding diathesis may also be caused by impaired wound healing (as in scurvy), or by thinning of the skin, such as in Cushing's syndrome. Genetic Some people lack genes that typically produce the protein coagulation factors that allow normal clotting. Various types of hemophilia and von Willebrand disease are the major genetic disorders associated with coagulopathy. Rare examples are Bernard–Soulier syndrome, Wiskott–Aldrich syndrome and Glanzmann's thrombasthenia. Gene therapy treatments may be a solution as they involve in the insertion of normal genes to replace defective genes causing for the genetic disorder. Gene therapy is a source of active research that hold promise for the future. Diagnosis Comparing coagulation tests Other conditions can also present similarly with bleeding after minor trauma or spontaneous bleeds and require exclusion before confirming the diagnosis of hemophilia. Some of these conditions include von Willebrand disease, scurvy, diseases of platelet dysfunction, deficiency of other coagulation factors like V, VII, X, or fibrinogen, Ehlers-Danlos syndrome, Fabry disease, disseminated intravascular coagulation, and child abuse. In von Willebrand disease, bleeding symptoms can be similar to mild hemophilia, but patients with von Willebrand disease have more mucosal bleeding compared to musculoskeletal bleeding seen in hemophilia. Von Willebrand disease is diagnosed by checking for von Willebrand factor antigen or von Willebrand factor multimers. [40] Similarly, in scurvy, Ehlers-Danlos syndrome, and Fabry disease; also, the bleeding is usually mucosal, unlike hemophilia, where it is musculoskeletal. In scurvy, there is a deficiency of vitamin C. [41] In Ehlers-Danlos syndrome, the skin is hyperextensible, and joints are hypermobile. The diagnosis is usually through clinical features, genetic testing, and tissue biopsy. [42] Similarly, in Fabry disease, patients may also have other organs being affected, including kidneys and heart, and have skin lesions called angiokeratomas. They also have pain in the extremities. Fabry disease is usually diagnosed with clinical findings and genetic testing. [43] In cases of platelet dysfunction disorders, bleeding is usually mucocutaneous, unlike hemophilia. Usually, these disorders are diagnosed by platelet aggregation studies or platelet electron microscopy. [44] In the deficiency of other coagulation factors, musculoskeletal bleeding is uncommon. In fact, sometimes thrombosis can occur, especially in patients with factor VII or fibrinogen deficiency or in patients with combined factor V and VIII deficiency. Specific coagulation factor assays usually confirm the diagnosis. Disseminated intravascular coagulation (DIC) that mimics hemophilia is hard to differentiate, but usually, there is an underlying condition in DIC, for example, acute promyelocytic leukemia. Diagnosis is usually carried out by blood tests that show decreased platelet count and the absence of factor VIII autoantibodies. Child abuse can sometimes be misidentified and confused with hemophilia, and it is essential to find inconsistencies in the history of how trauma has occurred. Other signs of malnourishment require vigilance, and x-rays may reveal evidence of fractures of different ages. [45] [46] – anemia, hypoplastic, congenital – anemia, Diamond–Blackfan – fanconi anemia – ataxia telangiectasia – blood coagulation disorders, inherited – activated protein C resistance – afibrinogenemia – antithrombin III deficiency – Bernard–Soulier syndrome – factor V deficiency – factor VII deficiency – factor X deficiency – factor XI deficiency – factor XII deficiency – factor XIII deficiency – hemophilia A – hemophilia B – Hermansky–Pudlak syndrome – hypoprothrombinemias – protein C deficiency – thrombasthenia – Von Willebrand disease – Wiskott–Aldrich syndrome – CADASIL – cardiomyopathy, hypertrophic, familial – cherubism The International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) is useful for assessing bleeding disorders. Its utility was tested in a small study, including patients with known inherited platelet disorders. The study demonstrated a specificity of 100%, a positive predictive value of 90%, and a negative predictive value of 100% using this assessment tool. [17] In the setting of von Willebrand disease, a BAT score >6 repeatedly correlates to a 99% probability of an inherited platelet defect such as BSS. [8] ] Similarly, other bleeding assessment tools like Molecular and Clinical Markers for the Diagnosis and Management (MCMDM) of type 1 von Willebrand's disease (VWD) and the World Health Organization Bleeding Assessment Tool are similar tools. An electronic version of MCMDM-type-1 VWD was developed in 2010. [17] Hemophilia is a sex-linked recessive genetic disorder characterized by the absence or deficiency of factor VIII (hemophilia A, orclassic hemophilia) or factor IX (hemophilia B, or Christmas disease) (Chap. 141). Hemophilia A constitutes 85% of cases. Spontaneous hemarthrosis is a common problem with both types of hemophilia and can lead to a deforming arthritis. The frequency and severity of hemarthrosis are related to the degree of clotting factor deficiency. Hemarthrosis is not common in other disorders of coagulation such as von Willebrand disease, factor V deficiency, warfarin therapy, or thrombocytopenia. Hemarthrosis occurs after 1 year of age, when a child begins to walk 2241 and run. In order of frequency, the joints most commonly affected are theknees,ankles,elbows,shoulders,andhips.Smalljointsofthehands and feet are occasionally involved. The authors report a case of hemarthrosis complicated by severe anemia related to a congenital connective tissue disease: Ehlers-Danlos syndrome. A boy fell down and suffered tumefaction of both knees with bilateral rupture of the rotula tendon. He underwent surgical reinsertion of each tendon on the rotula. He later showed an unexpected ongoing hematic effusion, with severe anemia. He was screened for coagulation disorders with no results. On taking a more detailed history and investigating the patient's phenotypical features, the authors diagnosed Ehlers-Danlos syndrome, hypermobile variant. The hemarthrosis and anemia were thus concluded to be consequences of excessive tissue fragility due to a congenital connective tissue disease.\nHere is the question:\nPEDIATRICS: An 18-month-old boy, with complete immunization schedule to date, who consults the Emergency Department for right knee swelling after playing in the park, without obvious trauma. In the directed anamnesis, the mother refers that an uncle of hers had similar problems. The ultrasound examination is compatible with hemarthrosis and in the analytical analysis only an APTT lengthening of 52'' (normal 25-35'') stands out. What is the most probable diagnostic hypothesis?\nHere are the potential choices:\n1. Marfan syndrome.\n2. Von-Willebrand's disease.\n3. Ehlers-Danlos disease.\n4. Hemophilia A.\n5. Bernard-Soulier disease.\nThe correct answer is: ",
        "gold_answer": "4 Hemophilia A.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A new family with a bleeding diathesis and FVIII deficiency secondary to abnormal binding of von Willebrand factor (vWF) to factor VIII (FVIII) is described. Two propositi of this family, an 18-year-old male and a 33-year-old female, both with a history of epistaxis, bruising, bleeding from the gums, epistaxis, hemarthrosis, and hematoma, were analyzed. Also additional members of the same family with no bleeding history were also studied. The propositi showed normal vWF activities, low FVIII activity; one of them had been diagnosed as having hemophilia A and the other was a hemophilia A carrier. Both showed a very poor response to treatment with FVIII concentrates and desmopressin (DDAVP) but a good clinical response to cryoprecipitate. APTT was prolonged and no inhibitory activity was noticeable in their plasmas. Thirty-five units per kilogram body weight of Hemofil M was infused to both propositi and FVIII reached basal level within 60 minutes of the infusion. No FVIII response at all was observed in the female after intravenous DDAVP administration. However, the male who received the infusion of 35 U/kg body weight of Humate-P achieved a normal FVIII level that was maintained for 12 hours. Multimeric analysis of vWF was normal in all the members studied. Von Willebrand factor domain for FVIII binding was assayed in the two propositi and in six other members of the same family by using a non-isotopic and sensitive method, a modification of the one previously described, using the Hemofil M concentrate as exogenous FVIII. The data obtained showed that both propositi had similar binding to that observed by using plasma of a patient with severe von Willebrand disease. Furthermore, five siblings had a decreased binding of vWF to FVIII, when compared with plasma from normal individuals or patients with hemophilia A. We also observed that, for screening purpose, the ratio of bound FVIII/immobilized vWF (at saturation of the anti-vWF and offering of 1 U/ml of exogenous FVIII) distinguished two levels of abnormality (normal range 0.70-1.15, propositi 0.004-0.007, and remaining members affected 0.25-0.42). The most probable explanation is that the propositi are homozygous or double heterozygous, the other five siblings affected being heterozygous for a recessive vWF defect. This more accessible assay presented here may be of help in routine analysis for diagnosing this type of von Willebrand disease, which has important implications for therapy and genetic counseling. To assess the frequency and characteristics of children with inherited bleeding disorders that were initially misdiagnosed, leading to inappropriate disease management. This study was conducted at the Haematology/Pathology Department of Fauji Foundation Hospital, Rawalpindi, Pakistan, from August 2014 to August 2018. Children who were diagnosed with an inherited bleeding disorder but did not respond to initial therapy were reevaluated. In total, 62 children were diagnosed with a bleeding disorder. Of these, 27 were diagnosed with an inherited bleeding disorder and 35 with an acquired bleeding disorder. Of the 27 children with inherited bleeding disorders, 18% (n = 5) were misdiagnosed and treated inappropriately. The median age of the misdiagnosed patients was 9 years (range, 5-13 years). Three patients with Bernard-Soulier syndrome had been misdiagnosed as having immune thrombocytopenic purpura, 1 patient with von Willebrand disease had been misdiagnosed as having hemophilia A, and 1 patient with haemophilia B had been misdiagnosed as having hemophilia A. There are chances of misdiagnosis and improper or invasive management if comprehensive laboratory evaluation and a thorough clinical evaluation are not performed in children with congenital bleeding disorders. Congenital bleeding disorders account for approximately one in 10,000 births. Dentists are often anxious about delivering treatment to this special group of patients. In the Irish Republic, patients with inherited bleeding disorders have their dental care co-ordinated centrally at the National Centre for Hereditary Coagulation Disorders (NCHCD), St James's Hospital, Dublin. Dental care is normally integrated with routine outpatient haematological appointments. This ensures regular monitoring of oral health and the early treatment of any hard/soft tissue pathology. This article describes, in simple diagrammatic form, the normal coagulation mechanism (Figures 1 and 2), explains common coagulation terms (Appendix 1), and examines the three most common congenital bleeding disorders: haemophilia A, haemophilia B, and von Willebrand disease. General recommendations based on the current literature are provided with respect to procedures that are appropriate to perform in a general dental practice setting. Although not discussed in this article, it is important to note that non-coagulation bleeding disorders also exist. These include: hereditary haemorrhagic telangiectasia; blood vessel wall defects resulting from connective tissue disorders such as Marfan syndrome and Ehlers-Danlos syndrome; and, platelet disorders such as Bernard-Soulier syndrome, resulting in defective platelet adhesion. Chronic menorrhagia causes anemia and impairment of life quality. In this study the aim was the screening of bleeding disorders in adolescents and young women with menorrhagia. The study was performed prospectively by pediatric hematologists. A form including demographic characteristics of the patients, bleedings other than menorrhagia, familial bleeding history, characteristics of the menorrhagia, and impairment of life quality due to menorrhagia was filled out by the researcher during a face-to-face interview with the patient. A pictorial blood assessment chart was also used for evaluation of blood loss. All patients underwent pelvic ultrasound sonography testing and women also received pelvic examination by gynecologists. Whole blood count, peripheral blood smear, blood group, serum transaminases, urea, creatinine, ferritin, PFA-100, PT, aPTT, INR, TT, fibrinogen, VWF:Ag, VWF:RCo, FVIII, and platelet aggregation assays were performed. Platelet aggregations were studied by lumiaggregometer. Out of 75 patients enrolled, 60 patients completed the study. The mean age was 20.68±10.34 (range: 10-48) years and 65% (n=39) of the patients were younger than 18 years. In 18 (46%) of the adolescents, menorrhagia subsided spontaneously. In 20% (n=12) of the patients, a bleeding disorder was detected (1 case of type 3 von Willebrand disease, 2 patients with low VWF:Ag, 1 case of probable von Willebrand disease, 3 cases of Bernard-Soulier syndrome, 2 cases of Glanzmann thrombasthenia, 2 cases of immune thrombocytopenic purpura, 1 case of congenital factor VII deficiency). In patients with menorrhagia, at least complete blood count, peripheral smear, aPTT, PT, VWF:Ag, VWF:RCo, FVIII, and fibrinogen assays must be performed. When there is history of nose and gum bleeding, platelet function assay by lumiaggregometer must also be performed. In nearly 50% of adolescents, menorrhagia is dysfunctional and transient. Detailed coagulation assays can be postponed in adolescents if bleeding history other than menorrhagia and/or family history of bleeding and/or parental consanguinity is absent. All subjects with menorrhagia must consult with gynecologists and hematologists. None declared. Ehlers-Danlos syndrome includes 11 distinct entities. The diversity of this collagen dysplasia and its combination with other abnormalities make it difficult to understand physiopathologically. A case of Ehlers-Danlos syndrome is reported, which is novel owing to its combination with clotting abnormalities and especially with muscular dystrophy. To our knowledge this has not previously been reported. The patient was a young man aged 16 years who presented with Ehlers-Danlos syndrome satisfying Perelman's diagnostic criteria. His father and two brothers had comparable clinical symptoms, but his mother and sister were healthy. The four male subjects had an increased cephalin-kaolin time, reduced levels of factor VIII and Willebrand's factor (but without haemophilia A or Willebrand's disease), and, especially, an abnormal platelet ATP secretion. The proband alone had muscular disease with bilateral quadriceps fatigability and amyotrophy. The muscle enzyme levels were greatly increased, the electromyographic trace was myogenic, and the biopsy showed severe muscular dystrophy. This new observation poses the problem of the relation between clotting abnormalities and collagen abnormalities in the Ehlers-Danlos syndrome. It is difficult to classify this case within any of the 11 known types because of its muscular manifestations. It may perhaps be a fortuitous combination or an extension of the nosological framework of this syndrome. Differential diagnosis The differential diagnosis for Bernard–Soulier syndrome includes both Glanzmann thrombasthenia and pediatric Von Willebrand disease. BSS platelets do not aggregate to ristocetin, and this defect is not corrected by the addition of normal plasma, distinguishing it from von Willebrand disease. Following is a table comparing its result with other platelet aggregation disorders: Treatment Bleeding events can be controlled by platelet transfusion. Most heterozygotes, with few exceptions, do not have a bleeding diathesis. BSS presents as a bleeding disorder due to the inability of platelets to bind and aggregate at sites of vascular endothelial injury. In the event of an individual with mucosal bleeding tranexamic acid can be given. The affected individual may need to avoid contact sports and medications such as aspirin, which can increase the possibility of bleeding. A potential complication is the possibility of the individual producing anti-platelet antibodies. He published a Swedish-language article in 1926 about the disease, titled Hereditär pseudohemofili (\"Hereditary pseudohemophilia\"). He referenced six previous publications from the years of 1876 to 1922, totalling 19 cases on families with bleeding diatheses. The earlier authors attributed the condition to hemophilia (even in the cases of females) or to thrombopathy, which was discovered shortly before as the cause of what had previously been known as purpura hemorrhagica or Werlhof's disease. Von Willebrand also conducted hematological examinations on Hjördis and some of her family members. He recorded a normal or slightly reduced number of platelets and an undisturbed clot retraction, unlike Glanzmann's thrombasthenia. The bleeding time (Duke) was greatly prolonged, extending to more than 2 hours in some cases, while the clotting time was within the normal range. He concluded that the disease was either a new form of thrombopathy or a condition of the capillary endothelium. – hemorrhagic disorders – afibrinogenemia – bernard-soulier syndrome – disseminated intravascular coagulation – factor v deficiency – factor vii deficiency – factor x deficiency – factor xi deficiency – factor xii deficiency – factor xiii deficiency – hemophilia a – hemophilia b – hypoprothrombinemias – platelet storage pool deficiency – hermanski-pudlak syndrome – purpura, thrombocytopenic, idiopathic – thrombasthenia – thrombocythemia, hemorrhagic – vascular hemostatic disorders – cryoglobulinemia – ehlers-danlos syndrome – hemangioma, cavernous – hemangioma, cavernous, central nervous system – multiple myeloma – pseudoxanthoma elasticum – purpura, hyperglobulinemic – purpura, schoenlein-henoch – scurvy – shwartzman phenomenon – telangiectasia, hereditary hemorrhagic – waldenstrom macroglobulinemia – vitamin k deficiency – hemorrhagic disease of newborn – von willebrand disease – waterhouse-friderichsen syndrome Epistaxis, superficial and deep hematomas, hemarthrosis, gastrointestinal bleeding, hematuria represent the most frequent hemorrhagic events in congenital coagulation disorders. Occasionally, bleeding manifestations occur in unusual sites or are peculiar. A clotting defect may alter the clinical aspect of skin conditions or infections (hemorrhagic scabies or varicella). Hemobilia may occur as a complication of transjugular liver biopsy in hemophilia or Bernard-Soulier syndrome. Hemarthrosis of small joints of feet and hands occur in patients with hemophilia treated with protease inhibitors. Intramedullary hematomas of long bones have been described in α2-plasmin inhibitor or fibrinogen deficiencies. Spleen fracture with consequent hemoperitoneum has been reported in patients with fibrinogen deficiency. Rectus muscle sheath hematoma may occur in patients with factor VII (FVII)or FX deficiency. Acute or subacute intestinal obstruction may be caused by intramural wall hematomas in hemophilia and von Willebrand (vW)-disease. Physicians should always keep in mind that a congenital hemorrhagic disorder may cause bleeding in any tissue of the body and therefore alter the normal clinical features of a given disease. Factor X deficiency Factor XI deficiency Hemophilia A Hemophilia B Bernard-Soulier syndrome Platelet function defects Antiplatelet drug ingestion Fibrinolytic defects The objective of the present study was to determine the pattern of inherited bleeding disorders in southern Iran and evaluate the effect of a comprehensive coagulation laboratory and related efforts. A total of 545 patients with inherited bleeding disorders were evaluated during 1992-2007 by a cross-sectional study. Data were collected by a data-gathering form. Statistical analysis was done using Statistical Package for the Social Sciences version 15. A P value less than 0.05 was considered statistically significant. Overall 411 patients had common bleeding disorders including 326 hemophilia A, 46 hemophilia B, and 39 von Willebrand disease. Seventy-nine patients had rare coagulation disorders including deficiency of factor VII (n = 26), factor X (n = 18), factor XIII (n = 9), factor I (n = 9), factor XI (n = 7), factor V (n = 4), combined factor VIII and factor V (n = 4), and combined factor X and factor VII (n = 2). Fifty-five patients had platelet disorders including 23 with Glanzmann's thrombasthenia, 15 with Bernard-Soulier syndrome, and 17 with other platelet disorders, most of which (45) were diagnosed after the establishment of the comprehensive coagulation laboratory. Annual mean number of new diagnosed patients with common and rare bleeding disorders increased from 29 +/- 4 to 38 +/- 17. The ratio of the patients diagnosed with rare bleeding disorders to common bleeding disorders significantly increased after the establishment of the comprehensive diagnosis laboratory (P < 0.001).It seems that implementation of collaborative projects by the Shiraz Hemophilia Society and the establishment of the comprehensive coagulation laboratory and treatment centers have been successful in increasing diagnosis of the inherited bleeding disorders and consequently better management of the patients. – blood coagulation disorders – coagulation protein disorders – activated protein c resistance – afibrinogenemia – factor v deficiency – factor vii deficiency – factor x deficiency – factor xi deficiency – factor xii deficiency – factor xiii deficiency – hemophilia a – hemophilia b – hypoprothrombinemias – von willebrand disease – disseminated intravascular coagulation – blood coagulation disorders, inherited – activated protein c resistance – afibrinogenemia – antithrombin iii deficiency – bernard-soulier syndrome – factor v deficiency – factor vii deficiency – factor x deficiency – factor xi deficiency – factor xii deficiency – factor xiii deficiency – hemophilia a – hemophilia b – hermanski-pudlak syndrome – hypoprothrombinemias – protein c deficiency – thrombasthenia – von willebrand disease – wiskott-aldrich syndrome – platelet storage pool deficiency – hermanski-pudlak syndrome – protein s deficiency Diagnosis Basic tests performed in any patient with bleeding problems are a complete blood count-CBC (especially platelet counts), activated partial thromboplastin time-APTT, prothrombin time with International Normalized Ratio-PTINR, thrombin time-TT, and fibrinogen level. Patients with abnormal tests typically undergo further testing for hemophilias. Other coagulation factor assays may be performed depending on the results of a coagulation screen. Patients with von Willebrand disease typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time. To determine the frequency of inherited bleeding disorders, its complications, and treatment modalities available for its treatment. Cross-sectional study. Patients with a history of bleeding tendency were tested for confirmation of the diagnosis. History and clinical findings were recorded. Laboratory analysis included prothrombin time (PT), activated partial thromboplastin time (APTT), bleeding time (BT), and fibrinogen assay. Patients with prolonged APTT were tested for factors VIII (FVIII) and IX (FIX). If FVIII was low, von Willebrand factor: antigen (vWF:Ag) and von Willebrand factor:ristocetin cofactor (vWF:RCo) were performed. When PT and APTT both were prolonged, FV, FX, and FII were tested. Platelet aggregation studies were done when there was isolated prolonged BT. Urea clot solubility test was done when all coagulation tests were normal. All patients with hemophilia A and B were evaluated for inhibitors. Of the 376 patients, inherited bleeding disorder was diagnosed in 318 (85%) cases. Median age of patients was 16.4 years. Hemophilia A was the commonest inherited bleeding disorder that was observed in 140 (37.2%) followed by vWD 68 (18.0%), platelet function disorders 48 (12.8%), and hemophilia B in 33 (8.8%) cases. We also found rare congenital factor deficiencies in 13 (3.4%), low VWF in 11 (3.0%) participants and 5 (1.3%) in female hemophilia carriers. Hemarthrosis was the most frequent symptom in hemophilia A and B (79.7%) involving knee joint. Inhibitor was detected in 21 (15%) cases. Fresh frozen plasma/cryoprecipitate were the most common modality of treatment. In 58 patients, no abnormality was detected in coagulation profile. Hemophilia A and vWD are the most common congenital bleeding disorders in this study. Hemarthrosis involving knee joint was the most common complication. Inhibitor was detected in a significant number of patients. Plasma is still the most common modality of treatment. Hemophilia is widely distributed all over the world, but little is known about its clinical profile in resource-limited regions. An insight into its clinical spectrum will help in the formulation of policies to improve the situation in these areas. To study the clinical profile of hemophiliacs (age <18 years) in Jodhpur region and screen them for transfusion-transmitted infections. A cross-sectional study conducted in the Department of Pediatrics, Umaid Hospital, Dr. S. N. Medical College, Jodhpur, over a period of 12 months. Out of a total of 56 cases enrolled, 51 (91%) cases were diagnosed as hemophilia A while 5 (9%) were diagnosed as hemophilia B. Positive family history was found in 26 (46%) cases. According to their factor levels, 25 (44%) cases had severe disease, 20 (36%) had moderate disease, and 11 (20%) had mild disease. The mean age of onset of symptoms and diagnosis was 1.73 ± 1.43 and 3.87 ± 3.84 years, respectively. First clinical presentation was posttraumatic bleed in 20 (36%), gum bleeds in 17 (30%), epistaxis in 4 (7%), joint bleeds in 4 (7%), skin bleeds in 4 (7%), and circumcision bleed in 3 (5%) cases. Knee joint was the predominant joint affected by hemarthrosis in 38 (68%), followed by ankle in 29 (52%), elbow in 20 (36%), and hip joint in 7 (13%) cases. All patients had a negative screening test for transfusion-transmitted infections. Occurrence of posttraumatic bleeds and gum bleeds in an otherwise normal child should warn the clinician for evaluation of hemophilia. Acquired hemophilia Ehlers-Danlos syndrome Factor XI deficiency Glanzmann thrombasthenia Haemophilia C Haemophilia type B Physical child abuse Platelet disorders Von Willebrand disease Normal values fall between 3 – 10 minutes depending on the method used. A disadvantage of Ivy's method is closure of puncture wound before stoppage of bleeding. Duke's method With the Duke;s method, the patient is pricked with a special needle or lancet, preferably on the earlobe or fingertip, after having been swabbed with alcohol. The prick is about 3–4 mm deep. The patient then wipes the blood every 30 seconds with a filter paper. The test ceases when bleeding ceases. The usual time is about 2–5 minutes. This method is not recommended and cannot be standardized because it can cause a large local hematoma. Interpretation Bleeding time is affected by platelet function, certain vascular disorders and von Willebrand Disease—not by other coagulation factors such as haemophilia. Diseases that cause prolonged bleeding time include thrombocytopenia, disseminated intravascular coagulation (DIC), Bernard-Soulier disease, and Glanzmann's thrombasthenia. Keeping an updated registry of bleeding disorders is crucial for planning care and documenting prevalence. We aimed to assess the prevalence of various bleeding disorders including rare inherited coagulation and platelet disorders concerning their clinico-epidemiological, diagnostic data and bleeding manifestations severity. Patients suffering from manifestations of bleeding or coagulation disorders presented to Hematology Clinic during 16 years were included and prospectively followed up. Demographics, clinical characteristics, complete blood count, bleeding, prothrombin and activated partial thromboplastin times, platelet aggregation tests and bone marrow aspiration were recorded. Overall 687 patients with bleeding disorders from total 2949 patients were identified. Inherited coagulation defects were found in 27.2%; hemophilia A (70.6%), hemophilia B (13.9%), factor I deficiency (2.3%), factor V deficiency (1.6%), factor X deficiency (4.2%), factor VII deficiency (2.6%), factor XIII deficiency (1.1%), combined factor deficiency (2.1%) and unclassified coagulation disorders in 1.6% of studied patients. Overall 72.7% had diagnosed with platelet disorders; immune thrombocytopenia was the commonest (74.8%), and inherited conditions represent (25.2%) in the following order: Glanzman's thrombasthenia (11.2%), von Willebrand disease (6.6%), Bernard-Soulier syndrome (1%) and Chediak Higashi in 0.4% and unclassified in 6%. Median age of diagnosis of coagulation and platelet disorders were 33 and 72 months. Presenting symptoms of coagulation disorders were: 25.1% post circumcision bleeding, 22.5% ecchymosis, 20.9% hemoarthrosis and 15% epistaxis. Symptoms of rare coagulation disorders were postcircumcision bleeding (20%), bleeding umbilical stump (20%), epistaxis (12%), hemoarthrosis (8%) and hematomas (4%). Presenting symptoms in rare inherited platelet disorders were purpura, ecchymosis, epistaxis and bleeding gums, respectively. Analysis of the clinico-epidemiological data of patients with bleeding disorders is a useful tool for monitoring and improving their quality of care. Causes other than coagulation Bleeding diathesis may also be caused by impaired wound healing (as in scurvy), or by thinning of the skin, such as in Cushing's syndrome. Genetic Some people lack genes that typically produce the protein coagulation factors that allow normal clotting. Various types of hemophilia and von Willebrand disease are the major genetic disorders associated with coagulopathy. Rare examples are Bernard–Soulier syndrome, Wiskott–Aldrich syndrome and Glanzmann's thrombasthenia. Gene therapy treatments may be a solution as they involve in the insertion of normal genes to replace defective genes causing for the genetic disorder. Gene therapy is a source of active research that hold promise for the future. Diagnosis Comparing coagulation tests Other conditions can also present similarly with bleeding after minor trauma or spontaneous bleeds and require exclusion before confirming the diagnosis of hemophilia. Some of these conditions include von Willebrand disease, scurvy, diseases of platelet dysfunction, deficiency of other coagulation factors like V, VII, X, or fibrinogen, Ehlers-Danlos syndrome, Fabry disease, disseminated intravascular coagulation, and child abuse. In von Willebrand disease, bleeding symptoms can be similar to mild hemophilia, but patients with von Willebrand disease have more mucosal bleeding compared to musculoskeletal bleeding seen in hemophilia. Von Willebrand disease is diagnosed by checking for von Willebrand factor antigen or von Willebrand factor multimers. [40] Similarly, in scurvy, Ehlers-Danlos syndrome, and Fabry disease; also, the bleeding is usually mucosal, unlike hemophilia, where it is musculoskeletal. In scurvy, there is a deficiency of vitamin C. [41] In Ehlers-Danlos syndrome, the skin is hyperextensible, and joints are hypermobile. The diagnosis is usually through clinical features, genetic testing, and tissue biopsy. [42] Similarly, in Fabry disease, patients may also have other organs being affected, including kidneys and heart, and have skin lesions called angiokeratomas. They also have pain in the extremities. Fabry disease is usually diagnosed with clinical findings and genetic testing. [43] In cases of platelet dysfunction disorders, bleeding is usually mucocutaneous, unlike hemophilia. Usually, these disorders are diagnosed by platelet aggregation studies or platelet electron microscopy. [44] In the deficiency of other coagulation factors, musculoskeletal bleeding is uncommon. In fact, sometimes thrombosis can occur, especially in patients with factor VII or fibrinogen deficiency or in patients with combined factor V and VIII deficiency. Specific coagulation factor assays usually confirm the diagnosis. Disseminated intravascular coagulation (DIC) that mimics hemophilia is hard to differentiate, but usually, there is an underlying condition in DIC, for example, acute promyelocytic leukemia. Diagnosis is usually carried out by blood tests that show decreased platelet count and the absence of factor VIII autoantibodies. Child abuse can sometimes be misidentified and confused with hemophilia, and it is essential to find inconsistencies in the history of how trauma has occurred. Other signs of malnourishment require vigilance, and x-rays may reveal evidence of fractures of different ages. [45] [46] – anemia, hypoplastic, congenital – anemia, Diamond–Blackfan – fanconi anemia – ataxia telangiectasia – blood coagulation disorders, inherited – activated protein C resistance – afibrinogenemia – antithrombin III deficiency – Bernard–Soulier syndrome – factor V deficiency – factor VII deficiency – factor X deficiency – factor XI deficiency – factor XII deficiency – factor XIII deficiency – hemophilia A – hemophilia B – Hermansky–Pudlak syndrome – hypoprothrombinemias – protein C deficiency – thrombasthenia – Von Willebrand disease – Wiskott–Aldrich syndrome – CADASIL – cardiomyopathy, hypertrophic, familial – cherubism The International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) is useful for assessing bleeding disorders. Its utility was tested in a small study, including patients with known inherited platelet disorders. The study demonstrated a specificity of 100%, a positive predictive value of 90%, and a negative predictive value of 100% using this assessment tool. [17] In the setting of von Willebrand disease, a BAT score >6 repeatedly correlates to a 99% probability of an inherited platelet defect such as BSS. [8] ] Similarly, other bleeding assessment tools like Molecular and Clinical Markers for the Diagnosis and Management (MCMDM) of type 1 von Willebrand's disease (VWD) and the World Health Organization Bleeding Assessment Tool are similar tools. An electronic version of MCMDM-type-1 VWD was developed in 2010. [17] Hemophilia is a sex-linked recessive genetic disorder characterized by the absence or deficiency of factor VIII (hemophilia A, orclassic hemophilia) or factor IX (hemophilia B, or Christmas disease) (Chap. 141). Hemophilia A constitutes 85% of cases. Spontaneous hemarthrosis is a common problem with both types of hemophilia and can lead to a deforming arthritis. The frequency and severity of hemarthrosis are related to the degree of clotting factor deficiency. Hemarthrosis is not common in other disorders of coagulation such as von Willebrand disease, factor V deficiency, warfarin therapy, or thrombocytopenia. Hemarthrosis occurs after 1 year of age, when a child begins to walk 2241 and run. In order of frequency, the joints most commonly affected are theknees,ankles,elbows,shoulders,andhips.Smalljointsofthehands and feet are occasionally involved. The authors report a case of hemarthrosis complicated by severe anemia related to a congenital connective tissue disease: Ehlers-Danlos syndrome. A boy fell down and suffered tumefaction of both knees with bilateral rupture of the rotula tendon. He underwent surgical reinsertion of each tendon on the rotula. He later showed an unexpected ongoing hematic effusion, with severe anemia. He was screened for coagulation disorders with no results. On taking a more detailed history and investigating the patient's phenotypical features, the authors diagnosed Ehlers-Danlos syndrome, hypermobile variant. The hemarthrosis and anemia were thus concluded to be consequences of excessive tissue fragility due to a congenital connective tissue disease.\nHere is the question:\nPEDIATRICS: An 18-month-old boy, with complete immunization schedule to date, who consults the Emergency Department for right knee swelling after playing in the park, without obvious trauma. In the directed anamnesis, the mother refers that an uncle of hers had similar problems. The ultrasound examination is compatible with hemarthrosis and in the analytical analysis only an APTT lengthening of 52'' (normal 25-35'') stands out. What is the most probable diagnostic hypothesis?\nHere are the potential choices:\n1. Marfan syndrome.\n2. Von-Willebrand's disease.\n3. Ehlers-Danlos disease.\n4. Hemophilia A.\n5. Bernard-Soulier disease.\nThe correct answer is: 4. Hemophilia A."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The aim of this study is to evaluate the efficiency of a treatment prescribed, in the course of an hospital consultation for sleep pathology, to patients suffering from chronic insomnia not improved by longstanding and sustained medication with hypnotic drugs. The basis of the treatment is a progressive but total withdrawal of hypnotics in so far taken regularly. The withdrawal of hypnotics was prescribed to 79 patients: 33 aged 17 to 39 years (group 1, mean age 30) and 46 aged 40 to 70 years (group 2, mean age 51). 41 showed primary psychophysiological insomnia and 28 showed insomnia associated with psychiatric disorders. In patients of group 1, the average durations were 8 years for insomnia and 3 years for sustained hypnotic use; these durations were 15 and 5 years respectively in patients of group 2. Hypnotic drug withdrawal was achieved without placebos in 3 months in group 1 patients and 5 months in group 2 patients. 65 patients completely stopped the continual use of hypnotics. Subjective improvement of insomnia was reported by 51 of these patients (as well as by 6 patients who were given simultaneous antidepressant therapy). 16 of the 51 improved patients have resorted to hypnotics occasionally (at intervals of 10 days or more). After complete withdrawal, patients went on consulting for various lengths of time: 5 months average for group 1, 14 months average for group 2. This study of a fairly large group of insomniacs shows the frequent ineffectiveness of a sustained use of currently available hypnotics. It also shows that two times out of three the complete stop of sustained hypnotic medication proved beneficial to the patient. To carry out an observational epidemiological survey (Studio Morfeo 2) in order to define the management procedures of insomnia in a large Italian population presenting directly to the general practitioner (GP). Each GP recruited five insomniac subjects in the course of 1 week or 5 consecutive office days over a period of 2 weeks. On each office day, a brief questionnaire (Q1) including five questions investigating insomnia symptoms and current use of treatment was administered to the first 10 patients who referred to the GP office for reasons associated with their own health. The first patient of each day classified as insomniac underwent a second investigation based on a more detailed questionnaire (Q2) including demographic variables, socio-economic status, general medical conditions, severity, duration and clinical features of insomnia, daytime dysfunction, sleep satisfaction and therapeutic management. In a primary care setting, insomnia symptoms are often persistent (>1 year), recurrent (>1/week) and accompanied by daytime consequences. Two out of three patients with insomnia symptoms are dissatisfied with their sleep. In most cases, insomnia symptoms are underrated both by the patients, who cover the problem or reject treatment, and by the GP, who limits intervention on the sleep disorder (scarcely modifying ongoing therapy both in responders and in non-responders). In responders, treatment was confirmed in 91% of cases and discontinued in only 2%. When there was no improvement, or if insomnia symptoms became worse (non-responders), treatment was nevertheless continued in 74.5% of cases, either maintaining the same ineffective dose, increasing the dose, or adding another drug or a non-pharmacological procedure. Regardless of specific medication, the Italian GP privileges the pharmacological approach, which is fourfold more frequent than non-pharmacological therapy (78.6 versus 18.2%). Non-benzodiazepine hypnotic drugs are mostly prescribed when the GP decides to apply medication in previously untreated patients with insomnia symptoms. Self-administration is not unusual among the patients with insomnia symptoms and is more common among non-responders. Italian GPs tend to confirm the ongoing therapy and avoid re-evaluation of the treatment regimen. Limited use of non-pharmacological treatment in the Italian primary care setting is in line with this conservative approach of the GPs who tend to be problem-solvers rather than problem-seekers. Insomnia is the most prevalent sleep disorder in the general population, and one of the most frequent reasons for consultation in the Sleep Units. Perampanel is an antiepileptic also effective on the structure of sleep, and in restless legs syndrome. We describe the first study that evaluates perampanel in patients with chronic insomnia. Observational retrospective cohorts study of 66 patients with chronic resistant insomnia, 33 exposed to perampanel, other 33 as non-exposed group. All patients attended in Neurology or Psychiatry Consultation, from November 2017 to November 2018. Patients included had been treated with more than 4 different drugs in the previous 4 years. We reviewed age, sex, insomnia etiology, years of evolution, number of previously used drugs, and the results of perampanel for insomnia after 3 months of treatment in the exposed cohort, measured by the improvement of 3 or more points in the ISI and Pittsburgh scales, as well as the average of hours of sleep gained. Non-exposed patients were matched with this variables, but never treated with perampanel. We have included 66 patients. In the exposed cohort: we describe 33 patients with chronic resistant insomnia, 20 women (60 %), 13 men (40 %). Average age 53.48 years, average time of evolution: 11.25 years. Main etiology: depression 13 cases (40 %). After the combination of perampanel 2-4 mg (100 %) with antidepressants (17 cases, 51.5 %) or anxiolytics (12 cases, 36.36 %) along 3 months: the total number of hours of sleep improves in 2.5 h, the scale ISI improves by 6 points (± 2.1 SD, p = 0.02), and Pittsburgh scale improves in 4 points (± 1.7, p = 0.04). In non-exposed cohort, the improvement of the ISI scale was 2.2 points (±0.8, p = 0.06), on the Pittsburgh scale was 1.6 points (± 0.5, p = 0.01). The main adverse effect was irritability in 3 patients, without withdrawal perampanel. The treatment was abandoned by 4 patients (12.12%): 1 due to persistent irritability (3%), 2 due to lack of efficacy (6 %), 1 due to pregnancy wish (3 %). The combination of Perampanel with an antidepressant, or an anxiolytic, improves the quality of sleep measured by ISI and Pittsburgh scales (statistically significant), probably due to its antagonistic action on glutamate. A clinical trial compared with placebo would be necessary to corroborate these results. Tolerance Chronic use of benzodiazepines, such as chlordiazepoxide, leads to the development of tolerance, with a decrease in number of benzodiazepine binding sites in mouse forebrain. The Committee of Review of Medicines, who carried out an extensive review of benzodiazepines including chlordiazepoxide, found—and were in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse (USA)—that there was little evidence that long-term use of benzodiazepines were beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep-promoting properties within 3–14 days of continuous use, and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after 4 months' continuous use due to the development of tolerance. Insomnia Barbiturates were introduced as hypnotics for patients with schizophrenia. It induced a state of deep and prolonged sleep. But this was not used for long because of adverse side effects. Anticonvulsant Phenobarbital was the first truly effective drug against epilepsy. It was discovered by accident when given to epileptic patients to help them sleep. The positive side effects were anticonvulsant properties that reduced seizure number and intensity. Sedation Pentobarbital is used as a hypnotic when analgesia is not required. It´s often used in CT imaging when sedation is needed. It is efficient, safe and the recovery time is short. In 2013 the barbiturates phenobarbital and butabarbital are still used as sedatives in certain cases as well as to antagonize the effects of drugs as ephedrine and theophylline. Phenobarbital is used in cases of drug withdrawal syndromes. It is used as normal and emergency treatment in some cases of epilepsy. Generally, these treatments are given after the behavioral treatment has failed. Drugs such as tranquilizers, though they may work well in treating insomnia, have a risk of abuse which is why these treatments are not the first resort. Some sleep disorders such as narcolepsy do require pharmacological treatment. See also Sleep disorder Sleep medicine Snoring References External links Sleep disorders sv:Somnologi Pharmacological treatments Pharmacological treatments are used to chemically treat sleep disturbances such as insomnia or excessive daytime sleepiness. The kinds of drugs used to treat sleep disorders include: anticonvulsants, anti-narcoleptics, anti-Parkinsonian drugs, benzodiazepines, non-benzodiazepine hypnotics, and opiates as well as the hormone melatonin and melatonin receptor stimulators. Anticonvulsants, opiates, and anti-Parkinsonian drugs are often used to treat restless legs syndrome. Furthermore, melatonin, benzodiazepines hypnotics, and non-benzodiazepine hypnotics may be used to treat insomnia. Finally, anti-narcoleptics help treat narcolepsy and excessive daytime sleepiness. Of particular interest are the benzodiazepine drugs which reduce insomnia by increasing the efficiency of GABA. GABA decreases the excitability of neurons by increasing the firing threshold. Benzodiazepine causes the GABA receptor to better bind to GABA, allowing the medication to induce sleep. In India, clobazam is approved for use as an adjunctive therapy in epilepsy, and in acute and chronic anxiety. In Japan, clobazam is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures. In New Zealand, clobazam is marketed as Frisium In the United Kingdom clobazam (Frisium) is approved for short-term (2–4 weeks) relief of acute anxiety in patients who have not responded to other drugs, with or without insomnia and without uncontrolled clinical depression. It was not approved in the United States until October 25, 2011, when it was approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older. Contraindications Clobazam should be used with great care in patients with the following disorders: Myasthenia gravis. Sleep apnea. Severe liver diseases such as cirrhosis and hepatitis. Severe respiratory failure. Good sleep is an important index of the quality of life in people and above all in old subjects. Among all the symptoms reported to general practitioner, insomnia is at the 3(rd) place and this is present in particular in the elderly. In elderly people high comorbidity and polytreatment are often present. We have studied 60 elderly people with history of insomnia and concomitant diseases: depression, dementia and behavioral disturbances. All the patients of the present study were visited in our outpatients' department. Three hypnotic drugs were used for the treatment of insomnia: zolpidem, or triazolam, or oxazepam, respectively at doses of 10mg/day, 0.125-0.25mg/day and 15.0mg/day. All the three drugs showed to be effective and safe; no paradoxical effects were observed. Sam is a 6-year-old boy with a diagnosis of autism spectrum disorder (ASD) who recently relocated and has an appointment with you, his new pediatric clinician, to establish care. He was previously followed by a psychiatrist for 2 years for additional diagnoses of insomnia, bipolar disorder, anxiety, attention deficit hyperactivity disorder, and intellectual disability. He has tried and (apparently) failed multiple psychotropic trials including stimulants, nonstimulants, mood stabilizers, atypical antipsychotics, and nonbenzodiazepine hypnotics. He has a delayed sleep onset and frequent night awakenings each night for the past 3 months, during which he \"screams, cries, and thrashes and can stay up for over an hour.\" His behaviors are described as irritable, self-injurious, and aggressive with no clear pattern of triggers according to his mother. He is nonverbal and communicates by leading and rarely pointing. The patient's current medication regimen includes clonidine 0.2 mg at night, lorazepam 1.5 mg as needed at night, olanzapine 5 mg twice daily, and diphenhydramine as needed for sleep/agitation. His mother is concerned that he is developing \"tolerance\" to the regimen and wants to wean him off some of the medications. His mother is struggling to take care of the patient given his worsening behavior and body habitus (body mass index >99%; z = 3.41).There is a family history of depression, anxiety, bipolar disorder, and autism. He has a 3-year-old sister, who is also diagnosed with ASD, though she is not as severely impacted. His mother's partner recently moved in along with 2 children of his own, aged 3 and 4 years. Sam attends a specialized school, where he receives behavior therapy and occupational therapy. He has undergone inpatient pediatric hospitalization twice, 1 time for 3 weeks and the other for 6 days, for aggressive behavior, and in both instances, he was discharged before inpatient psychiatric placement because of a lack of available beds.After urgent consultation with your local developmental and behavioral pediatrician, a slight reduction was made in the lorazepam because of concerns about tolerance and side effects. However, within a week of this, he was brought to the emergency department for continued self-injurious behavior and increased trouble with sleeping. His mother voiced concerns about his safety in the home, which were particularly related to aggression toward his younger sister. He was admitted to the pediatric inpatient floor for observation, and medication adjustment (increasing olanzapine), which was initially helpful in improving behavior, but mostly behavioral/environmental strategies were used to soothe him, including frequent wagon rides through the hospital corridors.Despite the patient being stable from the medical standpoint, Sam's mother did not feel comfortable taking him home. Social work contacted local community mental health services to pursue outpatient resources and respite care options and sought inpatient pediatric psychiatry. After several failed attempts to find placement, he remained in pediatric inpatient care for 1 and a half months with no acute medical interventions other than his oral medications.He was finally accepted to the in-state pediatric psychiatric facility when a bed was available. During his week-long stay, he had further medication adjustments with a decrease in olanzapine and optimization of his clonidine dose. During his psychiatric hospital stay, care coordination succeeded in arranging center-based applied behavior analysis interventions and respite care and parent training for his family. Sam began to show improvement in his overall agitation and aggression, requiring less clonazepam, and his mother then maintained outpatient follow-up.The day before discharge, you visit him in the hospital, and a medical student asks you why he was in the hospital for so long. How would you answer the question? The management of sleep disorders in elderly patients with internal diseases consists in the first line in rectifying pathophysiological disregulations. Only in the second line, proper hypnotics are to be prescribed. When considered as indispensable, these medicaments are selected according to their toxicity and side effects. In present time, Benzodiazepines are definitely preferred, whereas neuroleptic, anti-depressant and the older drugs are to be taken secondarly in account. We report on the case of a 45-year old female with chronic insomnia and refractory to hypnotics, who also has a - polygraphically documented - tolerance to the imidazopyridine \"zolpidem\". We discuss the main differential diagnosis and demonstrate a therapeutic regimen which allows a step-by-step replacement of hypnotics by sedative antidepressants. This interval replacement treatment reduces on the one hand the risk of developing a severe withdrawal syndrome. On the other hand the replacement by sedative antidepressants improves insomnia and insomnia-associated depressive symptoms. Finally, the clinical implications and rationale of a therapeutic approach with sedative antidepressants in chronic insomnia are discussed. Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol and other drugs. Chlordiazepoxide has a medium to long half-life but its active metabolite has a very long half-life. The drug has amnesic, anticonvulsant, anxiolytic, hypnotic, sedative and skeletal muscle relaxant properties. Chlordiazepoxide was patented in 1958 and approved for medical use in 1960. It was the first benzodiazepine to be synthesized and the discovery of chlordiazepoxide was by pure chance. Chlordiazepoxide and other benzodiazepines were initially accepted with widespread public approval but were followed with widespread public disapproval and recommendations for more restrictive medical guidelines for its use. Psychiatric patients often have residual intractable insomnia as a serious problem. Forty-eight psychiatrically ill patients (DSM-IV diagnoses) who had failed to respond to medicinal treatment for chronic insomnia were referred for and completed behavioral therapy as an adjunct to the pharmacologic treatment of their insomnia. The behavioral treatments included structured sleep hygiene, progressive muscle relaxation, stimulus control, and sleep restriction. The treatment program was accomplished in 6 sessions over 2 months. Follow-up evaluations were completed at 2, 6, and 12 months from the beginning of the treatment program. The outcome of the treatment program was evaluated in terms of the change in (1) self-reported specific sleep parameters, (2) self-ratings of sleep-related day-time state, (3) self-rating of quality of sleep, (4) the use of sleep medication, and (5) the therapist's global rating of improvement. There was a statistically significant change from the baseline in all self-reported specific sleep parameters after 2 months that was sustained after 6 and 12 months. Sleep-related characteristics of daytime state showed statistically significant changes after 2 and 6 months that were maintained after 12 months. Sleep quality had a statistically significant change after 2 months, continued to improve statistically after 6 months, and was maximum after 12 months. Over half the patients (52.7%; 20 of 38) either reduced their sleep medication by half or stopped it completely. The therapist's global rating showed an improvement in 29.2% (N = 14) of patients after 2 months, 56.2% (N = 27) after 6 months, and 68.7% (N = 33) after 12 months. The use of concomitant behavioral and pharmacologic treatment of chronic insomnia in psychiatrically ill patients results in improving sleep and sleep-related state and reduces the risk of return of insomnia for 10 months after finishing active treatment. Clinical trials conducted in general practice are more especially interesting as they enable to test a drug in the real conditions of use. On the other hand, these trials are beneficial to the G.P. (new image, rupture of his loneliness, change in his prescription habits, contact with hospitals). The methodology, as for hospital studies, must be rigorous. As a matter of fact, these two types of studies are additional and the cooperation between the G.P.'s and the pharmaceutical industry can conduct to the solution of specific problems: drug interaction--long-term therapeutic effect--new indications. This double blind cross over study comparing triazolam and nitrazepam conducted by G.P.'s on insomniacs is the first French clinical study intended for the registration application and done according to this methodology. This work is an exemple of the new opportunity offered to G.P.'s in future. The results have shown that: on 54 patients (23 male and 31 female) of an average age: 48, 32 have preferred triazolam, 13 have preferred nitrazepam, 9 have had no preference. Contraindications and interactions Cabotegravir/rilpivirine must not be combined with drugs that induce the liver enzyme CYP3A4, because they accelerate the inactivation of rilpivirine, and/or the enzmye UGT1A1, because they accelerate the inactivation of cabotegravir. These mechanisms potentially result in loss of effectiveness. Examples for such drugs are rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenytoin and phenobarbital. Adverse effects The most common side effects of the injectable combination therapy with rilpivirine are reactions at the injection site (in up to 84% of patients) such as pain and swelling, as well as headache (up to 12%) and fever or feeling hot (in 10%). Less common side effects (under 10%) are depressive disorders, insomnia, rashes, fatigue, musculoskeletal pain, nausea, sleep disorders, and dizziness. Pharmacology Insomnia, a more or less chronic sleep disturbance, is a very common symptom in psychiatric patients but also relatively freguent in the general population to a lesser degree. Two broad types of insomnia may often be distinguished: (1) difficulty falling asleep and frequent wakening, characteristic of anxiety states or obsessive worrying; and (2) early morning wakening, sometimes in a panic, suggestive of endogenous depression. The first group of patients respond well to minor tranquilizers and psychotherapy, whereas the second do well with tricyclic anti-depressants. Many studies in sleep laboratories have declineated the stages and cycles of sleep physiology and pathology, especially the importance of REM or dreaming sleep. The clinician should be cautious in the use of hypnotics like barbiturates which suppress REM sleep and produce a rebound increase on withdrawal, as well as problems of dependence of habituation. Flurazepam and chloral hydrate are considerably safer in this respect. Understanding sleep neurophysiology and biochemistry permits appropriate individual clinical management for both psychiatric patients and medical patients with conditions like peptic ulcer and nocturnal angina pectoris. for anesthetic purposes, and are also sometimes prescribed for anxiety or insomnia. This is not a common practice anymore, however, owing to the dangers of long-term use of barbiturates; they have been replaced by the benzodiazepines and Z-drugs such as zolpidem, zaleplon and eszopiclone for sleep. The final class of barbiturates are known as long-acting barbiturates (the most notable one being phenobarbital, which has a half-life of roughly 92 hours). This class of barbiturates is used almost exclusively as anticonvulsants, although on rare occasions they are prescribed for daytime sedation. Barbiturates in this class are not used for insomnia, because, owing to their extremely long half-life, patients would awake with a residual \"hang-over\" effect and feel groggy. The impossibility of treating patients with sleep disorders adequately means that, as specialists, we have to look for new pharmacological treatments and for this reason we examined the information in the paper by Salin Pascual (1999) about the increase in deep sleep when olanzapine is used as an antipsychotic drug. We decided to use this medication in six females and three males who were suffering from different sleep disorders that conditioned their chronic insomnia. The dosages of olanzapine used ranged from 2.5 and 10 mg in a single dose. The clinical history and progress were used to elaborate the results and conclusions. The result was positive in eight of the nine patients, five who were administered the medication as monotherapy and three as polytherapy. The population studied is insufficient to prove the effectiveness of the drug, but the fact that in eight of our patients the treatment clearly improved their symptoms leads us to think that this line of research must be continued. Non medication based strategies provide long lasting improvements to insomnia and are recommended as a first line and long-term strategy of management. Behavioral sleep medicine (BSM) tries to address insomnia with non-pharmacological treatments. The BSM strategies used to address chronic insomnia include attention to sleep hygiene, stimulus control, behavioral interventions, sleep-restriction therapy, paradoxical intention, patient education, and relaxation therapy. Some examples are keeping a journal, restricting the time spent awake in bed, practicing relaxation techniques, and maintaining a regular sleep schedule and a wake-up time. Behavioral therapy can assist a patient in developing new sleep behaviors to improve sleep quality and consolidation. Behavioral therapy may include, learning healthy sleep habits to promote sleep relaxation, undergoing light therapy to help with worry-reduction strategies and regulating the circadian clock. An enquiry into the handling by medical practitioners of sleeping problems among elderly patients was conducted in southern Lower Saxony by personal interview, combined with a standard questionnaire. A typical case report had been drafted concerning a 70-year-old, previously healthy widow: her complaints were \"nonspecific\" and could be classified as an example of either depression, of the onset of senile dementia or as within normal limits for age. This case report was presented by two interviewers to 145 general practitioners (GPs) and 14 neurologists in private practice (response rate of 83.2%) who were asked how they would have treated the patient's sleeping disorder. 30.3% of the GPs and 14.3% of the neurologists would initially not have prescribed medication. Only GPs (19.5%) mentioned possible herbal medication. Sedative neuroleptics were preferred by 57.1% of neurologists and 26.2% of GPs, while benzodiazepines would have been given by 14% of both groups. Antidepressive drugs and chloral hydrate were chosen less often (5.7% and 2.5%, respectively). These data support the finding of a high frequency of neuroleptic prescriptions given to the elderly. They also make clear that the possibility of treatment without drugs is usually not sufficiently explored. There is support showing positive sleep outcomes for people who follow more than one sleep hygiene recommendation. There is however no evidence that poor sleep hygiene can contribute to insomnia. While there is inconclusive evidence that sleep hygiene alone is effective as a treatment for insomnia, some research studies have shown improvement in insomnia for patients who receive sleep hygiene education in combination with cognitive behavioral therapy practices. Benzodiazepines and related drugs are the hypnotics of first choice. They shorten sleep latency, enhance sleep continuity and may prolong sleep duration. Their undesired effects include a persistent day-time sedation and ataxia when getting up at night. There is some risk of habit formation and dependence. For treating an acute insomnia, the prescription of hypnotics should be limited to a short duration (smallest package size), for treating chronic forms of insomnia they should have only an adjuvant role in therapy. Patients in general practice complaining of insomnia of recent origin have been studied in order to ascertain which factors may be of value in the detection of those more susceptible to drug dependence. The type of sleep disturbance was found to be of importance and a personal disturbance scale was found useful as a screening test in two-thirds of the patients. No difference was found in the development of dependence on amylobarbitone and nitrazepam. One of the most important factors in the prevention of drug dependence seems to be frequent review by the doctor after the first prescription and his cautionary advice to the patient. Antipsychotics Chlorpromazine, an antipsychotic and antiemetic drug which is classed as a \"major\" tranquilizer, may cause paradoxical effects such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states. Barbiturates Phenobarbital can cause hyperactivity in children. This may follow after a small dose of 20 mg, on condition of no phenobarbital administered in previous days. Prerequisity for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital. Barbiturates such as pentobarbital have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of attention deficit hyperactivity disorder. Intravenous caffeine administration can return these patients' behaviour to baseline levels. Psychological and behavioral therapies should be considered the first line treatment for chronic insomnia. Although cognitive behavioral therapy for insomnia (CBT-I) is considered the standard of care [1], several monotherapies, including sleep restriction therapy, stimulus control therapy, and relaxation training are also recommended in the treatment of chronic insomnia [2]. CBT-I is a multimodal intervention comprised of a combination of behavioral (eg, sleep restriction, stimulus control) and cognitive therapy strategies, and psychoeducation delivered in 4 to 10 weekly or biweekly sessions [3]. Given that insomnia is thought to be maintained by an interaction between unhelpful sleep-related beliefs and behaviors, the goal of CBT-I is to modify the maladaptive cognitions (eg, worry about the consequences of poor sleep), behaviors (eg, extended time in bed), and arousal (ie, physiological and mental hyperarousal) perpetuating the insomnia. CBT-I is efficacious when implemented alone or in combination with a pharmacologic agent. However, because of the potential for relapse upon discontinuation, CBT-I should be extended throughout drug tapering [4]. Although the treatment options should be guided by the available evidence supporting both psychological therapies and short-term hypnotic treatment, as well as treatment feasibility and availability, treatment selection should ultimately be guided by patient preference [5]. Despite its widespread use among treatment providers [6], the use of sleep hygiene education as a primary intervention for insomnia should be avoided. Sleep hygiene may be a necessary, but insufficient condition for promoting good sleep and should be considered an adjunct to another empirically supported treatment. The first-line drugs for treatment of status epilepticus are benzodiazepines, such as lorazepam or diazepam. If these fail, then phenytoin may be used, with phenobarbital being an alternative in the US, but used only third-line in the UK. Failing that, the only treatment is anaesthesia in intensive care. The World Health Organization (WHO) gives phenobarbital a first-line recommendation in the developing world and it is commonly used there. Phenobarbital is the first-line choice for the treatment of neonatal seizures. Concerns that neonatal seizures in themselves could be harmful make most physicians treat them aggressively. No reliable evidence, though, supports this approach. Phenobarbital is sometimes used for alcohol detoxification and benzodiazepine detoxification for its sedative and anti-convulsant properties. The benzodiazepines chlordiazepoxide (Librium) and oxazepam (Serax) have largely replaced phenobarbital for detoxification. Insomnia is a symptom that should be treated according to the underlying etiology. It is more common in elderly individuals and in women. Common causes of insomnia include acute situational factors, psychiatric disorders, use of various medications and illicit drugs, and medical disorders that cause pain, dyspnea or nausea. Pharmacotherapy should be generally restricted to use of the benzodiazepines, imidazopyridines (zolpidem) and occasionally tricyclic antidepressants. As a rule, hypnotic drugs should be used for less than two weeks to one month.\nHere is the question:\nPSYCHIATRY: We are consulted by an 84-year-old woman for insomnia of conciliation. After failing sleep hygiene measures, it is decided to initiate pharmacological treatment. Which of the following drugs would you select for the patient?\nHere are the potential choices:\n1. Diacepam.\n2. Lormetacepam.\n3. Phenobarbital.\n4. Chlordiazepoxide.\n5. Chloracepate.\nThe correct answer is: ",
        "gold_answer": "2 Lormetacepam.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The aim of this study is to evaluate the efficiency of a treatment prescribed, in the course of an hospital consultation for sleep pathology, to patients suffering from chronic insomnia not improved by longstanding and sustained medication with hypnotic drugs. The basis of the treatment is a progressive but total withdrawal of hypnotics in so far taken regularly. The withdrawal of hypnotics was prescribed to 79 patients: 33 aged 17 to 39 years (group 1, mean age 30) and 46 aged 40 to 70 years (group 2, mean age 51). 41 showed primary psychophysiological insomnia and 28 showed insomnia associated with psychiatric disorders. In patients of group 1, the average durations were 8 years for insomnia and 3 years for sustained hypnotic use; these durations were 15 and 5 years respectively in patients of group 2. Hypnotic drug withdrawal was achieved without placebos in 3 months in group 1 patients and 5 months in group 2 patients. 65 patients completely stopped the continual use of hypnotics. Subjective improvement of insomnia was reported by 51 of these patients (as well as by 6 patients who were given simultaneous antidepressant therapy). 16 of the 51 improved patients have resorted to hypnotics occasionally (at intervals of 10 days or more). After complete withdrawal, patients went on consulting for various lengths of time: 5 months average for group 1, 14 months average for group 2. This study of a fairly large group of insomniacs shows the frequent ineffectiveness of a sustained use of currently available hypnotics. It also shows that two times out of three the complete stop of sustained hypnotic medication proved beneficial to the patient. To carry out an observational epidemiological survey (Studio Morfeo 2) in order to define the management procedures of insomnia in a large Italian population presenting directly to the general practitioner (GP). Each GP recruited five insomniac subjects in the course of 1 week or 5 consecutive office days over a period of 2 weeks. On each office day, a brief questionnaire (Q1) including five questions investigating insomnia symptoms and current use of treatment was administered to the first 10 patients who referred to the GP office for reasons associated with their own health. The first patient of each day classified as insomniac underwent a second investigation based on a more detailed questionnaire (Q2) including demographic variables, socio-economic status, general medical conditions, severity, duration and clinical features of insomnia, daytime dysfunction, sleep satisfaction and therapeutic management. In a primary care setting, insomnia symptoms are often persistent (>1 year), recurrent (>1/week) and accompanied by daytime consequences. Two out of three patients with insomnia symptoms are dissatisfied with their sleep. In most cases, insomnia symptoms are underrated both by the patients, who cover the problem or reject treatment, and by the GP, who limits intervention on the sleep disorder (scarcely modifying ongoing therapy both in responders and in non-responders). In responders, treatment was confirmed in 91% of cases and discontinued in only 2%. When there was no improvement, or if insomnia symptoms became worse (non-responders), treatment was nevertheless continued in 74.5% of cases, either maintaining the same ineffective dose, increasing the dose, or adding another drug or a non-pharmacological procedure. Regardless of specific medication, the Italian GP privileges the pharmacological approach, which is fourfold more frequent than non-pharmacological therapy (78.6 versus 18.2%). Non-benzodiazepine hypnotic drugs are mostly prescribed when the GP decides to apply medication in previously untreated patients with insomnia symptoms. Self-administration is not unusual among the patients with insomnia symptoms and is more common among non-responders. Italian GPs tend to confirm the ongoing therapy and avoid re-evaluation of the treatment regimen. Limited use of non-pharmacological treatment in the Italian primary care setting is in line with this conservative approach of the GPs who tend to be problem-solvers rather than problem-seekers. Insomnia is the most prevalent sleep disorder in the general population, and one of the most frequent reasons for consultation in the Sleep Units. Perampanel is an antiepileptic also effective on the structure of sleep, and in restless legs syndrome. We describe the first study that evaluates perampanel in patients with chronic insomnia. Observational retrospective cohorts study of 66 patients with chronic resistant insomnia, 33 exposed to perampanel, other 33 as non-exposed group. All patients attended in Neurology or Psychiatry Consultation, from November 2017 to November 2018. Patients included had been treated with more than 4 different drugs in the previous 4 years. We reviewed age, sex, insomnia etiology, years of evolution, number of previously used drugs, and the results of perampanel for insomnia after 3 months of treatment in the exposed cohort, measured by the improvement of 3 or more points in the ISI and Pittsburgh scales, as well as the average of hours of sleep gained. Non-exposed patients were matched with this variables, but never treated with perampanel. We have included 66 patients. In the exposed cohort: we describe 33 patients with chronic resistant insomnia, 20 women (60 %), 13 men (40 %). Average age 53.48 years, average time of evolution: 11.25 years. Main etiology: depression 13 cases (40 %). After the combination of perampanel 2-4 mg (100 %) with antidepressants (17 cases, 51.5 %) or anxiolytics (12 cases, 36.36 %) along 3 months: the total number of hours of sleep improves in 2.5 h, the scale ISI improves by 6 points (± 2.1 SD, p = 0.02), and Pittsburgh scale improves in 4 points (± 1.7, p = 0.04). In non-exposed cohort, the improvement of the ISI scale was 2.2 points (±0.8, p = 0.06), on the Pittsburgh scale was 1.6 points (± 0.5, p = 0.01). The main adverse effect was irritability in 3 patients, without withdrawal perampanel. The treatment was abandoned by 4 patients (12.12%): 1 due to persistent irritability (3%), 2 due to lack of efficacy (6 %), 1 due to pregnancy wish (3 %). The combination of Perampanel with an antidepressant, or an anxiolytic, improves the quality of sleep measured by ISI and Pittsburgh scales (statistically significant), probably due to its antagonistic action on glutamate. A clinical trial compared with placebo would be necessary to corroborate these results. Tolerance Chronic use of benzodiazepines, such as chlordiazepoxide, leads to the development of tolerance, with a decrease in number of benzodiazepine binding sites in mouse forebrain. The Committee of Review of Medicines, who carried out an extensive review of benzodiazepines including chlordiazepoxide, found—and were in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse (USA)—that there was little evidence that long-term use of benzodiazepines were beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep-promoting properties within 3–14 days of continuous use, and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after 4 months' continuous use due to the development of tolerance. Insomnia Barbiturates were introduced as hypnotics for patients with schizophrenia. It induced a state of deep and prolonged sleep. But this was not used for long because of adverse side effects. Anticonvulsant Phenobarbital was the first truly effective drug against epilepsy. It was discovered by accident when given to epileptic patients to help them sleep. The positive side effects were anticonvulsant properties that reduced seizure number and intensity. Sedation Pentobarbital is used as a hypnotic when analgesia is not required. It´s often used in CT imaging when sedation is needed. It is efficient, safe and the recovery time is short. In 2013 the barbiturates phenobarbital and butabarbital are still used as sedatives in certain cases as well as to antagonize the effects of drugs as ephedrine and theophylline. Phenobarbital is used in cases of drug withdrawal syndromes. It is used as normal and emergency treatment in some cases of epilepsy. Generally, these treatments are given after the behavioral treatment has failed. Drugs such as tranquilizers, though they may work well in treating insomnia, have a risk of abuse which is why these treatments are not the first resort. Some sleep disorders such as narcolepsy do require pharmacological treatment. See also Sleep disorder Sleep medicine Snoring References External links Sleep disorders sv:Somnologi Pharmacological treatments Pharmacological treatments are used to chemically treat sleep disturbances such as insomnia or excessive daytime sleepiness. The kinds of drugs used to treat sleep disorders include: anticonvulsants, anti-narcoleptics, anti-Parkinsonian drugs, benzodiazepines, non-benzodiazepine hypnotics, and opiates as well as the hormone melatonin and melatonin receptor stimulators. Anticonvulsants, opiates, and anti-Parkinsonian drugs are often used to treat restless legs syndrome. Furthermore, melatonin, benzodiazepines hypnotics, and non-benzodiazepine hypnotics may be used to treat insomnia. Finally, anti-narcoleptics help treat narcolepsy and excessive daytime sleepiness. Of particular interest are the benzodiazepine drugs which reduce insomnia by increasing the efficiency of GABA. GABA decreases the excitability of neurons by increasing the firing threshold. Benzodiazepine causes the GABA receptor to better bind to GABA, allowing the medication to induce sleep. In India, clobazam is approved for use as an adjunctive therapy in epilepsy, and in acute and chronic anxiety. In Japan, clobazam is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures. In New Zealand, clobazam is marketed as Frisium In the United Kingdom clobazam (Frisium) is approved for short-term (2–4 weeks) relief of acute anxiety in patients who have not responded to other drugs, with or without insomnia and without uncontrolled clinical depression. It was not approved in the United States until October 25, 2011, when it was approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older. Contraindications Clobazam should be used with great care in patients with the following disorders: Myasthenia gravis. Sleep apnea. Severe liver diseases such as cirrhosis and hepatitis. Severe respiratory failure. Good sleep is an important index of the quality of life in people and above all in old subjects. Among all the symptoms reported to general practitioner, insomnia is at the 3(rd) place and this is present in particular in the elderly. In elderly people high comorbidity and polytreatment are often present. We have studied 60 elderly people with history of insomnia and concomitant diseases: depression, dementia and behavioral disturbances. All the patients of the present study were visited in our outpatients' department. Three hypnotic drugs were used for the treatment of insomnia: zolpidem, or triazolam, or oxazepam, respectively at doses of 10mg/day, 0.125-0.25mg/day and 15.0mg/day. All the three drugs showed to be effective and safe; no paradoxical effects were observed. Sam is a 6-year-old boy with a diagnosis of autism spectrum disorder (ASD) who recently relocated and has an appointment with you, his new pediatric clinician, to establish care. He was previously followed by a psychiatrist for 2 years for additional diagnoses of insomnia, bipolar disorder, anxiety, attention deficit hyperactivity disorder, and intellectual disability. He has tried and (apparently) failed multiple psychotropic trials including stimulants, nonstimulants, mood stabilizers, atypical antipsychotics, and nonbenzodiazepine hypnotics. He has a delayed sleep onset and frequent night awakenings each night for the past 3 months, during which he \"screams, cries, and thrashes and can stay up for over an hour.\" His behaviors are described as irritable, self-injurious, and aggressive with no clear pattern of triggers according to his mother. He is nonverbal and communicates by leading and rarely pointing. The patient's current medication regimen includes clonidine 0.2 mg at night, lorazepam 1.5 mg as needed at night, olanzapine 5 mg twice daily, and diphenhydramine as needed for sleep/agitation. His mother is concerned that he is developing \"tolerance\" to the regimen and wants to wean him off some of the medications. His mother is struggling to take care of the patient given his worsening behavior and body habitus (body mass index >99%; z = 3.41).There is a family history of depression, anxiety, bipolar disorder, and autism. He has a 3-year-old sister, who is also diagnosed with ASD, though she is not as severely impacted. His mother's partner recently moved in along with 2 children of his own, aged 3 and 4 years. Sam attends a specialized school, where he receives behavior therapy and occupational therapy. He has undergone inpatient pediatric hospitalization twice, 1 time for 3 weeks and the other for 6 days, for aggressive behavior, and in both instances, he was discharged before inpatient psychiatric placement because of a lack of available beds.After urgent consultation with your local developmental and behavioral pediatrician, a slight reduction was made in the lorazepam because of concerns about tolerance and side effects. However, within a week of this, he was brought to the emergency department for continued self-injurious behavior and increased trouble with sleeping. His mother voiced concerns about his safety in the home, which were particularly related to aggression toward his younger sister. He was admitted to the pediatric inpatient floor for observation, and medication adjustment (increasing olanzapine), which was initially helpful in improving behavior, but mostly behavioral/environmental strategies were used to soothe him, including frequent wagon rides through the hospital corridors.Despite the patient being stable from the medical standpoint, Sam's mother did not feel comfortable taking him home. Social work contacted local community mental health services to pursue outpatient resources and respite care options and sought inpatient pediatric psychiatry. After several failed attempts to find placement, he remained in pediatric inpatient care for 1 and a half months with no acute medical interventions other than his oral medications.He was finally accepted to the in-state pediatric psychiatric facility when a bed was available. During his week-long stay, he had further medication adjustments with a decrease in olanzapine and optimization of his clonidine dose. During his psychiatric hospital stay, care coordination succeeded in arranging center-based applied behavior analysis interventions and respite care and parent training for his family. Sam began to show improvement in his overall agitation and aggression, requiring less clonazepam, and his mother then maintained outpatient follow-up.The day before discharge, you visit him in the hospital, and a medical student asks you why he was in the hospital for so long. How would you answer the question? The management of sleep disorders in elderly patients with internal diseases consists in the first line in rectifying pathophysiological disregulations. Only in the second line, proper hypnotics are to be prescribed. When considered as indispensable, these medicaments are selected according to their toxicity and side effects. In present time, Benzodiazepines are definitely preferred, whereas neuroleptic, anti-depressant and the older drugs are to be taken secondarly in account. We report on the case of a 45-year old female with chronic insomnia and refractory to hypnotics, who also has a - polygraphically documented - tolerance to the imidazopyridine \"zolpidem\". We discuss the main differential diagnosis and demonstrate a therapeutic regimen which allows a step-by-step replacement of hypnotics by sedative antidepressants. This interval replacement treatment reduces on the one hand the risk of developing a severe withdrawal syndrome. On the other hand the replacement by sedative antidepressants improves insomnia and insomnia-associated depressive symptoms. Finally, the clinical implications and rationale of a therapeutic approach with sedative antidepressants in chronic insomnia are discussed. Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol and other drugs. Chlordiazepoxide has a medium to long half-life but its active metabolite has a very long half-life. The drug has amnesic, anticonvulsant, anxiolytic, hypnotic, sedative and skeletal muscle relaxant properties. Chlordiazepoxide was patented in 1958 and approved for medical use in 1960. It was the first benzodiazepine to be synthesized and the discovery of chlordiazepoxide was by pure chance. Chlordiazepoxide and other benzodiazepines were initially accepted with widespread public approval but were followed with widespread public disapproval and recommendations for more restrictive medical guidelines for its use. Psychiatric patients often have residual intractable insomnia as a serious problem. Forty-eight psychiatrically ill patients (DSM-IV diagnoses) who had failed to respond to medicinal treatment for chronic insomnia were referred for and completed behavioral therapy as an adjunct to the pharmacologic treatment of their insomnia. The behavioral treatments included structured sleep hygiene, progressive muscle relaxation, stimulus control, and sleep restriction. The treatment program was accomplished in 6 sessions over 2 months. Follow-up evaluations were completed at 2, 6, and 12 months from the beginning of the treatment program. The outcome of the treatment program was evaluated in terms of the change in (1) self-reported specific sleep parameters, (2) self-ratings of sleep-related day-time state, (3) self-rating of quality of sleep, (4) the use of sleep medication, and (5) the therapist's global rating of improvement. There was a statistically significant change from the baseline in all self-reported specific sleep parameters after 2 months that was sustained after 6 and 12 months. Sleep-related characteristics of daytime state showed statistically significant changes after 2 and 6 months that were maintained after 12 months. Sleep quality had a statistically significant change after 2 months, continued to improve statistically after 6 months, and was maximum after 12 months. Over half the patients (52.7%; 20 of 38) either reduced their sleep medication by half or stopped it completely. The therapist's global rating showed an improvement in 29.2% (N = 14) of patients after 2 months, 56.2% (N = 27) after 6 months, and 68.7% (N = 33) after 12 months. The use of concomitant behavioral and pharmacologic treatment of chronic insomnia in psychiatrically ill patients results in improving sleep and sleep-related state and reduces the risk of return of insomnia for 10 months after finishing active treatment. Clinical trials conducted in general practice are more especially interesting as they enable to test a drug in the real conditions of use. On the other hand, these trials are beneficial to the G.P. (new image, rupture of his loneliness, change in his prescription habits, contact with hospitals). The methodology, as for hospital studies, must be rigorous. As a matter of fact, these two types of studies are additional and the cooperation between the G.P.'s and the pharmaceutical industry can conduct to the solution of specific problems: drug interaction--long-term therapeutic effect--new indications. This double blind cross over study comparing triazolam and nitrazepam conducted by G.P.'s on insomniacs is the first French clinical study intended for the registration application and done according to this methodology. This work is an exemple of the new opportunity offered to G.P.'s in future. The results have shown that: on 54 patients (23 male and 31 female) of an average age: 48, 32 have preferred triazolam, 13 have preferred nitrazepam, 9 have had no preference. Contraindications and interactions Cabotegravir/rilpivirine must not be combined with drugs that induce the liver enzyme CYP3A4, because they accelerate the inactivation of rilpivirine, and/or the enzmye UGT1A1, because they accelerate the inactivation of cabotegravir. These mechanisms potentially result in loss of effectiveness. Examples for such drugs are rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenytoin and phenobarbital. Adverse effects The most common side effects of the injectable combination therapy with rilpivirine are reactions at the injection site (in up to 84% of patients) such as pain and swelling, as well as headache (up to 12%) and fever or feeling hot (in 10%). Less common side effects (under 10%) are depressive disorders, insomnia, rashes, fatigue, musculoskeletal pain, nausea, sleep disorders, and dizziness. Pharmacology Insomnia, a more or less chronic sleep disturbance, is a very common symptom in psychiatric patients but also relatively freguent in the general population to a lesser degree. Two broad types of insomnia may often be distinguished: (1) difficulty falling asleep and frequent wakening, characteristic of anxiety states or obsessive worrying; and (2) early morning wakening, sometimes in a panic, suggestive of endogenous depression. The first group of patients respond well to minor tranquilizers and psychotherapy, whereas the second do well with tricyclic anti-depressants. Many studies in sleep laboratories have declineated the stages and cycles of sleep physiology and pathology, especially the importance of REM or dreaming sleep. The clinician should be cautious in the use of hypnotics like barbiturates which suppress REM sleep and produce a rebound increase on withdrawal, as well as problems of dependence of habituation. Flurazepam and chloral hydrate are considerably safer in this respect. Understanding sleep neurophysiology and biochemistry permits appropriate individual clinical management for both psychiatric patients and medical patients with conditions like peptic ulcer and nocturnal angina pectoris. for anesthetic purposes, and are also sometimes prescribed for anxiety or insomnia. This is not a common practice anymore, however, owing to the dangers of long-term use of barbiturates; they have been replaced by the benzodiazepines and Z-drugs such as zolpidem, zaleplon and eszopiclone for sleep. The final class of barbiturates are known as long-acting barbiturates (the most notable one being phenobarbital, which has a half-life of roughly 92 hours). This class of barbiturates is used almost exclusively as anticonvulsants, although on rare occasions they are prescribed for daytime sedation. Barbiturates in this class are not used for insomnia, because, owing to their extremely long half-life, patients would awake with a residual \"hang-over\" effect and feel groggy. The impossibility of treating patients with sleep disorders adequately means that, as specialists, we have to look for new pharmacological treatments and for this reason we examined the information in the paper by Salin Pascual (1999) about the increase in deep sleep when olanzapine is used as an antipsychotic drug. We decided to use this medication in six females and three males who were suffering from different sleep disorders that conditioned their chronic insomnia. The dosages of olanzapine used ranged from 2.5 and 10 mg in a single dose. The clinical history and progress were used to elaborate the results and conclusions. The result was positive in eight of the nine patients, five who were administered the medication as monotherapy and three as polytherapy. The population studied is insufficient to prove the effectiveness of the drug, but the fact that in eight of our patients the treatment clearly improved their symptoms leads us to think that this line of research must be continued. Non medication based strategies provide long lasting improvements to insomnia and are recommended as a first line and long-term strategy of management. Behavioral sleep medicine (BSM) tries to address insomnia with non-pharmacological treatments. The BSM strategies used to address chronic insomnia include attention to sleep hygiene, stimulus control, behavioral interventions, sleep-restriction therapy, paradoxical intention, patient education, and relaxation therapy. Some examples are keeping a journal, restricting the time spent awake in bed, practicing relaxation techniques, and maintaining a regular sleep schedule and a wake-up time. Behavioral therapy can assist a patient in developing new sleep behaviors to improve sleep quality and consolidation. Behavioral therapy may include, learning healthy sleep habits to promote sleep relaxation, undergoing light therapy to help with worry-reduction strategies and regulating the circadian clock. An enquiry into the handling by medical practitioners of sleeping problems among elderly patients was conducted in southern Lower Saxony by personal interview, combined with a standard questionnaire. A typical case report had been drafted concerning a 70-year-old, previously healthy widow: her complaints were \"nonspecific\" and could be classified as an example of either depression, of the onset of senile dementia or as within normal limits for age. This case report was presented by two interviewers to 145 general practitioners (GPs) and 14 neurologists in private practice (response rate of 83.2%) who were asked how they would have treated the patient's sleeping disorder. 30.3% of the GPs and 14.3% of the neurologists would initially not have prescribed medication. Only GPs (19.5%) mentioned possible herbal medication. Sedative neuroleptics were preferred by 57.1% of neurologists and 26.2% of GPs, while benzodiazepines would have been given by 14% of both groups. Antidepressive drugs and chloral hydrate were chosen less often (5.7% and 2.5%, respectively). These data support the finding of a high frequency of neuroleptic prescriptions given to the elderly. They also make clear that the possibility of treatment without drugs is usually not sufficiently explored. There is support showing positive sleep outcomes for people who follow more than one sleep hygiene recommendation. There is however no evidence that poor sleep hygiene can contribute to insomnia. While there is inconclusive evidence that sleep hygiene alone is effective as a treatment for insomnia, some research studies have shown improvement in insomnia for patients who receive sleep hygiene education in combination with cognitive behavioral therapy practices. Benzodiazepines and related drugs are the hypnotics of first choice. They shorten sleep latency, enhance sleep continuity and may prolong sleep duration. Their undesired effects include a persistent day-time sedation and ataxia when getting up at night. There is some risk of habit formation and dependence. For treating an acute insomnia, the prescription of hypnotics should be limited to a short duration (smallest package size), for treating chronic forms of insomnia they should have only an adjuvant role in therapy. Patients in general practice complaining of insomnia of recent origin have been studied in order to ascertain which factors may be of value in the detection of those more susceptible to drug dependence. The type of sleep disturbance was found to be of importance and a personal disturbance scale was found useful as a screening test in two-thirds of the patients. No difference was found in the development of dependence on amylobarbitone and nitrazepam. One of the most important factors in the prevention of drug dependence seems to be frequent review by the doctor after the first prescription and his cautionary advice to the patient. Antipsychotics Chlorpromazine, an antipsychotic and antiemetic drug which is classed as a \"major\" tranquilizer, may cause paradoxical effects such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states. Barbiturates Phenobarbital can cause hyperactivity in children. This may follow after a small dose of 20 mg, on condition of no phenobarbital administered in previous days. Prerequisity for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital. Barbiturates such as pentobarbital have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of attention deficit hyperactivity disorder. Intravenous caffeine administration can return these patients' behaviour to baseline levels. Psychological and behavioral therapies should be considered the first line treatment for chronic insomnia. Although cognitive behavioral therapy for insomnia (CBT-I) is considered the standard of care [1], several monotherapies, including sleep restriction therapy, stimulus control therapy, and relaxation training are also recommended in the treatment of chronic insomnia [2]. CBT-I is a multimodal intervention comprised of a combination of behavioral (eg, sleep restriction, stimulus control) and cognitive therapy strategies, and psychoeducation delivered in 4 to 10 weekly or biweekly sessions [3]. Given that insomnia is thought to be maintained by an interaction between unhelpful sleep-related beliefs and behaviors, the goal of CBT-I is to modify the maladaptive cognitions (eg, worry about the consequences of poor sleep), behaviors (eg, extended time in bed), and arousal (ie, physiological and mental hyperarousal) perpetuating the insomnia. CBT-I is efficacious when implemented alone or in combination with a pharmacologic agent. However, because of the potential for relapse upon discontinuation, CBT-I should be extended throughout drug tapering [4]. Although the treatment options should be guided by the available evidence supporting both psychological therapies and short-term hypnotic treatment, as well as treatment feasibility and availability, treatment selection should ultimately be guided by patient preference [5]. Despite its widespread use among treatment providers [6], the use of sleep hygiene education as a primary intervention for insomnia should be avoided. Sleep hygiene may be a necessary, but insufficient condition for promoting good sleep and should be considered an adjunct to another empirically supported treatment. The first-line drugs for treatment of status epilepticus are benzodiazepines, such as lorazepam or diazepam. If these fail, then phenytoin may be used, with phenobarbital being an alternative in the US, but used only third-line in the UK. Failing that, the only treatment is anaesthesia in intensive care. The World Health Organization (WHO) gives phenobarbital a first-line recommendation in the developing world and it is commonly used there. Phenobarbital is the first-line choice for the treatment of neonatal seizures. Concerns that neonatal seizures in themselves could be harmful make most physicians treat them aggressively. No reliable evidence, though, supports this approach. Phenobarbital is sometimes used for alcohol detoxification and benzodiazepine detoxification for its sedative and anti-convulsant properties. The benzodiazepines chlordiazepoxide (Librium) and oxazepam (Serax) have largely replaced phenobarbital for detoxification. Insomnia is a symptom that should be treated according to the underlying etiology. It is more common in elderly individuals and in women. Common causes of insomnia include acute situational factors, psychiatric disorders, use of various medications and illicit drugs, and medical disorders that cause pain, dyspnea or nausea. Pharmacotherapy should be generally restricted to use of the benzodiazepines, imidazopyridines (zolpidem) and occasionally tricyclic antidepressants. As a rule, hypnotic drugs should be used for less than two weeks to one month.\nHere is the question:\nPSYCHIATRY: We are consulted by an 84-year-old woman for insomnia of conciliation. After failing sleep hygiene measures, it is decided to initiate pharmacological treatment. Which of the following drugs would you select for the patient?\nHere are the potential choices:\n1. Diacepam.\n2. Lormetacepam.\n3. Phenobarbital.\n4. Chlordiazepoxide.\n5. Chloracepate.\nThe correct answer is: 2. Lormetacepam."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 64-year-old man was admitted to our department because of muscle cramp, atrophy and weakness of the limbs together with difficulty in walking, which had gradually progressed from age 60. About 1 year prior to admission, he had noticed hand tremor and gynecomastia. On admission, neurological examination revealed diffuse muscle atrophy and weakness of the extremities, which were more obvious on the right side with preponderance in the right leg. Bilateral postural hand tremor was also more prominent on the right hand. Fasciculations were observed both in the extremities and tongue. The remaining cranial nerves and cerebellar functions were intact. Sensation was normal except for slightly decreased vibratory sense in the distal part of the legs. Deep tendon reflexes including jaw jerk were increased with the exception of hyporeflexia of the right leg. Babinski sign was negative bilaterally. Blood examination disclosed slight elevation of CK and fasting glucose level of 110 mg/dl. Glucose tolerance test showed a diabetic pattern. CSF examination showed total protein of 74 mg/dl and IgG of 12 mg/dl. On a series of endocrinological studies, there was no significant elevation of androgen and estrogen both in serum and urine except for slight elevation of serum E1 level. Serum LH and FSH, however, were markedly high, which responded far beyond the normal range following to 0.1 mg injection of LH-RH. These results suggested that gynecomastia might be caused by dysfunction of the hypothalamus-hypophysis system. Brain CT and spine MRI showed no abnormality. Muscle biopsy obtained from the right quadriceps femoris revealed neurogenic abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS) Signs and symptoms As a result of lower motor neuron degeneration, the symptoms of PMA include: muscle weakness muscle atrophy fasciculations Some patients have symptoms restricted only to the arms or legs (or in some cases just one of either). These cases are referred to as flail limb (either flail arm or flail leg) and are associated with a better prognosis. Diagnosis PMA is a diagnosis of exclusion, there is no specific test which can conclusively establish whether a patient has the condition. Instead, a number of other possibilities have to be ruled out, such as multifocal motor neuropathy or spinal muscular atrophy. Tests used in the diagnostic process include MRI, clinical examination, and EMG. EMG tests in patients who do have PMA usually show denervation (neuron death) in most affected body parts, and in some unaffected parts too. It typically takes longer to be diagnosed with PMA than ALS, an average of 20 months for PMA vs 15 months in ALS. A 57-year-old man developed severe muscle weakness and atrophy of the upper extremities within a five-month period. Neurological examination revealed severe weakness and atrophy in the scapular muscles and proximal and distal muscles of the upper extremities. Fasciculations were also observed in the various muscles of the upper extremities. There was neither muscle weakness, atrophy nor fasciculation in either his face, neck muscles or lower extremities. He had no pseudobulbar or bulbar signs. Tendon reflexes were mildly hyperactive in the jaw and lower extremities, and normal in the upper extremities. There were no pathological reflexes, spasticity or sensory disturbances. The needle EMG study revealed denervation potentials in all muscles of the upper extremities examined. The nerve conduction study revealed no findings of the conduction block. Cervical spine X-rays revealed the narrowing of the spinal foramens at the left C3/C4 and bilateral C4/C5, C5/C6, and C6/C7 intervertebral levels. In addition, magnetic resonance imaging (MRI) revealed compressions of the cervical cord at C4/C5 and C5/C6 intervertebral levels. These clinical and neuroradiological findings resembled those of the cervical spondylotic amyotrophy (CSA). However, the motor evoked potential (MEP) study revealed the pyramidal tract dysfunction above the levels of the pyramidal decussation. Furthermore, brain MRI revealed abnormal foci in both internal capsules which were characterized by hyperintense relative to cortical gray matter on T2-weighted images and still hyperintense to white matter on proton-density-weighted images. In addition, T2-weighted images demonstrated a low signal within the motor cortex and hyperintense lesions in the white matter of the precentral gyri. These MRI findings indicated the degeneration of the pyramidal tract and corresponded to those found in the patients with amyotrophic lateral sclerosis (ALS) which have been recently reported. It has been difficult to distinguish ALS from CSA. However, MEP and brain MRI studies were useful for distinguishing these two diseases in this patient. In addition, this patient showed typical MRI findings suggesting the degeneration of the pyramidal tract, although this patient had a relatively short course of illness and did not show obvious physical findings suggesting pyramidal tract dysfunction. We report an 80-year-old woman with progressive muscular atrophy predominantly involving her right lower extremity. She was well until 1992 (75 years of age) when she noted an onset of weakness in her right leg which had got progressively worse. She was admitted to our service in July 1994. On admission, general physical examination was unremarkable. She was alert and well oriented without dementia. Higher cerebral functions were normal. Cranial nerves also appeared intact. She dragged her right leg in walking. Mild to moderate weakness (2/5 to 4/5) was noted in muscles in her right lower extremity more in the distal part. Deep tendon reflexes were within normal limits, and the plantar response was flexor bilaterally. Sensation was intact. Laboratory examinations were also unremarkable except for slight increase in CK which was 470 IU/l. CSF was also normal. EMG revealed neurogenic changes in the lower extremities. She was admitted to Aoki Hospital on October 21, 1994, by that time, her weakness in the right lower extremity had gotten worse in that the muscle strength of the right extensor hallucis longus was 0 and tibialis anterior 2; muscle atrophy was also prominent in her right leg; the right ankle jerk could not be elicited. In the subsequent course, weakness and atrophy appeared in her left lower extremity, however, upper extremities and cranial nerves had never been affected. Babinski sign was always negative. In February 1996, she developed delusional ideation of self persecution, and showed difficulty in communication with medical staffs. She developed fever of 38.7 degrees C on June 13, 1996 expired on the next day. The patient was discussed in a neurological CPC, and the chief discussant arrived at the conclusion that the patient had a form of spinal muscular atrophy. Opinions were divided between ALS and spinal muscular atrophy. Post-mortem examination revealed marked loss of anterior horn neurons in the lumbar area with astrogliosis. Bunina bodies were seen in some of the remaining neurons. No myelin pallor was noted in the pyramidal tracts, however, atrophy and loss of Betz cells were noted in the motor cortex. Other cortical areas were unremarkable. The neuropathologist arrived at the conclusion that the patient had ALS. This patient was unique in that she had asymmetric atrophy and weakness limited to the lower extremities. This is quite unusual as ALS of four years duration. In addition, the patient developed some mental change which was thought to represent dementia by some participants. But no clear morphologic changes were seen to account for her mental change. A 70 year old woman had suffered from diabetes mellitus type 2 since she was 52. Three years before the surgery she had begun to experience weakness together with altered sensitivity in the right leg, which was regarded as having been caused by diabetic polyneuropathy. During the admission examination the level for algesia on the right-hand side was at about D 11, a distal paraparesis of the leg (3-4 degrees, Janda's classification), more intense on the right, hyperactive deep tendon reflexes, Babinski's reflex on both sides, and depressed abdominal cutaneous reflexes. The sensitivity to vibrations on the Malleolus medialis on both sides was 0/8. The patient could walk only with the help of a Rollator. Over the three-year period following onset of symptoms the following tests were carried out: motor nerve conduction speeds of the N. tibialis and N. peronaeus, electromyogram of the N. tibialis anterior and the M. gastrocnemius, somatosensory evoked potentials (SSEP) of the N. tibialis, which indicated a lesion in the peripheral nerves or nerve roots. Cranial computed tomography (CCT), CT scan of the lumbar spine (L3-S1) and angiological investigation elicited no significant pathological findings. An MRI of the thoracal spine showed a vertebra-sized dorsal tumor pressing on the spinal cord from left to right. By means of microsurgery the spinal tumor was completely removed. Suspected meningeoma was confirmed by histological analysis. During the post-surgical period, the incomplete paraplegia quickly regressed, and 7 weeks after the removal of the spinal meningeoma the patient was able to climb stairs. In case of slowly-developing paresis of the legs in diabetic patients, diabetic polyneuropathy should not be diagnosed without careful consideration, and rare spinal tumors should be considered as part of the differential diagnosis, especially if the blood glucose level is normal, and intensive physiotherapy brings no improvement in the patient's condition. Familial spastic paraplegia (FSP) with severe muscular atrophy of hands and feet is exceptional. Autosomal dominant forms were initially described by Silver in 1966. We report two cases, from the same Tunisian family, presenting FSP with severe amyotrophy of the hands. A brother and his sister, aged respectively 37 and 36 years old, presented practically the same clinical picture. Their parents were cousins. The female patient was hospitalized. Both patients developed gait disorders around the age of three years. Muscular atrophy of the hands arose much later, around the age of 20 years. The neurological examination disclosed a spastic gait with distal amyotrophy, severe in the hands and moderate in the feet. Sensitivity was preserved and there was no fasciculation. The spinal cord and cerebral MRI was normal. Electromyography (EMG) showed a neurogenic pattern in the distal muscles. Stimulation of the median, ulnar and sciatica nerves was ineffective. The somatosensory evoked potentials (EP) were delayed (upper limb) or desynchronised (lower limb). The auditory and visual EP were normal. The cerebrospinal fluid contained 1 mononuclear cell/mm3 and 10 mg protein/100 ml. Abnormalities of the cranio-vertebral junction, Arnold-Chiari malformation, syringomyelia and familial juvenile amyotrophic lateral sclerosis (ALS) were excluded and the diagnosis of Silver's syndrome was evoked. We report a patient with motor neuron syndrome similar to amyotrophic lateral sclerosis (ALS) and with spontaneous recovery. At the age 40, the woman developed progressive muscular weakness, atrophy and fasciculation in extremities. She also noted a dyspnea, tongue atrophy and dysphagia. A neurological examination 6 months after onset revealed i) a tongue atrophy and fasciculation, ii) diffuse muscule weakness and atrophy in face, neck and extremities, and iii) marked hyperreflexia in the four limbs and bilateral Babinski reflex, but iv) neither sensory disturbance nor ophthalmoplegia. Electromyogram (EMG) detected such denervation potentials as fibrillation potentials, fasciculation potentials, positive sharp waves and polyphasic or giant MUPs diffusely in the limb muscles. Peripheral nerve conduction study detected neither conduction block nor delay. Thus, she was diagnosed as suffering from ALS. However, since approximate 1 year after onset, her muscle weakness has gradually been getting better. Simultaneously, the dyspnea and dysphagia gradually improved. Two years after onset, an EMG examination detected chronic denervation potentials in the left musculus sternocleidomastoideus and a few on-going denervation potentials in the left musculus extensor carpi radialis, but no denervation potentials in other limb muscles. Fasciculation potentials were found in tongue muscles. Thus, the present case was thought to have a reversible motor neuron syndrome clinically quite similar to ALS. A mild increase in IgE (346 U/ml) and a low-titer IgM-class anti-GM1 antibody were found in her serum though its pathological significance was uncertain. Any immunological aberrance may account for the pathogenesis. It should be noted that clinically diagnosed cases of ALS may rarely recover spontaneously. Corticobasal degeneration (CBD) is an uncommon, sporadic, neurodegenerative disorder of mid- to late-adult life. We describe a further example of the pathologic heterogeneity of this condition. A 71-year-old woman initially presented dysarthria, clumsiness, progressive asymmetric bradykinesia, and rigidity in left arm. Rigidity gradually involved ipsilateral leg; postural instability with falls, blepharospasm, and dysphagia subsequently developed. She has been previously diagnosed as unresponsive Parkinson's Disease. At our clinical examination, she presented left upper-arm-fixed-dystonia, spasticity in left lower limb and pyramidal signs (Babinski and Hoffmann). Brain MRI showed asymmetric cortical atrophy in the right frontotemporal cortex. Neuropsychological examination showed an impairment in visuospatial functioning, frontal-executive dysfunction, and hemineglect. This case demonstrates that association of asymmetrical focal cortical and subcortical features remains the clinical hallmark of this condition. There are no absolute markers for the clinical diagnosis that is complicated by the variability of presentation involving also cognitive symptoms that are reviewed in the paper. Despite the difficulty of diagnosing CBD, somatosensory evoked potentials, motor evoked potentials, long latency reflexes, and correlations between results on electroencephalography (EEG) and electromyography (EMG) provide further support for a CBD diagnosis. These techniques are also used to identify neurophysiological correlates of the neurological signs of the disease. Hoover's sign (63% Sensitivity & 100% specificity): This test is commonly used to separate organic from the nonorganic cause of weakness or paralysis. An examiner's hand is placed below the heel of the affected leg, and the patient is asked to flex the hip of the normal leg against resistance. In organic disorders, there should not be any pressure on the examiner's hand on the affected side, while pressure is felt in patients with FNSD/CD. [20] Variable Strength (63% sensitivity and 97% specificity): The weakness is inconsistent with variable force at different locations. In patients with neurologic signs, nerve conduction studies disclose reduced amplitude of the ulnar sensory potentials. There may be decreased amplitude of the median motor evoked potentials as well, a mild but uniform slowing of the median motor conduction velocity, and a prolongation of the F-wave latency. Concentric needle examination of affected hand muscles reveals large-amplitude motor units, suggesting collateral reinnervation. Somatosensory evoked potentials may be a useful adjunct to the conventional nerve conduction and EMG studies (Yiannikas and Walsh). Brachial artery MR angiography is usually reserved for patients with a suspected arterial occlusion, an aneurysm, or an obvious cervical rib. The place of venography in the diagnostic workup is uncertain, for a number of otherwise normal individuals can occlude the subclavian vein by fully abducting the arm. The biceps and brachioradial reflexes on one or both sides may be depressed, sometimes in association with an increase in the triceps and finger reflexes. The hand or forearm muscles may undergo atrophy; in a few cases, the atrophy of hand muscles is severe. In such cases, the spondylotic compression, as judged by MRI or CT myelography, may be confined to the high cervical cord, well above the levels of the motor neurons that innervate these muscles. In patients with sensory loss, pain and thermal sensation often appear to be affected more than tactile sense. An unexpected Babinski sign has already been mentioned and a few fasciculations may be seen, especially in proximal arm muscles. Another unusual feature in advanced stages of cervical cord compression is the appearance of mirror movements of the hands, in which effortful attempts to make refined movements of the fingers of one hand, causes the opposite hand to move similarly. Monoplegia with Muscular Atrophy This is more frequent than monoplegia without muscular atrophy. Long-continued disuse of one limb may lead to atrophy, but it is usually of lesser degree than atrophy caused by lower motor neuron disease (denervation atrophy). In disuse atrophy, the tendon reflexes are retained and nerve conduction studies are normal. With denervation of muscles, there may be visible fasciculations and reduced or abolished tendon reflexes in addition to paralysis. The location of the lesion (in nerves, spinal roots, or spinal cord) can usually be determined by the pattern of weakness, by the associated neurologic symptoms and signs, and by special tests—MRI of the spine, examination of the cerebrospinal fluid (CSF), and electrical studies of nerve and muscle. If the limb is partially denervated, the EMG shows reduced numbers of motor unit potentials (often of large size) as well as fasciculations and fibrillations. Though various textbooks describe clinical manoeuvres that help detect subtle motor deficits, their sensitivity, specificity and predictive values have not been determined. We investigated the sensitivity, specificity and predictive values of various manoeuvres in order to determine the most sensitive and reliable test or combination thereof. Straight arm raising (Barré), pronator drift, Mingazzini's manoeuvre, finger tap, forearm roll, segmental strength and deep tendon reflexes were tested in 170 patients with (86) and without (84) a proven lesion in the motor areas confirmed by computed tomography. Segmental motor strength bad good specificity (97.5%) but poor sensitivity (38.9%) and negative predictive value (NPV) (58.7%). The forearm roll had a similar profile. Finger tap had a sensitivity of 73.3% and a specificity of 87.5%. Barré and pronator testing had a sensitivity and specificity of 92.2% and 90.0% respectively. Hyperreflexia had a sensitivity of 68.9% and a specificity of 87.5%. An abnormality of pronator, reflexes or finger tap had a sensitivity of 97%, and when these three tests were positive, specificity was 97%. When all six tests were positive, the positive predictive value was 100%, when all six tests were negative the NPV was 100%. The detailed segmental examination has very good specificity for detecting motor deficits, but the sensitivity and NPV are unacceptably low. Pronator drift with finger tap and reflexes is the most reliable and time-effective combination of tests for the detection of subtle motor lesions, and could replace the segmental motor examination as a screening for motor lesions. Examination of the motor system of a limb includes checking for muscle bulk and fasciculation, muscle tone at joints, the power of muscle groups, deep tendon reflexes, clonus, plantar response, and coordination. In cases of a lower motor neuron type weakness, there is early muscle wasting, fasciculations, hypotonia, hyporeflexia, and a normal plantar response. On the other hand, the upper motor neuron type of weakness is characterized by normal muscle bulk, hypertonia, hyperreflexia, clonus, and an extensor plantar response (positive Babinski’s sign). Furthermore, the preservation of deep tendon reflexes distinguishes myopathy from neuropathy. Hirayama's disease (HD), is a benign, self-limited, motor neuron disease, characterized by asymmetric weakness and atrophy of one or both distal upper extremities. In the present study we report the clinical, electrophysiological and MRI features of a group of Italian patients, with review of the literature. Moreover we propose an optimized MRI protocol for patients with suspected or diagnosed HD in order to make an early diagnosis and a standardized follow up. Eight patients with clinical suspicion of Hirayama disease underwent evaluation between January 2007 and November 2013. All patients underwent standard nerve conduction studies (NCS), electromyography (EMG) and motor/sensory evoked potentials (MEP/SEP). Cervical spine MRI studies were conducted with a 1.5 Tesla MRI scanner in neutral and flexion position, including sagittal T1-weighted sequences and sagittal and axial T2-weighted sequences. The following diagnostic features were evaluated: abnormal cervical curvature, localized cervical cord atrophy in the lower tract (C4-C7), presence of cord flattening (CF), intramedullary signal hyperintensity on T2 weighted sequences, anterior shifting of the posterior wall of the cervical dural sac (ASD) and presence of flow voids (EFV) in the posterior epidural space during flexion. All patients complained of weakness in hand muscles as initial symptoms, associated with hand tremor in three of them and abnormal sweating of the hand palm in two of them. No sensory deficits and weakness at lower limbs were reported by any patients. Distal deep tendon reflexes at upper limbs were absent in all patients with the absence of the right tricipital reflex in one of them. Deep tendon reflexes at lower limbs were normal and no signs of pyramidal tract involvement were present. The clinical involvement at onset was unilateral in six patients (three left-sided and three right-sided) and bilateral asymmetric in two of them, with the right side more affected. With the progression of the disease all patients but one experienced weakness and wasting of hand muscles and forearm bilaterally, but still asymmetric. The duration of the progression phase of the disease ranged from eight months to three years. In all patients, NCS and EMG findings were consistent with a spinal metameric disorder involving the C7-T1 myotomes bilaterally; sensory conduction and electrophysiologic features at lower limbs were normal. MEP and SEP were normal and we did not observe the disappearance of the spinal potential during the neck flexion in any of the patients. MRI is the best diagnostic tool in the diagnosis of HD; it can confirm clinical diagnosis and exclude other conditions responsible for the neurological deficits leading to a correct patient management and therapy, limiting arm impairment. On MRI all patients had loss of the normal cervical lordosis (100%). Five patients had loss of attachment of posterior dural sac and anterior dural shift on flexion MRI with presence of flow voids from venous plexus congestion (62.5%); three patients had no anterior dislocation of the dural sac and no epidural vein congestion. Two patients showed localized cord atrophy, one at C5-C6 and the other at C6-C7 level (25%). Three patients had T2 intramedullary hyperintensities (37.5%) and cord flattening (CF) was present in 5 patients of 8 (62.5%). HD is a rare entity and a self-limited condition, but it has to be early differentiated from other diseases that may determine myelopathy and amyotrophy to establish a correct therapy and limit arm impairment. MRI is very important to confirm the clinical suspect of HD and a standardized MRI protocol using axial and sagittal images in both neutral and flexing position is needed, in order to diagnose and follow up affected patients. We wish to discuss the value of the clinical history and examination in orientation of the diagnosis of probable multiple sclerosis (MS). We report the two year study of a woman who over the previous ten years had had three episodes of paraesthesia, with pins and needles in her left leg and other parts of the left side of her body, although never affecting head or neck. She also complained of tiring more than usual. In an outpatient clinic she was found to have a syndrome affecting the upper segments of the spinal cord, mainly involving the right side and resembling an incomplete Brown Sequard type syndrome. There were increased clinical muscle and deep reflexes. The most marked was that of the right deltoid (C5), bilateral fanning of the toes when the Babinski reflex was tested, Barré positive in the right leg, pins and needles and dysaesthesia on the left to an undetermined level. Function was well preserved when compared with the clinical signs found. The case was considered to be of monotopical MS. Spinal magnetic resonance findings confirmed the clinical diagnosis. We emphasise the value of careful clinical investigation directed towards the diagnosis of probable MS. We draw attention to the diagnostic value of the dissociation between the severe clinical alterations and the functional performance, which was surprisingly well maintained. Also we report the originality of the presence of bilateral fanning sign supporting the diagnosis of MS, occurring in a disease of adult life. We report a 54-year-old man with progressive proximal muscle atrophy and gynecomastia. The patient had an insidious onset of weakness in his lower extremities at age 14, in that he noted a difficulty in standing up from a chair. Soon after he noted some difficulty in climbing up stairs. At age 35, he noted weakness in his arms; his weakness slowly progressed in that he became unable to walk or stand alone before 40 years of age. He also noted gynecomastia at that age. He was admitted to our hospital for the work up on September 16, 1993, when he was 54-year-old. On admission, he was alert and oriented; his BP was 150/70 mmHg; he had bilateral gynecomastia, however, no other skeletal deformities were found. On neurologic examination, he was mentally sound without dementia, and his higher cerebral functions were normal. Cranial nerves also appeared intact without facial atrophy, dysarthria, or dysphagia; no atrophy was noted in the tongue. He had marked muscle atrophy in both upper and lower extremities more marked in the proximal portions; muscle strength was approximately in the range of 2/5 to 3/5 in the proximal parts, and 4/5 in the distal parts in both upper and lower extremities. No fasciculation was noted; muscle tone was flaccid; no ataxia was present. Deep reflexes were either lost or markedly diminished. No Babinski sign was noted. Sensation was intact. Laboratory examination revealed normal blood counts; serum CK was slightly increased to 131 IU/l; ECG showed complete right bundle branch block; EMG revealed no active units in the right biceps brachii, deltoid, quadriceps femoris, and triceps surae muscles; in other muscles tested, motor unit potentials of low amplitude and short duration were seen; in the right tibialis anterior muscle, however, motor unit potentials with an amplitude up to 6 m V were also seen. Nerve conduction velocities were normal. A diagnostic procedure was performed. He was discussed in the neurological CPC, and the chief discussant arrived at the conclusion that this patient had Becker type of progressive muscular dystrophy. In her differential diagnosis, the possibility of Kennedy-Alter-Sung syndrome was discussed because this patient had gynecomastia. However, the discussant excluded that possibility because of absence of both bulbar symptoms and typical neurogenic changes in his EMG. The diagnostic procedure was a muscle biopsy on the left tibialis anterior muscle. Histologic observation on HE stained specimens revealed marked inequality in the muscle fiber diameters, increase in endomysial nuclei, proliferation of connective tissue, and fiber splitting.(ABSTRACT TRUNCATED AT 400 WORDS) <bIntroduction:</b There are many phenotypic variants of chronic inflammatory demyelinating polyneuropathy. <bMethods:</bAn Ancient Greek aryvallos painted c. 480-450 BC, now on display at the Louvre museum, was meticulously studied regarding its painted surface, which presents an outpatient clinic in Ancient Greece. Other Ancient Greek works of art presenting medical activities have been also evaluated in order to reach informed conclusions regarding medical practice of that period. <bCase report:</b We report a rare case of the distal phenotype of chronic inflammatory demyelinating polyneuropathy with a subacute onset and rapidly progressive course. A 58-year-old male had distal, symmetric, predominantly motor impairment without ataxia and tremor. After a three-month duration of the disease, the patient had already complete paresis of the feet with absence of compound muscle action potentials (CMAPs) over the feet and lower leg muscles, but preserved proprioception and sural sensory nerve action potential. Cerebrospinal fluid protein level was elevated to 3.4 g/L. Demyelinating neuropathy was predominantly in the proximal segment of the nerves. Low amplitude of CMAPs was recorded hardly over the vastus medialis and rectus femoris muscles, while weakness and atrophy in these muscles were not. The patient was refractory to treatment. He died three years after disease onset. <bConclusion:</bWe described a new clinical-electrophysiological phenomenon, which was characterized as a decrease in the evoked electrical excitability at the femoral nerve stimulation site (decreased CMAP), while the natural physiological conduction of the impulse from the motor neuron to the muscle was not blocked (preserved muscle strength). This is a single-center retrospective study. The objective of this study was to study the clinical symptoms and electrophysiological features of C6-7 myelopathy. This study was conducted at the Department of Orthopedic surgery, Yamaguchi University Graduate school of medicine, Japan. A total of 20 patients with cervical compressive myelopathy were determined by spinal cord-evoked potentials or a single level of obvious magnetic resonance imaging (MRI)-documented cervical spinal cord compression. Neurological examinations included manual muscle testing and investigation of deep tendon reflex, including Hoffmann sign, and of sensory disturbance areas. Motor-evoked potentials (MEPs), compound muscle action potentials (CMAPs) and F-wave were recorded from bilateral abductor digit minim and abductor halluces muscles. Central motor conduction time was calculated as follows: MEPs latency-(CMAPs latency+F latency-1)/2 (ms). Eighteen patients (90%) had negative Hoffmann sign. Eight patients (40%) had no sensory disturbance in the upper limbs and 8 patients (40%) had no muscle weakness in the upper limbs. We determined that patients had cervical myelopathy when their central motor conduction time measured in abductor digit minim was longer than 6.76 ms (+2 s.d.). Using this definition, the sensitivity for myelopathy was 42.8%. Patients with C6-7 myelopathy may lack clinical symptoms in their hands and central motor conduction time measured in abductor digit minim tended to be less prolonged, and it only showed symptoms in their lower limbs as gait disturbance. Surgeons should bear in mind the possibility of disorders of caudal C6-7 when they encounter patients with no or few symptoms in their hands and with leg weakness or numbness.\nHere is the question:\nNEUROLOGY: A 65-year-old woman consults for weakness in the right hand that has spread in a few months to other muscle territories of both arms and legs, with distal predominance. On examination there is atrophy and fasciculations in different metameric territories with preserved sensitivity. There is a bilateral Babinski's sign, what is the diagnostic test that would confirm the suspected diagnosis?\nHere are the potential choices:\n1. Cerebral CT.\n2. Electromyographic study.\n3. Cerebral MRI.\n4. Multimodal evoked potentials.\nThe correct answer is: ",
        "gold_answer": "2 Electromyographic study.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 64-year-old man was admitted to our department because of muscle cramp, atrophy and weakness of the limbs together with difficulty in walking, which had gradually progressed from age 60. About 1 year prior to admission, he had noticed hand tremor and gynecomastia. On admission, neurological examination revealed diffuse muscle atrophy and weakness of the extremities, which were more obvious on the right side with preponderance in the right leg. Bilateral postural hand tremor was also more prominent on the right hand. Fasciculations were observed both in the extremities and tongue. The remaining cranial nerves and cerebellar functions were intact. Sensation was normal except for slightly decreased vibratory sense in the distal part of the legs. Deep tendon reflexes including jaw jerk were increased with the exception of hyporeflexia of the right leg. Babinski sign was negative bilaterally. Blood examination disclosed slight elevation of CK and fasting glucose level of 110 mg/dl. Glucose tolerance test showed a diabetic pattern. CSF examination showed total protein of 74 mg/dl and IgG of 12 mg/dl. On a series of endocrinological studies, there was no significant elevation of androgen and estrogen both in serum and urine except for slight elevation of serum E1 level. Serum LH and FSH, however, were markedly high, which responded far beyond the normal range following to 0.1 mg injection of LH-RH. These results suggested that gynecomastia might be caused by dysfunction of the hypothalamus-hypophysis system. Brain CT and spine MRI showed no abnormality. Muscle biopsy obtained from the right quadriceps femoris revealed neurogenic abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS) Signs and symptoms As a result of lower motor neuron degeneration, the symptoms of PMA include: muscle weakness muscle atrophy fasciculations Some patients have symptoms restricted only to the arms or legs (or in some cases just one of either). These cases are referred to as flail limb (either flail arm or flail leg) and are associated with a better prognosis. Diagnosis PMA is a diagnosis of exclusion, there is no specific test which can conclusively establish whether a patient has the condition. Instead, a number of other possibilities have to be ruled out, such as multifocal motor neuropathy or spinal muscular atrophy. Tests used in the diagnostic process include MRI, clinical examination, and EMG. EMG tests in patients who do have PMA usually show denervation (neuron death) in most affected body parts, and in some unaffected parts too. It typically takes longer to be diagnosed with PMA than ALS, an average of 20 months for PMA vs 15 months in ALS. A 57-year-old man developed severe muscle weakness and atrophy of the upper extremities within a five-month period. Neurological examination revealed severe weakness and atrophy in the scapular muscles and proximal and distal muscles of the upper extremities. Fasciculations were also observed in the various muscles of the upper extremities. There was neither muscle weakness, atrophy nor fasciculation in either his face, neck muscles or lower extremities. He had no pseudobulbar or bulbar signs. Tendon reflexes were mildly hyperactive in the jaw and lower extremities, and normal in the upper extremities. There were no pathological reflexes, spasticity or sensory disturbances. The needle EMG study revealed denervation potentials in all muscles of the upper extremities examined. The nerve conduction study revealed no findings of the conduction block. Cervical spine X-rays revealed the narrowing of the spinal foramens at the left C3/C4 and bilateral C4/C5, C5/C6, and C6/C7 intervertebral levels. In addition, magnetic resonance imaging (MRI) revealed compressions of the cervical cord at C4/C5 and C5/C6 intervertebral levels. These clinical and neuroradiological findings resembled those of the cervical spondylotic amyotrophy (CSA). However, the motor evoked potential (MEP) study revealed the pyramidal tract dysfunction above the levels of the pyramidal decussation. Furthermore, brain MRI revealed abnormal foci in both internal capsules which were characterized by hyperintense relative to cortical gray matter on T2-weighted images and still hyperintense to white matter on proton-density-weighted images. In addition, T2-weighted images demonstrated a low signal within the motor cortex and hyperintense lesions in the white matter of the precentral gyri. These MRI findings indicated the degeneration of the pyramidal tract and corresponded to those found in the patients with amyotrophic lateral sclerosis (ALS) which have been recently reported. It has been difficult to distinguish ALS from CSA. However, MEP and brain MRI studies were useful for distinguishing these two diseases in this patient. In addition, this patient showed typical MRI findings suggesting the degeneration of the pyramidal tract, although this patient had a relatively short course of illness and did not show obvious physical findings suggesting pyramidal tract dysfunction. We report an 80-year-old woman with progressive muscular atrophy predominantly involving her right lower extremity. She was well until 1992 (75 years of age) when she noted an onset of weakness in her right leg which had got progressively worse. She was admitted to our service in July 1994. On admission, general physical examination was unremarkable. She was alert and well oriented without dementia. Higher cerebral functions were normal. Cranial nerves also appeared intact. She dragged her right leg in walking. Mild to moderate weakness (2/5 to 4/5) was noted in muscles in her right lower extremity more in the distal part. Deep tendon reflexes were within normal limits, and the plantar response was flexor bilaterally. Sensation was intact. Laboratory examinations were also unremarkable except for slight increase in CK which was 470 IU/l. CSF was also normal. EMG revealed neurogenic changes in the lower extremities. She was admitted to Aoki Hospital on October 21, 1994, by that time, her weakness in the right lower extremity had gotten worse in that the muscle strength of the right extensor hallucis longus was 0 and tibialis anterior 2; muscle atrophy was also prominent in her right leg; the right ankle jerk could not be elicited. In the subsequent course, weakness and atrophy appeared in her left lower extremity, however, upper extremities and cranial nerves had never been affected. Babinski sign was always negative. In February 1996, she developed delusional ideation of self persecution, and showed difficulty in communication with medical staffs. She developed fever of 38.7 degrees C on June 13, 1996 expired on the next day. The patient was discussed in a neurological CPC, and the chief discussant arrived at the conclusion that the patient had a form of spinal muscular atrophy. Opinions were divided between ALS and spinal muscular atrophy. Post-mortem examination revealed marked loss of anterior horn neurons in the lumbar area with astrogliosis. Bunina bodies were seen in some of the remaining neurons. No myelin pallor was noted in the pyramidal tracts, however, atrophy and loss of Betz cells were noted in the motor cortex. Other cortical areas were unremarkable. The neuropathologist arrived at the conclusion that the patient had ALS. This patient was unique in that she had asymmetric atrophy and weakness limited to the lower extremities. This is quite unusual as ALS of four years duration. In addition, the patient developed some mental change which was thought to represent dementia by some participants. But no clear morphologic changes were seen to account for her mental change. A 70 year old woman had suffered from diabetes mellitus type 2 since she was 52. Three years before the surgery she had begun to experience weakness together with altered sensitivity in the right leg, which was regarded as having been caused by diabetic polyneuropathy. During the admission examination the level for algesia on the right-hand side was at about D 11, a distal paraparesis of the leg (3-4 degrees, Janda's classification), more intense on the right, hyperactive deep tendon reflexes, Babinski's reflex on both sides, and depressed abdominal cutaneous reflexes. The sensitivity to vibrations on the Malleolus medialis on both sides was 0/8. The patient could walk only with the help of a Rollator. Over the three-year period following onset of symptoms the following tests were carried out: motor nerve conduction speeds of the N. tibialis and N. peronaeus, electromyogram of the N. tibialis anterior and the M. gastrocnemius, somatosensory evoked potentials (SSEP) of the N. tibialis, which indicated a lesion in the peripheral nerves or nerve roots. Cranial computed tomography (CCT), CT scan of the lumbar spine (L3-S1) and angiological investigation elicited no significant pathological findings. An MRI of the thoracal spine showed a vertebra-sized dorsal tumor pressing on the spinal cord from left to right. By means of microsurgery the spinal tumor was completely removed. Suspected meningeoma was confirmed by histological analysis. During the post-surgical period, the incomplete paraplegia quickly regressed, and 7 weeks after the removal of the spinal meningeoma the patient was able to climb stairs. In case of slowly-developing paresis of the legs in diabetic patients, diabetic polyneuropathy should not be diagnosed without careful consideration, and rare spinal tumors should be considered as part of the differential diagnosis, especially if the blood glucose level is normal, and intensive physiotherapy brings no improvement in the patient's condition. Familial spastic paraplegia (FSP) with severe muscular atrophy of hands and feet is exceptional. Autosomal dominant forms were initially described by Silver in 1966. We report two cases, from the same Tunisian family, presenting FSP with severe amyotrophy of the hands. A brother and his sister, aged respectively 37 and 36 years old, presented practically the same clinical picture. Their parents were cousins. The female patient was hospitalized. Both patients developed gait disorders around the age of three years. Muscular atrophy of the hands arose much later, around the age of 20 years. The neurological examination disclosed a spastic gait with distal amyotrophy, severe in the hands and moderate in the feet. Sensitivity was preserved and there was no fasciculation. The spinal cord and cerebral MRI was normal. Electromyography (EMG) showed a neurogenic pattern in the distal muscles. Stimulation of the median, ulnar and sciatica nerves was ineffective. The somatosensory evoked potentials (EP) were delayed (upper limb) or desynchronised (lower limb). The auditory and visual EP were normal. The cerebrospinal fluid contained 1 mononuclear cell/mm3 and 10 mg protein/100 ml. Abnormalities of the cranio-vertebral junction, Arnold-Chiari malformation, syringomyelia and familial juvenile amyotrophic lateral sclerosis (ALS) were excluded and the diagnosis of Silver's syndrome was evoked. We report a patient with motor neuron syndrome similar to amyotrophic lateral sclerosis (ALS) and with spontaneous recovery. At the age 40, the woman developed progressive muscular weakness, atrophy and fasciculation in extremities. She also noted a dyspnea, tongue atrophy and dysphagia. A neurological examination 6 months after onset revealed i) a tongue atrophy and fasciculation, ii) diffuse muscule weakness and atrophy in face, neck and extremities, and iii) marked hyperreflexia in the four limbs and bilateral Babinski reflex, but iv) neither sensory disturbance nor ophthalmoplegia. Electromyogram (EMG) detected such denervation potentials as fibrillation potentials, fasciculation potentials, positive sharp waves and polyphasic or giant MUPs diffusely in the limb muscles. Peripheral nerve conduction study detected neither conduction block nor delay. Thus, she was diagnosed as suffering from ALS. However, since approximate 1 year after onset, her muscle weakness has gradually been getting better. Simultaneously, the dyspnea and dysphagia gradually improved. Two years after onset, an EMG examination detected chronic denervation potentials in the left musculus sternocleidomastoideus and a few on-going denervation potentials in the left musculus extensor carpi radialis, but no denervation potentials in other limb muscles. Fasciculation potentials were found in tongue muscles. Thus, the present case was thought to have a reversible motor neuron syndrome clinically quite similar to ALS. A mild increase in IgE (346 U/ml) and a low-titer IgM-class anti-GM1 antibody were found in her serum though its pathological significance was uncertain. Any immunological aberrance may account for the pathogenesis. It should be noted that clinically diagnosed cases of ALS may rarely recover spontaneously. Corticobasal degeneration (CBD) is an uncommon, sporadic, neurodegenerative disorder of mid- to late-adult life. We describe a further example of the pathologic heterogeneity of this condition. A 71-year-old woman initially presented dysarthria, clumsiness, progressive asymmetric bradykinesia, and rigidity in left arm. Rigidity gradually involved ipsilateral leg; postural instability with falls, blepharospasm, and dysphagia subsequently developed. She has been previously diagnosed as unresponsive Parkinson's Disease. At our clinical examination, she presented left upper-arm-fixed-dystonia, spasticity in left lower limb and pyramidal signs (Babinski and Hoffmann). Brain MRI showed asymmetric cortical atrophy in the right frontotemporal cortex. Neuropsychological examination showed an impairment in visuospatial functioning, frontal-executive dysfunction, and hemineglect. This case demonstrates that association of asymmetrical focal cortical and subcortical features remains the clinical hallmark of this condition. There are no absolute markers for the clinical diagnosis that is complicated by the variability of presentation involving also cognitive symptoms that are reviewed in the paper. Despite the difficulty of diagnosing CBD, somatosensory evoked potentials, motor evoked potentials, long latency reflexes, and correlations between results on electroencephalography (EEG) and electromyography (EMG) provide further support for a CBD diagnosis. These techniques are also used to identify neurophysiological correlates of the neurological signs of the disease. Hoover's sign (63% Sensitivity & 100% specificity): This test is commonly used to separate organic from the nonorganic cause of weakness or paralysis. An examiner's hand is placed below the heel of the affected leg, and the patient is asked to flex the hip of the normal leg against resistance. In organic disorders, there should not be any pressure on the examiner's hand on the affected side, while pressure is felt in patients with FNSD/CD. [20] Variable Strength (63% sensitivity and 97% specificity): The weakness is inconsistent with variable force at different locations. In patients with neurologic signs, nerve conduction studies disclose reduced amplitude of the ulnar sensory potentials. There may be decreased amplitude of the median motor evoked potentials as well, a mild but uniform slowing of the median motor conduction velocity, and a prolongation of the F-wave latency. Concentric needle examination of affected hand muscles reveals large-amplitude motor units, suggesting collateral reinnervation. Somatosensory evoked potentials may be a useful adjunct to the conventional nerve conduction and EMG studies (Yiannikas and Walsh). Brachial artery MR angiography is usually reserved for patients with a suspected arterial occlusion, an aneurysm, or an obvious cervical rib. The place of venography in the diagnostic workup is uncertain, for a number of otherwise normal individuals can occlude the subclavian vein by fully abducting the arm. The biceps and brachioradial reflexes on one or both sides may be depressed, sometimes in association with an increase in the triceps and finger reflexes. The hand or forearm muscles may undergo atrophy; in a few cases, the atrophy of hand muscles is severe. In such cases, the spondylotic compression, as judged by MRI or CT myelography, may be confined to the high cervical cord, well above the levels of the motor neurons that innervate these muscles. In patients with sensory loss, pain and thermal sensation often appear to be affected more than tactile sense. An unexpected Babinski sign has already been mentioned and a few fasciculations may be seen, especially in proximal arm muscles. Another unusual feature in advanced stages of cervical cord compression is the appearance of mirror movements of the hands, in which effortful attempts to make refined movements of the fingers of one hand, causes the opposite hand to move similarly. Monoplegia with Muscular Atrophy This is more frequent than monoplegia without muscular atrophy. Long-continued disuse of one limb may lead to atrophy, but it is usually of lesser degree than atrophy caused by lower motor neuron disease (denervation atrophy). In disuse atrophy, the tendon reflexes are retained and nerve conduction studies are normal. With denervation of muscles, there may be visible fasciculations and reduced or abolished tendon reflexes in addition to paralysis. The location of the lesion (in nerves, spinal roots, or spinal cord) can usually be determined by the pattern of weakness, by the associated neurologic symptoms and signs, and by special tests—MRI of the spine, examination of the cerebrospinal fluid (CSF), and electrical studies of nerve and muscle. If the limb is partially denervated, the EMG shows reduced numbers of motor unit potentials (often of large size) as well as fasciculations and fibrillations. Though various textbooks describe clinical manoeuvres that help detect subtle motor deficits, their sensitivity, specificity and predictive values have not been determined. We investigated the sensitivity, specificity and predictive values of various manoeuvres in order to determine the most sensitive and reliable test or combination thereof. Straight arm raising (Barré), pronator drift, Mingazzini's manoeuvre, finger tap, forearm roll, segmental strength and deep tendon reflexes were tested in 170 patients with (86) and without (84) a proven lesion in the motor areas confirmed by computed tomography. Segmental motor strength bad good specificity (97.5%) but poor sensitivity (38.9%) and negative predictive value (NPV) (58.7%). The forearm roll had a similar profile. Finger tap had a sensitivity of 73.3% and a specificity of 87.5%. Barré and pronator testing had a sensitivity and specificity of 92.2% and 90.0% respectively. Hyperreflexia had a sensitivity of 68.9% and a specificity of 87.5%. An abnormality of pronator, reflexes or finger tap had a sensitivity of 97%, and when these three tests were positive, specificity was 97%. When all six tests were positive, the positive predictive value was 100%, when all six tests were negative the NPV was 100%. The detailed segmental examination has very good specificity for detecting motor deficits, but the sensitivity and NPV are unacceptably low. Pronator drift with finger tap and reflexes is the most reliable and time-effective combination of tests for the detection of subtle motor lesions, and could replace the segmental motor examination as a screening for motor lesions. Examination of the motor system of a limb includes checking for muscle bulk and fasciculation, muscle tone at joints, the power of muscle groups, deep tendon reflexes, clonus, plantar response, and coordination. In cases of a lower motor neuron type weakness, there is early muscle wasting, fasciculations, hypotonia, hyporeflexia, and a normal plantar response. On the other hand, the upper motor neuron type of weakness is characterized by normal muscle bulk, hypertonia, hyperreflexia, clonus, and an extensor plantar response (positive Babinski’s sign). Furthermore, the preservation of deep tendon reflexes distinguishes myopathy from neuropathy. Hirayama's disease (HD), is a benign, self-limited, motor neuron disease, characterized by asymmetric weakness and atrophy of one or both distal upper extremities. In the present study we report the clinical, electrophysiological and MRI features of a group of Italian patients, with review of the literature. Moreover we propose an optimized MRI protocol for patients with suspected or diagnosed HD in order to make an early diagnosis and a standardized follow up. Eight patients with clinical suspicion of Hirayama disease underwent evaluation between January 2007 and November 2013. All patients underwent standard nerve conduction studies (NCS), electromyography (EMG) and motor/sensory evoked potentials (MEP/SEP). Cervical spine MRI studies were conducted with a 1.5 Tesla MRI scanner in neutral and flexion position, including sagittal T1-weighted sequences and sagittal and axial T2-weighted sequences. The following diagnostic features were evaluated: abnormal cervical curvature, localized cervical cord atrophy in the lower tract (C4-C7), presence of cord flattening (CF), intramedullary signal hyperintensity on T2 weighted sequences, anterior shifting of the posterior wall of the cervical dural sac (ASD) and presence of flow voids (EFV) in the posterior epidural space during flexion. All patients complained of weakness in hand muscles as initial symptoms, associated with hand tremor in three of them and abnormal sweating of the hand palm in two of them. No sensory deficits and weakness at lower limbs were reported by any patients. Distal deep tendon reflexes at upper limbs were absent in all patients with the absence of the right tricipital reflex in one of them. Deep tendon reflexes at lower limbs were normal and no signs of pyramidal tract involvement were present. The clinical involvement at onset was unilateral in six patients (three left-sided and three right-sided) and bilateral asymmetric in two of them, with the right side more affected. With the progression of the disease all patients but one experienced weakness and wasting of hand muscles and forearm bilaterally, but still asymmetric. The duration of the progression phase of the disease ranged from eight months to three years. In all patients, NCS and EMG findings were consistent with a spinal metameric disorder involving the C7-T1 myotomes bilaterally; sensory conduction and electrophysiologic features at lower limbs were normal. MEP and SEP were normal and we did not observe the disappearance of the spinal potential during the neck flexion in any of the patients. MRI is the best diagnostic tool in the diagnosis of HD; it can confirm clinical diagnosis and exclude other conditions responsible for the neurological deficits leading to a correct patient management and therapy, limiting arm impairment. On MRI all patients had loss of the normal cervical lordosis (100%). Five patients had loss of attachment of posterior dural sac and anterior dural shift on flexion MRI with presence of flow voids from venous plexus congestion (62.5%); three patients had no anterior dislocation of the dural sac and no epidural vein congestion. Two patients showed localized cord atrophy, one at C5-C6 and the other at C6-C7 level (25%). Three patients had T2 intramedullary hyperintensities (37.5%) and cord flattening (CF) was present in 5 patients of 8 (62.5%). HD is a rare entity and a self-limited condition, but it has to be early differentiated from other diseases that may determine myelopathy and amyotrophy to establish a correct therapy and limit arm impairment. MRI is very important to confirm the clinical suspect of HD and a standardized MRI protocol using axial and sagittal images in both neutral and flexing position is needed, in order to diagnose and follow up affected patients. We wish to discuss the value of the clinical history and examination in orientation of the diagnosis of probable multiple sclerosis (MS). We report the two year study of a woman who over the previous ten years had had three episodes of paraesthesia, with pins and needles in her left leg and other parts of the left side of her body, although never affecting head or neck. She also complained of tiring more than usual. In an outpatient clinic she was found to have a syndrome affecting the upper segments of the spinal cord, mainly involving the right side and resembling an incomplete Brown Sequard type syndrome. There were increased clinical muscle and deep reflexes. The most marked was that of the right deltoid (C5), bilateral fanning of the toes when the Babinski reflex was tested, Barré positive in the right leg, pins and needles and dysaesthesia on the left to an undetermined level. Function was well preserved when compared with the clinical signs found. The case was considered to be of monotopical MS. Spinal magnetic resonance findings confirmed the clinical diagnosis. We emphasise the value of careful clinical investigation directed towards the diagnosis of probable MS. We draw attention to the diagnostic value of the dissociation between the severe clinical alterations and the functional performance, which was surprisingly well maintained. Also we report the originality of the presence of bilateral fanning sign supporting the diagnosis of MS, occurring in a disease of adult life. We report a 54-year-old man with progressive proximal muscle atrophy and gynecomastia. The patient had an insidious onset of weakness in his lower extremities at age 14, in that he noted a difficulty in standing up from a chair. Soon after he noted some difficulty in climbing up stairs. At age 35, he noted weakness in his arms; his weakness slowly progressed in that he became unable to walk or stand alone before 40 years of age. He also noted gynecomastia at that age. He was admitted to our hospital for the work up on September 16, 1993, when he was 54-year-old. On admission, he was alert and oriented; his BP was 150/70 mmHg; he had bilateral gynecomastia, however, no other skeletal deformities were found. On neurologic examination, he was mentally sound without dementia, and his higher cerebral functions were normal. Cranial nerves also appeared intact without facial atrophy, dysarthria, or dysphagia; no atrophy was noted in the tongue. He had marked muscle atrophy in both upper and lower extremities more marked in the proximal portions; muscle strength was approximately in the range of 2/5 to 3/5 in the proximal parts, and 4/5 in the distal parts in both upper and lower extremities. No fasciculation was noted; muscle tone was flaccid; no ataxia was present. Deep reflexes were either lost or markedly diminished. No Babinski sign was noted. Sensation was intact. Laboratory examination revealed normal blood counts; serum CK was slightly increased to 131 IU/l; ECG showed complete right bundle branch block; EMG revealed no active units in the right biceps brachii, deltoid, quadriceps femoris, and triceps surae muscles; in other muscles tested, motor unit potentials of low amplitude and short duration were seen; in the right tibialis anterior muscle, however, motor unit potentials with an amplitude up to 6 m V were also seen. Nerve conduction velocities were normal. A diagnostic procedure was performed. He was discussed in the neurological CPC, and the chief discussant arrived at the conclusion that this patient had Becker type of progressive muscular dystrophy. In her differential diagnosis, the possibility of Kennedy-Alter-Sung syndrome was discussed because this patient had gynecomastia. However, the discussant excluded that possibility because of absence of both bulbar symptoms and typical neurogenic changes in his EMG. The diagnostic procedure was a muscle biopsy on the left tibialis anterior muscle. Histologic observation on HE stained specimens revealed marked inequality in the muscle fiber diameters, increase in endomysial nuclei, proliferation of connective tissue, and fiber splitting.(ABSTRACT TRUNCATED AT 400 WORDS) <bIntroduction:</b There are many phenotypic variants of chronic inflammatory demyelinating polyneuropathy. <bMethods:</bAn Ancient Greek aryvallos painted c. 480-450 BC, now on display at the Louvre museum, was meticulously studied regarding its painted surface, which presents an outpatient clinic in Ancient Greece. Other Ancient Greek works of art presenting medical activities have been also evaluated in order to reach informed conclusions regarding medical practice of that period. <bCase report:</b We report a rare case of the distal phenotype of chronic inflammatory demyelinating polyneuropathy with a subacute onset and rapidly progressive course. A 58-year-old male had distal, symmetric, predominantly motor impairment without ataxia and tremor. After a three-month duration of the disease, the patient had already complete paresis of the feet with absence of compound muscle action potentials (CMAPs) over the feet and lower leg muscles, but preserved proprioception and sural sensory nerve action potential. Cerebrospinal fluid protein level was elevated to 3.4 g/L. Demyelinating neuropathy was predominantly in the proximal segment of the nerves. Low amplitude of CMAPs was recorded hardly over the vastus medialis and rectus femoris muscles, while weakness and atrophy in these muscles were not. The patient was refractory to treatment. He died three years after disease onset. <bConclusion:</bWe described a new clinical-electrophysiological phenomenon, which was characterized as a decrease in the evoked electrical excitability at the femoral nerve stimulation site (decreased CMAP), while the natural physiological conduction of the impulse from the motor neuron to the muscle was not blocked (preserved muscle strength). This is a single-center retrospective study. The objective of this study was to study the clinical symptoms and electrophysiological features of C6-7 myelopathy. This study was conducted at the Department of Orthopedic surgery, Yamaguchi University Graduate school of medicine, Japan. A total of 20 patients with cervical compressive myelopathy were determined by spinal cord-evoked potentials or a single level of obvious magnetic resonance imaging (MRI)-documented cervical spinal cord compression. Neurological examinations included manual muscle testing and investigation of deep tendon reflex, including Hoffmann sign, and of sensory disturbance areas. Motor-evoked potentials (MEPs), compound muscle action potentials (CMAPs) and F-wave were recorded from bilateral abductor digit minim and abductor halluces muscles. Central motor conduction time was calculated as follows: MEPs latency-(CMAPs latency+F latency-1)/2 (ms). Eighteen patients (90%) had negative Hoffmann sign. Eight patients (40%) had no sensory disturbance in the upper limbs and 8 patients (40%) had no muscle weakness in the upper limbs. We determined that patients had cervical myelopathy when their central motor conduction time measured in abductor digit minim was longer than 6.76 ms (+2 s.d.). Using this definition, the sensitivity for myelopathy was 42.8%. Patients with C6-7 myelopathy may lack clinical symptoms in their hands and central motor conduction time measured in abductor digit minim tended to be less prolonged, and it only showed symptoms in their lower limbs as gait disturbance. Surgeons should bear in mind the possibility of disorders of caudal C6-7 when they encounter patients with no or few symptoms in their hands and with leg weakness or numbness.\nHere is the question:\nNEUROLOGY: A 65-year-old woman consults for weakness in the right hand that has spread in a few months to other muscle territories of both arms and legs, with distal predominance. On examination there is atrophy and fasciculations in different metameric territories with preserved sensitivity. There is a bilateral Babinski's sign, what is the diagnostic test that would confirm the suspected diagnosis?\nHere are the potential choices:\n1. Cerebral CT.\n2. Electromyographic study.\n3. Cerebral MRI.\n4. Multimodal evoked potentials.\nThe correct answer is: 4. Multimodal evoked potentials."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Despite many papers and instructional course lectures, therapeutic guidelines are not clearly defined about treatment of femoral neck fractures. The aim of this multicentric French symposium was to prospectively study the results of current therapeutic options in order to propose scientifically proven options. Three prospective studies were carried out in order to answer to these questions: (1) is it possible with anatomical reduction and stable fixation to lower the non union and osteonecrosis rate? (2) is functional treatment of Garden 1 fractures successful in more than 65 years patients? (3) what criteria are useful to choose the kind of arthroplasty for more than 65 years patients? For the 64 patients between 50 and 65 years old included in the first study, 44 ORIF and 17 prostheses were performed. No open reduction was performed in this series despite a 34% malreduction rate. The risk for displacement after functional treatment of Garden 1 fractures is 31%. For patients over 65 years old, almost fractures are treated in this series by an arthroplasty. The one-year mortality rate after displaced femoral neck fracture was 17%. Functional results were better in total hip prosthesis group than in bipolar or unipolar group. Non cemented stems were not safer than cemented ones in frail patients. For young patients, ORIF should be the treatment of choice: the initial displacement and its effects on the femoral head vascularisation, the quality of reduction and fixation are the two most significant factors for good outcome. For Garden 1, fractures in patients 65 years old or more, it is proposed to performed an internal fixation despite in two thirds of the cases, it should be unnecessary because non identification of predictive factors of failure. For patients over 65 years old, the type of arthroplasty to perform in displaced fractures is to be chosen according to the preoperative mobility and comorbidities. Because of acetabular erosion with long-term follow-up, it is clearly indicated to perform total hip replacement for patients with life expectancy of 10 years or more. For frail patients, unipolar arthroplasty is the best option. The place for bipolar or uncemented implants is not yet well-defined and more prospective trials are needed. In this multicentric study, results appear quite different in terms of mortality, or functional status. These differences seem to be related to technical choice, geriatric care, nutritional consideration or surgical organisation, all factors that may be of major importance for prognostic. Since November 1989 till the end of 2007 year we have been operatively treating 752 of acetabular hip fractures. We have analised 750 operated patients, two patients bilateral fractures. The follow up span lasts from 2 till 20 years. The age of treated patients is from 14 till 79 years old. These fractures were divided into those operated to 21 days after trauma--569 operated acetabulum. And those operated after 21 days after trauma--183 patients with the delayed reconstruction of acetabular fractures from 22 till 229 days. Both groups were provided detailed assesement. And next we compared fracture reduction of broken acetabulum and assesement of clinical treatment. The types of fractures were defined according to classification of Judet-Letournel. The criteria of fracture reduction due to Letournel. The clinical result was based on Merle d'Aubigne-Matta scale. In the group of treated patients till 3 weeks after trauma, we have received 83.8% of very good and good results, 6.9% fair results and 9.3% poor results. During fracture reduction: 75% very good, 4% in secondary joint congruence, 17.8% fair and 3.2% poor. After fair reduction there was always the right congrugence between the head and acetabulum. The displacements to 3 mm were left in more cases as a part after weight-bearing area. In trauma fracture trated after 3 weeks, the result was very good and good 66.1%, fair 14.8% and poor 19.1%. During fracture reduction: 49.7% very good, 4.4% secondary joint congruence, 32.8% fair and 13.1% poor. We have noticed the crucial corelation between fracture reduction and the final result of treatment. Additional traumae, especially head with long time loss of consciousness and the traumae of chest with insufficient breathing have indirect infulence on treatment results causing the longer operation waiting. The complexity fractures also indirectly influence on the result of treatment decreasing the chances on anathomical fracture reduction. To compare internal fixation, bipolar hemiarthroplasty and total hip arthroplasty for the management of displaced subcapital fracture of the hip in previously fit patients of 60 years or older. A prospective randomised clinical trial. This multicentre trial was carried out in 11 Scottish hospitals with acute orthopaedic trauma units. The participants were 298 previously fit patients of 60 years or older with displaced subcapital hip fractures. The three surgical interventions for comparison were reduction and fixation, bipolar hemiarthroplasty and total arthroplasty (total hip replacement). Participating surgeons elected to randomise patients either among all three types of operation (three-way randomisation) or just between fixation and hemiarthroplasty (two-way randomisation). Clinical outcomes were mortality rates, reoperation rates and the complication rates associated with each procedure. Functional outcome was measured using a hip specific questionnaire [Johanson Hip Rating Questionnaire (HRQ)] and a general health status questionnaire [EuroQol 5 Dimensions (EQ-5D)]. Economic analysis compared the costs in the randomised groups of hospital treatment for the initial and subsequent admissions for up to 2 years. Altogether, 207 patients were randomised among all three trial operations, and 91 between just fixation and bipolar hemiarthroplasty. There were no statistically significant differences in clinical outcomes, but confidence intervals (CIs) were wide. At 2 years fixation failure reached 37% among those allocated fixation and 39% had undergone further surgery. Further surgery rates after hemiarthroplasty and total hip replacement were 5% and 9%, respectively. The group allocated fixation had significantly worse HRQ and EQ-5D scores than both arthroplasty groups at 4 and 12 months. At 24 months the results still favoured arthroplasty, but the overall HRQ and EQ-5D scores were no longer statistically significant. Total hip replacement had the best patient-assessed outcome scores. At 24 months the overall HRQ and EQ-5D scores for total hip replacement were significantly better than for hemiarthroplasty. The mean costs for the initial episode ranged from 6384 pounds Sterling for fixation to 7633 pounds Sterling for total hip replacement. The cost differences were largely due to differences in theatre costs and the cost of prostheses and hardware. The cumulative cost over 2 years of hemiarthroplasty was around 3000 pounds Sterling lower than for fixation (95% CI 1227 pounds Sterling to 7192 pounds Sterling). Compared with total hip replacement, both fixation and hemiarthroplasty were characterised by increased costs arising from hip-replacement admissions. When total (initial episode and subsequent hip-related admissions) hip-related costs are compared, total hip replacement conferred a cost advantage of around 3000 pounds Sterling per patient (versus hemiarthroplasty, 95% CI -pounds Sterling 1400 to 7420 pounds Sterling). In fit, older patients the results of the study show a clear advantage for arthroplasty over fixation; arthroplasty was more clinically effective and probably less costly over a 2-year period postsurgery. The results suggest that total hip replacement has long-term advantages over bipolar hemiarthroplasty, but these findings are less definite. This study provided support for the use of total hip replacement to treat displaced intracapsular hip fractures in fit, older patients. A larger trial comparing total versus hemiarthroplasty for these fractures could help to verify these findings. It would also be useful to know whether the findings of this study apply to patients aged 60 years or less who are usually treated with reduction and fixation. A clinical trial comparing arthroplasty versus fixation in patients older than 40 years would be a logical extension of the current study. Surgery on the same day or day following the break is estimated to reduce postoperative mortality in people who are medically stable. Intracapsular fractures For low-grade fractures (Garden types 1 and 2), standard treatment is fixation of the fracture in situ with screws or a sliding screw/plate device. This treatment can also be offered for displaced fractures after the fracture has been reduced. Fractures managed by closed reduction can possibly be treated by percutaneously inserted screws. In elderly patients with displaced or intracapsular fractures many surgeons prefer to undertake a hemiarthroplasty, replacing the broken part of the bone with a metal implant. However, in elderly people who are medically well and still active, a total hip replacement may be indicated. Independently mobile older adults with hip fractures may benefit from a total hip replacement instead of hemiarthroplasty. To determine whether changing the consultant on-call schedule resulted in a reduction in time to theater for patients presenting with a hip fracture. Guidelines in the United Kingdom state that patients presenting with a neck of femur fracture should ideally be operated on the day of or the day after admission. However, there is a best practice tariff in the United Kingdom persuading trusts to operate on elderly patients with hip fracture within 36 hours of admission. Differing formats of daily trauma operating lists and varying consultant on-call schedules have the potential to affect a trusts ability to successfully meet such demands. This study retrospectively analyzed whether changing the on-call schedule from a system where the on-call consultant is changed on a daily basis to one which changes weekly resulted in a reduction in time to theater for such patients and an increase in best practice tariffs paid. With the initial rotation system, the average time to theater for a fractured neck of femur was 44 hours 46 minutes, with 44.7% of patients having a time to surgery of less than 36 hours. Patients in the modified system underwent surgery with an average time to theater of 32 hours 19 minutes. In 71.7% of these patients, time to surgery was less than 36 hours. This study demonstrates that changing the schedule to permit a consultant to have a 7-day period of trauma on call at a time instead of only 1 day dramatically reduced the time to theater for patients with hip fracture. This significantly reduced the number of these cases done outside 36 hours and increased trust financial reward. Posterior dislocation of the femoral head with fracture is an exceptional hip injury. Emergency reduction is required. Reposition into the acetabular cavity of the dislocated femoral head may not be feasible. Irreducibility, instability, and more rarely accidental fracture of the femoral neck may also occur. We encountered this latter complication in four patients and report here its frequency and mechanism and propose preventive therapeutic measures. Seventy dislocations and fracture-dislocations of the hip were treated in our unit from March 1997 to February 2003. Among these cases, fourteen hip dislocations were complicated by femoral head fractures. Fracture of the femoral neck occurred during reduction in four. All four cases occurred in men, mean age 49.7 years, who were traffic accident victims (drivers or passengers). There were two Pipkin IV fracture-dislocations and two Pipkin II. The first reduction, achieved under general anesthesia in an emergency setting, was performed by an orthopedic surgeon in one patient and a general surgeon in three patients. Arthroplasty was used to treat the femoral neck fracture in three patients and pinning in one. We reviewed retrospectively the clinical and imaging data before and after reduction. Sub-capital fracture situated 4.0 cm (mean, range 3.5-4.5 cm) from the lesser trochanter occurred in all four cases. The head remained attached above and posteriorly to the acetabulum and was rotated less than 90 degrees . The fragment remaining in the acetabulum was displaced in two cases. In one patient, the fracture-dislocation of the head was associated with a fracture of the posterior rim of the acetabulum. This complication appears to result from an abrupt inappropriate reduction movement. The neck fracture would occur when capsulomuscular retention of the femoral head is associated with a head defect which catches on the rim of the acetabulum during the reduction movement. Neck fracture during reduction of traumatic hip dislocation is a serious complication. Prevention of this iatrogenic event requires a slow, progressive reduction limiting the trauma to a minimum; first intention open surgery may be required in selected cases. To improve patient safety and quality in joint arthroplasty a certification of arthroplasty centers (EndoCert©) and a German arthroplasty register (EPRD) have been implemented. This should guarantee a long-term improvement in documentation of arthroplasty in the future. Although the stages of operations in elective and trauma-associated joint arthroplasty are comparable, the surgical preconditions are often quite different. As required by the German Society of Trauma Surgery (DGU) this study analyzed the current situation with respect to the proportion of fracture-associated joint arthroplasties among the total volume carried out in Germany. A uniform internet-based questionnaire was sent to all listed trauma centers in Germany by the central office of the DGU. In addition any information regarding hip joint arthroplasty in 2011 was collected from the Federal Statistical Office of Germany. The questionnaire was returned by 324 (47 %) out of 690 of the trauma centers contacted. A total of 34,135 total hip arthroplasties (THA) and 26,753 total knee arthroplasties (TKA) were carried out in 2011 by these clinics. The absolute numbers for total endoprosthesis replacement cited by the trauma centers were 5718 THAs and 3829 TKAs. According to the data from the Federal Statistical Office of Germany 131,966 hip fractures were registered in 2011, including 69,582 femoral neck fractures (patient age &gt;19 years) and 62,384 pertrochanteric fractures. From a total number of THAs of approximately 200,000 in Germany 47,695 (approximately 25 %) of these were associated with trauma. The data analyzed in this study and the results obtained from known literature sources demonstrate that THA is the most frequently performed procedure in trauma management of femoral neck fractures. Because of the ubiquitous and high incidence and the need for emergency treatment due to correlated risks and complications of delayed treatment, a high and standardized around the clock (24 h and 7 days a week) treatment option is mandatory. Long waiting times to treatment or transfer are inacceptable due to the increased mortality and complications. To study the effect of reserving articular capsule and traditional total hip replacement for old patients with unstable femoral neck fractures. From January 2010 to January 2015, one hundred and twenty patients with femoral neck fracture were retrospective review. Among them, sixty patients were treated with total hip arthroplasty reserving articular capsule, the others were treated with traditional total hip arthroplasty without reserving articular capsule. The gender of reserving articular capsule group and traditional group were (male/female) 34/26, 31/29 respectively; the age were (73.4±4.4), (72.3±4.1) years old, respectively. All patients were followed up for six months, the operation time, blood loss, length of stay, incidence of postoperative complications, incidence of postoperative hip dislocation and hip Harris score of the two groups were observed. The operative time of the reserving articular capsule group and traditional group were (95.68±6.90), (93.39±7.90) min (<iP</i&gt;0.05), and the blood loss were (998.78±15.20), (1 000.25±16.80) ml (<iP</i&gt;0.05). The time for hospital stay were (10.74±2.90), (13.25±2.20) days(<iP</i&lt;0.05). The Harris scores were 58.53±5.10, 49.38±4.90(<iP</i&lt;0.05) at 1 month after operation;91.08±7.50, 90.74±7.10(<iP</i&gt;0.05) at 6 months after operation. The method of reserving auricular capsule can not increase the operative time and the blood loss. But it has a favorable effect on decreasing the hospital stay, complication, the rate of early dislocation of the hip joint, improving the function of hip joint. Improvements in implant design, material combination and operating instruments have led to an increased number of resurfacing arthroplasties of the hip joint especially in younger patients. Therefore, there is generally a higher risk of periprosthetic fractures even with this type of prosthesis. These fractures are divided into mainly iatrogenic fractures of the head/neck part of the femur and trochanteric fractures of the femur caused by trauma. Especially in the second group preservation of the prosthesis is much desired since the patient cohort is often very young and active. We report on a 31-year-old male patient who suffered an intertrochanteric fracture (classification AO 31 A2.1) after resurfacing arthroplasty of the hip joint (McMinn BHR prosthesis). The patient was treated with 3 AO lag screws by the percutaneous technique following closed reduction. During follow-up 22 months after the operation the reduction was preserved and the fracture fully consolidated with a good range of motion of the hip joint. The Harris hip score gave a result of 97 points. In this retrospective study, we looked at the difference in 1 year mortality between two groups of patients who were operated for fracture of the hip. In cohort 1, 72% of the patients underwent surgery on the same day of admission, 15% of the patients were operated on the next day, the remaining 13% of the patients waited more than 1 day for surgery. The mean waiting time was 0.47 day. The percentage of patients who were operated on the same day of admission in cohort 2 was 18%. Sixty-nine percent of the patients had to wait 1 day before they were operated and 13% waited 2 days or more. The average waiting time was 1.01 days. The date of death for both the 166 patients in cohort 1 and the 197 patients in cohort 2, was obtained from the national mortality register and the 1 year mortality was calculated. These two groups of patients were from separate 12 month periods and the operations performed were either Dynamic Hip Screw (DHS) or hemiarthroplasty. The two groups were comparable in gender, age distribution and the types of operations. There was an increase of 10.1% (P&lt;0.025, chi(2), 1 d.f.; 95% CI 1.7-18.5) in the mortality of patients in cohort 2. The mortality data of the two cohorts was also analysed after dividing the patients into three groups according to their age. A statistically significant increase in mortality of 16.9% in patients over 80 years of age in cohort 2 was found. The difference in mortality was still statistically significant when only patients over 80 years of age and having a DHS operation were compared. Total mortality at 2 years after the operation was the same in the two cohorts. Mortality rate for patients in cohort 2 was less than that for cohort 1 patients during the second post-operative year. This study shows that survival at 1 year is better when patients who are medically fit for surgery are operated on the same day of admission. This survival advantage is more pronounced for patients who are over 80 years of age. The treatment of femoral neck fractures shows a relatively high number of poor outcomes, usually due to late complications, such as avascular necrosis of the femoral head or pseudoarthrosis. The latter may develop when the osteosynthesis of osteoporotic bone fails. The aim of this retrospective study was to evaluate a group of patients treated by osteo- synthesis for intra-capsular femoral neck fractures at our department, and to verify indication criteria and identify the therapeutic procedures that are best suited to our conditions. In the 1997-2001 period, a total of 81 patients with intra-capsular femoral neck fractures were operated on. Of these, 64 treated by dynamic hip screw (DHS) fixation were followed up for at least 5 years. There were 33 women and 31 men; the average age was 21.5 years (range, 21 to 74 years). The Garden classification was used to evaluate the displacement of femoral neck fractures. Preferably, osteosynthesis was carried out by closed reduction; only exceptionally was an extension device for the operating table used. A 135-degree sliding hip screw, with a short thread, directed to the head centre and a two-hole side plate were used most often.The average follow-up was 6.9 years. Evaluated were: the occurrence of late complications in relation to the length of time between injury and surgery, quality of fracture reduction, use of an anti-rotation screw and necessity of repeat surgery. Garden I or II fractures were diagnosed in 13 patients, 51 had Garden III or Garden IV fractures. Bone union without complications was achieved in 73.4 % of the patients within 12 months of surgery. Late complications were found in 26.6 %; of these, only one had Garden I fracture and the rest were Garden III and IV fractures. An anti-rotation screw was used in 39 patients (60.9 %) and its use had no effect on the development of late complications. Of the seven patients who developed pseudoarthrosis, the screw was used in four (57.1%); out of the nine patients with avascular necrosis, it was used in six (66.7 %). In the whole group, an unsatisfactory outcome of post-operative reduction was recorded in 29.7 %. In the patients with late complications this was found in 52.9 %, which was a statistically significant difference. Of the 17 patients with poor outcomes, 14 underwent total hip arthroplasty; in the patients with necrosis, arthroplasty was carried out at an average of 26 months post-operatively, in those with pseudoarthrosis it was at 7 months post-operatively. For the treatment of intra-capsular fractures of the femoral neck, surgery is the most frequent approach, but there are controversial views on various relevant issues. An important factor affecting the treatment outcome is the patient's bone quality. Our results show a direct relationship between the extent of fracture displacement and late complications, i.e., avascular necrosis and non-union. The quality of fracture reduction had a greater effect on fracture non-union than on the development of femoral head necrosis. The length of time between injury and surgery played a lesser role than it is believed. The use of an anti-rotation screw was not significantly related to the occurrence of late complications. The DHS method is economical and available, and provided sufficient results whose comparisons with the literature data show that this therapeutic approach is correct. 177 patients with fractures near the hip joint were operated on between January 1983 and December 1985. The fractures were treated with Ender pinnings, total endoprostheses and dynamic hip screws (compression screw fixation). Up to June 1984 surgery was performed after the patients had been allowed a stabilisation phase of 4 days on the average, but from July 1984 onwards we aimed at performing immediate surgery within 12 hours. The second group was compared with the first group in a retrospective study in respect of recumbent period and mortality (hospital mortality and mortality after 8 months). The period during which the patients had to remain recumbent in the hospital was found to be considerably shorter, but there were no statistically significant differences in respect of mortality. The causes and consequences are discussed. The reported incidence of avascular necrosis after femoral neck fracture fixation varies widely, and there is no consensus regarding its risk factors. We evaluated the incidence of avascular necrosis of the femoral head with the use of contemporary techniques for femoral neck fracture fixation. We then sought to determine what potential risk factors influenced the development of avascular necrosis.Between 1990 and 2005, one hundred sixty-three intracapsular femoral neck fractures in 163 patients were treated with internal fixation at our level-I trauma center. All patients were monitored until conversion to total hip arthroplasty or for a minimum of 2 years postoperatively. Ten patients (10 hips) died and 7 patients (7 hips) were lost to follow-up. The remaining 146 patients (146 hips) had a mean 5.2 years of follow-up (range, 3 months to 17 years). The incidence of avascular necrosis was 25.3% (37 hips). The average time to diagnosis of avascular necrosis was 18.8 months (range, 3-47 months). Patient sex, age, interval from injury to surgery, and mechanism of injury were statistically not associated with the development of avascular necrosis. The quality of fracture reduction, adequacy of fixation, degree of displacement, and comminution of the posterior cortex were significantly associated. After we controlled for patient and radiographic characteristics, multivariate analyses indicated that the important predictors for avascular necrosis are poor reduction (odds ratio=13.889) and initial displacement of the fracture (odds ratio=4.693). Early surgical fixation of femoral neck factures in elderly patients has been suggested to decrease morbidity and mortality and to improve treatment outcome. This study evaluates the effect of the implementation of a diagnosis-related group payment method in our hospital on waiting time for surgery and the short-term outcomes of elderly patients following surgical fixation of hip fractures. Demographic and clinical characteristics of 75 consecutive patients, who underwent surgery for hip fracture in our hospital, before the implementation of a diagnosis-related group payment method, were compared with those of 75 consecutive patients, who were operated on after the implementation of the payment system. Demographic characteristics were similar for both groups. Before the implementation of a diagnosis-related group payment method, 84% of the patients waited longer than 48 hours for surgery, compared to only 24% of patients after the implementation (p&lt;0.001). Medical considerations and operation room availability were the main reasons for delaying surgery in both groups. Mortality and morbidity rates during the hospital stay remained similar, regardless of the implementation of the payment method. The implementation of a diagnosis-related group payment method shortened the waiting time for surgical hip fixation in elderly patients treated in our hospital, with no effect on the mortality and complication rate during the hospital stay. The prolonged use of bisphosphonates has been associated with an increased rate of atypical femoral fracture. A 77-year-old woman with prolonged bisphosphonate use presented to our office with groin pain and end-stage arthritis, She was scheduled for a total hip replacement. Before the surgery and with minimal trauma, the patient then suffered a displaced atypical femoral fracture. She underwent a total hip replacement as a treatment for her fracture and her arthritis. Subsequently, the patient presented with pain in the contralateral thigh with an incomplete atypical femoral fracture. That side was also treated with a total hip arthroplasty. An uncemented stem with open reduction internal fixation and a long cemented stem were used on the complete fracture and incomplete fracture sides, respectively. At a follow-up of 2 years, the patient had no pain and had excellent function demonstrating the short-term success of both cemented and uncemented stems in total hip arthroplasty after atypical femoral fractures. Clinical guidelines for the management of hip fractures strongly emphasize the critical role of early surgery as a major factor affecting better health outcomes. Shortening the time from admission to pre-operative consultation by bringing the consultants to the emergency room, before patient admission to the orthopedic ward, is am efficient cost effective hospital policy that enables adherence to guideline recommendations. Early pre-operative specialist consultation is an efficient cost effective policy for preventing delay of surgery following hip fracture in the elderly. Bilateral posterior hip dislocations are very rare injury, requiring a very hight trauma energy. We present a case of 40-year-old male who sustained bilateral posterior hip dislocation with associated right femoral head fracture Pipkin type II following a hight energy trauma without neurovascular deficit. A prompt closed reduction was made, it was successful in lift hip but incomplete in right one, therefore, an open reduction was indicated, performed through a modified Hardinge approach permitting internal osteosynthesis with two Herbert screws. Posterior hip dislocations are an orthopaedic emergency that must be reduced within 6 h to avoid sciatic nerve compression and avascular necrosis (AVN). They are most often associated with femoral head fractures commonly known as Pipkin's fractures, that need anatomic reduction and osteosynthesis through posterior approaches, rarely external or anterior approaches. Anatomic and functional results were good at two years follow up excepting a right hip non-bridging heterotopic ossification; the patient returned to his work normally without any functional sequelae. Fractures of the hip are common, often occurring in frail elderly patients, but also in younger fit healthy patients following trauma. They have a significant associated mortality and major social and financial implications to patients and health care providers. Many guidelines are available for the management of these patients, mostly recommending early surgery for the best outcomes. As a result, healthcare authorities now put pressure on surgical teams to 'fast track' patients with a fracture of the hip, often misquoting the available literature, which in itself can be confusing and even conflicting. This paper has been written following an extensive review of the available literature. An attempt is made to clarify what is meant by early surgery (expeditious versus emergency), and we conclude with a personal view for the practical management of these patients of variable age, fitness and type of surgery performed within services that are often under considerable pressure of finance and available operating theatres and qualified staff. Cite this article: Bone Joint J 2016;98-B:1573-81.\nHere is the question:\nTRAUMATOLOGY: 25-year-old patient, who suffers a motorcycle accident on a Friday night. He is taken to the emergency room and diagnosed with abdominal trauma (negative echo-fast), mild head trauma (Glasgow = 14) and a displaced intracapsular fracture of the right hip. Hemodynamically she is stable, what would be the treatment of choice?\nHere are the potential choices:\n1. Reduction, open if necessary, and osteosynthesis of the fracture in the first 24-36 hours.\n2. Total hip resurfacing arthroplasty on Monday on a scheduled basis.\n3. Wait for improvement of the cranial trauma and schedule the following week a scheduled surgery consisting of reduction and osteosynthesis of the fracture.\n4. Given the risk of non-union of these types of fracture, I would perform an emergency bipolar hip hemiarthroplasty.\nThe correct answer is: ",
        "gold_answer": "1 Reduction, open if necessary, and osteosynthesis of the fracture in the first 24-36 hours.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Despite many papers and instructional course lectures, therapeutic guidelines are not clearly defined about treatment of femoral neck fractures. The aim of this multicentric French symposium was to prospectively study the results of current therapeutic options in order to propose scientifically proven options. Three prospective studies were carried out in order to answer to these questions: (1) is it possible with anatomical reduction and stable fixation to lower the non union and osteonecrosis rate? (2) is functional treatment of Garden 1 fractures successful in more than 65 years patients? (3) what criteria are useful to choose the kind of arthroplasty for more than 65 years patients? For the 64 patients between 50 and 65 years old included in the first study, 44 ORIF and 17 prostheses were performed. No open reduction was performed in this series despite a 34% malreduction rate. The risk for displacement after functional treatment of Garden 1 fractures is 31%. For patients over 65 years old, almost fractures are treated in this series by an arthroplasty. The one-year mortality rate after displaced femoral neck fracture was 17%. Functional results were better in total hip prosthesis group than in bipolar or unipolar group. Non cemented stems were not safer than cemented ones in frail patients. For young patients, ORIF should be the treatment of choice: the initial displacement and its effects on the femoral head vascularisation, the quality of reduction and fixation are the two most significant factors for good outcome. For Garden 1, fractures in patients 65 years old or more, it is proposed to performed an internal fixation despite in two thirds of the cases, it should be unnecessary because non identification of predictive factors of failure. For patients over 65 years old, the type of arthroplasty to perform in displaced fractures is to be chosen according to the preoperative mobility and comorbidities. Because of acetabular erosion with long-term follow-up, it is clearly indicated to perform total hip replacement for patients with life expectancy of 10 years or more. For frail patients, unipolar arthroplasty is the best option. The place for bipolar or uncemented implants is not yet well-defined and more prospective trials are needed. In this multicentric study, results appear quite different in terms of mortality, or functional status. These differences seem to be related to technical choice, geriatric care, nutritional consideration or surgical organisation, all factors that may be of major importance for prognostic. Since November 1989 till the end of 2007 year we have been operatively treating 752 of acetabular hip fractures. We have analised 750 operated patients, two patients bilateral fractures. The follow up span lasts from 2 till 20 years. The age of treated patients is from 14 till 79 years old. These fractures were divided into those operated to 21 days after trauma--569 operated acetabulum. And those operated after 21 days after trauma--183 patients with the delayed reconstruction of acetabular fractures from 22 till 229 days. Both groups were provided detailed assesement. And next we compared fracture reduction of broken acetabulum and assesement of clinical treatment. The types of fractures were defined according to classification of Judet-Letournel. The criteria of fracture reduction due to Letournel. The clinical result was based on Merle d'Aubigne-Matta scale. In the group of treated patients till 3 weeks after trauma, we have received 83.8% of very good and good results, 6.9% fair results and 9.3% poor results. During fracture reduction: 75% very good, 4% in secondary joint congruence, 17.8% fair and 3.2% poor. After fair reduction there was always the right congrugence between the head and acetabulum. The displacements to 3 mm were left in more cases as a part after weight-bearing area. In trauma fracture trated after 3 weeks, the result was very good and good 66.1%, fair 14.8% and poor 19.1%. During fracture reduction: 49.7% very good, 4.4% secondary joint congruence, 32.8% fair and 13.1% poor. We have noticed the crucial corelation between fracture reduction and the final result of treatment. Additional traumae, especially head with long time loss of consciousness and the traumae of chest with insufficient breathing have indirect infulence on treatment results causing the longer operation waiting. The complexity fractures also indirectly influence on the result of treatment decreasing the chances on anathomical fracture reduction. To compare internal fixation, bipolar hemiarthroplasty and total hip arthroplasty for the management of displaced subcapital fracture of the hip in previously fit patients of 60 years or older. A prospective randomised clinical trial. This multicentre trial was carried out in 11 Scottish hospitals with acute orthopaedic trauma units. The participants were 298 previously fit patients of 60 years or older with displaced subcapital hip fractures. The three surgical interventions for comparison were reduction and fixation, bipolar hemiarthroplasty and total arthroplasty (total hip replacement). Participating surgeons elected to randomise patients either among all three types of operation (three-way randomisation) or just between fixation and hemiarthroplasty (two-way randomisation). Clinical outcomes were mortality rates, reoperation rates and the complication rates associated with each procedure. Functional outcome was measured using a hip specific questionnaire [Johanson Hip Rating Questionnaire (HRQ)] and a general health status questionnaire [EuroQol 5 Dimensions (EQ-5D)]. Economic analysis compared the costs in the randomised groups of hospital treatment for the initial and subsequent admissions for up to 2 years. Altogether, 207 patients were randomised among all three trial operations, and 91 between just fixation and bipolar hemiarthroplasty. There were no statistically significant differences in clinical outcomes, but confidence intervals (CIs) were wide. At 2 years fixation failure reached 37% among those allocated fixation and 39% had undergone further surgery. Further surgery rates after hemiarthroplasty and total hip replacement were 5% and 9%, respectively. The group allocated fixation had significantly worse HRQ and EQ-5D scores than both arthroplasty groups at 4 and 12 months. At 24 months the results still favoured arthroplasty, but the overall HRQ and EQ-5D scores were no longer statistically significant. Total hip replacement had the best patient-assessed outcome scores. At 24 months the overall HRQ and EQ-5D scores for total hip replacement were significantly better than for hemiarthroplasty. The mean costs for the initial episode ranged from 6384 pounds Sterling for fixation to 7633 pounds Sterling for total hip replacement. The cost differences were largely due to differences in theatre costs and the cost of prostheses and hardware. The cumulative cost over 2 years of hemiarthroplasty was around 3000 pounds Sterling lower than for fixation (95% CI 1227 pounds Sterling to 7192 pounds Sterling). Compared with total hip replacement, both fixation and hemiarthroplasty were characterised by increased costs arising from hip-replacement admissions. When total (initial episode and subsequent hip-related admissions) hip-related costs are compared, total hip replacement conferred a cost advantage of around 3000 pounds Sterling per patient (versus hemiarthroplasty, 95% CI -pounds Sterling 1400 to 7420 pounds Sterling). In fit, older patients the results of the study show a clear advantage for arthroplasty over fixation; arthroplasty was more clinically effective and probably less costly over a 2-year period postsurgery. The results suggest that total hip replacement has long-term advantages over bipolar hemiarthroplasty, but these findings are less definite. This study provided support for the use of total hip replacement to treat displaced intracapsular hip fractures in fit, older patients. A larger trial comparing total versus hemiarthroplasty for these fractures could help to verify these findings. It would also be useful to know whether the findings of this study apply to patients aged 60 years or less who are usually treated with reduction and fixation. A clinical trial comparing arthroplasty versus fixation in patients older than 40 years would be a logical extension of the current study. Surgery on the same day or day following the break is estimated to reduce postoperative mortality in people who are medically stable. Intracapsular fractures For low-grade fractures (Garden types 1 and 2), standard treatment is fixation of the fracture in situ with screws or a sliding screw/plate device. This treatment can also be offered for displaced fractures after the fracture has been reduced. Fractures managed by closed reduction can possibly be treated by percutaneously inserted screws. In elderly patients with displaced or intracapsular fractures many surgeons prefer to undertake a hemiarthroplasty, replacing the broken part of the bone with a metal implant. However, in elderly people who are medically well and still active, a total hip replacement may be indicated. Independently mobile older adults with hip fractures may benefit from a total hip replacement instead of hemiarthroplasty. To determine whether changing the consultant on-call schedule resulted in a reduction in time to theater for patients presenting with a hip fracture. Guidelines in the United Kingdom state that patients presenting with a neck of femur fracture should ideally be operated on the day of or the day after admission. However, there is a best practice tariff in the United Kingdom persuading trusts to operate on elderly patients with hip fracture within 36 hours of admission. Differing formats of daily trauma operating lists and varying consultant on-call schedules have the potential to affect a trusts ability to successfully meet such demands. This study retrospectively analyzed whether changing the on-call schedule from a system where the on-call consultant is changed on a daily basis to one which changes weekly resulted in a reduction in time to theater for such patients and an increase in best practice tariffs paid. With the initial rotation system, the average time to theater for a fractured neck of femur was 44 hours 46 minutes, with 44.7% of patients having a time to surgery of less than 36 hours. Patients in the modified system underwent surgery with an average time to theater of 32 hours 19 minutes. In 71.7% of these patients, time to surgery was less than 36 hours. This study demonstrates that changing the schedule to permit a consultant to have a 7-day period of trauma on call at a time instead of only 1 day dramatically reduced the time to theater for patients with hip fracture. This significantly reduced the number of these cases done outside 36 hours and increased trust financial reward. Posterior dislocation of the femoral head with fracture is an exceptional hip injury. Emergency reduction is required. Reposition into the acetabular cavity of the dislocated femoral head may not be feasible. Irreducibility, instability, and more rarely accidental fracture of the femoral neck may also occur. We encountered this latter complication in four patients and report here its frequency and mechanism and propose preventive therapeutic measures. Seventy dislocations and fracture-dislocations of the hip were treated in our unit from March 1997 to February 2003. Among these cases, fourteen hip dislocations were complicated by femoral head fractures. Fracture of the femoral neck occurred during reduction in four. All four cases occurred in men, mean age 49.7 years, who were traffic accident victims (drivers or passengers). There were two Pipkin IV fracture-dislocations and two Pipkin II. The first reduction, achieved under general anesthesia in an emergency setting, was performed by an orthopedic surgeon in one patient and a general surgeon in three patients. Arthroplasty was used to treat the femoral neck fracture in three patients and pinning in one. We reviewed retrospectively the clinical and imaging data before and after reduction. Sub-capital fracture situated 4.0 cm (mean, range 3.5-4.5 cm) from the lesser trochanter occurred in all four cases. The head remained attached above and posteriorly to the acetabulum and was rotated less than 90 degrees . The fragment remaining in the acetabulum was displaced in two cases. In one patient, the fracture-dislocation of the head was associated with a fracture of the posterior rim of the acetabulum. This complication appears to result from an abrupt inappropriate reduction movement. The neck fracture would occur when capsulomuscular retention of the femoral head is associated with a head defect which catches on the rim of the acetabulum during the reduction movement. Neck fracture during reduction of traumatic hip dislocation is a serious complication. Prevention of this iatrogenic event requires a slow, progressive reduction limiting the trauma to a minimum; first intention open surgery may be required in selected cases. To improve patient safety and quality in joint arthroplasty a certification of arthroplasty centers (EndoCert©) and a German arthroplasty register (EPRD) have been implemented. This should guarantee a long-term improvement in documentation of arthroplasty in the future. Although the stages of operations in elective and trauma-associated joint arthroplasty are comparable, the surgical preconditions are often quite different. As required by the German Society of Trauma Surgery (DGU) this study analyzed the current situation with respect to the proportion of fracture-associated joint arthroplasties among the total volume carried out in Germany. A uniform internet-based questionnaire was sent to all listed trauma centers in Germany by the central office of the DGU. In addition any information regarding hip joint arthroplasty in 2011 was collected from the Federal Statistical Office of Germany. The questionnaire was returned by 324 (47 %) out of 690 of the trauma centers contacted. A total of 34,135 total hip arthroplasties (THA) and 26,753 total knee arthroplasties (TKA) were carried out in 2011 by these clinics. The absolute numbers for total endoprosthesis replacement cited by the trauma centers were 5718 THAs and 3829 TKAs. According to the data from the Federal Statistical Office of Germany 131,966 hip fractures were registered in 2011, including 69,582 femoral neck fractures (patient age &gt;19 years) and 62,384 pertrochanteric fractures. From a total number of THAs of approximately 200,000 in Germany 47,695 (approximately 25 %) of these were associated with trauma. The data analyzed in this study and the results obtained from known literature sources demonstrate that THA is the most frequently performed procedure in trauma management of femoral neck fractures. Because of the ubiquitous and high incidence and the need for emergency treatment due to correlated risks and complications of delayed treatment, a high and standardized around the clock (24 h and 7 days a week) treatment option is mandatory. Long waiting times to treatment or transfer are inacceptable due to the increased mortality and complications. To study the effect of reserving articular capsule and traditional total hip replacement for old patients with unstable femoral neck fractures. From January 2010 to January 2015, one hundred and twenty patients with femoral neck fracture were retrospective review. Among them, sixty patients were treated with total hip arthroplasty reserving articular capsule, the others were treated with traditional total hip arthroplasty without reserving articular capsule. The gender of reserving articular capsule group and traditional group were (male/female) 34/26, 31/29 respectively; the age were (73.4±4.4), (72.3±4.1) years old, respectively. All patients were followed up for six months, the operation time, blood loss, length of stay, incidence of postoperative complications, incidence of postoperative hip dislocation and hip Harris score of the two groups were observed. The operative time of the reserving articular capsule group and traditional group were (95.68±6.90), (93.39±7.90) min (<iP</i&gt;0.05), and the blood loss were (998.78±15.20), (1 000.25±16.80) ml (<iP</i&gt;0.05). The time for hospital stay were (10.74±2.90), (13.25±2.20) days(<iP</i&lt;0.05). The Harris scores were 58.53±5.10, 49.38±4.90(<iP</i&lt;0.05) at 1 month after operation;91.08±7.50, 90.74±7.10(<iP</i&gt;0.05) at 6 months after operation. The method of reserving auricular capsule can not increase the operative time and the blood loss. But it has a favorable effect on decreasing the hospital stay, complication, the rate of early dislocation of the hip joint, improving the function of hip joint. Improvements in implant design, material combination and operating instruments have led to an increased number of resurfacing arthroplasties of the hip joint especially in younger patients. Therefore, there is generally a higher risk of periprosthetic fractures even with this type of prosthesis. These fractures are divided into mainly iatrogenic fractures of the head/neck part of the femur and trochanteric fractures of the femur caused by trauma. Especially in the second group preservation of the prosthesis is much desired since the patient cohort is often very young and active. We report on a 31-year-old male patient who suffered an intertrochanteric fracture (classification AO 31 A2.1) after resurfacing arthroplasty of the hip joint (McMinn BHR prosthesis). The patient was treated with 3 AO lag screws by the percutaneous technique following closed reduction. During follow-up 22 months after the operation the reduction was preserved and the fracture fully consolidated with a good range of motion of the hip joint. The Harris hip score gave a result of 97 points. In this retrospective study, we looked at the difference in 1 year mortality between two groups of patients who were operated for fracture of the hip. In cohort 1, 72% of the patients underwent surgery on the same day of admission, 15% of the patients were operated on the next day, the remaining 13% of the patients waited more than 1 day for surgery. The mean waiting time was 0.47 day. The percentage of patients who were operated on the same day of admission in cohort 2 was 18%. Sixty-nine percent of the patients had to wait 1 day before they were operated and 13% waited 2 days or more. The average waiting time was 1.01 days. The date of death for both the 166 patients in cohort 1 and the 197 patients in cohort 2, was obtained from the national mortality register and the 1 year mortality was calculated. These two groups of patients were from separate 12 month periods and the operations performed were either Dynamic Hip Screw (DHS) or hemiarthroplasty. The two groups were comparable in gender, age distribution and the types of operations. There was an increase of 10.1% (P&lt;0.025, chi(2), 1 d.f.; 95% CI 1.7-18.5) in the mortality of patients in cohort 2. The mortality data of the two cohorts was also analysed after dividing the patients into three groups according to their age. A statistically significant increase in mortality of 16.9% in patients over 80 years of age in cohort 2 was found. The difference in mortality was still statistically significant when only patients over 80 years of age and having a DHS operation were compared. Total mortality at 2 years after the operation was the same in the two cohorts. Mortality rate for patients in cohort 2 was less than that for cohort 1 patients during the second post-operative year. This study shows that survival at 1 year is better when patients who are medically fit for surgery are operated on the same day of admission. This survival advantage is more pronounced for patients who are over 80 years of age. The treatment of femoral neck fractures shows a relatively high number of poor outcomes, usually due to late complications, such as avascular necrosis of the femoral head or pseudoarthrosis. The latter may develop when the osteosynthesis of osteoporotic bone fails. The aim of this retrospective study was to evaluate a group of patients treated by osteo- synthesis for intra-capsular femoral neck fractures at our department, and to verify indication criteria and identify the therapeutic procedures that are best suited to our conditions. In the 1997-2001 period, a total of 81 patients with intra-capsular femoral neck fractures were operated on. Of these, 64 treated by dynamic hip screw (DHS) fixation were followed up for at least 5 years. There were 33 women and 31 men; the average age was 21.5 years (range, 21 to 74 years). The Garden classification was used to evaluate the displacement of femoral neck fractures. Preferably, osteosynthesis was carried out by closed reduction; only exceptionally was an extension device for the operating table used. A 135-degree sliding hip screw, with a short thread, directed to the head centre and a two-hole side plate were used most often.The average follow-up was 6.9 years. Evaluated were: the occurrence of late complications in relation to the length of time between injury and surgery, quality of fracture reduction, use of an anti-rotation screw and necessity of repeat surgery. Garden I or II fractures were diagnosed in 13 patients, 51 had Garden III or Garden IV fractures. Bone union without complications was achieved in 73.4 % of the patients within 12 months of surgery. Late complications were found in 26.6 %; of these, only one had Garden I fracture and the rest were Garden III and IV fractures. An anti-rotation screw was used in 39 patients (60.9 %) and its use had no effect on the development of late complications. Of the seven patients who developed pseudoarthrosis, the screw was used in four (57.1%); out of the nine patients with avascular necrosis, it was used in six (66.7 %). In the whole group, an unsatisfactory outcome of post-operative reduction was recorded in 29.7 %. In the patients with late complications this was found in 52.9 %, which was a statistically significant difference. Of the 17 patients with poor outcomes, 14 underwent total hip arthroplasty; in the patients with necrosis, arthroplasty was carried out at an average of 26 months post-operatively, in those with pseudoarthrosis it was at 7 months post-operatively. For the treatment of intra-capsular fractures of the femoral neck, surgery is the most frequent approach, but there are controversial views on various relevant issues. An important factor affecting the treatment outcome is the patient's bone quality. Our results show a direct relationship between the extent of fracture displacement and late complications, i.e., avascular necrosis and non-union. The quality of fracture reduction had a greater effect on fracture non-union than on the development of femoral head necrosis. The length of time between injury and surgery played a lesser role than it is believed. The use of an anti-rotation screw was not significantly related to the occurrence of late complications. The DHS method is economical and available, and provided sufficient results whose comparisons with the literature data show that this therapeutic approach is correct. 177 patients with fractures near the hip joint were operated on between January 1983 and December 1985. The fractures were treated with Ender pinnings, total endoprostheses and dynamic hip screws (compression screw fixation). Up to June 1984 surgery was performed after the patients had been allowed a stabilisation phase of 4 days on the average, but from July 1984 onwards we aimed at performing immediate surgery within 12 hours. The second group was compared with the first group in a retrospective study in respect of recumbent period and mortality (hospital mortality and mortality after 8 months). The period during which the patients had to remain recumbent in the hospital was found to be considerably shorter, but there were no statistically significant differences in respect of mortality. The causes and consequences are discussed. The reported incidence of avascular necrosis after femoral neck fracture fixation varies widely, and there is no consensus regarding its risk factors. We evaluated the incidence of avascular necrosis of the femoral head with the use of contemporary techniques for femoral neck fracture fixation. We then sought to determine what potential risk factors influenced the development of avascular necrosis.Between 1990 and 2005, one hundred sixty-three intracapsular femoral neck fractures in 163 patients were treated with internal fixation at our level-I trauma center. All patients were monitored until conversion to total hip arthroplasty or for a minimum of 2 years postoperatively. Ten patients (10 hips) died and 7 patients (7 hips) were lost to follow-up. The remaining 146 patients (146 hips) had a mean 5.2 years of follow-up (range, 3 months to 17 years). The incidence of avascular necrosis was 25.3% (37 hips). The average time to diagnosis of avascular necrosis was 18.8 months (range, 3-47 months). Patient sex, age, interval from injury to surgery, and mechanism of injury were statistically not associated with the development of avascular necrosis. The quality of fracture reduction, adequacy of fixation, degree of displacement, and comminution of the posterior cortex were significantly associated. After we controlled for patient and radiographic characteristics, multivariate analyses indicated that the important predictors for avascular necrosis are poor reduction (odds ratio=13.889) and initial displacement of the fracture (odds ratio=4.693). Early surgical fixation of femoral neck factures in elderly patients has been suggested to decrease morbidity and mortality and to improve treatment outcome. This study evaluates the effect of the implementation of a diagnosis-related group payment method in our hospital on waiting time for surgery and the short-term outcomes of elderly patients following surgical fixation of hip fractures. Demographic and clinical characteristics of 75 consecutive patients, who underwent surgery for hip fracture in our hospital, before the implementation of a diagnosis-related group payment method, were compared with those of 75 consecutive patients, who were operated on after the implementation of the payment system. Demographic characteristics were similar for both groups. Before the implementation of a diagnosis-related group payment method, 84% of the patients waited longer than 48 hours for surgery, compared to only 24% of patients after the implementation (p&lt;0.001). Medical considerations and operation room availability were the main reasons for delaying surgery in both groups. Mortality and morbidity rates during the hospital stay remained similar, regardless of the implementation of the payment method. The implementation of a diagnosis-related group payment method shortened the waiting time for surgical hip fixation in elderly patients treated in our hospital, with no effect on the mortality and complication rate during the hospital stay. The prolonged use of bisphosphonates has been associated with an increased rate of atypical femoral fracture. A 77-year-old woman with prolonged bisphosphonate use presented to our office with groin pain and end-stage arthritis, She was scheduled for a total hip replacement. Before the surgery and with minimal trauma, the patient then suffered a displaced atypical femoral fracture. She underwent a total hip replacement as a treatment for her fracture and her arthritis. Subsequently, the patient presented with pain in the contralateral thigh with an incomplete atypical femoral fracture. That side was also treated with a total hip arthroplasty. An uncemented stem with open reduction internal fixation and a long cemented stem were used on the complete fracture and incomplete fracture sides, respectively. At a follow-up of 2 years, the patient had no pain and had excellent function demonstrating the short-term success of both cemented and uncemented stems in total hip arthroplasty after atypical femoral fractures. Clinical guidelines for the management of hip fractures strongly emphasize the critical role of early surgery as a major factor affecting better health outcomes. Shortening the time from admission to pre-operative consultation by bringing the consultants to the emergency room, before patient admission to the orthopedic ward, is am efficient cost effective hospital policy that enables adherence to guideline recommendations. Early pre-operative specialist consultation is an efficient cost effective policy for preventing delay of surgery following hip fracture in the elderly. Bilateral posterior hip dislocations are very rare injury, requiring a very hight trauma energy. We present a case of 40-year-old male who sustained bilateral posterior hip dislocation with associated right femoral head fracture Pipkin type II following a hight energy trauma without neurovascular deficit. A prompt closed reduction was made, it was successful in lift hip but incomplete in right one, therefore, an open reduction was indicated, performed through a modified Hardinge approach permitting internal osteosynthesis with two Herbert screws. Posterior hip dislocations are an orthopaedic emergency that must be reduced within 6 h to avoid sciatic nerve compression and avascular necrosis (AVN). They are most often associated with femoral head fractures commonly known as Pipkin's fractures, that need anatomic reduction and osteosynthesis through posterior approaches, rarely external or anterior approaches. Anatomic and functional results were good at two years follow up excepting a right hip non-bridging heterotopic ossification; the patient returned to his work normally without any functional sequelae. Fractures of the hip are common, often occurring in frail elderly patients, but also in younger fit healthy patients following trauma. They have a significant associated mortality and major social and financial implications to patients and health care providers. Many guidelines are available for the management of these patients, mostly recommending early surgery for the best outcomes. As a result, healthcare authorities now put pressure on surgical teams to 'fast track' patients with a fracture of the hip, often misquoting the available literature, which in itself can be confusing and even conflicting. This paper has been written following an extensive review of the available literature. An attempt is made to clarify what is meant by early surgery (expeditious versus emergency), and we conclude with a personal view for the practical management of these patients of variable age, fitness and type of surgery performed within services that are often under considerable pressure of finance and available operating theatres and qualified staff. Cite this article: Bone Joint J 2016;98-B:1573-81.\nHere is the question:\nTRAUMATOLOGY: 25-year-old patient, who suffers a motorcycle accident on a Friday night. He is taken to the emergency room and diagnosed with abdominal trauma (negative echo-fast), mild head trauma (Glasgow = 14) and a displaced intracapsular fracture of the right hip. Hemodynamically she is stable, what would be the treatment of choice?\nHere are the potential choices:\n1. Reduction, open if necessary, and osteosynthesis of the fracture in the first 24-36 hours.\n2. Total hip resurfacing arthroplasty on Monday on a scheduled basis.\n3. Wait for improvement of the cranial trauma and schedule the following week a scheduled surgery consisting of reduction and osteosynthesis of the fracture.\n4. Given the risk of non-union of these types of fracture, I would perform an emergency bipolar hip hemiarthroplasty.\nThe correct answer is: 1. Reduction, open if necessary, and osteosynthesis of the fracture in the first 24-36 hours."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Signs and symptoms The following are signs and symptoms that may be associated with an SI joint (SIJ) problem: Mechanical SIJ dysfunction usually causes a dull unilateral low back pain. The pain is often a mild to moderate ache around the dimple or posterior superior iliac spine (PSIS) region. The pain may become worse and sharp while doing activities such as standing up from a seated position or lifting the knee towards the chest during stair climbing. Pain is typically on one side or the other (unilateral PSIS pain), but the pain can occasionally be bilateral. When the pain of SIJ dysfunction is severe (which is infrequent), there can be referred pain into the hip, groin, and occasionally down the leg, but rarely does the pain radiate below the knee. Pain can be referred from the SIJ down into the buttock or back of the thigh, and rarely to the foot. Low back pain and stiffness, often unilateral, that often increases with prolonged sitting or prolonged walking. Further, a straight leg raise (SLR) test is a neurological maneuver performed while examining a patient presenting with lower back pain. This test is conducted with the patient lying supine while keeping the symptomatic leg straight by flexing the quadriceps. The examiner elevates the leg progressively at a slow pace. The test is deemed positive if it reproduces the patient's symptoms (pain and paresthesia) at an angle lower than 70° with radiation below the knee (Lasegue sign). This test is most helpful in diagnosing L4, L5, and S1 radiculopathies. The patient is asked to dorsiflex the foot while the examiner raises the leg (Bragaad sign) to increase the test's sensitivity. When executing the straight leg raise test, the examiner will slightly bend the patient's knee by 20° to 30°, which will lessen the pain. Then, manual pressure is applied in the popliteal fossa. The Bowstring sign is considered positive if it causes the same level of discomfort that the patient feels during a straight leg raise. [8] The Naffziger test involves reproducing pain via coughing. [9] A straight-leg raise has variable sensitivity and specificity and may or may not be present depending on the underlying cause. The straight-leg test is a passive examination where the patient first lies in a relaxed, supine position. The examiner then lifts the leg from the posterior aspect, flexing at the hip joint and keeping the knee in full extension or keeping the leg straight. Typically, pain that is reproduced between 30° to 70° of hip flexion and experienced primarily in the back is likely due to a lumbar disc herniation. Pain and parenthesis felt in the leg are possible due to lateralizing compression of a peripheral nerve. While not absolute, musculoskeletal causes of the pain usually reproduce pain above 70° of flexion and below 30° of flexion. More often the lateral hip pain is caused by disease of the gluteal tendons that secondarily inflames the bursa. This is most common in middle-aged women and is associated with a chronic and debilitating pain which does not respond to conservative treatment. Other causes of trochanteric bursitis include uneven leg length, iliotibial band syndrome, and weakness of the hip abductor muscles. Greater trochanteric pain syndrome can remain incorrectly diagnosed for years, because it shares the same pattern of pain with many other musculoskeletal conditions. Thus people with this condition may be labeled malingerers, or may undergo many ineffective treatments due to misdiagnosis. It may also coexist with low back pain, arthritis, and obesity. Signs and symptoms The primary symptom is hip pain, especially hip pain on the outer (lateral) side of the joint. This pain may appear when the affected person is walking or lying down on that side. Diagnosis A straight leg raise test is a neurological maneuver performed while examining a patient presenting with lower back pain. It is conducted with the patient lying supine while keeping the symptomatic leg straight by flexing the quadriceps. The examiner slowly elevates the leg progressively at a slow pace. The test is positive when it reproduces the patient's symptoms (pain and paresthesia) at an angle lower than 45 degrees with radiation below the knee (Lasegue sign). It is most helpful in diagnosing L4, L5, and S1 radiculopathies. The patient is asked to dorsiflex the foot while the examiner is raising the leg (Bragaad's sign) to increase the sensitivity of the test. Lumbar spinal canal stenosis (LSCS) was first described in 1954 by Verbiest, followed by the currently accepted international classification of LSCS in 1976 by Arnoldi. Briefly, LSCS is a nervous system syndrome that is characterized by neural symptoms in the lower extremities due to tightened cauda equina and spinal nerve root involvement. LSCS international classification consists of: (1) degenerative, (2) congenital developmental, (3) combined, (4) spondylolytic spondylolisthesis, (5) iatrogenic and (6) post traumatic stenosis. Degenerative stenosis-the most common type of LSCS-is caused by disc degeneration, osteoarthritis of the facet joint and hypertrophy of the ligamentum flavum. LSCS may also be the result of intervertebral disc degeneration, protruded intervertebral disc and/or bony spur compress cauda equina and spinal nerve root anteriorally, while degenerated facet joint and hypertrophied the ligamentum flavum compress cauda equina and spinal nerve root posteriorally? Most often, spondylolytic spondylolisthesis occurs at the fourth lumbar vertebrae in middle-aged women. As a result of a slipping forward of the vertebra, cauda equina and spinal nerve roots can be tightened between the edge behind the top of lower vertebra and frontal edge of the lower part of upper lamina. Typical clinical symptoms of LSCS are low back pain, leg pain and intermittent claudication. Low back pain is chronic with secondary radiating pain in the buttock. The leg pain is called \"sciatica\", which tends to appear on the back of thigh, in the lateral aspect of lower leg and calf muscles, and which intensifies when the patient is fatigued. Intermittent claudication is a symptom associated with this syndrome. Often, patients with LSCS find it impossible to walk because of increased numbness and pain in their leg. Many patients report that after squatting for a few minutes they are able to resume walking. LSCS patients may also report dysaesthesia in the perineum area, and may also report urinary dysfunction ranging from extreme urgency to urinary delay. Patients who present with symptoms of LSCS should be seen by an orthopedic surgeon. Correct diagnosis by imaging and clinical examination, with appropriate conservative or operative treatment in a timely fashion should be encouraged in order to prevent irreversible nerve damage. L5 Nerve - back, radiating into buttock, lateral thigh, lateral calf, and dorsum foot, great toe; sensory loss on the lateral calf, dorsum of the foot, webspace between first and second toe; weakness on hip abduction, knee flexion, foot dorsiflexion, toe extension and flexion, foot inversion and eversion; decreased semitendinosus/semimembranosus reflex. S1 Nerve - back, radiating into buttock, lateral or posterior thigh, posterior calf, lateral or plantar foot; sensory loss on the posterior calf, lateral or plantar aspect of foot;  weakness on hip extension, knee flexion, plantar flexion of the foot; Achilles tendon; Medial buttock, perineal, and perianal region; weakness may be minimal, with urinary and fecal incontinence as well as sexual dysfunction. S2-S4 Nerves - sacral or buttock pain radiating into the posterior aspect of the leg or the perineum; sensory deficit on the medial buttock, perineal, and perianal region; absent bulbocavernosus, anal wink reflex. Low back pain may be classified based on the signs and symptoms. Diffuse pain that does not change in response to particular movements, and is localized to the lower back without radiating beyond the buttocks, is classified as nonspecific, the most common classification. Pain that radiates down the leg below the knee, is located on one side (in the case of disc herniation), or is on both sides (in spinal stenosis), and changes in severity in response to certain positions or maneuvers is radicular, making up 7% of cases. Pain that is accompanied by red flags such as trauma, fever, a history of cancer or significant muscle weakness may indicate a more serious underlying problem and is classified as needing urgent or specialized attention. In most presentations, facetogenic lumbosacral pain often presents secondary to chronic pain alone. It should, however, be noted that facet joint pain may be referred distally into the lower limb, thus mimicking sciatica. In these cases of \"pseudo-radicular\" lumbar pain, patients typically experience radiation into the unilateral or bilateral buttocks and the trochanteric region (from L4 and L5 levels), the groin and thighs (from L2 to L5), ending above the knee, and without any neurologic deficits. At times, pain may radiate further down the lower extremity reaching the foot, thus mimicking sciatic pain. This may occur especially in the setting of rather large synovial cysts causing direct mechanical compression and creating ensuing inflammation to further irritate the surrounding nerve roots. [15] Facet joint pain is typically worse in the mornings and following periods of inactivity. Stress exercise, lumbar spinal extension or rotary motions, standing or sitting positions, and facet joint palpation may also elicit lumbar facetogenic pain. [2] Now ask the patient to do the following noting any painful, restricted or asymmetrical movements: Test rotation of the thoracic and lumbar spine. Gently hold the patient's hips still and ask them to: \"Turn your shoulders round as far as you can to the left, then do the same to the right.\" Test lateral flexion of the thoracic and lumbar spine: \"Stand up straight and then slide the palm of your right hand down your thigh towards your knee, bending your shoulder down to the side.\" \"Now do the same with your left hand down your left leg.\" \"Bend your left ear down towards your left shoulder and then your right ear down towards your right shoulder\" to test for pain free cervical spine lateral flexion. Now test for stiffness or pain flexing or extending the cervical spine: \"bend your neck forwards to try to touch your chin against your chest.\" \"bend your neck back to lift your chin.\" heavy-muscled athletesVenous claudicationEntire leg, but usually worse in thigh and groinTight, bursting painAfter walkingSubsides slowlyRelief speeded by elevationHistory of iliofemoral deep venous thrombosis, signs of venous congestion, edemaNerve root compression (e.g., herniated disk)Radiates down leg, usually posteriorlySharp lancinating painSoon, if not immediately after onsetNot quickly relieved (also often present at rest)Relief may be aided by adjusting back positionHistory of back problemsSymptomatic Baker’s cystBehind knee, down calfSwelling, soreness, tendernessWith exercisePresent at restNoneNot intermittentIntermittent claudication (hip, thigh, buttock)Hip, thigh, buttocksAching discomfort, weaknessAfter same degree of exerciseQuickly relievedNoneReproducibleHip arthritisHip, thigh, buttocksAching discomfortAfter variable degree of exerciseNot quickly relieved (and may be present at rest)More comfortable sitting, weight taken off legsVariable, may relate to activity L2, L3, and L4 lumbar radiculopathies are considered a group. This group has a marked overlap of the innervation of the anterior thigh muscles. [1] An acute injury in the distribution of L2, L3, and L4 will most commonly present with the patient experiencing radiating back pain to the anterior aspect of the thigh, which may progress into their knee, and possibly radiate to the medial aspect of the lower leg, into the foot. On examination, patients can have weakness during knee extension, hip adduction, and or hip flexion. There is often a loss of sensation over the anterior thigh along the area of pain. The patient may show a reduced patellar reflex (L4). [1] Activities that can make the symptoms worse include coughing, leg straightening, or sneezing. Greater trochanteric pain syndrome (GTPS) is a term used to describe chronic pain overlying the lateral aspect of the hip. This regional pain syndrome, once described as trochanteric bursitis, often mimics pain generated from other sources, including, but not limited to myofascial pain, degenerative joint disease, and spinal pathology. The incidence of greater trochanteric pain is reported to be approximately 1.8 patients per 1000 per year with the prevalence being higher in women, and patients with coexisting low back pain, osteoarthritis, iliotibial band tenderness, and obesity. Symptoms of GTPS consist of persistent pain in the lateral hip radiating along the lateral aspect of the thigh to the knee and occasionally below the knee and/or buttock. Physical examination reveals point tenderness in the posterolateral area of the greater trochanter. Most cases of GTPS are self-limited with conservative measures, such as physical therapy, weight loss, nonsteroidal antiinflammatory drugs and behavior modification, providing resolution of symptoms. Other treatment modalities include bursa or lateral hip injections performed with corticosteroid and local anesthetic. More invasive surgical interventions have anecdotally been reported to provide pain relief when conservative treatment modalities fail. 2692 LATERAL FEMORAL CUTANEOUS NEUROPATHY (MERALGIA PARESTHETICA) The lateral femoral cutaneous nerve arises from the upper lumbar plexus (spinal levels L2/3), crosses through the inguinal ligament near its attachment to the iliac bone, and supplies sensation to the anterior lateral thigh. The neuropathy affecting this nerve is also known as meralgia paresthetica. Symptoms and signs consist of paresthesias, numbness, and occasionally pain in the lateral thigh. Symptoms are increased by standing or walking and are relieved by sitting. There is normal strength, and knee reflexes are intact. The diagnosis is clinical, and further tests usually are not performed. EDx is only needed to rule out lumbar plexopathy, radiculopathy, or femoral neuropathy. If the symptoms and signs are classic, EMG is not necessary. Symptoms often resolve spontaneously over weeks or months, but the patient may be left with permanent numbness. Treatment consists of weight loss and avoiding tight belts. Analgesics Stenosis in the lumbar spine can lead to neurogenic claudication, myeloradiculopathy symptoms, sensory disturbances, motor weakness, and pathologic reflexes. Patients will present with complaints of cramping pain in the leg, calf, and or buttocks. They might report an increase in pain with walking or standing for prolonged periods and relief when sitting or leaning forward while using a shopping cart. [9] Disk herniation is most common at the L4-5 and L5-S1 levels. A herniated disk at L5-S1 can lead to plantarflexion weakness, decrease sensation in the lateral foot, and cause pain in the posterior leg. A disk herniation at L4-5 can lead to a foot drop and numbness in the large toe web and dorsal aspect of the foot. Lastly, an L3-4 disk herniation can lead to knee extension weakness, numbness in the medial foot, and pain in the anterior thigh. Patients with greater trochanteric pain syndrome usually have lateral hip pain, tenderness over and around the greater trochanter, pain at end-range hip rotation, abduction or adduction, pain with resisted hip abduction, and a positive Patrick-FABER (flexion abduction external rotation) test. Patients usually suffer from chronic back pain radiating to the posterolateral aspect of the thigh, leg paresthesias, and tenderness over the iliotibial tract. [6] They will often complain of the inability to lay on the affected hip. The mean duration of symptoms before treatment ranges from 7.1 weeks to 4.4 years. Young adults (18 to 35 years old) with hip pain often present with non-specific symptoms and vague findings from the history and physical examination, which may lead to a misdiagnosis of GTPS or trochanteric bursitis. [1] [4] The most characteristic syndrome affects the lumbar roots. Pain, which can be severe, begins in the low back or hip and spreads to the thigh and knee on one side; the discomfort has a deep, aching character with superimposed lancinating jabs and there is a propensity for pain to be most severe at night. Weakness and later atrophy are evident in the pelvic girdle and thigh muscles, although the distal muscles of the leg may also be affected. The weakness can progress for days or weeks (rarely, months). The patellar reflex is lost on the affected side. Curiously, we have found the opposite patellar reflex to be absent in some patients, without explanation. Deep and superficial sensation may be intact or mildly impaired, conforming to either a multiple nerve or multiple adjacent root distribution (i.e., L2 and L3, or L4 and L5). The pain lasts for several days and then gradually abates. Motor recovery is the rule although months and even years may elapse before it is complete. The same Gout is a metabolic disease secondary to an increased body pool of urate with hyperuricemia. Gout typically affects the peripheral joints and rarely involves the intra-spinal area. A 43-year-old man, who had metabolic syndrome s/p bariatric surgery and gout suffered from severe left low back pain with radiation to the lateral side of his left thigh and anterior side of his left leg for more than 7 days. His L-spine MRI showed an abnormal posterior epidural space occupying lesion at L4-L5 level. For tissue diagnosis and neural structures decompression, he underwent surgical removal of the epidural mass lesion. The surgical specimen showed a picture of gout and he got a good recovery after operation. The differential diagnoses of an epidural mass includes synovial cysts, ligament cyst, cystic neuromas, tumors, hematomas and abscesses. Gout in the spinal canal is difficult to diagnosis before surgery because it is rare and its clinical presentation and radiologic findings mimic tumor, abscess, tuberculosis, and degenerative spinal diseases. Patients with spinal gout may present with axial pain and a variety of neurological symptoms. Spinal gouty tophus should be considered in the different diagnoses of spinal epidural masses especially in patients with systemic gout. Surgery is needed for final diagnosis. If spinal gouty tophus is highly suspected during the surgery, the specimen should not be preserved with Formalin because birefringent crystals under polarized light is a unique feature for gouty tophus but they dissolve in Formalin. A straight leg raising can be helpful in lumbosacral radiculopathy. The mechanism of pain during a straight leg raise is increased dural tension placed upon the lumbosacral spine during the test. Patients lay supine during the test. The physician will flex the patient's quadriceps with the leg in extension as well as dorsiflex the patient's foot on the symptomatic side. Pain or reproduction of paresthesias is considered a positive test (Lasegue's sign). A Bowstring sign relieves this underlying radicular pain with flexion of the patient's knee on the affected side. The straight leg raising test is most helpful in the diagnosis of L4 and S1 radiculopathies. [11] [3] A rare case of acromegaly with radiculomyelopathy due to spinal canal stenosis is reported. A long history of acromegalic deformity was seen on this 55 years old acupuncture therapist for the last 18 years, while he had developed unusually increased appetite, profuse perspiration and gained weight. Fifteen years ago, acromegalic tendency became prominent and was accompanied by low back and knee pain. In 1974 CB-154 was administered in several occasions beside 4000 rads irradiation to the sella. After radiation therapy was completed his outlook was somewhat improved, although low back pain was aggravated and associated with atrophy of the left lower extremity. The neurological examination at admission in 1980 revealed acromegalic feature, increased DTRs on both upper and lower extremities, dysesthesia of feet and atrophy of the leg muscles in general, mainly due to diffuse atrophy. Patient bended knees due to pain and unable to walk. He had radiating pain in the postero-lateral aspect of the left lower extremity and some dysesthesia of feet, although no specific root lesion was identifiable. Spinal roentgenograms disclosed diffuse ossification of anterior and posterior longitudinal ligaments, and marked spondylotic changes. Although the low back pain was impending complaint of the patient, the hypophyseal tumor was advised to remove and transsphenoidal hypophyseal adenomectomy was performed. A good amount of softend tumor tissue was removed however, adenoma found markedly fibrotic. Low back pain and knee were decreased gradually, but intermittent claudication was evident. Acromegaly in association with spinal canal stenosis were reviewed in literature, and the relationship of growth hormone and therapeutic problems were discussed. A 49-year-old man presented to the hospital for spinal cord decompression surgery with left buttock and left leg pain. The patient described an acute burning pain radiating down from his left buttock to left lateral leg. He also noted a 13.6 kg weight loss in recent months. Physical examination showed decreased muscle bulk of the left thigh, decreased strength of the left hip, left knee flexors and extensors. Recent MRI spine showed mild canal narrowing and cord flattening in the lower thoracic spine. Serologic testing showed an elevated glucose of 17.9 mmol/L and haemoglobin A1c of 9.8%. Electromyography showed denervation of scattered muscles of the left knee flexors, hip flexors and adductors. In the setting of newly diagnosed diabetes mellitus, he was diagnosed with diabetic amyotrophy, started on insulin therapy, and his surgery was cancelled. Leg pain associated with walking is sometimes incorrectly attributed to hip osteoarthritis (OA) or lumbar spinal stenosis (LSS). This study compared physicians' values of signs and symptoms for diagnosing and differentiating hip OA and LSS to their clinical utility. Musculoskeletal physicians were surveyed with online questionnaires. Patients were recruited from hip and spine specialty practices. Seventy-seven hip OA and 79 LSS patients. Signs and symptoms of hip OA and LSS. Fifty-one of 66 invited musculoskeletal physicians completed online surveys about the values of 83 signs and symptoms for diagnosing hip OA and LSS. Of these, the most valued 32 symptoms and 13 physical examination items were applied to patients with symptomatic hip OA or LSS. Positive likelihood ratios (+LR) were calculated for each items' ability to differentiate hip OA from LSS, with a +LR&gt;2 set as indicating usefulness for favoring either diagnosis. Positive LRs were compared with surveyed physicians' values for each test. All symptoms were reported by some patients with each diagnosis. Only 11 of 32 physician-valued symptoms were useful for discriminating hip OA from LSS. Eight symptoms favored hip OA over LSS: groin pain (+LR=4.9); knee pain (+LR=2.2); pain that decreased with continued walking (+LR=3.9); pain that occurs immediately with walking (+LR=2.4); pain that occurs immediately with standing (+LR=2.1); pain getting in/out of a car (+LR=3.3); pain with dressing the symptomatic leg (+LR=3.1); and difficulty reaching the foot of the symptomatic leg while dressing (+LR=2.3). Three symptoms favored LSS over hip OA: pain below the knee (+LR=2.3); leg tingling and/or numbness (+LR=2.7); and some pain in both legs (+LR=2.5). Notable symptoms that did not discriminate hip OA from LSS included: pain is less while pushing a shopping cart (+LR=1.0); back pain (+LR=1.1); weakness and/or heaviness of leg (+LR=1.1); buttocks pain (+LR=1.2); poor balance or unsteadiness (+LR=1.2); pain that increased with weight-bearing on the painful leg (+LR=1.3), and step to gait on stairs (+LR=1.7). Consistent with physicians' expectations, 7 of 13 physical examination items strongly favored hip OA over LSS: limited weight-bearing on painful leg when standing (+LR=10); observed limp (+LR=9); and painful and restricted range-of-motion with any of five hip maneuvers (+LR range 21-99). Four of five tested neurological deficits (+LR range 3-8) favored the diagnosis of LSS over hip OA. There is substantial crossover of symptoms between hip OA and LSS, with some physician-valued symptoms useful for differentiating these disorders whereas others were not. Physicians recognize the value of the examination of gait, the hip, and lower extremity neurological function for differentiating hip OA from LSS. These tests should be routinely performed on all patients for which either diagnosis is considered. Awareness of these findings might reduce diagnostic errors. Cauda equina syndrome (CES) is most caused by lumbar disc herniation, and the associated treatment involves prompt surgical decompression. Rarer causes of CES include perineural (Tarlov) cysts. A 62-year-old female with history of rheumatoid arthritis, hip and knee replacements, and chronic low back pain presented with worsening back pain, left leg weakness and pain for 6 weeks, and bowel/bladder incontinence with diminished sensation in the perianal region for 24 h prior to presentation. MRI demonstrated severe spinal stenosis at L4-S1, central disc herniation at L5-S1, and compression of the cauda equina, consistent with CES. A lumbar decompression was performed. Patient did well at 2-week follow up, but presented 5 weeks post-discharge with increased left leg pain/weakness and genitalia anesthesia. Imaging was unremarkable. Two months later, the patient presented with diminished sensation in the buttocks and bilateral lower extremities and bowel/bladder incontinence. Imaging demonstrated a large cystic presacral mass with involvement of the left sciatic foramen and S3 neural foramen. A team of plastic, orthopedic, and neurological surgeons performed an S3 sacral laminectomy, foraminotomy, partial sacrectomy, and S3 rhizotomy, and excision of the large left hemorrhagic pudendal mass. Final pathology demonstrated a perineural cyst with organizing hemorrhage. On follow-up, the patient's pain and weakness improved. CES-like symptoms were initially attributed to a herniated disk. However, lumbar decompression did not resolve symptoms, prompting further radiographic evaluation at two separate presentations. This represents the first reported case of a pudendal tumor causing symptoms initially attributed to a herniated disc. The clinical syndrome of lumbar spinal stenosis (LSS) is a common diagnosis in older adults presenting with lower extremity pain. To systematically review the accuracy of the clinical examination for the diagnosis of the clinical syndrome of LSS. MEDLINE, EMBASE, and CINAHL searches of articles published from January 1966 to September 2010. Studies were included if they contained adequate data on the accuracy of the history and physical examination for diagnosing the clinical syndrome of LSS, using a reference standard of expert opinion with radiographic or anatomic confirmation. Two authors independently reviewed each study to determine eligibility, extract data, and appraise levels of evidence. Four studies evaluating 741 patients were identified. Among patients with lower extremity pain, the likelihood of the clinical syndrome of LSS was increased for individuals older than 70 years (likelihood ratio [LR], 2.0; 95% confidence interval [CI], 1.6-2.5), and was decreased for those younger than 60 years (LR, 0.40; 95% CI, 0.29-0.57). The most useful symptoms for increasing the likelihood of the clinical syndrome of LSS were having no pain when seated (LR, 7.4; 95% CI, 1.9-30), improvement of symptoms when bending forward (LR, 6.4; 95% CI, 4.1-9.9), the presence of bilateral buttock or leg pain (LR, 6.3; 95% CI, 3.1-13), and neurogenic claudication (LR, 3.7; 95% CI, 2.9-4.8). Absence of neurogenic claudication (LR, 0.23; 95% CI, 0.17-0.31) decreased the likelihood of the diagnosis. A wide-based gait (LR, 13; 95% CI, 1.9-95) and abnormal Romberg test result (LR, 4.2; 95% CI, 1.4-13) increased the likelihood of the clinical syndrome of LSS. A score of 7 or higher on a diagnostic support tool including history and examination findings increased the likelihood of the clinical syndrome of LSS (LR, 3.3; 95% CI, 2.7-4.0), while a score lower than 7 made the diagnosis much less likely (LR, 0.10; 95% CI, 0.06-0.16). The diagnosis of the clinical syndrome of LSS requires the appropriate clinical picture and radiographic findings. Absence of pain when seated and improvement of symptoms when bending forward are the most useful individual findings. Combinations of findings are most useful for identifying patients who are unlikely to have the diagnosis.\nHere is the question:\nTRAUMATOLOGY: A 61-year-old woman, administrative, with a history of overweight, hypertension, dyslipidemia and metabolic syndrome, who consults for pain in both buttocks, left trochanteric region, lateral aspect of the left thigh up to the knee and left leg up to the middle third. The pain appears when the lower limb is lifted with the knee extended, but is relieved when the knee is flexed. What is the first clinical suspicion?\nHere are the potential choices:\n1. Gouty arthritis of left hip.\n2. Left coxofemoral arthrosis.\n3. Radiated low back pain / lumbosciatica.\n4. Claudication due to canal stenosis.\nThe correct answer is: ",
        "gold_answer": "3 Radiated low back pain / lumbosciatica.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Signs and symptoms The following are signs and symptoms that may be associated with an SI joint (SIJ) problem: Mechanical SIJ dysfunction usually causes a dull unilateral low back pain. The pain is often a mild to moderate ache around the dimple or posterior superior iliac spine (PSIS) region. The pain may become worse and sharp while doing activities such as standing up from a seated position or lifting the knee towards the chest during stair climbing. Pain is typically on one side or the other (unilateral PSIS pain), but the pain can occasionally be bilateral. When the pain of SIJ dysfunction is severe (which is infrequent), there can be referred pain into the hip, groin, and occasionally down the leg, but rarely does the pain radiate below the knee. Pain can be referred from the SIJ down into the buttock or back of the thigh, and rarely to the foot. Low back pain and stiffness, often unilateral, that often increases with prolonged sitting or prolonged walking. Further, a straight leg raise (SLR) test is a neurological maneuver performed while examining a patient presenting with lower back pain. This test is conducted with the patient lying supine while keeping the symptomatic leg straight by flexing the quadriceps. The examiner elevates the leg progressively at a slow pace. The test is deemed positive if it reproduces the patient's symptoms (pain and paresthesia) at an angle lower than 70° with radiation below the knee (Lasegue sign). This test is most helpful in diagnosing L4, L5, and S1 radiculopathies. The patient is asked to dorsiflex the foot while the examiner raises the leg (Bragaad sign) to increase the test's sensitivity. When executing the straight leg raise test, the examiner will slightly bend the patient's knee by 20° to 30°, which will lessen the pain. Then, manual pressure is applied in the popliteal fossa. The Bowstring sign is considered positive if it causes the same level of discomfort that the patient feels during a straight leg raise. [8] The Naffziger test involves reproducing pain via coughing. [9] A straight-leg raise has variable sensitivity and specificity and may or may not be present depending on the underlying cause. The straight-leg test is a passive examination where the patient first lies in a relaxed, supine position. The examiner then lifts the leg from the posterior aspect, flexing at the hip joint and keeping the knee in full extension or keeping the leg straight. Typically, pain that is reproduced between 30° to 70° of hip flexion and experienced primarily in the back is likely due to a lumbar disc herniation. Pain and parenthesis felt in the leg are possible due to lateralizing compression of a peripheral nerve. While not absolute, musculoskeletal causes of the pain usually reproduce pain above 70° of flexion and below 30° of flexion. More often the lateral hip pain is caused by disease of the gluteal tendons that secondarily inflames the bursa. This is most common in middle-aged women and is associated with a chronic and debilitating pain which does not respond to conservative treatment. Other causes of trochanteric bursitis include uneven leg length, iliotibial band syndrome, and weakness of the hip abductor muscles. Greater trochanteric pain syndrome can remain incorrectly diagnosed for years, because it shares the same pattern of pain with many other musculoskeletal conditions. Thus people with this condition may be labeled malingerers, or may undergo many ineffective treatments due to misdiagnosis. It may also coexist with low back pain, arthritis, and obesity. Signs and symptoms The primary symptom is hip pain, especially hip pain on the outer (lateral) side of the joint. This pain may appear when the affected person is walking or lying down on that side. Diagnosis A straight leg raise test is a neurological maneuver performed while examining a patient presenting with lower back pain. It is conducted with the patient lying supine while keeping the symptomatic leg straight by flexing the quadriceps. The examiner slowly elevates the leg progressively at a slow pace. The test is positive when it reproduces the patient's symptoms (pain and paresthesia) at an angle lower than 45 degrees with radiation below the knee (Lasegue sign). It is most helpful in diagnosing L4, L5, and S1 radiculopathies. The patient is asked to dorsiflex the foot while the examiner is raising the leg (Bragaad's sign) to increase the sensitivity of the test. Lumbar spinal canal stenosis (LSCS) was first described in 1954 by Verbiest, followed by the currently accepted international classification of LSCS in 1976 by Arnoldi. Briefly, LSCS is a nervous system syndrome that is characterized by neural symptoms in the lower extremities due to tightened cauda equina and spinal nerve root involvement. LSCS international classification consists of: (1) degenerative, (2) congenital developmental, (3) combined, (4) spondylolytic spondylolisthesis, (5) iatrogenic and (6) post traumatic stenosis. Degenerative stenosis-the most common type of LSCS-is caused by disc degeneration, osteoarthritis of the facet joint and hypertrophy of the ligamentum flavum. LSCS may also be the result of intervertebral disc degeneration, protruded intervertebral disc and/or bony spur compress cauda equina and spinal nerve root anteriorally, while degenerated facet joint and hypertrophied the ligamentum flavum compress cauda equina and spinal nerve root posteriorally? Most often, spondylolytic spondylolisthesis occurs at the fourth lumbar vertebrae in middle-aged women. As a result of a slipping forward of the vertebra, cauda equina and spinal nerve roots can be tightened between the edge behind the top of lower vertebra and frontal edge of the lower part of upper lamina. Typical clinical symptoms of LSCS are low back pain, leg pain and intermittent claudication. Low back pain is chronic with secondary radiating pain in the buttock. The leg pain is called \"sciatica\", which tends to appear on the back of thigh, in the lateral aspect of lower leg and calf muscles, and which intensifies when the patient is fatigued. Intermittent claudication is a symptom associated with this syndrome. Often, patients with LSCS find it impossible to walk because of increased numbness and pain in their leg. Many patients report that after squatting for a few minutes they are able to resume walking. LSCS patients may also report dysaesthesia in the perineum area, and may also report urinary dysfunction ranging from extreme urgency to urinary delay. Patients who present with symptoms of LSCS should be seen by an orthopedic surgeon. Correct diagnosis by imaging and clinical examination, with appropriate conservative or operative treatment in a timely fashion should be encouraged in order to prevent irreversible nerve damage. L5 Nerve - back, radiating into buttock, lateral thigh, lateral calf, and dorsum foot, great toe; sensory loss on the lateral calf, dorsum of the foot, webspace between first and second toe; weakness on hip abduction, knee flexion, foot dorsiflexion, toe extension and flexion, foot inversion and eversion; decreased semitendinosus/semimembranosus reflex. S1 Nerve - back, radiating into buttock, lateral or posterior thigh, posterior calf, lateral or plantar foot; sensory loss on the posterior calf, lateral or plantar aspect of foot;  weakness on hip extension, knee flexion, plantar flexion of the foot; Achilles tendon; Medial buttock, perineal, and perianal region; weakness may be minimal, with urinary and fecal incontinence as well as sexual dysfunction. S2-S4 Nerves - sacral or buttock pain radiating into the posterior aspect of the leg or the perineum; sensory deficit on the medial buttock, perineal, and perianal region; absent bulbocavernosus, anal wink reflex. Low back pain may be classified based on the signs and symptoms. Diffuse pain that does not change in response to particular movements, and is localized to the lower back without radiating beyond the buttocks, is classified as nonspecific, the most common classification. Pain that radiates down the leg below the knee, is located on one side (in the case of disc herniation), or is on both sides (in spinal stenosis), and changes in severity in response to certain positions or maneuvers is radicular, making up 7% of cases. Pain that is accompanied by red flags such as trauma, fever, a history of cancer or significant muscle weakness may indicate a more serious underlying problem and is classified as needing urgent or specialized attention. In most presentations, facetogenic lumbosacral pain often presents secondary to chronic pain alone. It should, however, be noted that facet joint pain may be referred distally into the lower limb, thus mimicking sciatica. In these cases of \"pseudo-radicular\" lumbar pain, patients typically experience radiation into the unilateral or bilateral buttocks and the trochanteric region (from L4 and L5 levels), the groin and thighs (from L2 to L5), ending above the knee, and without any neurologic deficits. At times, pain may radiate further down the lower extremity reaching the foot, thus mimicking sciatic pain. This may occur especially in the setting of rather large synovial cysts causing direct mechanical compression and creating ensuing inflammation to further irritate the surrounding nerve roots. [15] Facet joint pain is typically worse in the mornings and following periods of inactivity. Stress exercise, lumbar spinal extension or rotary motions, standing or sitting positions, and facet joint palpation may also elicit lumbar facetogenic pain. [2] Now ask the patient to do the following noting any painful, restricted or asymmetrical movements: Test rotation of the thoracic and lumbar spine. Gently hold the patient's hips still and ask them to: \"Turn your shoulders round as far as you can to the left, then do the same to the right.\" Test lateral flexion of the thoracic and lumbar spine: \"Stand up straight and then slide the palm of your right hand down your thigh towards your knee, bending your shoulder down to the side.\" \"Now do the same with your left hand down your left leg.\" \"Bend your left ear down towards your left shoulder and then your right ear down towards your right shoulder\" to test for pain free cervical spine lateral flexion. Now test for stiffness or pain flexing or extending the cervical spine: \"bend your neck forwards to try to touch your chin against your chest.\" \"bend your neck back to lift your chin.\" heavy-muscled athletesVenous claudicationEntire leg, but usually worse in thigh and groinTight, bursting painAfter walkingSubsides slowlyRelief speeded by elevationHistory of iliofemoral deep venous thrombosis, signs of venous congestion, edemaNerve root compression (e.g., herniated disk)Radiates down leg, usually posteriorlySharp lancinating painSoon, if not immediately after onsetNot quickly relieved (also often present at rest)Relief may be aided by adjusting back positionHistory of back problemsSymptomatic Baker’s cystBehind knee, down calfSwelling, soreness, tendernessWith exercisePresent at restNoneNot intermittentIntermittent claudication (hip, thigh, buttock)Hip, thigh, buttocksAching discomfort, weaknessAfter same degree of exerciseQuickly relievedNoneReproducibleHip arthritisHip, thigh, buttocksAching discomfortAfter variable degree of exerciseNot quickly relieved (and may be present at rest)More comfortable sitting, weight taken off legsVariable, may relate to activity L2, L3, and L4 lumbar radiculopathies are considered a group. This group has a marked overlap of the innervation of the anterior thigh muscles. [1] An acute injury in the distribution of L2, L3, and L4 will most commonly present with the patient experiencing radiating back pain to the anterior aspect of the thigh, which may progress into their knee, and possibly radiate to the medial aspect of the lower leg, into the foot. On examination, patients can have weakness during knee extension, hip adduction, and or hip flexion. There is often a loss of sensation over the anterior thigh along the area of pain. The patient may show a reduced patellar reflex (L4). [1] Activities that can make the symptoms worse include coughing, leg straightening, or sneezing. Greater trochanteric pain syndrome (GTPS) is a term used to describe chronic pain overlying the lateral aspect of the hip. This regional pain syndrome, once described as trochanteric bursitis, often mimics pain generated from other sources, including, but not limited to myofascial pain, degenerative joint disease, and spinal pathology. The incidence of greater trochanteric pain is reported to be approximately 1.8 patients per 1000 per year with the prevalence being higher in women, and patients with coexisting low back pain, osteoarthritis, iliotibial band tenderness, and obesity. Symptoms of GTPS consist of persistent pain in the lateral hip radiating along the lateral aspect of the thigh to the knee and occasionally below the knee and/or buttock. Physical examination reveals point tenderness in the posterolateral area of the greater trochanter. Most cases of GTPS are self-limited with conservative measures, such as physical therapy, weight loss, nonsteroidal antiinflammatory drugs and behavior modification, providing resolution of symptoms. Other treatment modalities include bursa or lateral hip injections performed with corticosteroid and local anesthetic. More invasive surgical interventions have anecdotally been reported to provide pain relief when conservative treatment modalities fail. 2692 LATERAL FEMORAL CUTANEOUS NEUROPATHY (MERALGIA PARESTHETICA) The lateral femoral cutaneous nerve arises from the upper lumbar plexus (spinal levels L2/3), crosses through the inguinal ligament near its attachment to the iliac bone, and supplies sensation to the anterior lateral thigh. The neuropathy affecting this nerve is also known as meralgia paresthetica. Symptoms and signs consist of paresthesias, numbness, and occasionally pain in the lateral thigh. Symptoms are increased by standing or walking and are relieved by sitting. There is normal strength, and knee reflexes are intact. The diagnosis is clinical, and further tests usually are not performed. EDx is only needed to rule out lumbar plexopathy, radiculopathy, or femoral neuropathy. If the symptoms and signs are classic, EMG is not necessary. Symptoms often resolve spontaneously over weeks or months, but the patient may be left with permanent numbness. Treatment consists of weight loss and avoiding tight belts. Analgesics Stenosis in the lumbar spine can lead to neurogenic claudication, myeloradiculopathy symptoms, sensory disturbances, motor weakness, and pathologic reflexes. Patients will present with complaints of cramping pain in the leg, calf, and or buttocks. They might report an increase in pain with walking or standing for prolonged periods and relief when sitting or leaning forward while using a shopping cart. [9] Disk herniation is most common at the L4-5 and L5-S1 levels. A herniated disk at L5-S1 can lead to plantarflexion weakness, decrease sensation in the lateral foot, and cause pain in the posterior leg. A disk herniation at L4-5 can lead to a foot drop and numbness in the large toe web and dorsal aspect of the foot. Lastly, an L3-4 disk herniation can lead to knee extension weakness, numbness in the medial foot, and pain in the anterior thigh. Patients with greater trochanteric pain syndrome usually have lateral hip pain, tenderness over and around the greater trochanter, pain at end-range hip rotation, abduction or adduction, pain with resisted hip abduction, and a positive Patrick-FABER (flexion abduction external rotation) test. Patients usually suffer from chronic back pain radiating to the posterolateral aspect of the thigh, leg paresthesias, and tenderness over the iliotibial tract. [6] They will often complain of the inability to lay on the affected hip. The mean duration of symptoms before treatment ranges from 7.1 weeks to 4.4 years. Young adults (18 to 35 years old) with hip pain often present with non-specific symptoms and vague findings from the history and physical examination, which may lead to a misdiagnosis of GTPS or trochanteric bursitis. [1] [4] The most characteristic syndrome affects the lumbar roots. Pain, which can be severe, begins in the low back or hip and spreads to the thigh and knee on one side; the discomfort has a deep, aching character with superimposed lancinating jabs and there is a propensity for pain to be most severe at night. Weakness and later atrophy are evident in the pelvic girdle and thigh muscles, although the distal muscles of the leg may also be affected. The weakness can progress for days or weeks (rarely, months). The patellar reflex is lost on the affected side. Curiously, we have found the opposite patellar reflex to be absent in some patients, without explanation. Deep and superficial sensation may be intact or mildly impaired, conforming to either a multiple nerve or multiple adjacent root distribution (i.e., L2 and L3, or L4 and L5). The pain lasts for several days and then gradually abates. Motor recovery is the rule although months and even years may elapse before it is complete. The same Gout is a metabolic disease secondary to an increased body pool of urate with hyperuricemia. Gout typically affects the peripheral joints and rarely involves the intra-spinal area. A 43-year-old man, who had metabolic syndrome s/p bariatric surgery and gout suffered from severe left low back pain with radiation to the lateral side of his left thigh and anterior side of his left leg for more than 7 days. His L-spine MRI showed an abnormal posterior epidural space occupying lesion at L4-L5 level. For tissue diagnosis and neural structures decompression, he underwent surgical removal of the epidural mass lesion. The surgical specimen showed a picture of gout and he got a good recovery after operation. The differential diagnoses of an epidural mass includes synovial cysts, ligament cyst, cystic neuromas, tumors, hematomas and abscesses. Gout in the spinal canal is difficult to diagnosis before surgery because it is rare and its clinical presentation and radiologic findings mimic tumor, abscess, tuberculosis, and degenerative spinal diseases. Patients with spinal gout may present with axial pain and a variety of neurological symptoms. Spinal gouty tophus should be considered in the different diagnoses of spinal epidural masses especially in patients with systemic gout. Surgery is needed for final diagnosis. If spinal gouty tophus is highly suspected during the surgery, the specimen should not be preserved with Formalin because birefringent crystals under polarized light is a unique feature for gouty tophus but they dissolve in Formalin. A straight leg raising can be helpful in lumbosacral radiculopathy. The mechanism of pain during a straight leg raise is increased dural tension placed upon the lumbosacral spine during the test. Patients lay supine during the test. The physician will flex the patient's quadriceps with the leg in extension as well as dorsiflex the patient's foot on the symptomatic side. Pain or reproduction of paresthesias is considered a positive test (Lasegue's sign). A Bowstring sign relieves this underlying radicular pain with flexion of the patient's knee on the affected side. The straight leg raising test is most helpful in the diagnosis of L4 and S1 radiculopathies. [11] [3] A rare case of acromegaly with radiculomyelopathy due to spinal canal stenosis is reported. A long history of acromegalic deformity was seen on this 55 years old acupuncture therapist for the last 18 years, while he had developed unusually increased appetite, profuse perspiration and gained weight. Fifteen years ago, acromegalic tendency became prominent and was accompanied by low back and knee pain. In 1974 CB-154 was administered in several occasions beside 4000 rads irradiation to the sella. After radiation therapy was completed his outlook was somewhat improved, although low back pain was aggravated and associated with atrophy of the left lower extremity. The neurological examination at admission in 1980 revealed acromegalic feature, increased DTRs on both upper and lower extremities, dysesthesia of feet and atrophy of the leg muscles in general, mainly due to diffuse atrophy. Patient bended knees due to pain and unable to walk. He had radiating pain in the postero-lateral aspect of the left lower extremity and some dysesthesia of feet, although no specific root lesion was identifiable. Spinal roentgenograms disclosed diffuse ossification of anterior and posterior longitudinal ligaments, and marked spondylotic changes. Although the low back pain was impending complaint of the patient, the hypophyseal tumor was advised to remove and transsphenoidal hypophyseal adenomectomy was performed. A good amount of softend tumor tissue was removed however, adenoma found markedly fibrotic. Low back pain and knee were decreased gradually, but intermittent claudication was evident. Acromegaly in association with spinal canal stenosis were reviewed in literature, and the relationship of growth hormone and therapeutic problems were discussed. A 49-year-old man presented to the hospital for spinal cord decompression surgery with left buttock and left leg pain. The patient described an acute burning pain radiating down from his left buttock to left lateral leg. He also noted a 13.6 kg weight loss in recent months. Physical examination showed decreased muscle bulk of the left thigh, decreased strength of the left hip, left knee flexors and extensors. Recent MRI spine showed mild canal narrowing and cord flattening in the lower thoracic spine. Serologic testing showed an elevated glucose of 17.9 mmol/L and haemoglobin A1c of 9.8%. Electromyography showed denervation of scattered muscles of the left knee flexors, hip flexors and adductors. In the setting of newly diagnosed diabetes mellitus, he was diagnosed with diabetic amyotrophy, started on insulin therapy, and his surgery was cancelled. Leg pain associated with walking is sometimes incorrectly attributed to hip osteoarthritis (OA) or lumbar spinal stenosis (LSS). This study compared physicians' values of signs and symptoms for diagnosing and differentiating hip OA and LSS to their clinical utility. Musculoskeletal physicians were surveyed with online questionnaires. Patients were recruited from hip and spine specialty practices. Seventy-seven hip OA and 79 LSS patients. Signs and symptoms of hip OA and LSS. Fifty-one of 66 invited musculoskeletal physicians completed online surveys about the values of 83 signs and symptoms for diagnosing hip OA and LSS. Of these, the most valued 32 symptoms and 13 physical examination items were applied to patients with symptomatic hip OA or LSS. Positive likelihood ratios (+LR) were calculated for each items' ability to differentiate hip OA from LSS, with a +LR&gt;2 set as indicating usefulness for favoring either diagnosis. Positive LRs were compared with surveyed physicians' values for each test. All symptoms were reported by some patients with each diagnosis. Only 11 of 32 physician-valued symptoms were useful for discriminating hip OA from LSS. Eight symptoms favored hip OA over LSS: groin pain (+LR=4.9); knee pain (+LR=2.2); pain that decreased with continued walking (+LR=3.9); pain that occurs immediately with walking (+LR=2.4); pain that occurs immediately with standing (+LR=2.1); pain getting in/out of a car (+LR=3.3); pain with dressing the symptomatic leg (+LR=3.1); and difficulty reaching the foot of the symptomatic leg while dressing (+LR=2.3). Three symptoms favored LSS over hip OA: pain below the knee (+LR=2.3); leg tingling and/or numbness (+LR=2.7); and some pain in both legs (+LR=2.5). Notable symptoms that did not discriminate hip OA from LSS included: pain is less while pushing a shopping cart (+LR=1.0); back pain (+LR=1.1); weakness and/or heaviness of leg (+LR=1.1); buttocks pain (+LR=1.2); poor balance or unsteadiness (+LR=1.2); pain that increased with weight-bearing on the painful leg (+LR=1.3), and step to gait on stairs (+LR=1.7). Consistent with physicians' expectations, 7 of 13 physical examination items strongly favored hip OA over LSS: limited weight-bearing on painful leg when standing (+LR=10); observed limp (+LR=9); and painful and restricted range-of-motion with any of five hip maneuvers (+LR range 21-99). Four of five tested neurological deficits (+LR range 3-8) favored the diagnosis of LSS over hip OA. There is substantial crossover of symptoms between hip OA and LSS, with some physician-valued symptoms useful for differentiating these disorders whereas others were not. Physicians recognize the value of the examination of gait, the hip, and lower extremity neurological function for differentiating hip OA from LSS. These tests should be routinely performed on all patients for which either diagnosis is considered. Awareness of these findings might reduce diagnostic errors. Cauda equina syndrome (CES) is most caused by lumbar disc herniation, and the associated treatment involves prompt surgical decompression. Rarer causes of CES include perineural (Tarlov) cysts. A 62-year-old female with history of rheumatoid arthritis, hip and knee replacements, and chronic low back pain presented with worsening back pain, left leg weakness and pain for 6 weeks, and bowel/bladder incontinence with diminished sensation in the perianal region for 24 h prior to presentation. MRI demonstrated severe spinal stenosis at L4-S1, central disc herniation at L5-S1, and compression of the cauda equina, consistent with CES. A lumbar decompression was performed. Patient did well at 2-week follow up, but presented 5 weeks post-discharge with increased left leg pain/weakness and genitalia anesthesia. Imaging was unremarkable. Two months later, the patient presented with diminished sensation in the buttocks and bilateral lower extremities and bowel/bladder incontinence. Imaging demonstrated a large cystic presacral mass with involvement of the left sciatic foramen and S3 neural foramen. A team of plastic, orthopedic, and neurological surgeons performed an S3 sacral laminectomy, foraminotomy, partial sacrectomy, and S3 rhizotomy, and excision of the large left hemorrhagic pudendal mass. Final pathology demonstrated a perineural cyst with organizing hemorrhage. On follow-up, the patient's pain and weakness improved. CES-like symptoms were initially attributed to a herniated disk. However, lumbar decompression did not resolve symptoms, prompting further radiographic evaluation at two separate presentations. This represents the first reported case of a pudendal tumor causing symptoms initially attributed to a herniated disc. The clinical syndrome of lumbar spinal stenosis (LSS) is a common diagnosis in older adults presenting with lower extremity pain. To systematically review the accuracy of the clinical examination for the diagnosis of the clinical syndrome of LSS. MEDLINE, EMBASE, and CINAHL searches of articles published from January 1966 to September 2010. Studies were included if they contained adequate data on the accuracy of the history and physical examination for diagnosing the clinical syndrome of LSS, using a reference standard of expert opinion with radiographic or anatomic confirmation. Two authors independently reviewed each study to determine eligibility, extract data, and appraise levels of evidence. Four studies evaluating 741 patients were identified. Among patients with lower extremity pain, the likelihood of the clinical syndrome of LSS was increased for individuals older than 70 years (likelihood ratio [LR], 2.0; 95% confidence interval [CI], 1.6-2.5), and was decreased for those younger than 60 years (LR, 0.40; 95% CI, 0.29-0.57). The most useful symptoms for increasing the likelihood of the clinical syndrome of LSS were having no pain when seated (LR, 7.4; 95% CI, 1.9-30), improvement of symptoms when bending forward (LR, 6.4; 95% CI, 4.1-9.9), the presence of bilateral buttock or leg pain (LR, 6.3; 95% CI, 3.1-13), and neurogenic claudication (LR, 3.7; 95% CI, 2.9-4.8). Absence of neurogenic claudication (LR, 0.23; 95% CI, 0.17-0.31) decreased the likelihood of the diagnosis. A wide-based gait (LR, 13; 95% CI, 1.9-95) and abnormal Romberg test result (LR, 4.2; 95% CI, 1.4-13) increased the likelihood of the clinical syndrome of LSS. A score of 7 or higher on a diagnostic support tool including history and examination findings increased the likelihood of the clinical syndrome of LSS (LR, 3.3; 95% CI, 2.7-4.0), while a score lower than 7 made the diagnosis much less likely (LR, 0.10; 95% CI, 0.06-0.16). The diagnosis of the clinical syndrome of LSS requires the appropriate clinical picture and radiographic findings. Absence of pain when seated and improvement of symptoms when bending forward are the most useful individual findings. Combinations of findings are most useful for identifying patients who are unlikely to have the diagnosis.\nHere is the question:\nTRAUMATOLOGY: A 61-year-old woman, administrative, with a history of overweight, hypertension, dyslipidemia and metabolic syndrome, who consults for pain in both buttocks, left trochanteric region, lateral aspect of the left thigh up to the knee and left leg up to the middle third. The pain appears when the lower limb is lifted with the knee extended, but is relieved when the knee is flexed. What is the first clinical suspicion?\nHere are the potential choices:\n1. Gouty arthritis of left hip.\n2. Left coxofemoral arthrosis.\n3. Radiated low back pain / lumbosciatica.\n4. Claudication due to canal stenosis.\nThe correct answer is: 3. Radiated low back pain / lumbosciatica."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Intention tremors can be a first sign of multiple sclerosis, since loss or deterioration of motor function and sensitivity are often one of the first symptoms of cerebellar lesions. Intention tremors have a variety of other recorded causes as well. These include a variety of neurological disorders, such as stroke, alcoholism, alcohol withdrawal, peripheral neuropathy, Wilson's disease, Creutzfeldt–Jakob disease, Guillain–Barré syndrome and fragile X syndrome, as well as brain tumors, low blood sugar, hyperthyroidism, hypoparathyroidism, insulinoma, normal aging, and traumatic brain injury. Holmes tremor, a rubral or midbrain tremor, is another form of tremor that includes intention tremors, among other symptoms. This disease affects the proximal muscles of the head, shoulders, and neck. Tremors of this disease occur at frequencies of 2–4 Hz or more. A 28-year-old man with Hirayama disease presented with a peculiar hand posture called \"horn hand\" (\"main en corne\"). The patient noticed that he could not extend his 3rd and 4th fingers when extending the fingers of his right hand 1 year prior to presentation. On neurological examination, the strength of the finger extension is severely weak in the 1st, 3rd and 4th fingers, causing a drop finger posture, but it is only moderately weak in the 2nd and 5th fingers, enabling him to sustain the extension finger posture. The finger posture is like a bull's horns and is named \"horn hand\". Amyotrophy of the ulnar side of the right forearm, so-called \"oblique amyotrophy\", and amyotrophy of the right hand are observed. MRI examination reveals atrophy of the lower cervical spinal cord and compression of it in the neck flexion posture. Diagnosis of Hirayama disease (juvenile muscular atrophy of the distal upper extremity) is confirmed. Horn hand has been reported so far in some cases of lead neuropathy, chronic inflammatory demyelinating polyneuropathy, and distal myopathy; a \"peripheral\" horn hand is characterized by partial and selective lesion of the radial nerve or of the finger extensor muscles. Meanwhile, a \"spinal\" horn hand in this patient with Hirayama disease represents the partial and selective lesion of the spinal anterior horn neurons. Amyotrophy is progressive wasting of muscle tissues. Muscle pain is also a symptom. It can occur in middle-aged males with type 2 diabetes. It also occurs with motor neuron disease. Differential diagnosis The following are considered differential diagnosis for Amyotrophy: compressive and infective causes of polyradiculopathy structural disc diseases chronic demyelinating neuropathies See also Diabetic amyotrophy Monomelic amyotrophy Amyotrophic lateral sclerosis References External links Muscular disorders A 75-year-old man had noticed muscle atrophy and weakness of his right hand and forearm at the age of 25. The symptoms slowly progressed and then stopped. Right hand tremor appeared at about age 40. There was no symptom in his left upper extremity, and his gait was normal. He now shows severe muscle atrophy in his right hand and forearm. There was distally dominant weakness of the right upper extremity and his hand grip was 0 kg on the right and 25 kg on the left. On admission there was no weakness in the bilateral lower extremities. He had postural tremor in both hands and fingers. The tendon reflexes were hypoactive in the upper extremities and normal in the lower extremities. Abnormalities in the superficial sensation were unremarkable, whereas vibration sensation in both the upper and lower extremities was mildly disturbed. Electromyography revealed chronic denervation, especially in the right upper extremity. The sensory nerve conduction study results and somatosensory evoked potentials in the upper extremities were normal. Cervical MRI demonstrated spondylotic changes, canal stenosis from the C5 to C7 levels, and compression of the spinal cord. His hand tremor was dominant on the right with a peak frequency of about 7 Hz. Tremor frequency and power were decreased by mechanical load. Hirayama's disease (juvenile muscular atrophy of unilateral upper extremity) was the most probable diagnosis, although aging might have produced various additional abnormalities. The tremor seen in this patient showed characteristics of enhanced physiological tremor. The disease is rare and several cited cases deviate from the expected norm, making diagnosis more difficult. Proposed diagnostic criteria: Distal predominant muscle weakness and atrophy in forearm and hand Involvement of the unilateral upper extremity almost always all the time Onset between the ages of 10 to early 20s Insidious onset with gradual progression for the first several years, followed by stabilization No lower extremity involvement No sensory disturbance and tendon reflex abnormalities Exclusion of other diseases (e.g., motor neuron disease, multifocal motor neuropathy, brachial plexopathy, spinal cord tumors, syringomyelia, cervical vertebral abnormalities, anterior interosseous, or deep ulnar neuropathy) Median nerve compression at the hand and wrist is called carpal tunnel syndrome. It is the most common type of nerve injury and results from compression of the median nerve at the wrist as it passes between the carpal bones and the flexor retinaculum. It is typically the result of repetitive use of the hands but can be the result of other factors such as obesity, diabetes, pregnancy, and hypothyroidism. Patients often report numbness, tingling, and pain that worsens at night. These symptoms can be elicited from activities that involve prolonged wrist flexion and/or extension. Shaking the hand may alleviate the symptoms. They may also be weakness and clumsiness of the hand with activities such as gripping and grasping. The physical exam is an important component in the diagnosis of carpal tunnel as it can help distinguish carpal tunnel from other diagnoses such as proximal median neuropathy (pronator syndrome) and cervical radiculopathy. Sensory symptoms involve the thumb, index, long, and lateral half of the ring finger. There will be no sensory loss at the thenar eminence with carpal tunnel syndrome when compared to more proximal lesions. If motor weakness is present, it is typically evident with weakness of thumb abduction. There may also be atrophy of the thenar eminence as the median nerve innervates many muscles in this region. Signs that will be absent in carpal tunnel syndrome include weakness in forearm pronation, finger abduction, and finger extension. There are several provocative tests used to diagnose carpal tunnel syndrome [8] [10] : Diagnosticians must always evaluate the neck in patients with presumed median nerve injury or carpal tunnel syndrome. Double crush syndrome is defined as an injury to a nerve at both a distal site of compression as well as proximally such as in the case of a coexistent cervical disk herniation or foraminal stenosis. This condition is most commonly identified when patients have an unsatisfactory resolution of symptoms after a carpal tunnel release. [10] Osterman et al. found in a prospective study that patients who suffered from double crush syndrome reported more \"paresthesias\" rather than \"numbness\" compared to patients who had isolated carpal tunnel syndrome. He also found that grip strength was decreased more with double crush syndrome compared to carpal tunnel syndrome. [11] Of note, radiography of the cervical spine is not currently recommended for evaluation of double crush syndrome by current literature, particularly in the older patient population as there is a very high incidence of asymptomatic degenerative changes of the spine. MRI may be useful but is cost-prohibitive and not necessary in most cases. Therefore, history and physical examination with documentation of such examination techniques as Spurling's cervical spine maneuver to identify cervical nerve root compression, are important tools to identify double crush syndromes. [10] [12] [13] Most types of polyneuropathy progress fairly slowly, over months or years, but rapidly progressive polyneuropathy also occurs. It is important to recognize that at one time it was thought that many of the cases of small fiber peripheral neuropathy with typical symptoms of tingling, pain, and loss of sensation in the feet and hands were due to glucose intolerance before a diagnosis of diabetes or pre-diabetes. However, in August 2015, the Mayo Clinic published a scientific study in the Journal of the Neurological Sciences showing \"no significant increase in...symptoms...in the prediabetes group\", and stated that \"A search for alternate neuropathy causes is needed in patients with prediabetes.\" The treatment of polyneuropathies is aimed firstly at eliminating or controlling the cause, secondly at maintaining muscle strength and physical function, and thirdly at controlling symptoms such as neuropathic pain. In early stages of the disease MMA may be confused for amyotrophic lateral sclerosis (ALS), cervical spondylotic amyotrophy (CSA), and other challenging neurological diseases, as well as conditions that are minor but that call for very different treatments, such as advanced carpal tunnel syndrome (CTS). Symptoms somewhat differ. Pain and tingling in the hand is typically present in CTS and absent from MMA; loss of function presents differently; with careful electrophysiological study and neurological exams the two are distinguished. In early stages, ALS, SCA, and MMA, presentation may be similar. Both CSA and ALS ultimately have more extensive symptoms. MMA is more prevalent in young people while ALS and CSA are more common in older populations. With ALS, hand symptoms usually more commonly both proximal and distal vs in MMA mostly distal only, and with ALS fasciculations (twitching) are often present in upper extremities, but rarely in MMA. MMA is usually eliminated from Over the years, the authors have encountered young men with localized and asymmetrical amyotrophy of the forearm that became arrested and did not advance over a decade or two, typical of Hirayama disease. Reports of such a partial cervical spinal amyotrophy have appeared (Hirayama et al; Moreno Martinez et al). In the type described by Hirayama and associates, young men are affected with progressive and asymmetrical amyotrophy of the forearm and hand that has been traced to ligamentous hypertrophy and buckling in the ventral spinal canal. This causes a compression of the cervical spinal cord gray matter, presumably by a chronic ischemic effect as discussed in detail in Chap. 42. In a familial variety of pure restricted amyotrophy, only the vocal cords became paralyzed over a period of years in adult life; only later were the hands affected. Unlike herniated lumbar discs, cervical ones, if large and centrally situated, result in compression of the spinal cord (Fig. 10-6). The centrally situated disc is often painless, and the cord syndrome may simulate multiple sclerosis or a degenerative neurologic disease. Bilateral hand numbness, paresthesia, or similar altered sensation is common. Failure to consider a protruded cervical disc in patients with obscure symptoms in the legs, including stiffness and falling, is a common error. A vague sensory change can often be detected on the thorax, the rostral margin of which is several dermatomes below the level of compression. The diagnosis and the level of disc protrusion can be confirmed by MRI or by CT myelography. Nerve conduction studies, F responses, and EMG are helpful in confirming the level of root compression and distinguishing pain of radicular origin from that originating in the brachial plexus or in individual nerves of the arm (see “Brachial Neuritis” in Chap. 43). Isolated mononeuropathies may cause symptoms beyond the territory supplied by the affected nerve, but abnormalities on examination typically are confined to appropriate anatomic boundaries. In multiple mononeuropathies, symptoms and signs occur in discrete territories supplied by different individual nerves and—as more nerves are affected—may simulate a polyneuropathy if deficits become confluent. With polyneuropathies, sensory deficits are generally graded, distal, and symmetric in distribution (Chap. 459). Dysesthesias, followed by numbness, begin in the toes and ascend symmetrically. When dysesthesias reach the knees, they usually also have appeared in the fingertips. The process is nerve length–dependent, and the deficit is often described as “stocking-glove” in type. Involvement of both hands and feet also occurs with lesions of the upper cervical cord or the brainstem, but an upper level of the sensory disturbance may then be found on the trunk and other evidence of a central Carpal tunnel syndrome is a common disorder of the hand. This disorder results from compression of an important nerve in the wrist. Disorders like diabetes mellitus, thyroid or rheumatoid arthritis can narrow the tunnel and cause impingement of the nerve. Carpal tunnel syndrome also occurs in people who overuse their hand or perform repetitive actions like using a computer key board, a cashiers machine or a musical instrument. When the nerve is compressed, it can result in disabling symptoms like numbness, tingling, or pain in the middle three fingers. As the condition progresses, it can lead to muscle weakness and inability to hold objects. The pain frequently occurs at night and can even radiate to the shoulder. Even though the diagnosis is straightforward, the treatment is not satisfactory. both hands and feet also occurs with lesions of the upper cervical cord or the brainstem, but an upper level of the sensory disturbance may then be found on the trunk and other evidence of a central lesion may be present, such as sphincter involvement or signs of an upper motor neuron lesion (Chap. 30). Although most polyneuropathies are pansensory and affect all modalities of sensation, selective sensory dysfunction according to nerve fiber size may occur. Small-fiber polyneuropa-161 thies are characterized by burning, painful dysesthesias with reduced pinprick and thermal sensation but with sparing of proprioception, motor function, and deep tendon reflexes. Touch is involved variably; when it is spared, the sensory pattern is referred to as exhibiting sensory dissociation. Sensory dissociation may occur also with spinal cord lesions as well as small-fiber neuropathies. Large-fiber polyneuropathies are characterized by vibration and position sense deficits, imbalance, absent tendon The objective of the presented study was to motile that cumulative trauma disorders of the upper extremities in recent years leads to arising morbidity and applications for compensation for occupational diseases. This rise is probably not associated with an increase of this disorder but a different awareness of workers and doctors as regards the possible adverse effect of forceful and frequently repeated movements of the upper extremities on their function, extended diagnostics and notification. It is important to master the diagnosis of these diseases and interpretation of auxiliary examinations to prevent inadequate payment of damages to the affected subjects and on the other hand to prevent breakdown or in adequate function of the financial provisions in this area. A number of syndromes of the mentioned conditions has very few objective symptoms and abnormal results of auxiliary examinations. The diagnosis of stenotic syndromes has a compared with other disorders great support in electrophysiological techniques, their high sensitivity and specificity (1, 15). The authors discuss therefore their problems and suggest electrophysiological criteria of medium grade affections in the carpal tunnel syndrome which is the condition for compensation for occupational disease and which so far was defined only roughly in this country. Multiple sclerosis Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease, meaning that the myelin sheath of neurons is damaged. Symptoms of MS include visual and sensation problems, muscle weakness, numbness and tingling all over, muscle spasms, poor coordination, and depression. Also, patients with MS have reported extreme fatigue and dizziness, tremors, and bladder leakage. Myelopathy Myelopathy is an injury to the spinal cord due to severe compression that may result from trauma, congenital stenosis, degenerative disease or disc herniation. The spinal cord is a group of nerves housed inside the spine that runs almost its entire length. Tourette's We report a 72-year-old woman who died of respitory failure. History included onset of diabetes mellitus at the age of 67 years and hypertension at the age of 72 years. The patient had been in good health otherwise until 2000, when she had onset of numbness or tingling of the bilateral lower limbs. On December 3, 2000, she was admitted to a hospital in the vicinity of her home because of the above-mentioned complaints. Neurological examinations revealed progressive paraplegia. Symptoms and signs suggested Guillain-Barré syndrome. Examinations of cerebrospinal fluids revealed cell count of 338/3 (mono 72%, poly 18%) and protein value of 100 mg/dl. Later the patient course deteriorated. On December 15, 2000, she was admitted to Hakujikai Memorial Hospital for the second time. Ten days later, MRI examination showed diffuse swelling of the spinal cord from the cervical (C 3/4) level to the thoracic level. Gd-enhanced T 1-weighted MRI performed 22 days later showed a partially enhanced lesion at the thoracic (Th 5/6) level of the spinal cord. The patient was treated with steroid therapy (methylprednisolone 500 mg/dl). She died of respiratory failure on January 6, 2001. The patient was presented in a neurological CPC. Neurological and imaging findings suggested a transverse myelopathy. However, there were several points in this case that were unusual for a typical transverse myelopathy, such as total sensory loss below spinal segments of thoracic level (Th 5) and motor weakness of the upper limbs of upper segment of the same level. A clinical neurologist concluded that the patient had subacute transverse myelopathy with fused multiple pathy pathologic lesions. We discussed whether this case was a transverse myelopathy or multiple sclerosis. Post mortem examination revealed acute necrotic myelopathy affecting the spinal cord from the second cervical to the tenth thoracic vertebrae, with conspicuous infiltration of CD 68-positive macrophages involving both gray and white matter, partially necrotic associated with scattered UCHL-1 dominants lymphocytic infiltration of T cells around vessels. There were relatively older lesions with demyelinating features in the spinal roots that were particularly dominant in the anterior roots. No demyelinated plaques in the optic chiasm, tracts and nerves, or in the cerebero-cerebellar white matter were found. Systemic pathological diagnosis was lung edema with fresh hemorrhage, pancreatic atrophy consistent with diabetes mellitus and choleductlithiasis. Repetitive nerve stimulation Interpretation of nerve conductions The interpretation of nerve conduction studies is complex and requires the expertise of health care practitioners such as clinical neurophysiologists, medical neurologists, physical therapists, chiropractic neurologists or physiatrists. In general, different pathological processes result in changes in latencies, motor, and/or sensory amplitudes, or slowing of the conduction velocities to differing degrees. For example, slowing of the NCV usually indicates there is damage to the myelin. Another example, slowing across the wrist for the motor and sensory latencies of the median nerve indicates focal compression of the median nerve at the wrist, called carpal tunnel syndrome. On the other hand, slowing of all nerve conductions in more than one limb indicates generalized diseased nerves, or generalized peripheral neuropathy. People with diabetes mellitus often develop generalized peripheral neuropathy. Roughly 75% of patients experience pain, but it is less than what would be expected based on the severity of the clinical and radiographic findings. Pathogenesis Any condition resulting in decreased peripheral sensation, proprioception, and fine motor control: Diabetes mellitus neuropathy (the most common in the U.S. today, resulting in destruction of foot and ankle joints), with Charcot joints in 1/600-700 diabetics; related to long-term high blood glucose levels. Alcoholic neuropathy Cerebral palsy Leprosy Syphilis (tabes dorsalis), caused by the organism Treponema pallidum Spinal cord injury Myelomeningocele Syringomyelia Intra-articular steroid injections Congenital insensitivity to pain Peroneal muscular atrophy We described a 48-year-old, right-handed woman who manifested left hand clumsiness after damage to the dorsal column of the high cervical cord due to probable multiple sclerosis. On February 29, 1996, she developed a weakness in the right limbs. Subsequently, she suffered numbness and clumsiness in the left limbs, even though muscle strength of the left limbs was preserved. Seventeen days later, she was referred to our hospital. A T2-weighted MRI after admission demonstrated high signal intensities in the left dorsal column and the right antero-lateral part of the cervical cord at the C1 to C3 vertebral level. Under the diagnosis of probable multiple sclerosis, steroid pulse therapy was applied twice and she gradually regained muscle strength in the right limbs and sensation in the left limbs. One month later, elemental sensations such as pain, touch, temperature, vibration, and position, as well as discriminative sensations such as localization sensation, two-point discrimination, barognosis, pinch-press discrimination, and graphesthesia in the left limbs returned to normal. However, her left hand remained clumsy, especially when she tried to manipulate objects. She also showed a great difficulty in sustaining a constant level of pinching force by the left thumb and index finger, and in localizing her right thumb placed in space with the left hand with her eyes closed. She stated herself that she could not sense at all how her left hand and fingers were moving. Somatosensory evoked potentials recorded from the right scalp showed that the NI was poorly organized and the patency of subsequent peaks was delayed. Transcranial magnetic stimulation revealed that the pyramidal tract from the right motor cortex to the left cervical cord was functionally intact. These observations lead us to conclude as follows: (1) the patient's left hand clumsiness is probably due to the disturbance of kinesthesia, which is crucial to activate temporo-spatial patterns of complex hand and finger movements as well as to maintain long sequences of simple motor execution without vision; and (2) kinesthesia is a specific sensation that is presumably conveyed by the dorsal columns and could be selectively affected by a cervical cord lesion. Distal hereditary motor neuropathy type V is a particular type of neuropathic disorder. In general, distal hereditary motor neuropathies affect the axons of distal motor neurons and are characterized by progressive weakness and atrophy of muscles of the extremities. It is common for them to be called \"spinal forms of Charcot-Marie-Tooth disease (CMT)\", because the diseases are closely related in symptoms and genetic cause. The diagnostic difference in these diseases is the presence of sensory loss in the extremities. There are seven classifications of dHMNs, each defined by patterns of inheritance, age of onset, severity, and muscle groups involved. Type V (sometimes notated as Type 5) is a disorder characterized by autosomal dominance, weakness of the upper limbs that is progressive and symmetrical, and atrophy of the small muscles of the hands. Neurological symptoms Some symptoms (e.g., weakness, confusion, and fatigue) may be due to anemia or hypercalcemia. Headache, visual changes, and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein. Finally, radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome, and other neuropathies (due to infiltration of peripheral nerves by amyloid) may occur. It may give rise to paraplegia in late-presenting cases. When the disease is well-controlled, neurological symptoms may result from current treatments, some of which may cause peripheral neuropathy, manifesting itself as numbness or pain in the hands, feet, and lower legs. The review of the literature on the natural history of the carpal tunnel syndrome is presented. It is shown that the condition is characterised by non-uniform and unpredictable clinical course, in which besides the progressive type of evolution, a regressive one (characterised by spontaneous resolution of symptoms) and type of stable clinical picture (with episodes of exacerbation and resolution of symptoms) exist. Proportion of prevalence of particular types of clinical courses is not precisely estimated, but it appears that at least a half of the cases is of non-progressive type. Non-operative treatment of the condition may be effective in those particular cases, without risk of the development of severe neurological complications as a consequence of impairment of the median nerve. The evidence form analysed studies shows that in carpal tunnel syndrome, the clinical symptoms and signs and nerve conduction disturbances have different natural histories. Clinical features are subjected to greater temporal fluctuations than electrophysiological findings, and they frequently do not correlate one with another. There is not common opinion about efficacy of intervention in extreme carpal tunnel syndrome, characterised by severe conduction disturbances in electrophysiological tests and fixed neurological deficits, however surgical decompression of the carpal tunnel appears to be more promising than decline of the treatment. The natural history of the syndrome occurred in the course of other diseases (or conditions, e.g. pregnancy) is different, depending on the type of the disease itself. In the commonest systemic diseases associated with carpal tunnel syndrome, such as diabetes, hypothyroidism and rheumatoid arthritis, there is not common opinion about their prognostic effect on the natural course of the syndrome. Hirayama's disease (HD), is a benign, self-limited, motor neuron disease, characterized by asymmetric weakness and atrophy of one or both distal upper extremities. In the present study we report the clinical, electrophysiological and MRI features of a group of Italian patients, with review of the literature. Moreover we propose an optimized MRI protocol for patients with suspected or diagnosed HD in order to make an early diagnosis and a standardized follow up. Eight patients with clinical suspicion of Hirayama disease underwent evaluation between January 2007 and November 2013. All patients underwent standard nerve conduction studies (NCS), electromyography (EMG) and motor/sensory evoked potentials (MEP/SEP). Cervical spine MRI studies were conducted with a 1.5 Tesla MRI scanner in neutral and flexion position, including sagittal T1-weighted sequences and sagittal and axial T2-weighted sequences. The following diagnostic features were evaluated: abnormal cervical curvature, localized cervical cord atrophy in the lower tract (C4-C7), presence of cord flattening (CF), intramedullary signal hyperintensity on T2 weighted sequences, anterior shifting of the posterior wall of the cervical dural sac (ASD) and presence of flow voids (EFV) in the posterior epidural space during flexion. All patients complained of weakness in hand muscles as initial symptoms, associated with hand tremor in three of them and abnormal sweating of the hand palm in two of them. No sensory deficits and weakness at lower limbs were reported by any patients. Distal deep tendon reflexes at upper limbs were absent in all patients with the absence of the right tricipital reflex in one of them. Deep tendon reflexes at lower limbs were normal and no signs of pyramidal tract involvement were present. The clinical involvement at onset was unilateral in six patients (three left-sided and three right-sided) and bilateral asymmetric in two of them, with the right side more affected. With the progression of the disease all patients but one experienced weakness and wasting of hand muscles and forearm bilaterally, but still asymmetric. The duration of the progression phase of the disease ranged from eight months to three years. In all patients, NCS and EMG findings were consistent with a spinal metameric disorder involving the C7-T1 myotomes bilaterally; sensory conduction and electrophysiologic features at lower limbs were normal. MEP and SEP were normal and we did not observe the disappearance of the spinal potential during the neck flexion in any of the patients. MRI is the best diagnostic tool in the diagnosis of HD; it can confirm clinical diagnosis and exclude other conditions responsible for the neurological deficits leading to a correct patient management and therapy, limiting arm impairment. On MRI all patients had loss of the normal cervical lordosis (100%). Five patients had loss of attachment of posterior dural sac and anterior dural shift on flexion MRI with presence of flow voids from venous plexus congestion (62.5%); three patients had no anterior dislocation of the dural sac and no epidural vein congestion. Two patients showed localized cord atrophy, one at C5-C6 and the other at C6-C7 level (25%). Three patients had T2 intramedullary hyperintensities (37.5%) and cord flattening (CF) was present in 5 patients of 8 (62.5%). HD is a rare entity and a self-limited condition, but it has to be early differentiated from other diseases that may determine myelopathy and amyotrophy to establish a correct therapy and limit arm impairment. MRI is very important to confirm the clinical suspect of HD and a standardized MRI protocol using axial and sagittal images in both neutral and flexing position is needed, in order to diagnose and follow up affected patients.\nHere is the question:\nNEUROLOGY AND NEUROSURGERY: A 32-year-old diabetic patient on insulin therapy with good control of his blood glucose levels comes to your office with tingling in both hands, with a sensation of corking and thermal insensitivity of progressive onset over the course of 2 weeks. She does not report visual disturbances, strength deficit, motor clumsiness or other symptoms. On examination she found anesthesia to pain and temperature in both hands and distal forearms; positional and vibratory sensitivity were preserved. There is no muscle atrophy or strength deficit. Muscle reflexes are normal and symmetrical. There is no dysmetria, dysdiadochokinesia or intention tremor. The rest of the neurological examination is strictly normal. Indicate the most likely diagnosis in this case:\nHere are the potential choices:\n1. Peripheral sensitvo symmetric distal peripheral neuropathy of diabetic cause.\n2. Compressive cervical spinal cord injury.\n3. Bilateral carpal tunnel syndrome.\n4. Multiple sclerosis type demyelinating disease.\n5. Central cervical spinal cord injury.\nThe correct answer is: ",
        "gold_answer": "5 Central cervical spinal cord injury.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Intention tremors can be a first sign of multiple sclerosis, since loss or deterioration of motor function and sensitivity are often one of the first symptoms of cerebellar lesions. Intention tremors have a variety of other recorded causes as well. These include a variety of neurological disorders, such as stroke, alcoholism, alcohol withdrawal, peripheral neuropathy, Wilson's disease, Creutzfeldt–Jakob disease, Guillain–Barré syndrome and fragile X syndrome, as well as brain tumors, low blood sugar, hyperthyroidism, hypoparathyroidism, insulinoma, normal aging, and traumatic brain injury. Holmes tremor, a rubral or midbrain tremor, is another form of tremor that includes intention tremors, among other symptoms. This disease affects the proximal muscles of the head, shoulders, and neck. Tremors of this disease occur at frequencies of 2–4 Hz or more. A 28-year-old man with Hirayama disease presented with a peculiar hand posture called \"horn hand\" (\"main en corne\"). The patient noticed that he could not extend his 3rd and 4th fingers when extending the fingers of his right hand 1 year prior to presentation. On neurological examination, the strength of the finger extension is severely weak in the 1st, 3rd and 4th fingers, causing a drop finger posture, but it is only moderately weak in the 2nd and 5th fingers, enabling him to sustain the extension finger posture. The finger posture is like a bull's horns and is named \"horn hand\". Amyotrophy of the ulnar side of the right forearm, so-called \"oblique amyotrophy\", and amyotrophy of the right hand are observed. MRI examination reveals atrophy of the lower cervical spinal cord and compression of it in the neck flexion posture. Diagnosis of Hirayama disease (juvenile muscular atrophy of the distal upper extremity) is confirmed. Horn hand has been reported so far in some cases of lead neuropathy, chronic inflammatory demyelinating polyneuropathy, and distal myopathy; a \"peripheral\" horn hand is characterized by partial and selective lesion of the radial nerve or of the finger extensor muscles. Meanwhile, a \"spinal\" horn hand in this patient with Hirayama disease represents the partial and selective lesion of the spinal anterior horn neurons. Amyotrophy is progressive wasting of muscle tissues. Muscle pain is also a symptom. It can occur in middle-aged males with type 2 diabetes. It also occurs with motor neuron disease. Differential diagnosis The following are considered differential diagnosis for Amyotrophy: compressive and infective causes of polyradiculopathy structural disc diseases chronic demyelinating neuropathies See also Diabetic amyotrophy Monomelic amyotrophy Amyotrophic lateral sclerosis References External links Muscular disorders A 75-year-old man had noticed muscle atrophy and weakness of his right hand and forearm at the age of 25. The symptoms slowly progressed and then stopped. Right hand tremor appeared at about age 40. There was no symptom in his left upper extremity, and his gait was normal. He now shows severe muscle atrophy in his right hand and forearm. There was distally dominant weakness of the right upper extremity and his hand grip was 0 kg on the right and 25 kg on the left. On admission there was no weakness in the bilateral lower extremities. He had postural tremor in both hands and fingers. The tendon reflexes were hypoactive in the upper extremities and normal in the lower extremities. Abnormalities in the superficial sensation were unremarkable, whereas vibration sensation in both the upper and lower extremities was mildly disturbed. Electromyography revealed chronic denervation, especially in the right upper extremity. The sensory nerve conduction study results and somatosensory evoked potentials in the upper extremities were normal. Cervical MRI demonstrated spondylotic changes, canal stenosis from the C5 to C7 levels, and compression of the spinal cord. His hand tremor was dominant on the right with a peak frequency of about 7 Hz. Tremor frequency and power were decreased by mechanical load. Hirayama's disease (juvenile muscular atrophy of unilateral upper extremity) was the most probable diagnosis, although aging might have produced various additional abnormalities. The tremor seen in this patient showed characteristics of enhanced physiological tremor. The disease is rare and several cited cases deviate from the expected norm, making diagnosis more difficult. Proposed diagnostic criteria: Distal predominant muscle weakness and atrophy in forearm and hand Involvement of the unilateral upper extremity almost always all the time Onset between the ages of 10 to early 20s Insidious onset with gradual progression for the first several years, followed by stabilization No lower extremity involvement No sensory disturbance and tendon reflex abnormalities Exclusion of other diseases (e.g., motor neuron disease, multifocal motor neuropathy, brachial plexopathy, spinal cord tumors, syringomyelia, cervical vertebral abnormalities, anterior interosseous, or deep ulnar neuropathy) Median nerve compression at the hand and wrist is called carpal tunnel syndrome. It is the most common type of nerve injury and results from compression of the median nerve at the wrist as it passes between the carpal bones and the flexor retinaculum. It is typically the result of repetitive use of the hands but can be the result of other factors such as obesity, diabetes, pregnancy, and hypothyroidism. Patients often report numbness, tingling, and pain that worsens at night. These symptoms can be elicited from activities that involve prolonged wrist flexion and/or extension. Shaking the hand may alleviate the symptoms. They may also be weakness and clumsiness of the hand with activities such as gripping and grasping. The physical exam is an important component in the diagnosis of carpal tunnel as it can help distinguish carpal tunnel from other diagnoses such as proximal median neuropathy (pronator syndrome) and cervical radiculopathy. Sensory symptoms involve the thumb, index, long, and lateral half of the ring finger. There will be no sensory loss at the thenar eminence with carpal tunnel syndrome when compared to more proximal lesions. If motor weakness is present, it is typically evident with weakness of thumb abduction. There may also be atrophy of the thenar eminence as the median nerve innervates many muscles in this region. Signs that will be absent in carpal tunnel syndrome include weakness in forearm pronation, finger abduction, and finger extension. There are several provocative tests used to diagnose carpal tunnel syndrome [8] [10] : Diagnosticians must always evaluate the neck in patients with presumed median nerve injury or carpal tunnel syndrome. Double crush syndrome is defined as an injury to a nerve at both a distal site of compression as well as proximally such as in the case of a coexistent cervical disk herniation or foraminal stenosis. This condition is most commonly identified when patients have an unsatisfactory resolution of symptoms after a carpal tunnel release. [10] Osterman et al. found in a prospective study that patients who suffered from double crush syndrome reported more \"paresthesias\" rather than \"numbness\" compared to patients who had isolated carpal tunnel syndrome. He also found that grip strength was decreased more with double crush syndrome compared to carpal tunnel syndrome. [11] Of note, radiography of the cervical spine is not currently recommended for evaluation of double crush syndrome by current literature, particularly in the older patient population as there is a very high incidence of asymptomatic degenerative changes of the spine. MRI may be useful but is cost-prohibitive and not necessary in most cases. Therefore, history and physical examination with documentation of such examination techniques as Spurling's cervical spine maneuver to identify cervical nerve root compression, are important tools to identify double crush syndromes. [10] [12] [13] Most types of polyneuropathy progress fairly slowly, over months or years, but rapidly progressive polyneuropathy also occurs. It is important to recognize that at one time it was thought that many of the cases of small fiber peripheral neuropathy with typical symptoms of tingling, pain, and loss of sensation in the feet and hands were due to glucose intolerance before a diagnosis of diabetes or pre-diabetes. However, in August 2015, the Mayo Clinic published a scientific study in the Journal of the Neurological Sciences showing \"no significant increase in...symptoms...in the prediabetes group\", and stated that \"A search for alternate neuropathy causes is needed in patients with prediabetes.\" The treatment of polyneuropathies is aimed firstly at eliminating or controlling the cause, secondly at maintaining muscle strength and physical function, and thirdly at controlling symptoms such as neuropathic pain. In early stages of the disease MMA may be confused for amyotrophic lateral sclerosis (ALS), cervical spondylotic amyotrophy (CSA), and other challenging neurological diseases, as well as conditions that are minor but that call for very different treatments, such as advanced carpal tunnel syndrome (CTS). Symptoms somewhat differ. Pain and tingling in the hand is typically present in CTS and absent from MMA; loss of function presents differently; with careful electrophysiological study and neurological exams the two are distinguished. In early stages, ALS, SCA, and MMA, presentation may be similar. Both CSA and ALS ultimately have more extensive symptoms. MMA is more prevalent in young people while ALS and CSA are more common in older populations. With ALS, hand symptoms usually more commonly both proximal and distal vs in MMA mostly distal only, and with ALS fasciculations (twitching) are often present in upper extremities, but rarely in MMA. MMA is usually eliminated from Over the years, the authors have encountered young men with localized and asymmetrical amyotrophy of the forearm that became arrested and did not advance over a decade or two, typical of Hirayama disease. Reports of such a partial cervical spinal amyotrophy have appeared (Hirayama et al; Moreno Martinez et al). In the type described by Hirayama and associates, young men are affected with progressive and asymmetrical amyotrophy of the forearm and hand that has been traced to ligamentous hypertrophy and buckling in the ventral spinal canal. This causes a compression of the cervical spinal cord gray matter, presumably by a chronic ischemic effect as discussed in detail in Chap. 42. In a familial variety of pure restricted amyotrophy, only the vocal cords became paralyzed over a period of years in adult life; only later were the hands affected. Unlike herniated lumbar discs, cervical ones, if large and centrally situated, result in compression of the spinal cord (Fig. 10-6). The centrally situated disc is often painless, and the cord syndrome may simulate multiple sclerosis or a degenerative neurologic disease. Bilateral hand numbness, paresthesia, or similar altered sensation is common. Failure to consider a protruded cervical disc in patients with obscure symptoms in the legs, including stiffness and falling, is a common error. A vague sensory change can often be detected on the thorax, the rostral margin of which is several dermatomes below the level of compression. The diagnosis and the level of disc protrusion can be confirmed by MRI or by CT myelography. Nerve conduction studies, F responses, and EMG are helpful in confirming the level of root compression and distinguishing pain of radicular origin from that originating in the brachial plexus or in individual nerves of the arm (see “Brachial Neuritis” in Chap. 43). Isolated mononeuropathies may cause symptoms beyond the territory supplied by the affected nerve, but abnormalities on examination typically are confined to appropriate anatomic boundaries. In multiple mononeuropathies, symptoms and signs occur in discrete territories supplied by different individual nerves and—as more nerves are affected—may simulate a polyneuropathy if deficits become confluent. With polyneuropathies, sensory deficits are generally graded, distal, and symmetric in distribution (Chap. 459). Dysesthesias, followed by numbness, begin in the toes and ascend symmetrically. When dysesthesias reach the knees, they usually also have appeared in the fingertips. The process is nerve length–dependent, and the deficit is often described as “stocking-glove” in type. Involvement of both hands and feet also occurs with lesions of the upper cervical cord or the brainstem, but an upper level of the sensory disturbance may then be found on the trunk and other evidence of a central Carpal tunnel syndrome is a common disorder of the hand. This disorder results from compression of an important nerve in the wrist. Disorders like diabetes mellitus, thyroid or rheumatoid arthritis can narrow the tunnel and cause impingement of the nerve. Carpal tunnel syndrome also occurs in people who overuse their hand or perform repetitive actions like using a computer key board, a cashiers machine or a musical instrument. When the nerve is compressed, it can result in disabling symptoms like numbness, tingling, or pain in the middle three fingers. As the condition progresses, it can lead to muscle weakness and inability to hold objects. The pain frequently occurs at night and can even radiate to the shoulder. Even though the diagnosis is straightforward, the treatment is not satisfactory. both hands and feet also occurs with lesions of the upper cervical cord or the brainstem, but an upper level of the sensory disturbance may then be found on the trunk and other evidence of a central lesion may be present, such as sphincter involvement or signs of an upper motor neuron lesion (Chap. 30). Although most polyneuropathies are pansensory and affect all modalities of sensation, selective sensory dysfunction according to nerve fiber size may occur. Small-fiber polyneuropa-161 thies are characterized by burning, painful dysesthesias with reduced pinprick and thermal sensation but with sparing of proprioception, motor function, and deep tendon reflexes. Touch is involved variably; when it is spared, the sensory pattern is referred to as exhibiting sensory dissociation. Sensory dissociation may occur also with spinal cord lesions as well as small-fiber neuropathies. Large-fiber polyneuropathies are characterized by vibration and position sense deficits, imbalance, absent tendon The objective of the presented study was to motile that cumulative trauma disorders of the upper extremities in recent years leads to arising morbidity and applications for compensation for occupational diseases. This rise is probably not associated with an increase of this disorder but a different awareness of workers and doctors as regards the possible adverse effect of forceful and frequently repeated movements of the upper extremities on their function, extended diagnostics and notification. It is important to master the diagnosis of these diseases and interpretation of auxiliary examinations to prevent inadequate payment of damages to the affected subjects and on the other hand to prevent breakdown or in adequate function of the financial provisions in this area. A number of syndromes of the mentioned conditions has very few objective symptoms and abnormal results of auxiliary examinations. The diagnosis of stenotic syndromes has a compared with other disorders great support in electrophysiological techniques, their high sensitivity and specificity (1, 15). The authors discuss therefore their problems and suggest electrophysiological criteria of medium grade affections in the carpal tunnel syndrome which is the condition for compensation for occupational disease and which so far was defined only roughly in this country. Multiple sclerosis Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease, meaning that the myelin sheath of neurons is damaged. Symptoms of MS include visual and sensation problems, muscle weakness, numbness and tingling all over, muscle spasms, poor coordination, and depression. Also, patients with MS have reported extreme fatigue and dizziness, tremors, and bladder leakage. Myelopathy Myelopathy is an injury to the spinal cord due to severe compression that may result from trauma, congenital stenosis, degenerative disease or disc herniation. The spinal cord is a group of nerves housed inside the spine that runs almost its entire length. Tourette's We report a 72-year-old woman who died of respitory failure. History included onset of diabetes mellitus at the age of 67 years and hypertension at the age of 72 years. The patient had been in good health otherwise until 2000, when she had onset of numbness or tingling of the bilateral lower limbs. On December 3, 2000, she was admitted to a hospital in the vicinity of her home because of the above-mentioned complaints. Neurological examinations revealed progressive paraplegia. Symptoms and signs suggested Guillain-Barré syndrome. Examinations of cerebrospinal fluids revealed cell count of 338/3 (mono 72%, poly 18%) and protein value of 100 mg/dl. Later the patient course deteriorated. On December 15, 2000, she was admitted to Hakujikai Memorial Hospital for the second time. Ten days later, MRI examination showed diffuse swelling of the spinal cord from the cervical (C 3/4) level to the thoracic level. Gd-enhanced T 1-weighted MRI performed 22 days later showed a partially enhanced lesion at the thoracic (Th 5/6) level of the spinal cord. The patient was treated with steroid therapy (methylprednisolone 500 mg/dl). She died of respiratory failure on January 6, 2001. The patient was presented in a neurological CPC. Neurological and imaging findings suggested a transverse myelopathy. However, there were several points in this case that were unusual for a typical transverse myelopathy, such as total sensory loss below spinal segments of thoracic level (Th 5) and motor weakness of the upper limbs of upper segment of the same level. A clinical neurologist concluded that the patient had subacute transverse myelopathy with fused multiple pathy pathologic lesions. We discussed whether this case was a transverse myelopathy or multiple sclerosis. Post mortem examination revealed acute necrotic myelopathy affecting the spinal cord from the second cervical to the tenth thoracic vertebrae, with conspicuous infiltration of CD 68-positive macrophages involving both gray and white matter, partially necrotic associated with scattered UCHL-1 dominants lymphocytic infiltration of T cells around vessels. There were relatively older lesions with demyelinating features in the spinal roots that were particularly dominant in the anterior roots. No demyelinated plaques in the optic chiasm, tracts and nerves, or in the cerebero-cerebellar white matter were found. Systemic pathological diagnosis was lung edema with fresh hemorrhage, pancreatic atrophy consistent with diabetes mellitus and choleductlithiasis. Repetitive nerve stimulation Interpretation of nerve conductions The interpretation of nerve conduction studies is complex and requires the expertise of health care practitioners such as clinical neurophysiologists, medical neurologists, physical therapists, chiropractic neurologists or physiatrists. In general, different pathological processes result in changes in latencies, motor, and/or sensory amplitudes, or slowing of the conduction velocities to differing degrees. For example, slowing of the NCV usually indicates there is damage to the myelin. Another example, slowing across the wrist for the motor and sensory latencies of the median nerve indicates focal compression of the median nerve at the wrist, called carpal tunnel syndrome. On the other hand, slowing of all nerve conductions in more than one limb indicates generalized diseased nerves, or generalized peripheral neuropathy. People with diabetes mellitus often develop generalized peripheral neuropathy. Roughly 75% of patients experience pain, but it is less than what would be expected based on the severity of the clinical and radiographic findings. Pathogenesis Any condition resulting in decreased peripheral sensation, proprioception, and fine motor control: Diabetes mellitus neuropathy (the most common in the U.S. today, resulting in destruction of foot and ankle joints), with Charcot joints in 1/600-700 diabetics; related to long-term high blood glucose levels. Alcoholic neuropathy Cerebral palsy Leprosy Syphilis (tabes dorsalis), caused by the organism Treponema pallidum Spinal cord injury Myelomeningocele Syringomyelia Intra-articular steroid injections Congenital insensitivity to pain Peroneal muscular atrophy We described a 48-year-old, right-handed woman who manifested left hand clumsiness after damage to the dorsal column of the high cervical cord due to probable multiple sclerosis. On February 29, 1996, she developed a weakness in the right limbs. Subsequently, she suffered numbness and clumsiness in the left limbs, even though muscle strength of the left limbs was preserved. Seventeen days later, she was referred to our hospital. A T2-weighted MRI after admission demonstrated high signal intensities in the left dorsal column and the right antero-lateral part of the cervical cord at the C1 to C3 vertebral level. Under the diagnosis of probable multiple sclerosis, steroid pulse therapy was applied twice and she gradually regained muscle strength in the right limbs and sensation in the left limbs. One month later, elemental sensations such as pain, touch, temperature, vibration, and position, as well as discriminative sensations such as localization sensation, two-point discrimination, barognosis, pinch-press discrimination, and graphesthesia in the left limbs returned to normal. However, her left hand remained clumsy, especially when she tried to manipulate objects. She also showed a great difficulty in sustaining a constant level of pinching force by the left thumb and index finger, and in localizing her right thumb placed in space with the left hand with her eyes closed. She stated herself that she could not sense at all how her left hand and fingers were moving. Somatosensory evoked potentials recorded from the right scalp showed that the NI was poorly organized and the patency of subsequent peaks was delayed. Transcranial magnetic stimulation revealed that the pyramidal tract from the right motor cortex to the left cervical cord was functionally intact. These observations lead us to conclude as follows: (1) the patient's left hand clumsiness is probably due to the disturbance of kinesthesia, which is crucial to activate temporo-spatial patterns of complex hand and finger movements as well as to maintain long sequences of simple motor execution without vision; and (2) kinesthesia is a specific sensation that is presumably conveyed by the dorsal columns and could be selectively affected by a cervical cord lesion. Distal hereditary motor neuropathy type V is a particular type of neuropathic disorder. In general, distal hereditary motor neuropathies affect the axons of distal motor neurons and are characterized by progressive weakness and atrophy of muscles of the extremities. It is common for them to be called \"spinal forms of Charcot-Marie-Tooth disease (CMT)\", because the diseases are closely related in symptoms and genetic cause. The diagnostic difference in these diseases is the presence of sensory loss in the extremities. There are seven classifications of dHMNs, each defined by patterns of inheritance, age of onset, severity, and muscle groups involved. Type V (sometimes notated as Type 5) is a disorder characterized by autosomal dominance, weakness of the upper limbs that is progressive and symmetrical, and atrophy of the small muscles of the hands. Neurological symptoms Some symptoms (e.g., weakness, confusion, and fatigue) may be due to anemia or hypercalcemia. Headache, visual changes, and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein. Finally, radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome, and other neuropathies (due to infiltration of peripheral nerves by amyloid) may occur. It may give rise to paraplegia in late-presenting cases. When the disease is well-controlled, neurological symptoms may result from current treatments, some of which may cause peripheral neuropathy, manifesting itself as numbness or pain in the hands, feet, and lower legs. The review of the literature on the natural history of the carpal tunnel syndrome is presented. It is shown that the condition is characterised by non-uniform and unpredictable clinical course, in which besides the progressive type of evolution, a regressive one (characterised by spontaneous resolution of symptoms) and type of stable clinical picture (with episodes of exacerbation and resolution of symptoms) exist. Proportion of prevalence of particular types of clinical courses is not precisely estimated, but it appears that at least a half of the cases is of non-progressive type. Non-operative treatment of the condition may be effective in those particular cases, without risk of the development of severe neurological complications as a consequence of impairment of the median nerve. The evidence form analysed studies shows that in carpal tunnel syndrome, the clinical symptoms and signs and nerve conduction disturbances have different natural histories. Clinical features are subjected to greater temporal fluctuations than electrophysiological findings, and they frequently do not correlate one with another. There is not common opinion about efficacy of intervention in extreme carpal tunnel syndrome, characterised by severe conduction disturbances in electrophysiological tests and fixed neurological deficits, however surgical decompression of the carpal tunnel appears to be more promising than decline of the treatment. The natural history of the syndrome occurred in the course of other diseases (or conditions, e.g. pregnancy) is different, depending on the type of the disease itself. In the commonest systemic diseases associated with carpal tunnel syndrome, such as diabetes, hypothyroidism and rheumatoid arthritis, there is not common opinion about their prognostic effect on the natural course of the syndrome. Hirayama's disease (HD), is a benign, self-limited, motor neuron disease, characterized by asymmetric weakness and atrophy of one or both distal upper extremities. In the present study we report the clinical, electrophysiological and MRI features of a group of Italian patients, with review of the literature. Moreover we propose an optimized MRI protocol for patients with suspected or diagnosed HD in order to make an early diagnosis and a standardized follow up. Eight patients with clinical suspicion of Hirayama disease underwent evaluation between January 2007 and November 2013. All patients underwent standard nerve conduction studies (NCS), electromyography (EMG) and motor/sensory evoked potentials (MEP/SEP). Cervical spine MRI studies were conducted with a 1.5 Tesla MRI scanner in neutral and flexion position, including sagittal T1-weighted sequences and sagittal and axial T2-weighted sequences. The following diagnostic features were evaluated: abnormal cervical curvature, localized cervical cord atrophy in the lower tract (C4-C7), presence of cord flattening (CF), intramedullary signal hyperintensity on T2 weighted sequences, anterior shifting of the posterior wall of the cervical dural sac (ASD) and presence of flow voids (EFV) in the posterior epidural space during flexion. All patients complained of weakness in hand muscles as initial symptoms, associated with hand tremor in three of them and abnormal sweating of the hand palm in two of them. No sensory deficits and weakness at lower limbs were reported by any patients. Distal deep tendon reflexes at upper limbs were absent in all patients with the absence of the right tricipital reflex in one of them. Deep tendon reflexes at lower limbs were normal and no signs of pyramidal tract involvement were present. The clinical involvement at onset was unilateral in six patients (three left-sided and three right-sided) and bilateral asymmetric in two of them, with the right side more affected. With the progression of the disease all patients but one experienced weakness and wasting of hand muscles and forearm bilaterally, but still asymmetric. The duration of the progression phase of the disease ranged from eight months to three years. In all patients, NCS and EMG findings were consistent with a spinal metameric disorder involving the C7-T1 myotomes bilaterally; sensory conduction and electrophysiologic features at lower limbs were normal. MEP and SEP were normal and we did not observe the disappearance of the spinal potential during the neck flexion in any of the patients. MRI is the best diagnostic tool in the diagnosis of HD; it can confirm clinical diagnosis and exclude other conditions responsible for the neurological deficits leading to a correct patient management and therapy, limiting arm impairment. On MRI all patients had loss of the normal cervical lordosis (100%). Five patients had loss of attachment of posterior dural sac and anterior dural shift on flexion MRI with presence of flow voids from venous plexus congestion (62.5%); three patients had no anterior dislocation of the dural sac and no epidural vein congestion. Two patients showed localized cord atrophy, one at C5-C6 and the other at C6-C7 level (25%). Three patients had T2 intramedullary hyperintensities (37.5%) and cord flattening (CF) was present in 5 patients of 8 (62.5%). HD is a rare entity and a self-limited condition, but it has to be early differentiated from other diseases that may determine myelopathy and amyotrophy to establish a correct therapy and limit arm impairment. MRI is very important to confirm the clinical suspect of HD and a standardized MRI protocol using axial and sagittal images in both neutral and flexing position is needed, in order to diagnose and follow up affected patients.\nHere is the question:\nNEUROLOGY AND NEUROSURGERY: A 32-year-old diabetic patient on insulin therapy with good control of his blood glucose levels comes to your office with tingling in both hands, with a sensation of corking and thermal insensitivity of progressive onset over the course of 2 weeks. She does not report visual disturbances, strength deficit, motor clumsiness or other symptoms. On examination she found anesthesia to pain and temperature in both hands and distal forearms; positional and vibratory sensitivity were preserved. There is no muscle atrophy or strength deficit. Muscle reflexes are normal and symmetrical. There is no dysmetria, dysdiadochokinesia or intention tremor. The rest of the neurological examination is strictly normal. Indicate the most likely diagnosis in this case:\nHere are the potential choices:\n1. Peripheral sensitvo symmetric distal peripheral neuropathy of diabetic cause.\n2. Compressive cervical spinal cord injury.\n3. Bilateral carpal tunnel syndrome.\n4. Multiple sclerosis type demyelinating disease.\n5. Central cervical spinal cord injury.\nThe correct answer is: 1. Peripheral sensitvo symmetric distal peripheral neuropathy of diabetic cause."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n We report two cases of rheumatoid arthritis (RA) who later had developed after polymyositis (PM). The first patient was 64-year old male who experienced muscular weakness of the four limbs in proximity 10 years ago. He was diagnosed as PM because of the elevated serum CK and the myogenic pattern of EMG, and his symptoms were improved by treatment with corticosteroid. He started to complain polyarthralgia 2 years ago, followed by interstitial pneumonia, pleuritis and skin ulcer. He was admitted because of exacerbated polyarthralgia, multiple subcutaneous nodules, skin eruption and fever. The level of serum CK was within normal range but CRP was elevated and CH 50 was decreased. The laboratory examination showed positive cryoglobulin and high titer of rheumatoid factor, but anti-Jo 1 antibody was negative. The hand X-ray showed bone erosions in bilateral wrist joints. Skin biopsy revealed leukocytoclastic vasculitis. Based on these findings, he was diagnosed as malignant RA. He was successfully treated with methylprednisolone pulse therapy, cyclophosphamide and prostaglandin E 1. The second patient was 77-year old male with pneumoconiosis who experienced muscular weakness of the four limbs in proximity 4 years ago. He was diagnosed as PM based on his clinical and laboratory findings and was treated with temporary corticosteroid. He started to have polyarthralgia last year, and he was admitted because of increasing arthralgia after the treatment of pulmonary tuberculosis. The level of serum CK was slightly elevated due to hypothyroidism, and CRP was highly elevated. Rheumatoid factor and cryoglobulin were positive, but anti-Jo 1 antibody was negative. The hand X-ray showed bone erosions in bilateral wrist joints. Crystals of pyrophosphate calcium was observed in knee joints. He was diagnosed as RA associate with pseudogout. His symptoms were relieved with corticosteroid, salazosulfapyridine and anti-tuberculous therapy. These two cases had altered their clinical features from PM to definite RA, and both had pulmonary complications. Previous reports described the cases of RA followed by PM, most of which were induced by such drugs as D-penicillamine, but the cases of PM who later had developed RA are extremely unusual. The overlapped cases of RA and PM tend to highly associate with pulmonary lesions. Dear Editor, Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by diverse patterns of auto-antibody production with multi-organ affectation. Cutaneous involvement, either alone or in association with other systemic illnesses, is one of its most common manifestations (1). Dermatologic disorders like malar and discoid rashes are quite suggestive of SLE. However, the occurrence of non-specific skin lesions like erythema multiforme (EM) in patients with SLE (Rowell syndrome) can rarely occur (1). In such patients, a diagnosis of SLE may be missed or delayed in the absence of other overt clinical features of lupus. Herein we report a case of recurring EM-like eruptions as the cardinal cutaneous manifestation of previously undiagnosed, active SLE in a young Nigerian woman. A 26-year-old Nigerian woman presented with a three-day history of non-pruritic, generalized, and target-like, erythematous annular patches and plaques which mostly affected the trunk. A few lesions had presented with crusting and erosions at the time of examination (Figure 1). Associated symptoms included oral painful ulcers, low grade fever, and malaise. The patient had no other systemic symptoms and her prior drug history was not remarkable. Her erythrocyte sedimentation rate (ESR) was 66 mm/hour using the Westergren method. Screening for HIV and hepatitis B and C was negative. Herpes simplex, cytomegalovirus, and Epstein Barr viruses could not be screened for. Other baseline investigations (complete blood count, electrolytes, urea and creatinine as well as urinalysis) were within normal limits. The patient was managed as a case of EM of an unidentified inciting agent and her symptoms resolved with supportive care and antibiotics. However, she developed a recurrence about 5 weeks later, with more extensive and coalescent skin lesions (Figure 2). Additionally, there was a new onset of alopecia and pain in the small joints of the hands as well as both knees and ankles. At this time, the patient's ESR had gone up to 112 mm/h and she had developed significant proteinuria, with a protein creatinine ratio of 1.3 g/g (reference &lt;0.5 g/g). Her antinuclear antibody (ANA) titer was high (1:320) with a speckled pattern. Anti-Smith antibody was also positive. A renal biopsy was declined. A tentative diagnosis of Rowell syndrome was made. The patient was started on high-dose steroids and hydroxychloroquine 200 mg twice daily. Subsequent care included the use of mycophenolate mofetil 1 g twice daily for 6 months. This was then changed to azathioprine at 50 mg twice daily. Follow-up after 6 months showed sustained clearance of skin lesions, resolution of fever and joint pains, as well as improvement in the renal profile, with a urine protein-creatinine ratio of 0.77 g/g. The presence of systemic lupus erythematosus, EM-like lesions, and a speckled pattern of antinuclear antibody in our patient fulfils the revised diagnostic criteria for RS put forward by Zeitouni et al. at the turn of the twenty-first century (2). Considering the rarity of EM-like lesions in SLE and the possibility of constitutional symptoms in EM, a diagnosis of RS may be readily overlooked in patients like the one described, whose major cutaneous manifestation of severe active SLE was EM-like lesions. In contrast to classic EM, where skin lesions are concentrated in the extremities, a predominant truncal distribution of EM-like lesions as found in our patient may favor a clinical consideration of RS (3). However, some authors have challenged the existence of Rowell syndrome as a distinct clinical laboratory entity. Arguments put forward in this regard include the fact that none of the immunological markers that have been described in RS are specific to any disorder. Additionally, the annular polycyclic dermatosis seen in sub-acute cutaneous lupus erythematosus (SCLE) can be difficult to clinically and histologically differentiate from EM (4,5). Patients with SLE also have a higher likelihood of developing adverse drug reactions (6). The inherent complexity of SLE may make for delayed and oftentimes difficult diagnosis, especially in a country where immunologic tests are expensive and rheumatologists are scarce. When patients do occasionally present with recurrences of skin lesions in the spectrum of EM, Steven-Johnson syndrome, and toxic epidermal necrolysis in the absence of a definite inciting agent, undiagnosed lupus may indeed be present in some of these individuals and should be considered in the differential diagnosis. In conclusion, while it is very rare, SLE may present first with recurrent episodes of EM-like rash. Despite the various possibilities which underlie their association, prompt identification and treatment of SLE in patients presenting with EM is important to prevent death or irreversible organ damage. A 65-year-old woman developed erythema, papules and nodules over the body. Some nodules of her auricles and hands like string beads. Besides, she suffered from symmetrical swelling and pain of multiple joints, morning stiffness with deformity of joints; She had elevated erythrocyte sedimentation rate and C reactive protein levels; Her rheumatoid factor and antinuclear antibody were positive; Joints destruction was found with X-ray imaging; Skin pathology showed Dermal infiltrate of abundant histiocytes, part of them with a ground-glass appearance; A CD68 immunohistochemical stain was positive and the cells were negative for S100, CD1a. These findings were diagnostic evidences of multicentric reticulohistiocytosis (MRH). The patient received high-dose of glucocorticoids combinated with immunosuppressive agents, and achieved a satisfactory effect. MRH was a rare multisystem disease characterized by papulonodular mucocutaneous and destructive arthritis, and its pathogeny was not yet completely understood. The typical lesions of MRH were hard papules or nodules that usually occured on the hands, face and arms. Classic coral bead appearance from periungual cutaneous nodules that were characteristic of MRH. MRH was an inflammatory joint disease, affecting almost all the appendicular joints and characterized by joint multiple, symmetrical, destructive, progressive disability. Joints destruction of the distal interphalangeal joints was a unique feature of MRH. In addition to skin and joints, it could also involve other systems. There were no diagnostic laboratory markers for MRH. Laboratory examinations had often been found to be non-specific. Imageological examination mainly showed bone and joint destruction. Skin biopsy was the best test to diagnose MRH, the typical histopathological findings included an infiltrate with histiocytes and multinucleated giant cells with a ground-glass appearing in eosinophilic cytoplasm, and the immunohistochemical stain was positive for CD68. The diagnosis was typically made based on the clinical presentation, supportive radiographic findings and skin biopsy. MRH was easily possible to mistake for other more common autoimmune conditions, such as rheumatoid arthritis, psoriatic arthritis, osteoarthritis, and dermatomyositis, but the distinctive clinical, radiographic, and histologic features could aid in differentiating these diseases. MRH could mimic other rheumatic diseases, besides, it could also coexist with cancer or other autoimmune disorders. There was no standardized treatment for MRH. However, Nonsteroidal anti-inflammatory drugs, glucocorticoid, Immunosuppressant, biologic medications, and bisphosphonates had been used with varying degrees of curative effect. Treatment with glucocorticoid combined with immunosuppressants were effective for rash and arthritis, early use of them should be strongly considered, and refractory cases could be treated with biological agents. By reporting a MRH case and reviewing literature, this paper aims to help the clinicians improve the understanding of this rare disease, and suggests that when one diagnosis cannot explain the whole picture of the disease, and further evidence should be sought to confirm the diagnosis. A 78-year-old female patient was referred to our hospital with treatment-resistant seronegative anti-citrullinated protein antibodies (ACPA)-negative rheumatoid arthritis. The course was characterized by high inflammatory activity and rapid progression of the erosive changes. Under the required high-dose prednisolone therapy, osteoporosis and a deep venous thrombosis (DVT) with pulmonary embolism developed. A physical examination revealed symmetrical, painful, synovial swelling of the metacarpophalangeal, proximal-interphalangeal and distal-interphalangeal (MCP, PIP, and DIP) joints, finger joint-related violaceous erythema, contractures of the long fingers, and advanced deformities bilaterally. Pain and weakness in the muscles of her proximal extremities led to difficulties in raising her arms and climbing stairs. The results of laboratory tests showed negative RF (rheumatoid factor) and ACPAs, positive ANA (anti-nuclear antibodies) with titer 1:5120, a nuclear fluorescence pattern and a positive anti-Mi-2 Antibodies in the myositis blot. Conventional x-ray showed erosive and advanced mutilating joint changes in both hands. A magnetic resonance imaging (MRI) of the proximal extremities showed a pronounced muscle atrophy without sights of active myositis.This clinical constellation leads to the diagnosis of an amyopathic dermatomyositis. The patient was started on intravenous prednisone 100 mg daily, 4 days, followed by rapid dose tapering in the setting of accompanying risk factors such as Osteoporosis, arterial Hypertension and blurred vision. This treatment leads to improvement of symptoms. The basic therapy was switched to Rituximab. An extended tumor search was recommended on an outpatient basis. A seronegative, ACPA negative, therapy-resistant RA with a rapidly progressive erosive course requires a diagnostic re-evaluation. An erosive, rapidly progressing polyarthritis is commonly seen as manifestation of the subtype inflammatory myopathies associated with anti-Jo 1 antibodies, known as anti-synthetase syndrome. However, associations with the presence of other myositis specific antibodies (MSA) have been also described. The anti-Mi-2 Antibodies are highly specific for dermatomyositis (DM).Amyopathic DM is not common, but the disease course and prognosis do not differ significantly from myopathic DM.As a sudden presentation of DM may be of paraneoplastic origin a further examination in order to exclude malignancy are indicated. Diagnosis: Symptom complex suggestive of SLE Order laboratory tests: ANA, CBC, platelets, urinalysis All tests normal symptoms subside All tests normal symptoms persist ANA positive Not SLE Not SLE Treatment Repeat ANA, add anti-dsDNA, anti-Ro All negative Some positive Definite SLE (˜4 criteria, Table 378-3) Possible SLE (<4 criteria, Table 378-3) Not lifeor organ-threatening Lifeor organ-threatening Quality of life: Acceptable Quality of life: Not acceptable High-dose glucocorticoids, usually with addition of second agent Conservative manage-ment (Table 378-5) Conservative treatment plus low-dose glucocorticoids Consider belimumab Mycophenolate mofetil (or myfortic acid) Cyclophosphamide Low or high dose Do not exceed 6 months of Rx After response, d/c cyclophosphamide; maintain with mycophenolate or azathioprine No response Response Taper dose of all agents, especially glucocorticoids Belimumab, Rituximab, calcineurin inhibitors, or experimental therapies Dear Editor, Rowell's syndrome is a rare disease, characterized by the appearance of erythema multiforme (EM)-like lesions in patients with lupus erythematosus. It was initially reported by Rowell (1) in 1963 and its existence as a separate clinical entity is currently under debate (2,3). A few cases may have been induced by drugs such as systemic antimycotics, antibiotics, anticonvulsants, and more recently proton pump inhibitors (PPIs). CASE REPORT We present the case of a 67-year-old woman with subacute cutaneous lupus erythematosus (SCLE) and EM-like lesions who fulfilled all the criteria for Rowell's syndrome. The patient had lupus arthritis for two years and was treated with oral methylprednisolone 8 mg/day and hydroxychloroquine 200 mg/day. She started receiving 20 mg of omeprazole daily for gastroprotection. The patient also had arterial hypertension with no current treatment, osteoporosis, and an L1 vertebral fracture. The dermatological examination revealed multiple erythematous infiltrated plaques involving mainly the sun-exposed areas (neck, chest, upper back, and shoulders). Cutaneous lesions had an annular or target pattern and a tendency to form hemorrhagic crusts and scales at the margins (Figure 1, A). The mucous membranes were unaffected. Histological examination (hematoxylin and eosin ×200) found epidermal atrophy, vacuolar degeneration of the basal layer, and sparse perivascular lymphocytic infiltrate in the dermis - features corresponding to lupus erythematosus (Figure 2, A). Single eosinophilic necrotic keratinocytes characteristic for erythema multiforme were observed in the epidermis (Figure 2, B). Direct immunofluorescence (IF) from lesional skin showed granular deposits of C3 on the dermo-epidermal junction. Lupus band test from sun-protected, nonlesional skin was negative. On indirect IF a speckled pattern antinuclear antibodies (ANA) with &gt;1:1280 titers were detected. Anti-Ro (&gt;200 U/mL) and anti-La (&gt;200 U/mL) antibodies were also positive. The blood cell count and differential analysis were within reference ranges. The 24-hour urine protein test showed a non-significant proteinuria - 0.36 g/24h. Photo-testing was impossible considering the extent of the skin lesions. The therapeutic approach consisted of increasing the hydroxychloroquine dose to 400 mg/day, substituting PPI with famotidine 20 mg/day p.o. and ceftriaxone 2 g/day for the superinfection with Ps. aeruginosa, which led to a clinical improvement (Figure 1, B). The methylprednisolone dose remained unchanged due to already existing severe adverse effects. DISCUSSION The diagnosis was based on Zeitouni et al.'s classification (4). The three main criteria are as follows: lupus erythematosus, EM-like lesions, and speckled pattern of ANA. Our patient met all three major and one minor criteria, namely the presence of anti-Ro and anti-La antibodies. As for the other minor criteria, RF was negative and no chilblains were found. Although there was a continuous time lapse (more than 1 year) between the initiation of omeprazole intake and the diagnosis of Rowell's syndrome, we suggest that the connection is probable. For instance, the latency differs depending on the incriminated medication in drug induced SCLE. Longer periods are reported for diuretics and calcium blockers, while the time interval is shorter for chemotherapeutic drugs and antimycotics (5). Our suspicions were further confirmed by the fact that the lesions improved promptly within a month after discontinuation of omeprazole and doubling the dose of hydroxychloroquine. PPIs are reported to be a major cause of drug-induced SCLE (6,7). According to Laurinaviciene et al., the most common drugs involved are PPIs, thiazide diuretics, antifungals, chemotherapeutics, statins, and antiepileptics (6). However, very few cases of Rowell's syndrome are found to be drug-related. The culprit drugs include: oral terbinafine (8,9), norfloxacin (10), sodium valproate (11) and esomeprazole (12) (Table 1). CONCLUSION Despite the common clinical and immunological features shared between SCLE, drug-induced SCLE and EM, Rowell's syndrome seems to be a separate entity rather than a coincidental association. Finally, according to our knowledge this case would be the second of Rowell's syndrome due to PPIs. Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder. The exact pathogenesis is unknown but believed to have multiple etiologies. The Yamaguchi criteria are used to aid in the diagnosis of AOSD. Typical characteristics are spiking fevers, febrile rash, arthritis, and the absence of other serologic markers of rheumatic diseases. We present a case of a 31-year-old Hispanic female who presented with fevers, arthritis, febrile rash, high ferritin levels, and cervical and axillary lymphadenopathies. The unique feature of our case is that the patient was positive for antinuclear antibody (ANA) titers of greater than 1:640 and anti-Ro antibody. She responded with the pulse dose steroids and later prescribed methotrexate and tapered off prednisone with improvement in her symptoms. Eosinophilic fasciitis is a rare disease from the group of scleroderma-like connective tissue diseases with unclear etiopathogenesis. It may be occasionally accompanied with other eosinophilic or autoimmune dysfunctions (1,2). Lack of international diagnostic criteria and treatment consensus may lead to diagnostic and therapeutic difficulties. The 61-year-old man with no significant personal or family pathological history was admitted to the Dermatology Department presenting persistent induration for several months as well as erythema and pain of the shins that gradually extended to thighs and forearms, with limited mobility of peripheral joints. (Figure 1) Additional tests showed leukocytosis with 16% eosinophilia, elevated CRP, and hypergammaglobulinemia. Borrelia burgdorferi antibodies (classes IgM and IgG) were negative twice. A biopsy that included deep fascia was taken for histopathological examination. Antinuclear antibody screening was negative, but the direct immunofluorescence showed complexes in the dermo-epidermal junction and around the vessels. The diagnostics conducted toward malignant process showed no disturbing abnormalities (i.e. tumor markers in serum, chest, and abdomen computed tomography imaging, panendoscopy). The treatment was carried out with cephalosporin and nonsteroidal anti-inflammatory drugs (NSAIDs). The condition did not improve much but was stable. Histopathological results were indicative of eosinophilic fasciitis with fibrous thickening of deep fascia and perivascular infiltrations of plasma cells and lymphocytes; oral prednisone was initiated and the condition begin to improve. After 12 weeks, we observed disease progression with fever and very hard and cyanic skin lesions, which presented as an orange peel with linear furrows over the superficial venous vessels (Figure 2). The lesions extended to the trunk and caused troubles in moving. A complex rehabilitative intervention was started to minimize the inflammatory fascial restrictions. The prednisolone dose was increased, and oral methotrexate was added. After two weeks, the patient suffered from abdominal pain and periodic bleeding diarrhea. Methotrexate was suspected of inducing gastrointestinal adverse effects, and antipyretic NSAIDs were completely withdrawn. Colonoscopy showed features of mucosal edema with erythema, and histopathological examination revealed eosinophilic colitis. The patient was referred to a gastroenterologist, and methotrexate was ceased and switched to azathioprine. In summary, the consensus therapy of the rheumatologist, dermatologist, and gastroenterologist consisted of prednisolone and azathioprine. As of this writing, the patient's condition is gradually improving. The most characteristic symptoms of eosinophilic fasciitis is sudden onset with induration, sclerosis, and pain of the skin, with subcutaneous tissue and fascia usually appearing on the upper and lower limbs (3,4). The skin surface forms a characteristic orange peel appearance. The \"groove\" sign refers to the linear furrows over the superficial vessels of the extremities (1). Typical abnormalities are eosinophilia, elevated CRP, and hypergammaglobulinemia. The presence of eosinophilia is the most characteristic feature, occurring in 60-93% cases, but it is not necessary for diagnosis (1,5). Antinuclear antibodies are commonly absent with positive lesional direct immunofluorescence (6). If antinuclear antibodies are positive, it is recommended to broaden the diagnostic process to include other connective tissue diseases. Eosinophilia must be differentiated from hematological disorders and paraneoplastic syndrome. (4,6). Eosinophilic colitis is an eosinophilic gastrointestinal disease (EGID). It is the least frequent manifestation of EGID. It may be associated with connective tissue diseases, mostly systemic sclerosis - to our knowledge, there is no information in the literature about coexisting eosinophilic fasciitis. (7,8). The case described herein demonstrated that such a connection may occur. In treatment, it is important to prevent the patient from contractures and to maintain joint mobility by appropriate physiotherapy (2,9). The fascia forms a functional integral and continuous structure. Inflammation of one part of it changes the elasticity of the whole and produces fascial restrictions with movement limitation and pain. The fascia is profusely innervated, which favors constriction as a result of inflammation, and is also poorly vascularized which disrupts its regeneration (9,10). Myofascial techniques improve fascia elasticity by breaking up the tissue adhesions caused by inflammation (11). Eosinophilic fasciitis is a rare clinical entity, but knowing the possible clinical symptoms and laboratory abnormalities should help in taking the appropriate diagnostic path. It is important to treat the patient with attention to all concomitant diseases in consultation with different specialists. Several developments during the past two decades have changed the therapeutic landscape in RA. They include (1) the emergence of methotrexate as the disease-modifying antirheumatic drug (DMARD) of first choice for the treatment of early RA; (2) the development of novel highly efficacious biologicals that can be used alone or in combination with methotrexate; and (3) the proven superiority of combination DMARD regimens over methotrexate alone. The medications used for the treatment of RA may be divided into broad categories: nonsteroidal anti-inflammatory drugs (NSAIDs); glucocorticoids, such as prednisone and methylprednisolone; conventional DMARDs; and biologic DMARDs (Table 380-2). Although disease for some patients with RA is managed adequately with a single DMARD, such as methotrexate, the situation in most cases demands the use of a combination DMARD regimen that may vary in its components over the treatment course depending on fluctuations in disease activity and emergence of Enzyme-linked immunosorbent assay (ELISA) ELISA for bullous pemphigoid are commercially available to test for circulating Ig against NC16A domain of BP180 and BP230, known as bullous pemphigoid antigen 2 [BPAg2] and bullous pemphigoid antigen 1 [BPAg1] respectively. Antibodies to BP180NC16A domain is useful for the diagnosis of bullous pemphigoid as it has a sensitivity of 89% and specificity of 98%. Detection of BP180 and/or BP230 antibodies in serum does not give a confirmative diagnosis of bullous pemphigoid. A study has reported that 7% were tested positive for one or both autoantibodies in one series of 337 people without bullous pemphigoid. ELISA findings should be correlated with DIF to reduce the risk of misdiagnosis. Treatment The treatment for bullous pemphigoid include: 1. Corticosteroids i. Topical Corticosteroids ii. Systemic corticosteroids 2. Glucocorticoid-sparing drugs i. Immunosuppressive drugs ii. Anti-inflammatory drugs 3. Biologic therapy Treatment Treatment with either glucocorticoids, methotrexate, anakinra, or tocilizumab has been examined. Anakinra has been shown to resolve the clinical features of the disease in 87% of patients. It also induces remission in half of corticosteroid-resistant patients. The results of another study were similar, with half of the patients responding to treatment with Anakinra. Canakinumab, an antibody to interleukin-1 beta, is indicated for treatment in patients who respond poorly to other treatments. Prognosis 25% of cases progress to severe destructive arthritis. In the United States, mortality is estimated at about 4% and in Europe, mortality is estimated at 21.7%. History Still's disease is named after English physician Sir George Frederic Still (1861–1941). It was characterized by EG Bywaters in 1971. References External links Arthritis Pediatrics Rheumatology Connective tissue diseases Inflammatory polyarthropathies Idiopathic diseases Rare diseases Classification On the basis of detected autoantibodies, autoimmune hepatitis can be classified into three subtypes but have no distinct clinical presentations. Type 1 autoimmune hepatitis. Positive antibodies include: Antinuclear antibody (ANA) Anti-smooth muscle antibody (ASMA) - 65% of people Anti-actin antibodies Anti-mitochondrial antibodies - rare except for overlap syndromes with primary biliary cholangitis Anti-soluble liver antigen/liver pancreas antibody antigen - 20% of people Anti-double stranded DNA - 30% of people Atypical perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) Type 2 autoimmune hepatitis. Positive antibodies include: Liver Kidney Microsomal antibody (LKM-1) Anti-liver cytosol antibody-1 (SLC-1) Autoantibody negative autoimmune hepatitis. Lack positive ANA, ASMA, LKM-1, etc. antibody panels but present with clinical features of autoimmune hepatitis that resolve with standard treatment. FIGUrE 390-10 Approach to chronic disease is based on whether glucocorticoid therapy is tolerated or not. Hydroxychloroquine 200–400 mg qd 400 mg qd Eye exam q6–12 mo Ocular B: Some forms of D: Routine eye exam disease Azathioprine 50–150 mg qd 50–200 mg qd CBC, renal q2mo Hematologic, nausea C: Some forms D: Routine hematologic chronic disease monitoring Abbreviations: CBC, complete blood count; PPD, purified protein derivative test for tuberculosis. Source: Adapted from RP Baughman, O Selroos: Evidence-based approach to treatment of sarcoidosis, in PG Gibson et al (eds): Evidence-Based Respiratory Medicine. Oxford, BMJ Books Blackwell, 2005, pp 491–508.\nHere is the question:\nRHEUMATOLOGY: A 37-year-old man presents with arthritis of the metacarpophalangeal joints of both hands and right pleuritis. Bilateral malar erythema is seen on examination. Positive antinuclear antibodies were detected (titer 1/640), with anti native DNA antibodies also positive; anti-Sm negative What would be the initial treatment of choice for this patient?\nHere are the potential choices:\n1. Glucocorticoids at high doses.\n2. Glucocorticoids and mycophenolate.\n3. Nonsteroidal anti-inflammatory drugs and antimalarials.\n4. The picture will probably be self-limited and does not require treatment.\nThe correct answer is: ",
        "gold_answer": "1 Glucocorticoids at high doses.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n We report two cases of rheumatoid arthritis (RA) who later had developed after polymyositis (PM). The first patient was 64-year old male who experienced muscular weakness of the four limbs in proximity 10 years ago. He was diagnosed as PM because of the elevated serum CK and the myogenic pattern of EMG, and his symptoms were improved by treatment with corticosteroid. He started to complain polyarthralgia 2 years ago, followed by interstitial pneumonia, pleuritis and skin ulcer. He was admitted because of exacerbated polyarthralgia, multiple subcutaneous nodules, skin eruption and fever. The level of serum CK was within normal range but CRP was elevated and CH 50 was decreased. The laboratory examination showed positive cryoglobulin and high titer of rheumatoid factor, but anti-Jo 1 antibody was negative. The hand X-ray showed bone erosions in bilateral wrist joints. Skin biopsy revealed leukocytoclastic vasculitis. Based on these findings, he was diagnosed as malignant RA. He was successfully treated with methylprednisolone pulse therapy, cyclophosphamide and prostaglandin E 1. The second patient was 77-year old male with pneumoconiosis who experienced muscular weakness of the four limbs in proximity 4 years ago. He was diagnosed as PM based on his clinical and laboratory findings and was treated with temporary corticosteroid. He started to have polyarthralgia last year, and he was admitted because of increasing arthralgia after the treatment of pulmonary tuberculosis. The level of serum CK was slightly elevated due to hypothyroidism, and CRP was highly elevated. Rheumatoid factor and cryoglobulin were positive, but anti-Jo 1 antibody was negative. The hand X-ray showed bone erosions in bilateral wrist joints. Crystals of pyrophosphate calcium was observed in knee joints. He was diagnosed as RA associate with pseudogout. His symptoms were relieved with corticosteroid, salazosulfapyridine and anti-tuberculous therapy. These two cases had altered their clinical features from PM to definite RA, and both had pulmonary complications. Previous reports described the cases of RA followed by PM, most of which were induced by such drugs as D-penicillamine, but the cases of PM who later had developed RA are extremely unusual. The overlapped cases of RA and PM tend to highly associate with pulmonary lesions. Dear Editor, Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by diverse patterns of auto-antibody production with multi-organ affectation. Cutaneous involvement, either alone or in association with other systemic illnesses, is one of its most common manifestations (1). Dermatologic disorders like malar and discoid rashes are quite suggestive of SLE. However, the occurrence of non-specific skin lesions like erythema multiforme (EM) in patients with SLE (Rowell syndrome) can rarely occur (1). In such patients, a diagnosis of SLE may be missed or delayed in the absence of other overt clinical features of lupus. Herein we report a case of recurring EM-like eruptions as the cardinal cutaneous manifestation of previously undiagnosed, active SLE in a young Nigerian woman. A 26-year-old Nigerian woman presented with a three-day history of non-pruritic, generalized, and target-like, erythematous annular patches and plaques which mostly affected the trunk. A few lesions had presented with crusting and erosions at the time of examination (Figure 1). Associated symptoms included oral painful ulcers, low grade fever, and malaise. The patient had no other systemic symptoms and her prior drug history was not remarkable. Her erythrocyte sedimentation rate (ESR) was 66 mm/hour using the Westergren method. Screening for HIV and hepatitis B and C was negative. Herpes simplex, cytomegalovirus, and Epstein Barr viruses could not be screened for. Other baseline investigations (complete blood count, electrolytes, urea and creatinine as well as urinalysis) were within normal limits. The patient was managed as a case of EM of an unidentified inciting agent and her symptoms resolved with supportive care and antibiotics. However, she developed a recurrence about 5 weeks later, with more extensive and coalescent skin lesions (Figure 2). Additionally, there was a new onset of alopecia and pain in the small joints of the hands as well as both knees and ankles. At this time, the patient's ESR had gone up to 112 mm/h and she had developed significant proteinuria, with a protein creatinine ratio of 1.3 g/g (reference &lt;0.5 g/g). Her antinuclear antibody (ANA) titer was high (1:320) with a speckled pattern. Anti-Smith antibody was also positive. A renal biopsy was declined. A tentative diagnosis of Rowell syndrome was made. The patient was started on high-dose steroids and hydroxychloroquine 200 mg twice daily. Subsequent care included the use of mycophenolate mofetil 1 g twice daily for 6 months. This was then changed to azathioprine at 50 mg twice daily. Follow-up after 6 months showed sustained clearance of skin lesions, resolution of fever and joint pains, as well as improvement in the renal profile, with a urine protein-creatinine ratio of 0.77 g/g. The presence of systemic lupus erythematosus, EM-like lesions, and a speckled pattern of antinuclear antibody in our patient fulfils the revised diagnostic criteria for RS put forward by Zeitouni et al. at the turn of the twenty-first century (2). Considering the rarity of EM-like lesions in SLE and the possibility of constitutional symptoms in EM, a diagnosis of RS may be readily overlooked in patients like the one described, whose major cutaneous manifestation of severe active SLE was EM-like lesions. In contrast to classic EM, where skin lesions are concentrated in the extremities, a predominant truncal distribution of EM-like lesions as found in our patient may favor a clinical consideration of RS (3). However, some authors have challenged the existence of Rowell syndrome as a distinct clinical laboratory entity. Arguments put forward in this regard include the fact that none of the immunological markers that have been described in RS are specific to any disorder. Additionally, the annular polycyclic dermatosis seen in sub-acute cutaneous lupus erythematosus (SCLE) can be difficult to clinically and histologically differentiate from EM (4,5). Patients with SLE also have a higher likelihood of developing adverse drug reactions (6). The inherent complexity of SLE may make for delayed and oftentimes difficult diagnosis, especially in a country where immunologic tests are expensive and rheumatologists are scarce. When patients do occasionally present with recurrences of skin lesions in the spectrum of EM, Steven-Johnson syndrome, and toxic epidermal necrolysis in the absence of a definite inciting agent, undiagnosed lupus may indeed be present in some of these individuals and should be considered in the differential diagnosis. In conclusion, while it is very rare, SLE may present first with recurrent episodes of EM-like rash. Despite the various possibilities which underlie their association, prompt identification and treatment of SLE in patients presenting with EM is important to prevent death or irreversible organ damage. A 65-year-old woman developed erythema, papules and nodules over the body. Some nodules of her auricles and hands like string beads. Besides, she suffered from symmetrical swelling and pain of multiple joints, morning stiffness with deformity of joints; She had elevated erythrocyte sedimentation rate and C reactive protein levels; Her rheumatoid factor and antinuclear antibody were positive; Joints destruction was found with X-ray imaging; Skin pathology showed Dermal infiltrate of abundant histiocytes, part of them with a ground-glass appearance; A CD68 immunohistochemical stain was positive and the cells were negative for S100, CD1a. These findings were diagnostic evidences of multicentric reticulohistiocytosis (MRH). The patient received high-dose of glucocorticoids combinated with immunosuppressive agents, and achieved a satisfactory effect. MRH was a rare multisystem disease characterized by papulonodular mucocutaneous and destructive arthritis, and its pathogeny was not yet completely understood. The typical lesions of MRH were hard papules or nodules that usually occured on the hands, face and arms. Classic coral bead appearance from periungual cutaneous nodules that were characteristic of MRH. MRH was an inflammatory joint disease, affecting almost all the appendicular joints and characterized by joint multiple, symmetrical, destructive, progressive disability. Joints destruction of the distal interphalangeal joints was a unique feature of MRH. In addition to skin and joints, it could also involve other systems. There were no diagnostic laboratory markers for MRH. Laboratory examinations had often been found to be non-specific. Imageological examination mainly showed bone and joint destruction. Skin biopsy was the best test to diagnose MRH, the typical histopathological findings included an infiltrate with histiocytes and multinucleated giant cells with a ground-glass appearing in eosinophilic cytoplasm, and the immunohistochemical stain was positive for CD68. The diagnosis was typically made based on the clinical presentation, supportive radiographic findings and skin biopsy. MRH was easily possible to mistake for other more common autoimmune conditions, such as rheumatoid arthritis, psoriatic arthritis, osteoarthritis, and dermatomyositis, but the distinctive clinical, radiographic, and histologic features could aid in differentiating these diseases. MRH could mimic other rheumatic diseases, besides, it could also coexist with cancer or other autoimmune disorders. There was no standardized treatment for MRH. However, Nonsteroidal anti-inflammatory drugs, glucocorticoid, Immunosuppressant, biologic medications, and bisphosphonates had been used with varying degrees of curative effect. Treatment with glucocorticoid combined with immunosuppressants were effective for rash and arthritis, early use of them should be strongly considered, and refractory cases could be treated with biological agents. By reporting a MRH case and reviewing literature, this paper aims to help the clinicians improve the understanding of this rare disease, and suggests that when one diagnosis cannot explain the whole picture of the disease, and further evidence should be sought to confirm the diagnosis. A 78-year-old female patient was referred to our hospital with treatment-resistant seronegative anti-citrullinated protein antibodies (ACPA)-negative rheumatoid arthritis. The course was characterized by high inflammatory activity and rapid progression of the erosive changes. Under the required high-dose prednisolone therapy, osteoporosis and a deep venous thrombosis (DVT) with pulmonary embolism developed. A physical examination revealed symmetrical, painful, synovial swelling of the metacarpophalangeal, proximal-interphalangeal and distal-interphalangeal (MCP, PIP, and DIP) joints, finger joint-related violaceous erythema, contractures of the long fingers, and advanced deformities bilaterally. Pain and weakness in the muscles of her proximal extremities led to difficulties in raising her arms and climbing stairs. The results of laboratory tests showed negative RF (rheumatoid factor) and ACPAs, positive ANA (anti-nuclear antibodies) with titer 1:5120, a nuclear fluorescence pattern and a positive anti-Mi-2 Antibodies in the myositis blot. Conventional x-ray showed erosive and advanced mutilating joint changes in both hands. A magnetic resonance imaging (MRI) of the proximal extremities showed a pronounced muscle atrophy without sights of active myositis.This clinical constellation leads to the diagnosis of an amyopathic dermatomyositis. The patient was started on intravenous prednisone 100 mg daily, 4 days, followed by rapid dose tapering in the setting of accompanying risk factors such as Osteoporosis, arterial Hypertension and blurred vision. This treatment leads to improvement of symptoms. The basic therapy was switched to Rituximab. An extended tumor search was recommended on an outpatient basis. A seronegative, ACPA negative, therapy-resistant RA with a rapidly progressive erosive course requires a diagnostic re-evaluation. An erosive, rapidly progressing polyarthritis is commonly seen as manifestation of the subtype inflammatory myopathies associated with anti-Jo 1 antibodies, known as anti-synthetase syndrome. However, associations with the presence of other myositis specific antibodies (MSA) have been also described. The anti-Mi-2 Antibodies are highly specific for dermatomyositis (DM).Amyopathic DM is not common, but the disease course and prognosis do not differ significantly from myopathic DM.As a sudden presentation of DM may be of paraneoplastic origin a further examination in order to exclude malignancy are indicated. Diagnosis: Symptom complex suggestive of SLE Order laboratory tests: ANA, CBC, platelets, urinalysis All tests normal symptoms subside All tests normal symptoms persist ANA positive Not SLE Not SLE Treatment Repeat ANA, add anti-dsDNA, anti-Ro All negative Some positive Definite SLE (˜4 criteria, Table 378-3) Possible SLE (<4 criteria, Table 378-3) Not lifeor organ-threatening Lifeor organ-threatening Quality of life: Acceptable Quality of life: Not acceptable High-dose glucocorticoids, usually with addition of second agent Conservative manage-ment (Table 378-5) Conservative treatment plus low-dose glucocorticoids Consider belimumab Mycophenolate mofetil (or myfortic acid) Cyclophosphamide Low or high dose Do not exceed 6 months of Rx After response, d/c cyclophosphamide; maintain with mycophenolate or azathioprine No response Response Taper dose of all agents, especially glucocorticoids Belimumab, Rituximab, calcineurin inhibitors, or experimental therapies Dear Editor, Rowell's syndrome is a rare disease, characterized by the appearance of erythema multiforme (EM)-like lesions in patients with lupus erythematosus. It was initially reported by Rowell (1) in 1963 and its existence as a separate clinical entity is currently under debate (2,3). A few cases may have been induced by drugs such as systemic antimycotics, antibiotics, anticonvulsants, and more recently proton pump inhibitors (PPIs). CASE REPORT We present the case of a 67-year-old woman with subacute cutaneous lupus erythematosus (SCLE) and EM-like lesions who fulfilled all the criteria for Rowell's syndrome. The patient had lupus arthritis for two years and was treated with oral methylprednisolone 8 mg/day and hydroxychloroquine 200 mg/day. She started receiving 20 mg of omeprazole daily for gastroprotection. The patient also had arterial hypertension with no current treatment, osteoporosis, and an L1 vertebral fracture. The dermatological examination revealed multiple erythematous infiltrated plaques involving mainly the sun-exposed areas (neck, chest, upper back, and shoulders). Cutaneous lesions had an annular or target pattern and a tendency to form hemorrhagic crusts and scales at the margins (Figure 1, A). The mucous membranes were unaffected. Histological examination (hematoxylin and eosin ×200) found epidermal atrophy, vacuolar degeneration of the basal layer, and sparse perivascular lymphocytic infiltrate in the dermis - features corresponding to lupus erythematosus (Figure 2, A). Single eosinophilic necrotic keratinocytes characteristic for erythema multiforme were observed in the epidermis (Figure 2, B). Direct immunofluorescence (IF) from lesional skin showed granular deposits of C3 on the dermo-epidermal junction. Lupus band test from sun-protected, nonlesional skin was negative. On indirect IF a speckled pattern antinuclear antibodies (ANA) with &gt;1:1280 titers were detected. Anti-Ro (&gt;200 U/mL) and anti-La (&gt;200 U/mL) antibodies were also positive. The blood cell count and differential analysis were within reference ranges. The 24-hour urine protein test showed a non-significant proteinuria - 0.36 g/24h. Photo-testing was impossible considering the extent of the skin lesions. The therapeutic approach consisted of increasing the hydroxychloroquine dose to 400 mg/day, substituting PPI with famotidine 20 mg/day p.o. and ceftriaxone 2 g/day for the superinfection with Ps. aeruginosa, which led to a clinical improvement (Figure 1, B). The methylprednisolone dose remained unchanged due to already existing severe adverse effects. DISCUSSION The diagnosis was based on Zeitouni et al.'s classification (4). The three main criteria are as follows: lupus erythematosus, EM-like lesions, and speckled pattern of ANA. Our patient met all three major and one minor criteria, namely the presence of anti-Ro and anti-La antibodies. As for the other minor criteria, RF was negative and no chilblains were found. Although there was a continuous time lapse (more than 1 year) between the initiation of omeprazole intake and the diagnosis of Rowell's syndrome, we suggest that the connection is probable. For instance, the latency differs depending on the incriminated medication in drug induced SCLE. Longer periods are reported for diuretics and calcium blockers, while the time interval is shorter for chemotherapeutic drugs and antimycotics (5). Our suspicions were further confirmed by the fact that the lesions improved promptly within a month after discontinuation of omeprazole and doubling the dose of hydroxychloroquine. PPIs are reported to be a major cause of drug-induced SCLE (6,7). According to Laurinaviciene et al., the most common drugs involved are PPIs, thiazide diuretics, antifungals, chemotherapeutics, statins, and antiepileptics (6). However, very few cases of Rowell's syndrome are found to be drug-related. The culprit drugs include: oral terbinafine (8,9), norfloxacin (10), sodium valproate (11) and esomeprazole (12) (Table 1). CONCLUSION Despite the common clinical and immunological features shared between SCLE, drug-induced SCLE and EM, Rowell's syndrome seems to be a separate entity rather than a coincidental association. Finally, according to our knowledge this case would be the second of Rowell's syndrome due to PPIs. Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder. The exact pathogenesis is unknown but believed to have multiple etiologies. The Yamaguchi criteria are used to aid in the diagnosis of AOSD. Typical characteristics are spiking fevers, febrile rash, arthritis, and the absence of other serologic markers of rheumatic diseases. We present a case of a 31-year-old Hispanic female who presented with fevers, arthritis, febrile rash, high ferritin levels, and cervical and axillary lymphadenopathies. The unique feature of our case is that the patient was positive for antinuclear antibody (ANA) titers of greater than 1:640 and anti-Ro antibody. She responded with the pulse dose steroids and later prescribed methotrexate and tapered off prednisone with improvement in her symptoms. Eosinophilic fasciitis is a rare disease from the group of scleroderma-like connective tissue diseases with unclear etiopathogenesis. It may be occasionally accompanied with other eosinophilic or autoimmune dysfunctions (1,2). Lack of international diagnostic criteria and treatment consensus may lead to diagnostic and therapeutic difficulties. The 61-year-old man with no significant personal or family pathological history was admitted to the Dermatology Department presenting persistent induration for several months as well as erythema and pain of the shins that gradually extended to thighs and forearms, with limited mobility of peripheral joints. (Figure 1) Additional tests showed leukocytosis with 16% eosinophilia, elevated CRP, and hypergammaglobulinemia. Borrelia burgdorferi antibodies (classes IgM and IgG) were negative twice. A biopsy that included deep fascia was taken for histopathological examination. Antinuclear antibody screening was negative, but the direct immunofluorescence showed complexes in the dermo-epidermal junction and around the vessels. The diagnostics conducted toward malignant process showed no disturbing abnormalities (i.e. tumor markers in serum, chest, and abdomen computed tomography imaging, panendoscopy). The treatment was carried out with cephalosporin and nonsteroidal anti-inflammatory drugs (NSAIDs). The condition did not improve much but was stable. Histopathological results were indicative of eosinophilic fasciitis with fibrous thickening of deep fascia and perivascular infiltrations of plasma cells and lymphocytes; oral prednisone was initiated and the condition begin to improve. After 12 weeks, we observed disease progression with fever and very hard and cyanic skin lesions, which presented as an orange peel with linear furrows over the superficial venous vessels (Figure 2). The lesions extended to the trunk and caused troubles in moving. A complex rehabilitative intervention was started to minimize the inflammatory fascial restrictions. The prednisolone dose was increased, and oral methotrexate was added. After two weeks, the patient suffered from abdominal pain and periodic bleeding diarrhea. Methotrexate was suspected of inducing gastrointestinal adverse effects, and antipyretic NSAIDs were completely withdrawn. Colonoscopy showed features of mucosal edema with erythema, and histopathological examination revealed eosinophilic colitis. The patient was referred to a gastroenterologist, and methotrexate was ceased and switched to azathioprine. In summary, the consensus therapy of the rheumatologist, dermatologist, and gastroenterologist consisted of prednisolone and azathioprine. As of this writing, the patient's condition is gradually improving. The most characteristic symptoms of eosinophilic fasciitis is sudden onset with induration, sclerosis, and pain of the skin, with subcutaneous tissue and fascia usually appearing on the upper and lower limbs (3,4). The skin surface forms a characteristic orange peel appearance. The \"groove\" sign refers to the linear furrows over the superficial vessels of the extremities (1). Typical abnormalities are eosinophilia, elevated CRP, and hypergammaglobulinemia. The presence of eosinophilia is the most characteristic feature, occurring in 60-93% cases, but it is not necessary for diagnosis (1,5). Antinuclear antibodies are commonly absent with positive lesional direct immunofluorescence (6). If antinuclear antibodies are positive, it is recommended to broaden the diagnostic process to include other connective tissue diseases. Eosinophilia must be differentiated from hematological disorders and paraneoplastic syndrome. (4,6). Eosinophilic colitis is an eosinophilic gastrointestinal disease (EGID). It is the least frequent manifestation of EGID. It may be associated with connective tissue diseases, mostly systemic sclerosis - to our knowledge, there is no information in the literature about coexisting eosinophilic fasciitis. (7,8). The case described herein demonstrated that such a connection may occur. In treatment, it is important to prevent the patient from contractures and to maintain joint mobility by appropriate physiotherapy (2,9). The fascia forms a functional integral and continuous structure. Inflammation of one part of it changes the elasticity of the whole and produces fascial restrictions with movement limitation and pain. The fascia is profusely innervated, which favors constriction as a result of inflammation, and is also poorly vascularized which disrupts its regeneration (9,10). Myofascial techniques improve fascia elasticity by breaking up the tissue adhesions caused by inflammation (11). Eosinophilic fasciitis is a rare clinical entity, but knowing the possible clinical symptoms and laboratory abnormalities should help in taking the appropriate diagnostic path. It is important to treat the patient with attention to all concomitant diseases in consultation with different specialists. Several developments during the past two decades have changed the therapeutic landscape in RA. They include (1) the emergence of methotrexate as the disease-modifying antirheumatic drug (DMARD) of first choice for the treatment of early RA; (2) the development of novel highly efficacious biologicals that can be used alone or in combination with methotrexate; and (3) the proven superiority of combination DMARD regimens over methotrexate alone. The medications used for the treatment of RA may be divided into broad categories: nonsteroidal anti-inflammatory drugs (NSAIDs); glucocorticoids, such as prednisone and methylprednisolone; conventional DMARDs; and biologic DMARDs (Table 380-2). Although disease for some patients with RA is managed adequately with a single DMARD, such as methotrexate, the situation in most cases demands the use of a combination DMARD regimen that may vary in its components over the treatment course depending on fluctuations in disease activity and emergence of Enzyme-linked immunosorbent assay (ELISA) ELISA for bullous pemphigoid are commercially available to test for circulating Ig against NC16A domain of BP180 and BP230, known as bullous pemphigoid antigen 2 [BPAg2] and bullous pemphigoid antigen 1 [BPAg1] respectively. Antibodies to BP180NC16A domain is useful for the diagnosis of bullous pemphigoid as it has a sensitivity of 89% and specificity of 98%. Detection of BP180 and/or BP230 antibodies in serum does not give a confirmative diagnosis of bullous pemphigoid. A study has reported that 7% were tested positive for one or both autoantibodies in one series of 337 people without bullous pemphigoid. ELISA findings should be correlated with DIF to reduce the risk of misdiagnosis. Treatment The treatment for bullous pemphigoid include: 1. Corticosteroids i. Topical Corticosteroids ii. Systemic corticosteroids 2. Glucocorticoid-sparing drugs i. Immunosuppressive drugs ii. Anti-inflammatory drugs 3. Biologic therapy Treatment Treatment with either glucocorticoids, methotrexate, anakinra, or tocilizumab has been examined. Anakinra has been shown to resolve the clinical features of the disease in 87% of patients. It also induces remission in half of corticosteroid-resistant patients. The results of another study were similar, with half of the patients responding to treatment with Anakinra. Canakinumab, an antibody to interleukin-1 beta, is indicated for treatment in patients who respond poorly to other treatments. Prognosis 25% of cases progress to severe destructive arthritis. In the United States, mortality is estimated at about 4% and in Europe, mortality is estimated at 21.7%. History Still's disease is named after English physician Sir George Frederic Still (1861–1941). It was characterized by EG Bywaters in 1971. References External links Arthritis Pediatrics Rheumatology Connective tissue diseases Inflammatory polyarthropathies Idiopathic diseases Rare diseases Classification On the basis of detected autoantibodies, autoimmune hepatitis can be classified into three subtypes but have no distinct clinical presentations. Type 1 autoimmune hepatitis. Positive antibodies include: Antinuclear antibody (ANA) Anti-smooth muscle antibody (ASMA) - 65% of people Anti-actin antibodies Anti-mitochondrial antibodies - rare except for overlap syndromes with primary biliary cholangitis Anti-soluble liver antigen/liver pancreas antibody antigen - 20% of people Anti-double stranded DNA - 30% of people Atypical perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) Type 2 autoimmune hepatitis. Positive antibodies include: Liver Kidney Microsomal antibody (LKM-1) Anti-liver cytosol antibody-1 (SLC-1) Autoantibody negative autoimmune hepatitis. Lack positive ANA, ASMA, LKM-1, etc. antibody panels but present with clinical features of autoimmune hepatitis that resolve with standard treatment. FIGUrE 390-10 Approach to chronic disease is based on whether glucocorticoid therapy is tolerated or not. Hydroxychloroquine 200–400 mg qd 400 mg qd Eye exam q6–12 mo Ocular B: Some forms of D: Routine eye exam disease Azathioprine 50–150 mg qd 50–200 mg qd CBC, renal q2mo Hematologic, nausea C: Some forms D: Routine hematologic chronic disease monitoring Abbreviations: CBC, complete blood count; PPD, purified protein derivative test for tuberculosis. Source: Adapted from RP Baughman, O Selroos: Evidence-based approach to treatment of sarcoidosis, in PG Gibson et al (eds): Evidence-Based Respiratory Medicine. Oxford, BMJ Books Blackwell, 2005, pp 491–508.\nHere is the question:\nRHEUMATOLOGY: A 37-year-old man presents with arthritis of the metacarpophalangeal joints of both hands and right pleuritis. Bilateral malar erythema is seen on examination. Positive antinuclear antibodies were detected (titer 1/640), with anti native DNA antibodies also positive; anti-Sm negative What would be the initial treatment of choice for this patient?\nHere are the potential choices:\n1. Glucocorticoids at high doses.\n2. Glucocorticoids and mycophenolate.\n3. Nonsteroidal anti-inflammatory drugs and antimalarials.\n4. The picture will probably be self-limited and does not require treatment.\nThe correct answer is: 2. Glucocorticoids and mycophenolate."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Diagnosis The most useful information for accurate diagnosis is the symptoms and weakness pattern. If the quadriceps are spared but the hamstrings and iliopsoas are severely affected in a person between ages of 20 - 40, it is very likely HIBM will be at the top of the differential diagnosis. The doctor may order any or all of the following tests to ascertain if a person has IBM2: Blood test for serum Creatine Kinase (CK or CPK); Nerve Conduction Study (NCS) / Electomyography (EMG); Muscle Biopsy; Magnetic Resonance Imaging (MRI) or Computer Tomography (CT) Scan to determine true sparing of quadriceps; Blood Test or Buccal swab for genetic testing; In terms of the diagnosis of Becker muscular dystrophy symptom development resembles that of Duchenne muscular dystrophy. A physical exam indicates lack of pectoral and upper arm muscles, especially when the disease is unnoticed through the early teen years. Muscle wasting begins in the legs and pelvis, then progresses to the muscles of the shoulders and neck. Calf muscle enlargement (pseudohypertrophy) is quite obvious. Among the exams/tests performed are: Muscle biopsy (removes a small piece of muscle tissue, usually from the thigh, to check for dystrophin in muscle cells.) Creatine kinase test (checks the level of Creatine Kinase proteins in the blood. Creatine Kinase proteins are normally found inside of healthy muscle cells, but can be found in the blood when muscle cells are damaged.) Electromyography (shows that weakness is caused by destruction of muscle tissue rather than by damage to nerves.) A 68-year-old man with a 2-month history of progressive weakness and spontaneous pain in proximal limb muscles presented to our hospital with a dropped head. He started experiencing progressive dysphagia several days before admission. On admission, he had muscle weakness of the limbs and neck extensors with edema and induration in distal extremities. Laboratory tests showed elevation of muscle enzymes. FDG-PET/CT demonstrated multiple hypermetabolic lymph nodes, but the primary site was not identified; thus, metastatic carcinoma of unknown primary origin was considered. The patient was diagnosed with anti-nuclear matrix protein 2 antibody-positive paraneoplastic myopathy based on serum tests. Histological findings of the left biceps brachii muscle biopsy revealed severe variation in fiber size and perifascicular myofiber atrophy. Myofibers exhibited myxovirus resistance protein A expression predominantly in the perifascicular region. Following intravenous methylprednisolone pulse therapy and intravenous immunoglobulin, the patient's muscle strength improved with normalization of muscle enzyme levels. The dropped head was considered to have resulted from the preferential involvement of neck extensors based on the observed FDG-PET/CT uptake in neck extensors. A diagnosis of inclusion body myositis was historically dependent on muscle biopsy results. Antibodies to cytoplasmic 5'-nucleotidase (cN1A; NT5C1A) have been strongly associated with the condition. In the clinical context of classic history and positive antibodies, a muscle biopsy might be unnecessary. Differential diagnosis IBM is often initially misdiagnosed as polymyositis. A course of prednisone is typically completed with no improvement and eventually, sIBM is confirmed. sIBM weakness comes on over months or years and progresses steadily, whereas polymyositis has an onset of weeks or months. Other forms of muscular dystrophy (e.g. limb girdle) must be considered as well. Other features include a long head, low set ears and a short neck. The respiratory muscles can be moderately to severely affected and problems with breathing are common. Genetics The most common causes are mutations in the RYR1 and SEPN1 genes. In these cases the inheritance is autosomal recessive. Less common recessive mutations causing this condition include those in the TTN, MEGF10 and CACNA1S genes. Automsomal dominant mutations associated with this disease include those in MYH7 and CACNA1S. The pathogenesis is not well understood at present. Diagnosis The diagnosis may be suspected on clinical grounds. On blood testing the creatinine kinase may be raised. Imaging with ultrasound or MRI will show abnormalities in the affected muscles but these changes are not diagnostic. The diagnostic test is a muscle biopsy. Diagnosis In terms of diagnosis of Fukuyama congenital muscular dystrophy, serum creatine kinase concentration and muscle biopsies can be obtained to help determine if the individual has FMCD. FKTN molecular genetic testing is used to determine a mutation in the FKTN gene after a serum creatine kinase concentration, muscle biopsies, and/or MRI imaging have presented abnormalities indicative of FCMD, the presence of the symptoms indicates Fukuyama congenital muscular dystrophy. The available genetic test include: Linkage analysis Deletion analysis Sequence analysis - exons Sequence analysis - entire coding region Treatment A case of polymyositis with repeated dysphagia and muscle weakness associated with peculiar findings of skin was reported. The patient was a 67-year-old man. His birth and development was normal. There was no family history of neuromuscular disease. On 26th March 1987 he was admitted to a hospital because of dysarthria and dysphagia after fever and diagnosed as having viral myositis. His conditions improved spontaneously with bed rest and he left hospital on 14th April. On 23rd April he had chill and sore throat with fever. On 27th he was admitted to the same hospital because of dysarthria and muscle weakness of the proximal portion of the upper limbs. These symptoms also improved with bed rest. He had repeated these symptoms several times and then he was admitted to our hospital on 12th June. On examination he showed the skin pigmentation under the right eye and the eruption in the back of hands and the buttocks. Muscle weakness was observed in the proximal portion of the upper limbs and the neck flexor. Laboratory tests in admission were as follows: sGOT 49 mU/ml, sGPT 104 mU/ml, LDH 1064 mU/ml, CPK 565 mM/ml, aldolase 25.2 IU/1/37 degrees C. Electromyography showed the typical myogenic changes and biopsy of left biceps brachii revealed inflammatory cells in the muscle fiber which are specific to polymyositis. Immuno-histochemical study is performed to analyse the subpopulation of mononuclear cells in biopsied muscle and skin. Mononuclear cells infiltrated into perimysium, endomysium and epidermis were positive for T11 and T8, but less positive for T4, B1 and Leu11. On the basis of these findings he was diagnosed as having \"polymyositis syndrome\". Further causes of neuromuscular diseases are : Inflammatory muscle disorders Polymyalgia rheumatica (or \"muscle rheumatism\") is an inflammatory condition that mainly occurs in the elderly; it is associated with giant-cell arteritis(It often responds to prednisolone). Polymyositis is an autoimmune condition in which the muscle is affected. Rhabdomyolysis is the breakdown of muscular tissue due to any cause. Tumors Smooth muscle: leiomyoma (benign) Striated muscle: rhabdomyoma (benign) Diagnosis Diagnostic procedures that may reveal muscular disorders include direct clinical observations. This usually starts with the observation of bulk, possible atrophy or loss of muscle tone. Neuromuscular disease can also be diagnosed by various blood tests and using electrodiagnostic medicine tests including electromyography (measuring electrical activity in muscles) and nerve conduction studies. Genetic testing is an important part of diagnosing inherited neuromuscular conditions. With calpain 3 mutation, proteins typically found at the triad are reduced, including CaMKII (Ca2+/calmodulin-dependent protein kinase II). Decreased CaMKII activity impairs induction of slow oxidative gene expression, which in turn impairs genes involving the mitochondria and lipid metabolism. Diagnosis Genetic testing is the most definitive test. If genetic testing is not available, a muscle biopsy with protein immunoanalysis can be used. Biopsy shows general dystrophic features, such as areas of muscle death, variability in muscle size, nuclei in the center of muscle fibers, and disorganized muscle fibers within muscle cells. Serum creatine kinase, a nonspecific marker of muscle damage, can be elevated early in the disease. Facioscapulohumeral muscular dystrophy (FSHD) can present similarly, although facial weakness and asymetrical weakness is common in FSHD. Management As of 2019, no disease modifying pharmaceuticals are known. The angiofollicular lymphoid hyperplasia, first described in 1954 by Castleman in the mediastinum, is a quite rare pseudolymphoma where there are few subcutaneous localizations. Since 1954, more than 300 observations were published including mediastino-pulmonary forms (about 60 p. 100 of the cases) intra-abdominal forms (15 p. 100 of the cases) and superficial forms which represent 25 p. 100 of the cases and associate superficial ganglionic, intra-muscular and subcutaneous localizations. The authors report the observation of a 44-year-old negro who had a subcutaneous tumefaction of the left elbow which appeared recently without a functional sign nor a biological change. The histological findings allowed the diagnosis of Castleman's pseudolymphoma in a hyalino-vascular form or Flendrig's type II. The evolution was marked a few weeks later by a local recurrence of which a second surgery has secured the recovery. The detailed study of the 76 cases of Castleman's superficial pseudo-tumours published in the literature allows us to recall the features of this disease which affects especially the young adult without prevalence of sex at about 25 years old. The circumstances of discovery are univocal, isolated palpable subcutaneous tumefaction in most of the cases. The localizations are distributed by decreasing incidence as following: latero-cervical, axillary, sus-clavicular, inguinal, vulvar, abdominal wall, shoulder, arm, forearm with a few bifocal forms. The histological aspect associated a predominant lymphoid population and vessels with fibro-hyalinous wall which morphological variations have permitted to individualize three forms: a plasmocytic form or Flendrig's type I which should be a stage of beginning often associated with hematological changes, a hyalino-vascular form or Flendrig's type II more frequent and a mixed form or intermediary type. The immunofluorescence, histo-enzymology and immunohistochemistry studies reveal a changeable polyclonal plasmocytosis and a predominance of T-suppressors in the lymphocytic population. The histological differential diagnosis of the superficial forms of the Castleman's pseudolymphoma is rarely set with certain lymphoma in case of ganglionic localization. On the other hand isolated subcutaneous localizations must be distinguished of the Kimura's disease and of the angiolymphoid hyperplasia with eosinophils where the vessels have a different morphology. The evolution is favorable in most of the cases and surgical exeresis insures the recovery.(ABSTRACT TRUNCATED AT 400 WORDS) Diagnosis Medical diagnosis for the MEB usually involves the study of family history, measurement of serum CPK level, molecular testing, muscle biopsy and imaging study. Physical examination People with MEB have distinctive facial dysmorphisms. Rounded forehead, thin and drooping lip, micrognathia, midface retrusion, short nasal bridge are the possible indicative evidence for diagnosis. Assessment of motor and mental development, visual ability also provide clues. Genetic test Genetic test can analyze the genome of infants for confirmation of the specific genetic mutation. Mutation in the POMGNT1 is the determinant in the diagnosis of MEB. Several mutations like [c.1539+1G→A], [c.879+5G→T] are the prevalent nucleotide change found in affected people. The commonly used practices collect fetal DNA by chronic villus sampling, followed by linkage analysis and direct sequencing to conclude the POMGNT1 gene sequence. Strategy for the diagnosis of a muscle weakness includes two steps: to rely the weakness to a muscular origin and to find the aetiology. A muscular deficit is purely motor, without sensory signs, involving mainly axial and proximal muscles. The essential informations for aetiological characterization are: 1st) a family history, indicating a genetic origin, 2nd the chronological profile, 3rd) the clinical pattern (deficit topography, modification of muscle volume, fatigability, contractures, myotonia, oculobulbar, respiratory or cardiac involvement), 4th) investigations (CK level, EMG, muscle imaging muscle, biopsy, genetic testing). Two autosomal dominant myopathies begin in adulthood: Steinert's myotonic dystrophy characterized by myotonia facial and distal weakness and atrophy, plurisystemic involvement and facio-scapulo-peroneal dystrophy with asymmetric facial and scapulo-humeral weakness. If the evolution is rapid and family history absent, a curable myopathy (inflammatory, toxic, iatrogenic, and endocrine) is to be looked for. Inclusion body myositis is the most frequent myopathy after the age of 50 years. Case 1. A 23-year-old white housewife presented with an erythematous violaceous rash on her face, neck, chest, and limbs, particularly over the dorsum of the hands and fingers; diffuse alopecia; and an inability to climb stairs and get up from a low seat. The clinical examination showed red to violaceous well-demarcated plaques on sun-exposed areas on the dorsum of the fingers and hands, with periungual erythema and telangiectasia; facial erythema; and heliotrope rash. There was also symmetric involvement of proximal muscles of the limbs. Laboratory examination showed hypergammaglobulinemia, elevated serum aspartate aminotransferase, and serum alanine aminotransferase; normal activities of creatinokinase, lactate dehydrogenase, and aldolase; an antinuclear antibody titer of 1:40 with a speckled pattern; negative anti-DNA and anti-Scl70; and normal serum complement levels (C3, C4, and CH50). Urinalysis results were within normal limits. Skin biopsy histopathology showed hyperkeratosis, edema of the upper epidermis, scattered inflammatory infiltrate, and focal accumulation of mucin in the form of acid mucopolysaccharides. Deep asymptomatic nodules on the inner upper limbs appeared later. Histopathology of these lesions showed focal areas of lobular panniculitis in the subcutaneous tissue, with lymphoplasmocytic inflammatory infiltrate without vasculitis (Figure 1 and Figure 2). Case 2. A 29-year-old white housewife presented with an erythematous violaceous rash on her face, neck, chest, and lower extremities. Clinical examination showed red to violaceous well-demarcated aching plaques on the internal surface of the thighs and tips of the fingers; periungual erythema and digital petechiae; Raynaud's phenomenon; and bilateral ulnar and cervical enlarged lymph nodes. Laboratory examination showed elevated serum aspartate aminotransferase, alanine aminotransferase, creatinokinase, lactate dehydrogenase, and aldolase; negative venereal disease research test results; an antinuclear antibody titer of 1:1024 with speckled pattern; negative anti-DNA and anti-Scl70; and normal serum complement levels (C3, C4, and CH50). Urinalysis results were within normal limits. Histopathology of the deep asymptomatic nodule on the inner left thigh showed lobular panniculitis with a scattered inflammatory infiltrate and diffuse fat necrosis, in addition to calcium deposition between the lipocytes and microcysts without vasculitis (Figure 3). We concur with the idea that congenital muscular dystrophy (CMD) is a distinct clinical entity, and report 17 patients (2 negroes and 15 whites; 12 M and 5 F; median age 6 years, range 1 to 24 years) with genetic, clinical, laboratorial, electrophysiological and histochemical studies. All our cases have an inheritance compatible with an autosomal recessive pattern. A decrease in fetal movements was reported by 57% of the mothers, generalized hypotonia at birth was present in 82%, limb girdle and neck weakness, absent or decreased deep tendon reflexes, and limb contractures were present in all. Severe muscular wasting was found in 41%. Calf pseudo-hypertrophy was observed in one patient. A patient was severely mentally retarded and another was borderline. During a 30-month follow-up, the muscle weakness of the majority remained essentially unchanged but the degree of motor activity deteriorated and was proportional to the worsening of the limb contractures. Serum CK levels were normal or increased to a maximum of 8 times. The electromyogram was myopathic in 74%, neurogenic in 13% and normal in 13%. CT scans showed a symmetrical white matter hypodensity in the hemispheres in 8 cases. All but 5 patients were operated upon to release the limb contractures and all were submitted to physical therapy. The contractures recurred in 4 patients submitted to surgery and were probably related to the cessation of physical therapy. Diagnosis The symptoms of a metabolic myopathy can be easily confused with the symptoms of another disease. In most cases, a Muscle biopsy is necessary for an accurate diagnosis of the cause of muscle weakness. A blood test can be done under normal circumstances to test for genetic differences and signs of tissue breakdown, or with an added cardio portion that can indicate if muscle breakdown is occurring. An electromyography is sometimes taken in order to rule out other disorders if the cause of fatigue is unknown. Differentiating between different types of metabolic myopathies can be difficult due to the similar symptoms of each type such as Myoglobinuria and exercise intolerance. It has to be determined whether the patient has fixed or exercise induced manifestations, and if exercise related what kind of exercise, before extensive exercise related lab testing is done to determine the underlying cause. A 61-year-old civil engineer began to have slowly progressive muscle atrophy in the right shoulder and the left arm at 56 years of age. Muscle wasting became manifest in the left thigh at 59 years and in the right thigh at 60 years. He had mild difficulty in climbing and descending stairs. On examination, although he had notable muscle atrophy in the right trapezius and proximal muscles in the upper and lower extremities, his muscle strength was relatively well preserved. The muscle atrophy was asymmetrical; the right periscapular region and the left upper and lower extremities were more markedly atrophic. In addition, multiple foci of the striking muscle atrophy were noted in the upper trunk and the proximal limb muscles. Fasciculation was not present. Deep tendon reflexes were normal with no pathologic reflexes. Except for a moderately elevated serum creatine kinase level of 709 Ul/l (normal 40-170) and mildly elevated serum myoglobin level of 100 ng/ml (normal &lt; 60), no laboratory tests showed abnormal values suggesting an inflammatory process. Motor and sensory nerve conduction velocities were within normal limits. Electromyography disclosed myopathic and neuropathic changes. Computed tomography (CT) of skeletal muscles showed asymmetrical muscle atrophy and patchy low-density foci. In biopsied left quadriceps and right gastrocnemius muscles which showed partially low density on CT, there was marked variation in muscle fiber size, with necrotic and regenerating fibers, an increased number of centrally placed nuclei, and interstitial fibrosis. There were numerous foci of mononuclear inflammatory cellular infiltration, especially around the blood vessels.(ABSTRACT TRUNCATED AT 250 WORDS) In addition to these main issues of distinguishing PM and DM from IBM, currently aided by antibody testing, we call attention to the following problems that we have encountered in connection with diagnosis: 1. The patient with proximal muscle weakness is incorrectly diagnosed as having progressive muscular dystrophy (actually, the opposite pertains more often). Points in favor of myositis are (1) lack of family history (although many dystrophies have recessive inheritance); (2) older age at onset; (3) rapid evolution of weakness; (4) evidence, past or present, of other connective tissue diseases; (5) high serum CK values (again, can be high in certain dystrophies); (6) marked degeneration and regeneration in muscle biopsy; and, finally, if there is still doubt, (7) unmistakable improvement with corticosteroid therapy. A muscle biopsy may be taken from the semimembranosis or semitendinosis (hamstring) muscles. The biopsy is stained for glycogen, and the intensity of stain uptake in the muscle, as well as the presence of any inclusions, helps to determine the diagnosis of PSSM. This test is the only method for diagnosing Type 2 PSSM. Horses with Type 1 PSSM will usually have between 1.5-2 times the normal levels of glycogen in their skeletal muscle. While abnormalities indicating muscle damage can be seen on histologic sections of muscle as young as 1 month of age, abnormal polysaccharide accumulation may take up to 3 years to develop. Management A 39-year-old female suffered from diffuse goiter, palpitation, finger tremor and body weight loss for about one year. Then she developed acute onset of myalgia and swelling of calves, and muscle weakness of proximal limbs. She could not walk because of myalgia and muscle weakness, and was admitted to our hospital 4 days after the onset of muscle symptoms. On admission, her pulse was 110 per minute and she had finger tremor of 11-12 Hz. The thyroid gland was markedly and diffusely enlarged with an elastic soft surface. She presented muscle weakness of proximal limbs and neck, and had intermittent swelling and myalgia on calves. Deep tendon reflexes were increased in all extremities. The erythrocyte sedimentation rate was 22 mm per hour. Eosinophilia was not recognized. Serum CK level was elevated to 671 IU/l. Serum free T3 was higher than 21.7 pg/ml and free T4 was also elevated to 10.19 ng /dl. Serum TSH was lower than 0.05 microU/ml and thyroid stimulating antibody was 1,302.0%. Muscle biopsy of her left gastrocnemius muscle revealed markedly hypertrophic fascia with inflammatory cellular infiltration on HE staining. Inflammatory change was also recognized in muscle tissue and in perivascular region of perimysium. Variation of fiber size, necrotic fibers, and central nuclei were also seen. From these clinical and laboratory findings she was diagnosed as having Basedow's disease associated with fasciitis and polymyositis. Her thyroid function was improved by anti-thyroid drug, and swelling and myalgia of sural regions and weakness of proximal limbs were also improved by steroid therapy. Only one case of Basedow's disease associated with fasciitis and seven cases of that associated polymyositis have so far been reported. This is the first case report of fasciitis associated with Basedow's disease and polymyositis. A 73-year-old woman with progressive proximal-dominant muscular atrophy and weakness was described. She had been well until 70-year-old, when she found difficulty in standing up from sitting position. At age 72 years, she could not raise her arms. Neurological examination showed muscular wasting and weakness in the proximal parts of extremities, shoulder and pelvic girdle. In the thigh, the flexors and adductors were severely affected. Muscular weakness was also observed in m. tibialis anterior. Serum CK and aldolase were normal. Electromyography showed low voltage short duration motor unit potentials with positive sharp waves and fibrillations. Rimmed vacuoles were observed in 4.8% of muscle fibers in biopsy sample obtained from right m. quadriceps femoris. No inflammatory cells, PAS-positive materials and inclusion bodies were observed in the sample. This case differs from distal myopathy with rimmed vacuoles, because the onset was very late and her muscular weakness and atrophy was proximal dominant. This case also differs from inclusion body myositis, because muscle biopsy revealed no inflammatory cells or inclusion body. Diagnosis Schwartz–Jampel syndrome is diagnosed on the basis of characteristic facial features, skeletal features and myotonia. Blood tests may show elevated serum creatine kinase or aldolase. X-rays, muscle biopsy or electromyography (EMG) may be useful. Genetic testing for the HSPG2 gene may confirm diagnosis. Treatment There is no cure for Schwartz–Jampel syndrome. Treatment is aimed at reducing muscle stiffness and cramping and may include massage, muscle warming and gradual strengthening exercises. Muscle relaxants or anti-seizure medications, especially carbamazepine, may be used. Eye symptoms such as blepharospasm might be relieved by Botox. Otherwise, a variety of surgical procedures have been found to be effective. Malignant hyperthermia, a potential complication of surgery, is a greater risk for people Schwartz–Jampel syndrome and an important consideration when considering surgery. Prognosis Most people with Schwartz–Jampel syndrome have a nearly normal life expectancy. The authors describe the case of a 36 years old woman suffering from muscular weakness with proximo-distal distribution to legs, and proximal to arms. The disease, appeared during the third decade of life, is slowly becoming more serious. Hematochemical analyses are all within a normal standard; EMG and histopathologic findings prove the existence of both a protopathic and neurogenic trouble in studied muscles. A therapy based on prednisone (50 mg/die) and ACTH (1 mg each 5 days) for a fourty days period doesn't cause essential changes in symptomatology. A cousin (on her mother's side) of our patient suffers from probable \"sporadic distal myopathy\". The authors discuss if the disease, shown by this patient, may be considered as an atypical form of SDM or if, what appears more probable, it must be nosographically framed as \"scapuloperoneal atrophy\". Blood testing may be used to measure serum creatine kinase, which ranges from normal to slightly elevated in those with BD. Skeletal muscle biopsies are used to examine muscle fibers. Biopsies in individuals with BD often show variation in muscle fiber size, atrophied fast-twitch muscle fibers, and increased nuclei number. Electromyography (EMG) can be used in diagnosis to rule out myotonia, or muscle stiffness that is detected by EMG. Individuals with BD have stiff muscles but normal EMG results (pseudo-myotonia), where no myotonic discharges are detected. Genetic testing may also be used in the diagnosis of BD to look for mutations in ATP2A1. Since only some forms of the disease are associated with ATP2A1, results of genetic testing do not always confirm a diagnosis of BD, but are useful to rule out other similar disorders. Treatment A 64-year-old woman was admitted to our hospital because of muscle weakness and atrophy in the extremities. Four years before admission, he was noticed to have elevated creatine kinase (CK) level, but had no further evaluation. Two years later, she became difficult in standing up and needed a wheelchair. Six months before admission, she noticed muscle wasting in the buttock, thigh, bilateral forearms, and weakness in the upper limbs. On neurologic examination, she had weakness in sternocleidomastoid and all limb muscles, predominantly in the distal portion of the upper extremities. Laboratory study revealed elevated CK, LDH, and aldolase levels, and myogenic change with fibrillation on needle EMG. Muscle biopsy showed myopathic changes with infiltration of mononuclear cells and rimmed vacuoles. The clinical manifestations as well as poor response to corticosteroids therapy were supportive of the diagnosis of inclusion body myositis. However, the distribution of muscle weakness in her wrist, weaker in the extensors than in the flexors, was not characteristic to IBM. This problem was solved by the right forearm MRI which showed a high signal intensity area in flexor muscles, but not in extensors on T1 and T2 weighted images. Accordingly, the muscle MRI of forearm was a diagnostic aid of IBM in this patient. Diagnosis MRI: Multifocal infarct-like cortical areas in different stages of ischemic evolution, areas that do not conform to any known vascular territory. Initial lesions often occur in the occipital or parietal lobes with eventual involvement of the cerebellum, cerebral cortex, basal ganglia, and thalamus. Lactate levels are often elevated in serum and cerebrospinal fluid. MR spectroscopy may show an elevated lactate peak in affected and even unaffected brain areas. Muscle biopsy shows ragged red fibers. However, genetic evaluation should be done first, which eliminates the need for muscle biopsy in most cases. Diagnosis may be molecular or clinical: Stroke-like episodes before 40 years old Encephalopathy with seizures or dementia Blood lactic acidosis* or ragged red fibers on muscle biopsy 20 patients afflicted with primary hypothyroidism were studied in order to evaluate the association of clinical or sub-clinical myopathy, detected by neurophysiological (electromyography) (EMG) or neuropathological methods (muscular biopsy with enzymatic study). 70% of the patients had muscular weakness (moderate in 30% and severe in 40%) of the scapular and pelvic muscles. 60% of the patients had muscular cramps. There was no myodema nor muscular atrophy or hypertrophy. Seric CPK was high in 70% of the cases. EMG was myopathic in 65%. All cases with weakness registered EMG alterations. The histological findings were import findings were important. The enzymatic techniques showed alterations of the fiber subtypes in 90% of the cases. The type I fibers had sarcolemmal and mitochondrial accumules in 85% and 70% had areas without oxidative activity, similar to \"core\". In this study, we did not find any correlation between the evolution time of hypothyroidism, hormonal levels, CPK increase, and muscular weakness. The EMG was myopathic in cases with severe weakness, however, in patients with moderate weakness it could also prove abnormal. There was no correlation between the electric myopathic pattern, CPK levels and thyroid hormones.\nHere is the question:\nRHEUMATOLOGY: A 75-year-old woman consults for violaceous lesions on the hands and neck together with progressive muscle weakness of 3 months of evolution. What diagnostic tests, among those indicated, can be useful for the diagnosis?\nHere are the potential choices:\n1. Determination of serum aldolase.\n2. Electroencephalogram.\n3. Biopsy of subcutaneous cellular tissue.\n4. Determination of anti-smooth muscle antibodies.\n5. Genetic study of their descendants.\nThe correct answer is: ",
        "gold_answer": "1 Determination of serum aldolase.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Diagnosis The most useful information for accurate diagnosis is the symptoms and weakness pattern. If the quadriceps are spared but the hamstrings and iliopsoas are severely affected in a person between ages of 20 - 40, it is very likely HIBM will be at the top of the differential diagnosis. The doctor may order any or all of the following tests to ascertain if a person has IBM2: Blood test for serum Creatine Kinase (CK or CPK); Nerve Conduction Study (NCS) / Electomyography (EMG); Muscle Biopsy; Magnetic Resonance Imaging (MRI) or Computer Tomography (CT) Scan to determine true sparing of quadriceps; Blood Test or Buccal swab for genetic testing; In terms of the diagnosis of Becker muscular dystrophy symptom development resembles that of Duchenne muscular dystrophy. A physical exam indicates lack of pectoral and upper arm muscles, especially when the disease is unnoticed through the early teen years. Muscle wasting begins in the legs and pelvis, then progresses to the muscles of the shoulders and neck. Calf muscle enlargement (pseudohypertrophy) is quite obvious. Among the exams/tests performed are: Muscle biopsy (removes a small piece of muscle tissue, usually from the thigh, to check for dystrophin in muscle cells.) Creatine kinase test (checks the level of Creatine Kinase proteins in the blood. Creatine Kinase proteins are normally found inside of healthy muscle cells, but can be found in the blood when muscle cells are damaged.) Electromyography (shows that weakness is caused by destruction of muscle tissue rather than by damage to nerves.) A 68-year-old man with a 2-month history of progressive weakness and spontaneous pain in proximal limb muscles presented to our hospital with a dropped head. He started experiencing progressive dysphagia several days before admission. On admission, he had muscle weakness of the limbs and neck extensors with edema and induration in distal extremities. Laboratory tests showed elevation of muscle enzymes. FDG-PET/CT demonstrated multiple hypermetabolic lymph nodes, but the primary site was not identified; thus, metastatic carcinoma of unknown primary origin was considered. The patient was diagnosed with anti-nuclear matrix protein 2 antibody-positive paraneoplastic myopathy based on serum tests. Histological findings of the left biceps brachii muscle biopsy revealed severe variation in fiber size and perifascicular myofiber atrophy. Myofibers exhibited myxovirus resistance protein A expression predominantly in the perifascicular region. Following intravenous methylprednisolone pulse therapy and intravenous immunoglobulin, the patient's muscle strength improved with normalization of muscle enzyme levels. The dropped head was considered to have resulted from the preferential involvement of neck extensors based on the observed FDG-PET/CT uptake in neck extensors. A diagnosis of inclusion body myositis was historically dependent on muscle biopsy results. Antibodies to cytoplasmic 5'-nucleotidase (cN1A; NT5C1A) have been strongly associated with the condition. In the clinical context of classic history and positive antibodies, a muscle biopsy might be unnecessary. Differential diagnosis IBM is often initially misdiagnosed as polymyositis. A course of prednisone is typically completed with no improvement and eventually, sIBM is confirmed. sIBM weakness comes on over months or years and progresses steadily, whereas polymyositis has an onset of weeks or months. Other forms of muscular dystrophy (e.g. limb girdle) must be considered as well. Other features include a long head, low set ears and a short neck. The respiratory muscles can be moderately to severely affected and problems with breathing are common. Genetics The most common causes are mutations in the RYR1 and SEPN1 genes. In these cases the inheritance is autosomal recessive. Less common recessive mutations causing this condition include those in the TTN, MEGF10 and CACNA1S genes. Automsomal dominant mutations associated with this disease include those in MYH7 and CACNA1S. The pathogenesis is not well understood at present. Diagnosis The diagnosis may be suspected on clinical grounds. On blood testing the creatinine kinase may be raised. Imaging with ultrasound or MRI will show abnormalities in the affected muscles but these changes are not diagnostic. The diagnostic test is a muscle biopsy. Diagnosis In terms of diagnosis of Fukuyama congenital muscular dystrophy, serum creatine kinase concentration and muscle biopsies can be obtained to help determine if the individual has FMCD. FKTN molecular genetic testing is used to determine a mutation in the FKTN gene after a serum creatine kinase concentration, muscle biopsies, and/or MRI imaging have presented abnormalities indicative of FCMD, the presence of the symptoms indicates Fukuyama congenital muscular dystrophy. The available genetic test include: Linkage analysis Deletion analysis Sequence analysis - exons Sequence analysis - entire coding region Treatment A case of polymyositis with repeated dysphagia and muscle weakness associated with peculiar findings of skin was reported. The patient was a 67-year-old man. His birth and development was normal. There was no family history of neuromuscular disease. On 26th March 1987 he was admitted to a hospital because of dysarthria and dysphagia after fever and diagnosed as having viral myositis. His conditions improved spontaneously with bed rest and he left hospital on 14th April. On 23rd April he had chill and sore throat with fever. On 27th he was admitted to the same hospital because of dysarthria and muscle weakness of the proximal portion of the upper limbs. These symptoms also improved with bed rest. He had repeated these symptoms several times and then he was admitted to our hospital on 12th June. On examination he showed the skin pigmentation under the right eye and the eruption in the back of hands and the buttocks. Muscle weakness was observed in the proximal portion of the upper limbs and the neck flexor. Laboratory tests in admission were as follows: sGOT 49 mU/ml, sGPT 104 mU/ml, LDH 1064 mU/ml, CPK 565 mM/ml, aldolase 25.2 IU/1/37 degrees C. Electromyography showed the typical myogenic changes and biopsy of left biceps brachii revealed inflammatory cells in the muscle fiber which are specific to polymyositis. Immuno-histochemical study is performed to analyse the subpopulation of mononuclear cells in biopsied muscle and skin. Mononuclear cells infiltrated into perimysium, endomysium and epidermis were positive for T11 and T8, but less positive for T4, B1 and Leu11. On the basis of these findings he was diagnosed as having \"polymyositis syndrome\". Further causes of neuromuscular diseases are : Inflammatory muscle disorders Polymyalgia rheumatica (or \"muscle rheumatism\") is an inflammatory condition that mainly occurs in the elderly; it is associated with giant-cell arteritis(It often responds to prednisolone). Polymyositis is an autoimmune condition in which the muscle is affected. Rhabdomyolysis is the breakdown of muscular tissue due to any cause. Tumors Smooth muscle: leiomyoma (benign) Striated muscle: rhabdomyoma (benign) Diagnosis Diagnostic procedures that may reveal muscular disorders include direct clinical observations. This usually starts with the observation of bulk, possible atrophy or loss of muscle tone. Neuromuscular disease can also be diagnosed by various blood tests and using electrodiagnostic medicine tests including electromyography (measuring electrical activity in muscles) and nerve conduction studies. Genetic testing is an important part of diagnosing inherited neuromuscular conditions. With calpain 3 mutation, proteins typically found at the triad are reduced, including CaMKII (Ca2+/calmodulin-dependent protein kinase II). Decreased CaMKII activity impairs induction of slow oxidative gene expression, which in turn impairs genes involving the mitochondria and lipid metabolism. Diagnosis Genetic testing is the most definitive test. If genetic testing is not available, a muscle biopsy with protein immunoanalysis can be used. Biopsy shows general dystrophic features, such as areas of muscle death, variability in muscle size, nuclei in the center of muscle fibers, and disorganized muscle fibers within muscle cells. Serum creatine kinase, a nonspecific marker of muscle damage, can be elevated early in the disease. Facioscapulohumeral muscular dystrophy (FSHD) can present similarly, although facial weakness and asymetrical weakness is common in FSHD. Management As of 2019, no disease modifying pharmaceuticals are known. The angiofollicular lymphoid hyperplasia, first described in 1954 by Castleman in the mediastinum, is a quite rare pseudolymphoma where there are few subcutaneous localizations. Since 1954, more than 300 observations were published including mediastino-pulmonary forms (about 60 p. 100 of the cases) intra-abdominal forms (15 p. 100 of the cases) and superficial forms which represent 25 p. 100 of the cases and associate superficial ganglionic, intra-muscular and subcutaneous localizations. The authors report the observation of a 44-year-old negro who had a subcutaneous tumefaction of the left elbow which appeared recently without a functional sign nor a biological change. The histological findings allowed the diagnosis of Castleman's pseudolymphoma in a hyalino-vascular form or Flendrig's type II. The evolution was marked a few weeks later by a local recurrence of which a second surgery has secured the recovery. The detailed study of the 76 cases of Castleman's superficial pseudo-tumours published in the literature allows us to recall the features of this disease which affects especially the young adult without prevalence of sex at about 25 years old. The circumstances of discovery are univocal, isolated palpable subcutaneous tumefaction in most of the cases. The localizations are distributed by decreasing incidence as following: latero-cervical, axillary, sus-clavicular, inguinal, vulvar, abdominal wall, shoulder, arm, forearm with a few bifocal forms. The histological aspect associated a predominant lymphoid population and vessels with fibro-hyalinous wall which morphological variations have permitted to individualize three forms: a plasmocytic form or Flendrig's type I which should be a stage of beginning often associated with hematological changes, a hyalino-vascular form or Flendrig's type II more frequent and a mixed form or intermediary type. The immunofluorescence, histo-enzymology and immunohistochemistry studies reveal a changeable polyclonal plasmocytosis and a predominance of T-suppressors in the lymphocytic population. The histological differential diagnosis of the superficial forms of the Castleman's pseudolymphoma is rarely set with certain lymphoma in case of ganglionic localization. On the other hand isolated subcutaneous localizations must be distinguished of the Kimura's disease and of the angiolymphoid hyperplasia with eosinophils where the vessels have a different morphology. The evolution is favorable in most of the cases and surgical exeresis insures the recovery.(ABSTRACT TRUNCATED AT 400 WORDS) Diagnosis Medical diagnosis for the MEB usually involves the study of family history, measurement of serum CPK level, molecular testing, muscle biopsy and imaging study. Physical examination People with MEB have distinctive facial dysmorphisms. Rounded forehead, thin and drooping lip, micrognathia, midface retrusion, short nasal bridge are the possible indicative evidence for diagnosis. Assessment of motor and mental development, visual ability also provide clues. Genetic test Genetic test can analyze the genome of infants for confirmation of the specific genetic mutation. Mutation in the POMGNT1 is the determinant in the diagnosis of MEB. Several mutations like [c.1539+1G→A], [c.879+5G→T] are the prevalent nucleotide change found in affected people. The commonly used practices collect fetal DNA by chronic villus sampling, followed by linkage analysis and direct sequencing to conclude the POMGNT1 gene sequence. Strategy for the diagnosis of a muscle weakness includes two steps: to rely the weakness to a muscular origin and to find the aetiology. A muscular deficit is purely motor, without sensory signs, involving mainly axial and proximal muscles. The essential informations for aetiological characterization are: 1st) a family history, indicating a genetic origin, 2nd the chronological profile, 3rd) the clinical pattern (deficit topography, modification of muscle volume, fatigability, contractures, myotonia, oculobulbar, respiratory or cardiac involvement), 4th) investigations (CK level, EMG, muscle imaging muscle, biopsy, genetic testing). Two autosomal dominant myopathies begin in adulthood: Steinert's myotonic dystrophy characterized by myotonia facial and distal weakness and atrophy, plurisystemic involvement and facio-scapulo-peroneal dystrophy with asymmetric facial and scapulo-humeral weakness. If the evolution is rapid and family history absent, a curable myopathy (inflammatory, toxic, iatrogenic, and endocrine) is to be looked for. Inclusion body myositis is the most frequent myopathy after the age of 50 years. Case 1. A 23-year-old white housewife presented with an erythematous violaceous rash on her face, neck, chest, and limbs, particularly over the dorsum of the hands and fingers; diffuse alopecia; and an inability to climb stairs and get up from a low seat. The clinical examination showed red to violaceous well-demarcated plaques on sun-exposed areas on the dorsum of the fingers and hands, with periungual erythema and telangiectasia; facial erythema; and heliotrope rash. There was also symmetric involvement of proximal muscles of the limbs. Laboratory examination showed hypergammaglobulinemia, elevated serum aspartate aminotransferase, and serum alanine aminotransferase; normal activities of creatinokinase, lactate dehydrogenase, and aldolase; an antinuclear antibody titer of 1:40 with a speckled pattern; negative anti-DNA and anti-Scl70; and normal serum complement levels (C3, C4, and CH50). Urinalysis results were within normal limits. Skin biopsy histopathology showed hyperkeratosis, edema of the upper epidermis, scattered inflammatory infiltrate, and focal accumulation of mucin in the form of acid mucopolysaccharides. Deep asymptomatic nodules on the inner upper limbs appeared later. Histopathology of these lesions showed focal areas of lobular panniculitis in the subcutaneous tissue, with lymphoplasmocytic inflammatory infiltrate without vasculitis (Figure 1 and Figure 2). Case 2. A 29-year-old white housewife presented with an erythematous violaceous rash on her face, neck, chest, and lower extremities. Clinical examination showed red to violaceous well-demarcated aching plaques on the internal surface of the thighs and tips of the fingers; periungual erythema and digital petechiae; Raynaud's phenomenon; and bilateral ulnar and cervical enlarged lymph nodes. Laboratory examination showed elevated serum aspartate aminotransferase, alanine aminotransferase, creatinokinase, lactate dehydrogenase, and aldolase; negative venereal disease research test results; an antinuclear antibody titer of 1:1024 with speckled pattern; negative anti-DNA and anti-Scl70; and normal serum complement levels (C3, C4, and CH50). Urinalysis results were within normal limits. Histopathology of the deep asymptomatic nodule on the inner left thigh showed lobular panniculitis with a scattered inflammatory infiltrate and diffuse fat necrosis, in addition to calcium deposition between the lipocytes and microcysts without vasculitis (Figure 3). We concur with the idea that congenital muscular dystrophy (CMD) is a distinct clinical entity, and report 17 patients (2 negroes and 15 whites; 12 M and 5 F; median age 6 years, range 1 to 24 years) with genetic, clinical, laboratorial, electrophysiological and histochemical studies. All our cases have an inheritance compatible with an autosomal recessive pattern. A decrease in fetal movements was reported by 57% of the mothers, generalized hypotonia at birth was present in 82%, limb girdle and neck weakness, absent or decreased deep tendon reflexes, and limb contractures were present in all. Severe muscular wasting was found in 41%. Calf pseudo-hypertrophy was observed in one patient. A patient was severely mentally retarded and another was borderline. During a 30-month follow-up, the muscle weakness of the majority remained essentially unchanged but the degree of motor activity deteriorated and was proportional to the worsening of the limb contractures. Serum CK levels were normal or increased to a maximum of 8 times. The electromyogram was myopathic in 74%, neurogenic in 13% and normal in 13%. CT scans showed a symmetrical white matter hypodensity in the hemispheres in 8 cases. All but 5 patients were operated upon to release the limb contractures and all were submitted to physical therapy. The contractures recurred in 4 patients submitted to surgery and were probably related to the cessation of physical therapy. Diagnosis The symptoms of a metabolic myopathy can be easily confused with the symptoms of another disease. In most cases, a Muscle biopsy is necessary for an accurate diagnosis of the cause of muscle weakness. A blood test can be done under normal circumstances to test for genetic differences and signs of tissue breakdown, or with an added cardio portion that can indicate if muscle breakdown is occurring. An electromyography is sometimes taken in order to rule out other disorders if the cause of fatigue is unknown. Differentiating between different types of metabolic myopathies can be difficult due to the similar symptoms of each type such as Myoglobinuria and exercise intolerance. It has to be determined whether the patient has fixed or exercise induced manifestations, and if exercise related what kind of exercise, before extensive exercise related lab testing is done to determine the underlying cause. A 61-year-old civil engineer began to have slowly progressive muscle atrophy in the right shoulder and the left arm at 56 years of age. Muscle wasting became manifest in the left thigh at 59 years and in the right thigh at 60 years. He had mild difficulty in climbing and descending stairs. On examination, although he had notable muscle atrophy in the right trapezius and proximal muscles in the upper and lower extremities, his muscle strength was relatively well preserved. The muscle atrophy was asymmetrical; the right periscapular region and the left upper and lower extremities were more markedly atrophic. In addition, multiple foci of the striking muscle atrophy were noted in the upper trunk and the proximal limb muscles. Fasciculation was not present. Deep tendon reflexes were normal with no pathologic reflexes. Except for a moderately elevated serum creatine kinase level of 709 Ul/l (normal 40-170) and mildly elevated serum myoglobin level of 100 ng/ml (normal &lt; 60), no laboratory tests showed abnormal values suggesting an inflammatory process. Motor and sensory nerve conduction velocities were within normal limits. Electromyography disclosed myopathic and neuropathic changes. Computed tomography (CT) of skeletal muscles showed asymmetrical muscle atrophy and patchy low-density foci. In biopsied left quadriceps and right gastrocnemius muscles which showed partially low density on CT, there was marked variation in muscle fiber size, with necrotic and regenerating fibers, an increased number of centrally placed nuclei, and interstitial fibrosis. There were numerous foci of mononuclear inflammatory cellular infiltration, especially around the blood vessels.(ABSTRACT TRUNCATED AT 250 WORDS) In addition to these main issues of distinguishing PM and DM from IBM, currently aided by antibody testing, we call attention to the following problems that we have encountered in connection with diagnosis: 1. The patient with proximal muscle weakness is incorrectly diagnosed as having progressive muscular dystrophy (actually, the opposite pertains more often). Points in favor of myositis are (1) lack of family history (although many dystrophies have recessive inheritance); (2) older age at onset; (3) rapid evolution of weakness; (4) evidence, past or present, of other connective tissue diseases; (5) high serum CK values (again, can be high in certain dystrophies); (6) marked degeneration and regeneration in muscle biopsy; and, finally, if there is still doubt, (7) unmistakable improvement with corticosteroid therapy. A muscle biopsy may be taken from the semimembranosis or semitendinosis (hamstring) muscles. The biopsy is stained for glycogen, and the intensity of stain uptake in the muscle, as well as the presence of any inclusions, helps to determine the diagnosis of PSSM. This test is the only method for diagnosing Type 2 PSSM. Horses with Type 1 PSSM will usually have between 1.5-2 times the normal levels of glycogen in their skeletal muscle. While abnormalities indicating muscle damage can be seen on histologic sections of muscle as young as 1 month of age, abnormal polysaccharide accumulation may take up to 3 years to develop. Management A 39-year-old female suffered from diffuse goiter, palpitation, finger tremor and body weight loss for about one year. Then she developed acute onset of myalgia and swelling of calves, and muscle weakness of proximal limbs. She could not walk because of myalgia and muscle weakness, and was admitted to our hospital 4 days after the onset of muscle symptoms. On admission, her pulse was 110 per minute and she had finger tremor of 11-12 Hz. The thyroid gland was markedly and diffusely enlarged with an elastic soft surface. She presented muscle weakness of proximal limbs and neck, and had intermittent swelling and myalgia on calves. Deep tendon reflexes were increased in all extremities. The erythrocyte sedimentation rate was 22 mm per hour. Eosinophilia was not recognized. Serum CK level was elevated to 671 IU/l. Serum free T3 was higher than 21.7 pg/ml and free T4 was also elevated to 10.19 ng /dl. Serum TSH was lower than 0.05 microU/ml and thyroid stimulating antibody was 1,302.0%. Muscle biopsy of her left gastrocnemius muscle revealed markedly hypertrophic fascia with inflammatory cellular infiltration on HE staining. Inflammatory change was also recognized in muscle tissue and in perivascular region of perimysium. Variation of fiber size, necrotic fibers, and central nuclei were also seen. From these clinical and laboratory findings she was diagnosed as having Basedow's disease associated with fasciitis and polymyositis. Her thyroid function was improved by anti-thyroid drug, and swelling and myalgia of sural regions and weakness of proximal limbs were also improved by steroid therapy. Only one case of Basedow's disease associated with fasciitis and seven cases of that associated polymyositis have so far been reported. This is the first case report of fasciitis associated with Basedow's disease and polymyositis. A 73-year-old woman with progressive proximal-dominant muscular atrophy and weakness was described. She had been well until 70-year-old, when she found difficulty in standing up from sitting position. At age 72 years, she could not raise her arms. Neurological examination showed muscular wasting and weakness in the proximal parts of extremities, shoulder and pelvic girdle. In the thigh, the flexors and adductors were severely affected. Muscular weakness was also observed in m. tibialis anterior. Serum CK and aldolase were normal. Electromyography showed low voltage short duration motor unit potentials with positive sharp waves and fibrillations. Rimmed vacuoles were observed in 4.8% of muscle fibers in biopsy sample obtained from right m. quadriceps femoris. No inflammatory cells, PAS-positive materials and inclusion bodies were observed in the sample. This case differs from distal myopathy with rimmed vacuoles, because the onset was very late and her muscular weakness and atrophy was proximal dominant. This case also differs from inclusion body myositis, because muscle biopsy revealed no inflammatory cells or inclusion body. Diagnosis Schwartz–Jampel syndrome is diagnosed on the basis of characteristic facial features, skeletal features and myotonia. Blood tests may show elevated serum creatine kinase or aldolase. X-rays, muscle biopsy or electromyography (EMG) may be useful. Genetic testing for the HSPG2 gene may confirm diagnosis. Treatment There is no cure for Schwartz–Jampel syndrome. Treatment is aimed at reducing muscle stiffness and cramping and may include massage, muscle warming and gradual strengthening exercises. Muscle relaxants or anti-seizure medications, especially carbamazepine, may be used. Eye symptoms such as blepharospasm might be relieved by Botox. Otherwise, a variety of surgical procedures have been found to be effective. Malignant hyperthermia, a potential complication of surgery, is a greater risk for people Schwartz–Jampel syndrome and an important consideration when considering surgery. Prognosis Most people with Schwartz–Jampel syndrome have a nearly normal life expectancy. The authors describe the case of a 36 years old woman suffering from muscular weakness with proximo-distal distribution to legs, and proximal to arms. The disease, appeared during the third decade of life, is slowly becoming more serious. Hematochemical analyses are all within a normal standard; EMG and histopathologic findings prove the existence of both a protopathic and neurogenic trouble in studied muscles. A therapy based on prednisone (50 mg/die) and ACTH (1 mg each 5 days) for a fourty days period doesn't cause essential changes in symptomatology. A cousin (on her mother's side) of our patient suffers from probable \"sporadic distal myopathy\". The authors discuss if the disease, shown by this patient, may be considered as an atypical form of SDM or if, what appears more probable, it must be nosographically framed as \"scapuloperoneal atrophy\". Blood testing may be used to measure serum creatine kinase, which ranges from normal to slightly elevated in those with BD. Skeletal muscle biopsies are used to examine muscle fibers. Biopsies in individuals with BD often show variation in muscle fiber size, atrophied fast-twitch muscle fibers, and increased nuclei number. Electromyography (EMG) can be used in diagnosis to rule out myotonia, or muscle stiffness that is detected by EMG. Individuals with BD have stiff muscles but normal EMG results (pseudo-myotonia), where no myotonic discharges are detected. Genetic testing may also be used in the diagnosis of BD to look for mutations in ATP2A1. Since only some forms of the disease are associated with ATP2A1, results of genetic testing do not always confirm a diagnosis of BD, but are useful to rule out other similar disorders. Treatment A 64-year-old woman was admitted to our hospital because of muscle weakness and atrophy in the extremities. Four years before admission, he was noticed to have elevated creatine kinase (CK) level, but had no further evaluation. Two years later, she became difficult in standing up and needed a wheelchair. Six months before admission, she noticed muscle wasting in the buttock, thigh, bilateral forearms, and weakness in the upper limbs. On neurologic examination, she had weakness in sternocleidomastoid and all limb muscles, predominantly in the distal portion of the upper extremities. Laboratory study revealed elevated CK, LDH, and aldolase levels, and myogenic change with fibrillation on needle EMG. Muscle biopsy showed myopathic changes with infiltration of mononuclear cells and rimmed vacuoles. The clinical manifestations as well as poor response to corticosteroids therapy were supportive of the diagnosis of inclusion body myositis. However, the distribution of muscle weakness in her wrist, weaker in the extensors than in the flexors, was not characteristic to IBM. This problem was solved by the right forearm MRI which showed a high signal intensity area in flexor muscles, but not in extensors on T1 and T2 weighted images. Accordingly, the muscle MRI of forearm was a diagnostic aid of IBM in this patient. Diagnosis MRI: Multifocal infarct-like cortical areas in different stages of ischemic evolution, areas that do not conform to any known vascular territory. Initial lesions often occur in the occipital or parietal lobes with eventual involvement of the cerebellum, cerebral cortex, basal ganglia, and thalamus. Lactate levels are often elevated in serum and cerebrospinal fluid. MR spectroscopy may show an elevated lactate peak in affected and even unaffected brain areas. Muscle biopsy shows ragged red fibers. However, genetic evaluation should be done first, which eliminates the need for muscle biopsy in most cases. Diagnosis may be molecular or clinical: Stroke-like episodes before 40 years old Encephalopathy with seizures or dementia Blood lactic acidosis* or ragged red fibers on muscle biopsy 20 patients afflicted with primary hypothyroidism were studied in order to evaluate the association of clinical or sub-clinical myopathy, detected by neurophysiological (electromyography) (EMG) or neuropathological methods (muscular biopsy with enzymatic study). 70% of the patients had muscular weakness (moderate in 30% and severe in 40%) of the scapular and pelvic muscles. 60% of the patients had muscular cramps. There was no myodema nor muscular atrophy or hypertrophy. Seric CPK was high in 70% of the cases. EMG was myopathic in 65%. All cases with weakness registered EMG alterations. The histological findings were import findings were important. The enzymatic techniques showed alterations of the fiber subtypes in 90% of the cases. The type I fibers had sarcolemmal and mitochondrial accumules in 85% and 70% had areas without oxidative activity, similar to \"core\". In this study, we did not find any correlation between the evolution time of hypothyroidism, hormonal levels, CPK increase, and muscular weakness. The EMG was myopathic in cases with severe weakness, however, in patients with moderate weakness it could also prove abnormal. There was no correlation between the electric myopathic pattern, CPK levels and thyroid hormones.\nHere is the question:\nRHEUMATOLOGY: A 75-year-old woman consults for violaceous lesions on the hands and neck together with progressive muscle weakness of 3 months of evolution. What diagnostic tests, among those indicated, can be useful for the diagnosis?\nHere are the potential choices:\n1. Determination of serum aldolase.\n2. Electroencephalogram.\n3. Biopsy of subcutaneous cellular tissue.\n4. Determination of anti-smooth muscle antibodies.\n5. Genetic study of their descendants.\nThe correct answer is: 3. Biopsy of subcutaneous cellular tissue."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n COPD is a chronic pathological condition of the respiratory system characterized by persistent and partially reversible airflow obstruction, to which variably contribute remodeling of bronchi (chronic bronchitis), bronchioles (small airway disease) and lung parenchyma (pulmonary emphysema). COPD can cause important systemic effects and be associated with complications and comorbidities. The diagnosis of COPD is based on the presence of respiratory symptoms and/or a history of exposure to risk factors, and the demonstration of airflow obstruction by spirometry. GARD of WHO has defined COPD \"a preventable and treatable disease\". The integration among general practitioner, chest physician as well as other specialists, whenever required, assures the best management of the COPD person, when specific targets to be achieved are well defined in a diagnostic and therapeutic route, previously designed and shared with appropriateness. The first-line pharmacologic treatment of COPD is represented by inhaled long-acting bronchodilators. In symptomatic patients, with pre-bronchodilator FEV1 &lt; 60%predicted and ≥ 2 exacerbations/year, ICS may be added to LABA. The use of fixed-dose, single-inhaler combination may improve the adherence to treatment. Long term oxygen therapy (LTOT) is indicated in stable patients, at rest while receiving the best possible treatment, and exhibiting a PaO2 ≤ 55 mmHg (SO2&lt;88%) or PaO2 values between 56 and 59 mmHg (SO2 &lt; 89%) associated with pulmonary arterial hypertension, cor pulmonale, or edema of the lower limbs or hematocrit &gt; 55%. Respiratory rehabilitation is addressed to patients with chronic respiratory disease in all stages of severity who report symptoms and limitation of their daily activity. It must be integrated in an individual patient tailored treatment as it improves dyspnea, exercise performance, and quality of life. Acute exacerbation of COPD is a sudden worsening of usual symptoms in a person with COPD, over and beyond normal daily variability that requires treatment modification. The pharmacologic therapy can be applied at home and includes the administration of drugs used during the stable phase by increasing the dose or modifying the route, and adding, whenever required, drugs as antibiotics or systemic corticosteroids. In case of patients who because of COPD severity and/or of exacerbations do not respond promptly to treatment at home hospital admission should be considered. Patients with \"severe or \"very severe COPD who experience exacerbations should be carried out in respiratory unit, based on the severity of acute respiratory failure. An integrated system is required in the community in order to ensure adequate treatments also outside acute care hospital settings and rehabilitation centers. This article is being simultaneusly published in Multidisciplinary Respiratory Medicine 2014; 9:25. Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and is estimated to be responsible for 119,000 deaths in the year 2000 alone. Additionally, COPD places a tremendous burden on the health care system, with estimated annual costs of US 24 billion dollars in 2000, and it is generally expected that costs will continue to rise as more individuals are diagnosed. COPD was responsible for approximately 8 million physician outpatient visits, 1.5 million emergency department visits and 726,000 hospitalizations, also in the year 2000. The objective of this article is to review current, pertinent clinical issues in the management of patients with COPD, with estimates of their relative utility and efficacy. COPD is a disease characterized by airflow limitation that is not fully reversible. Patients with COPD may frequently experience symptoms of chronic cough with sputum production, dyspnea, and reduced exercise capacity. They may frequently experience exacerbations characterized by increased symptoms that often require medical intervention. The diagnosis of COPD is usually fairly straightforward and made in a cigarette smoker, with the aforementioned symptoms and airflow obstruction measured by spirometry. Spirometry should be performed in all patients in whom COPD is suspected, as it provides useful prognostic information and may be used to stage the disease. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has provided evidenced-based management guidelines for COPD. GOLD guidelines advocate staging COPD by spirometry and make specific treatment recommendations based on COPD stage. The most important risk factor for the development of COPD is cigarette smoking, and smoking cessation has been shown to reduce all-cause mortality and to alter the natural history of COPD. Smoking cessation strategies that employ both counseling and medications like buproprion and nicotine replacement are most effective, but relapse rates remain high. It has not been shown that medications like bronchodilators or inhaled steroids change the natural history of COPD, nor do they reduce mortality, but they can affect other important outcomes. Long-acting bronchodilators, including beta- 2-adrenergic agonists such as salmeterol and formoterol, and the anticholinergic agent tiotropium, improve lung function and exercise tolerance, reduce symptoms, and modestly reduce exacerbation rates. Long-acting bronchodilators are indicated for all COPD patients with chronic symptoms. Short-acting bronchodilators are indicated for rescue when acute symptoms occur. Inhaled corticosteroids minimally improve lung function, but, importantly, reduce exacerbation rates and are indicated in severe COPD or when exacerbations are frequent. Continuous oxygen therapy has been shown to reduce mortality when severe hypoxemia is present and can improve quality of life when moderate hypoxia is present. Finally, well-designed, multidisciplinary disease management programs and pulmonary rehabilitation can improve important disease outcomes in a cost-effective manner. COPD is a common, preventable disease that affects a significant number of people. It may be managed by utilizing various readily available medical therapies, as well as other nonpharmacologic interventions, such as pulmonary rehabilitation. Proper coordination of care is important in this disease, and efforts should be focused on improving quality of life and reduction of symptoms. COPD is a chronic pathological condition of the respiratory system characterized by persistent and partially reversible airflow obstruction, to which variably contribute remodeling of bronchi (chronic bronchitis), bronchioles (small airway disease) and lung parenchyma (pulmonary emphysema). COPD can cause important systemic effects and be associated with complications and comorbidities. The diagnosis of COPD is based on the presence of respiratory symptoms and/or a history of exposure to risk factors, and the demonstration of airflow obstruction by spirometry. GARD of WHO has defined COPD \"a preventable and treatable disease\". The integration among general practitioner, chest physician as well as other specialists, whenever required, assures the best management of the COPD person, when specific targets to be achieved are well defined in a diagnostic and therapeutic route, previously designed and shared with appropriateness. The first-line pharmacologic treatment of COPD is represented by inhaled long-acting bronchodilators. In symptomatic patients, with pre-bronchodilator FEV1 &lt; 60% predicted and ≥ 2 exacerbations/year, ICS may be added to LABA. The use of fixed-dose, single-inhaler combination may improve the adherence to treatment. Long term oxygen therapy (LTOT) is indicated in stable patients, at rest while receiving the best possible treatment, and exhibiting a PaO2 ≤ 55 mmHg (SO2 &lt; 88%) or PaO2 values between 56 and 59 mmHg (SO2 &lt; 89%) associated with pulmonary arterial hypertension, cor pulmonale, or edema of the lower limbs or hematocrit &gt; 55%. Respiratory rehabilitation is addressed to patients with chronic respiratory disease in all stages of severity who report symptoms and limitation of their daily activity. It must be integrated in an individual patient tailored treatment as it improves dyspnea, exercise performance, and quality of life. Acute exacerbation of COPD is a sudden worsening of usual symptoms in a person with COPD, over and beyond normal daily variability that requires treatment modification. The pharmacologic therapy can be applied at home and includes the administration of drugs used during the stable phase by increasing the dose or modifying the route, and adding, whenever required, drugs as antibiotics or systemic corticosteroids. In case of patients who because of COPD severity and/or of exacerbations do not respond promptly to treatment at home hospital admission should be considered. Patients with \"severe\" or \"very severe\" COPD who experience exacerbations should be carried out in respiratory unit, based on the severity of acute respiratory failure. An integrated system is required in the community in order to ensure adequate treatments also outside acute care hospital settings and rehabilitation centers. This article is being simultaneously published in Sarcoidosis Vasc Diffuse Lung Dis 2014, 31(Suppl. 1);3-21.  The aim of this study was to investigate relationships between acute exacerbation and Forced Expiratory Volume 1 second (FEV1) improvement after treatment with combined long-acting beta-agonist (LABA) and inhaled corticosteroid (ICS) in patients with chronic obstructive pulmonary disease (COPD). A total of 137 COPD patients were classified as responders or nonresponders according to FEV1 improvement after 3 months of LABA/ICS treatment in fourteen referral hospitals in Korea. Exacerbation occurrence in these two subgroups was compared over a period of 1 yr. Eighty of the 137 COPD patients (58.4%) were classified as responders and 57 (41.6%) as nonresponders. Acute exacerbations occurred in 25 patients (31.3%) in the responder group and in 26 patients (45.6%) in the nonresponder group (P=0.086). FEV1 improvement after LABA/ICS treatment was a significant prognostic factor for fewer acute exacerbations in a multivariate Cox proportional hazard model adjusted for age, sex, FEV1, smoking history, 6 min walk distance, body mass index, exacerbation history in the previous year, and dyspnea scale.Three-month treatment response to LABA/ICS might be a prognostic factor for the occurrence of acute exacerbation in COPD patients.  Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease (COPD). However, the benefit of inhaled glucocorticoids in addition to two long-acting bronchodilators has not been fully explored. In this 12-month, double-blind, parallel-group study, 2485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium (at a dose of 18 μg once daily), salmeterol (50 μg twice daily), and the inhaled glucocorticoid fluticasone propionate (500 μg twice daily) during a 6-week run-in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period. The primary end point was the time to the first moderate or severe COPD exacerbation. Spirometric findings, health status, and dyspnea were also monitored. As compared with continued glucocorticoid use, glucocorticoid withdrawal met the prespecified noninferiority criterion of 1.20 for the upper limit of the 95% confidence interval (CI) with respect to the first moderate or severe COPD exacerbation (hazard ratio, 1.06; 95% CI, 0.94 to 1.19). At week 18, when glucocorticoid withdrawal was complete, the adjusted mean reduction from baseline in the trough forced expiratory volume in 1 second was 38 ml greater in the glucocorticoid-withdrawal group than in the glucocorticoid-continuation group (P&lt;0.001); a similar between-group difference (43 ml) was seen at week 52 (P=0.001). No change in dyspnea and minor changes in health status occurred in the glucocorticoid-withdrawal group. In patients with severe COPD receiving tiotropium plus salmeterol, the risk of moderate or severe exacerbations was similar among those who discontinued inhaled glucocorticoids and those who continued glucocorticoid therapy. However, there was a greater decrease in lung function during the final step of glucocorticoid withdrawal. (Funded by Boehringer Ingelheim Pharma; WISDOM ClinicalTrials.gov number, NCT00975195.). Exacerbations are critical events in chronic pulmonary obstructive disease (COPD). The frequency of COPD exacerbations is associated with the prognosis, including mortality, but no useful biomarker has been established. The present retrospective study investigated 481 COPD patients. Clinical features in the stable period were compared between patients who experienced severe exacerbation (n = 88, 18.3%) and those who never experienced severe exacerbation (n = 393, 81.7%). In the patients who experienced exacerbations, clinical features were also compared between frequent exacerbators (exacerbation rate ≥ 2 times/year, n = 27, 30.7%) and infrequent exacerbators (1 time/year, n = 61, 69.3%). Compared to COPD patients who never experienced exacerbations, body mass index (BMI), serum albumin, and pulmonary functions were significantly lower, and the cardiovascular disease comorbidity rate, COPD assessment test score, modified Medical Research Council dyspnea scale, and use of long-term oxygen therapy, long-acting β<sub2</sub adrenergic agonist therapy, inhaled corticosteroid therapy, and macrolide therapy were significantly higher in COPD patients with exacerbations (all p &lt; 0.01). In patients who experienced exacerbations, frequent exacerbators had significantly lower % forced expiratory volume in 1.0 s and a higher risk of critical exacerbations, percentage of blood eosinophils, history of mechanical ventilation use, and use of long-term oxygen therapy and of macrolide therapy than infrequent exacerbators (all p &lt; 0.01). On multivariate analysis, the percentage of blood eosinophils was the parameter most correlated with exacerbation frequency (β value [95% confidence interval] 1.45 [1.12-1.88], p &lt; 0.01). Blood eosinophil in the stable period is the factor most correlated with the frequency of severe exacerbations. The patients in this study was registered retrospectively. Management of exacerbations People with COPD can experience exacerbations (flare-ups) that are commonly caused by respiratory tract infections. The symptoms that worsen are not specific to COPD and differential diagnoses need to be considered. Acute exacerbations are typically treated by increasing the use of short-acting bronchodilators including a combination of a short-acting inhaled beta agonist and short-acting anticholinergic. These medications can be given either via a metered-dose inhaler with a spacer or via a nebulizer, with both appearing to be equally effective. Nebulization may be easier for those who are more unwell. Oxygen supplementation can be useful. Excessive oxygen; however, can result in increased levels and a decreased level of consciousness. Corticosteroids given orally can improve lung function and shorten hospital stays but their use is recommended for only five to seven days; longer courses increase the risk of pneumonia and death. The diagnosis of COPD is established through spirometry although other pulmonary function tests can be helpful. A chest X-ray is often ordered to look for hyperinflation and rule out other lung conditions but the lung damage of COPD is not always visible on a chest x-ray. Emphysema, for example, can only be seen on CT scan. The main form of long term management involves the use of inhaled bronchodilators (specifically beta agonists and anticholinergics) and inhaled corticosteroids. Many patients eventually require oxygen supplementation at home. In severe cases that are difficult to control, chronic treatment with oral corticosteroids may be necessary, although this is fraught with significant side effects. The treatment of COPD (Chronic Obstructive Pulmonary Disease) aims to improve the patients's well-being and to reduce mortality, morbidity and the development of exacerbations. This study was thus designed to compare the efficacy and tolerability of salmeterol/fluticasone combination with tiotropium in patients with moderate COPD. This was an open, prospective, randomized trial in COPD patients whose FEV1 (forced expiratory volume in 1 second) levels were between 80% and 50% predicted. A total of 44 patients who met the inclusion and exlusion criteria and who gave written informed consent were included in the study. At the end of the two week wash-out period, the patients were randomized to receive either salmeterol 50 µg/fluticasone 500 µg combination as dry powder inhaler twice daily (SF Group) or tiotropium dry powder inhaler 18 µg once daily (T Group) for one year. These were equally distributed in the two groups (22 patients in each study group). At follow-up, the patients were required to come to the outpatient clinic at the third, sixth, ninth and twelfth months. There were no statistically significant difference between the two groups with regards to demographic features and baseline measurements. There were 1.2 ± 1.7 exacerbations in SF Group and 2.1 ± 2.2 exacerbations in T Group (p= 0.070). The time to the first exacerbation was 4.2 ± 4.0 and 4.2 ± 3.3 months, respectively (p= 0.697). The number of severe exacerbations that resulted in admission to the emergency department or hospital was 0.6 ± 1.0 and 1.1 ± 1.4, respectively (p= 0.245). Significant improvements were observed in CAT (CPOD Assessment Test) scores in both groups during the treatment period (p&lt; 0.0001); but there was no difference between the two groups. This study has shown that in patients with moderate COPD, treatment with combined corticosteroid and long-acting beta-2 agonist provides similar improvements in pulmonary function tests, patient-reported outcomes and exercise capacity as compared a long-acting anticholinergics. The efficacy of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease (COPD) remains controversial because of a lack of placebo-controlled studies. We compared the effect of inhaled fluticasone propionate with placebo in the treatment of patients with COPD. We used a randomised, double-blind, placebo-controlled design. We enrolled from 13 European countries, New Zealand, and South Africa, 281 outpatient current or ex-smokers, aged between 50 and 75 years. They had a forced expiratory volume in 1 s (FEV1) of between 35% and 90% of predicted normal values, a ratio of FEV1 to forced vital capacity of 70% or less and bronchodilator reversibility of less than 15%, as well as a history of chronic bronchitis. Patients were randomly assigned fluticasone propionate 500 microg (n=142) or placebo (n=139) twice daily via a metered-dose inhaler for 6 months. The main outcome measures were the number of patients who had at least one exacerbation by the end of treatment, the number and severity of exacerbations, clinic lung function, diary card symptoms and peak expiratory flow and 6 min walking distance. 51 (37%) patients in the placebo group compared with 45 (32%) in the fluticasone propionate group had had at least one exacerbation by the end of treatment (p=0.449). Significantly more patients had moderate or severe exacerbations in the placebo group than in the fluticasone propionate group (86% vs 60%, p&lt;0.001). Diary-card and clinic morning peak expiratory flows improved significantly in the fluticasone propionate group (p&lt;0.001, p=0.048, respectively), as did clinic FEV1 (p&lt;0.001), forced vital capacity (p&lt;0.001), and mid-expiratory flow (p=0.01). Symptom scores for median daily cough and sputum volume were significantly lower with fluticasone propionate treatment than with placebo (p=0.004 and p=0.016, respectively). At the end of treatment, patients on fluticasone propionate had increased their 6 min walking distance significantly more than those on placebo (p=0.032). Fluticasone propionate was tolerated as well as placebo, with few adverse effects and without a clinically important effect on mean serum cortisol concentration. Fluticasone propionate may be of clinical benefit in patients with COPD over at least 6 months. Inhaled corticosteroids may have an important role in the long-term treatment of COPD. Chronic obstructive pulmonary disease (COPD) is characterized by slow progressive deterioration of respiratory function with systemic effects which have a great impact on health-related quality of life (HRQoL). The severity of airflow limitation in COPD, as reflected by forced expiratory volume in one second (FEV1) does not represent the systemic consequences of COPD. Hence, a multidimensional grading system, BODE index (Body mass index, Airflow obstruction, Dyspnea and Exercise capacity) that assessed both the pulmonary and systemic manifestations has recently been proposed to provide useful prognostic information and predict the outcome in COPD patients. The objective of this study was to evaluate the relationship between BODE index and health-related quality of life (HRQOL) in stable COPD patients and its usefulness in predicting the disease exacerbations. Sixty stable COPD patients who presented in the out-patient departments of Medicine and Pulmonology were recruited over one year period. We evaluated them by body-mass index, forced expiratory volume in one second (FEV1), Modified Medical Research Council dyspnea scale and six minute walk test (6MWT). BODE index was calculated using these variables. Disease duration, number of exacerbations and hospitalization in the previous year were recorded. We also administered the St. George's Respiratory Questionnaire (SGRQ) to assess the health related quality of life (HRQoL) in these patients. BODE scores were categorized into four quartiles, quartile one to four with scores of 0-2, 3-4, 5-6 and 7-10, respectively. According to BODE score, (16) 26.7% of patients were BODE 1, (27) 45% BODE 2, (15) 25% BODE 3 and (2) 3.3% were BODE 4. Higher BODE quartiles were associated with higher total SGRQ scores and SGRQ subscale scores (symptom, activity and impact). Very strong correlations were found between BODE quartiles and total SGRQ scores (<iP</i &lt; 0.01). Among the components of BODE index, the decrease in the FEV1 (%predicted) and 6MWD, and the increase of MMRC dyspnea grade were associated with worsening of health status (increase in total SGRQ and SGRQ subscales). BODE index also correlated with the acute exacerbations (<iP</i &lt; 0.0012) during one year follow-up. BODE index strongly correlated with the HRQoL and also reliably predicted acute exacerbations in stable COPD patients.   The aim of this study was to describe the management and prognosis related to a hospital admission for acute exacerbation of chronic obstructive pulmonary disease and to compare results to an earlier study.   This is a retrospective study of 300 consecutively discharged patients admitted in 2006-2007 with an exacerbation of chronic obstructive pulmonary disease from three respiratory departments. Data were collected from patient charts and compared with a replicate study done in 2001.   The mean age was 72.1years; 61.7% were women. Mean forced expiratory volume in 1s was 37.6% of predicted. On admission, 11.3% were treated with non-invasive ventilation, and 84.3% were given systemic corticosteroids. In-hospital mortality was 4.7%. At discharge, treatment with inhaled corticosteroids or at least one long-acting bronchodilator was given to 86.7% and 89% of patients, respectively, which was significantly higher than for similarly sampled patients in 2001. Mortality in 30days and 1year after discharge was 4.5% and 25.5%, respectively, compared with 5.5% and 30.3% in 2001, the 12-month mortality being significantly lower (P=0.03). Readmission rate in the 12months following discharge was 42.3%. Long-term oxygen treatment, treatment with anti-dysrhythmic drugs and lack of outpatient follow-up were independent predictors of 1-year mortality. Risk of readmission was increased with dependence in self-care activities, previous admissions and treatment with strong analgesics.   Over a period of 6years, a significantly higher number of patients are being treated according to guidelines. Survival following discharge increased over the same period. In addition to smoking, acute exacerbations are considered to be a contributing factor to progression of chronic obstructive pulmonary disease (COPD). However, these findings come from studies including active smokers, while results in ex-smokers are scarce and contradictory. The purpose of this study was to evaluate if frequent acute moderate exacerbations are associated with an accelerated decline in forced expiratory volume in one second (FEV1) and impairment of functional and clinical outcomes in ex-smoking COPD patients. A cohort of 100 ex-smoking patients recruited for a 2-year follow-up study was evaluated at inclusion and at 6-monthly scheduled visits while in a stable condition. Evaluation included anthropometry, spirometry, inspiratory capacity, peripheral capillary oxygen saturation, severity of dyspnea, a 6-minute walking test, BODE (Body mass index, airflow Obstruction, Dyspnea, Exercise performance) index, and quality of life (St George's Respiratory Questionnaire and Chronic Respiratory Disease Questionnaire). Severity of exacerbation was graded as moderate or severe according to health care utilization. Patients were classified as infrequent exacerbators if they had no or one acute exacerbation/year and frequent exacerbators if they had two or more acute exacerbations/year. Random effects modeling, within hierarchical linear modeling, was used for analysis. During follow-up, 419 (96% moderate) acute exacerbations were registered. At baseline, frequent exacerbators had more severe disease than infrequent exacerbators according to their FEV1 and BODE index, and also showed greater impairment in inspiratory capacity, forced vital capacity, peripheral capillary oxygen saturation, 6-minute walking test, and quality of life. However, no significant difference in FEV1 decline over time was found between the two groups (54.7±13 mL/year versus 85.4±15.9 mL/year in frequent exacerbators and infrequent exacerbators, respectively). This was also the case for all other measurements. Our results suggest that frequent moderate exacerbations do not contribute to accelerated clinical and functional decline in COPD patients who are ex-smokers. Acute exacerbation of chronic obstructive pulmonary disease (COPD) is defined by modification of the usual COPD symptoms, dyspnea, coughing and sputum, beyond daily variations, with a sudden onset, and requiring modification of the usual treatment. Exacerbations stud the course of COPD. Their frequency is variable, averaging 1-2 per year. Their frequency generally increases with COPD severity. Exacerbations impair patients' quality of life and aggravate disease prognosis by accelerating the decline in FEV1, the primary indicator of respiratory function. The most frequent causes of exacerbations are viral and bacterial respiratory infections and pollution. No cause is identified for nearly one third of all exacerbations. Most exacerbations can be treated at home, if a careful search for signs of clinical severity is negative. Treatment combines inhaled bronchodilator agents (beta-2 agonists, combined if necessary with anticholinergics) and oral corticosteroid therapy (prednisone: 0.5 mg/kg/d for 1 week) when the COPD is severe or signs of severity accompany the exacerbation. Antibiotic therapy is justified when the sputum appears purulent. Severe exacerbation may require oxygen therapy in cases of severe hypoxemia (PaO(2)&lt;60 mm Hg) or mechanically assisted ventilation, essentially by noninvasive ventilation in cases of respiratory acidosis (pH&lt;7.35). Noninvasive ventilation improves dyspnea and respiratory acidosis, diminishes respiratory frequency, intubation, duration of hospitalization, nosocomial infections, and mortality. Pulmonary follow-up is necessary after an exacerbation, especially to prevent the recurrence of exacerbations by measures that have been demonstrated to be effective, including help in smoking cessation, adaptation of COPD treatment, vaccination against influenza and pneumonia (pneumococci), and respiratory rehabilitation. Early diagnosis and rapid treatment of exacerbations can limit their impact, improve quality of life, and reduce the risk of hospitalization.\nHere is the question:\nPNEUMOLOGY AND THORACIC SURGERY: A 67-year-old man, ex-smoker, with a diagnosis of severe COPD (multidimensional index BODE 5, FEVl 38%, body mass index 23, dyspnea index according to the mMRC 3 scale, distance covered in the 6-minute walk test 260 m) who has had 3 hospital admissions for exacerbation of his COPD in the last 7 months, comes to the consultation. She also has a history of hypertension, ischemic heart disease with AMI 5 years ago and intermittent claudication. In the clinical examination, there is a decrease in vesicular murmur with expiratory wheezing in both lung fields and an oximetry saturation of 88%. Which of the following therapeutic strategies would NOT be recommended for this patient?\nHere are the potential choices:\n1. Adjustment of inhaled therapy with long-acting bronchodilators combining anticholinergics and beta-2 adrenergics with inhaled glucocorticoids.\n2. Start oral glucocorticoids for 6 months to control exacerbations.\n3. Check that the patient performs the inhalation technique correctly.\n4. Initiate chronic home oxygen therapy regimen.\nThe correct answer is: ",
        "gold_answer": "2 Start oral glucocorticoids for 6 months to control exacerbations.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n COPD is a chronic pathological condition of the respiratory system characterized by persistent and partially reversible airflow obstruction, to which variably contribute remodeling of bronchi (chronic bronchitis), bronchioles (small airway disease) and lung parenchyma (pulmonary emphysema). COPD can cause important systemic effects and be associated with complications and comorbidities. The diagnosis of COPD is based on the presence of respiratory symptoms and/or a history of exposure to risk factors, and the demonstration of airflow obstruction by spirometry. GARD of WHO has defined COPD \"a preventable and treatable disease\". The integration among general practitioner, chest physician as well as other specialists, whenever required, assures the best management of the COPD person, when specific targets to be achieved are well defined in a diagnostic and therapeutic route, previously designed and shared with appropriateness. The first-line pharmacologic treatment of COPD is represented by inhaled long-acting bronchodilators. In symptomatic patients, with pre-bronchodilator FEV1 &lt; 60%predicted and ≥ 2 exacerbations/year, ICS may be added to LABA. The use of fixed-dose, single-inhaler combination may improve the adherence to treatment. Long term oxygen therapy (LTOT) is indicated in stable patients, at rest while receiving the best possible treatment, and exhibiting a PaO2 ≤ 55 mmHg (SO2&lt;88%) or PaO2 values between 56 and 59 mmHg (SO2 &lt; 89%) associated with pulmonary arterial hypertension, cor pulmonale, or edema of the lower limbs or hematocrit &gt; 55%. Respiratory rehabilitation is addressed to patients with chronic respiratory disease in all stages of severity who report symptoms and limitation of their daily activity. It must be integrated in an individual patient tailored treatment as it improves dyspnea, exercise performance, and quality of life. Acute exacerbation of COPD is a sudden worsening of usual symptoms in a person with COPD, over and beyond normal daily variability that requires treatment modification. The pharmacologic therapy can be applied at home and includes the administration of drugs used during the stable phase by increasing the dose or modifying the route, and adding, whenever required, drugs as antibiotics or systemic corticosteroids. In case of patients who because of COPD severity and/or of exacerbations do not respond promptly to treatment at home hospital admission should be considered. Patients with \"severe or \"very severe COPD who experience exacerbations should be carried out in respiratory unit, based on the severity of acute respiratory failure. An integrated system is required in the community in order to ensure adequate treatments also outside acute care hospital settings and rehabilitation centers. This article is being simultaneusly published in Multidisciplinary Respiratory Medicine 2014; 9:25. Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and is estimated to be responsible for 119,000 deaths in the year 2000 alone. Additionally, COPD places a tremendous burden on the health care system, with estimated annual costs of US 24 billion dollars in 2000, and it is generally expected that costs will continue to rise as more individuals are diagnosed. COPD was responsible for approximately 8 million physician outpatient visits, 1.5 million emergency department visits and 726,000 hospitalizations, also in the year 2000. The objective of this article is to review current, pertinent clinical issues in the management of patients with COPD, with estimates of their relative utility and efficacy. COPD is a disease characterized by airflow limitation that is not fully reversible. Patients with COPD may frequently experience symptoms of chronic cough with sputum production, dyspnea, and reduced exercise capacity. They may frequently experience exacerbations characterized by increased symptoms that often require medical intervention. The diagnosis of COPD is usually fairly straightforward and made in a cigarette smoker, with the aforementioned symptoms and airflow obstruction measured by spirometry. Spirometry should be performed in all patients in whom COPD is suspected, as it provides useful prognostic information and may be used to stage the disease. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has provided evidenced-based management guidelines for COPD. GOLD guidelines advocate staging COPD by spirometry and make specific treatment recommendations based on COPD stage. The most important risk factor for the development of COPD is cigarette smoking, and smoking cessation has been shown to reduce all-cause mortality and to alter the natural history of COPD. Smoking cessation strategies that employ both counseling and medications like buproprion and nicotine replacement are most effective, but relapse rates remain high. It has not been shown that medications like bronchodilators or inhaled steroids change the natural history of COPD, nor do they reduce mortality, but they can affect other important outcomes. Long-acting bronchodilators, including beta- 2-adrenergic agonists such as salmeterol and formoterol, and the anticholinergic agent tiotropium, improve lung function and exercise tolerance, reduce symptoms, and modestly reduce exacerbation rates. Long-acting bronchodilators are indicated for all COPD patients with chronic symptoms. Short-acting bronchodilators are indicated for rescue when acute symptoms occur. Inhaled corticosteroids minimally improve lung function, but, importantly, reduce exacerbation rates and are indicated in severe COPD or when exacerbations are frequent. Continuous oxygen therapy has been shown to reduce mortality when severe hypoxemia is present and can improve quality of life when moderate hypoxia is present. Finally, well-designed, multidisciplinary disease management programs and pulmonary rehabilitation can improve important disease outcomes in a cost-effective manner. COPD is a common, preventable disease that affects a significant number of people. It may be managed by utilizing various readily available medical therapies, as well as other nonpharmacologic interventions, such as pulmonary rehabilitation. Proper coordination of care is important in this disease, and efforts should be focused on improving quality of life and reduction of symptoms. COPD is a chronic pathological condition of the respiratory system characterized by persistent and partially reversible airflow obstruction, to which variably contribute remodeling of bronchi (chronic bronchitis), bronchioles (small airway disease) and lung parenchyma (pulmonary emphysema). COPD can cause important systemic effects and be associated with complications and comorbidities. The diagnosis of COPD is based on the presence of respiratory symptoms and/or a history of exposure to risk factors, and the demonstration of airflow obstruction by spirometry. GARD of WHO has defined COPD \"a preventable and treatable disease\". The integration among general practitioner, chest physician as well as other specialists, whenever required, assures the best management of the COPD person, when specific targets to be achieved are well defined in a diagnostic and therapeutic route, previously designed and shared with appropriateness. The first-line pharmacologic treatment of COPD is represented by inhaled long-acting bronchodilators. In symptomatic patients, with pre-bronchodilator FEV1 &lt; 60% predicted and ≥ 2 exacerbations/year, ICS may be added to LABA. The use of fixed-dose, single-inhaler combination may improve the adherence to treatment. Long term oxygen therapy (LTOT) is indicated in stable patients, at rest while receiving the best possible treatment, and exhibiting a PaO2 ≤ 55 mmHg (SO2 &lt; 88%) or PaO2 values between 56 and 59 mmHg (SO2 &lt; 89%) associated with pulmonary arterial hypertension, cor pulmonale, or edema of the lower limbs or hematocrit &gt; 55%. Respiratory rehabilitation is addressed to patients with chronic respiratory disease in all stages of severity who report symptoms and limitation of their daily activity. It must be integrated in an individual patient tailored treatment as it improves dyspnea, exercise performance, and quality of life. Acute exacerbation of COPD is a sudden worsening of usual symptoms in a person with COPD, over and beyond normal daily variability that requires treatment modification. The pharmacologic therapy can be applied at home and includes the administration of drugs used during the stable phase by increasing the dose or modifying the route, and adding, whenever required, drugs as antibiotics or systemic corticosteroids. In case of patients who because of COPD severity and/or of exacerbations do not respond promptly to treatment at home hospital admission should be considered. Patients with \"severe\" or \"very severe\" COPD who experience exacerbations should be carried out in respiratory unit, based on the severity of acute respiratory failure. An integrated system is required in the community in order to ensure adequate treatments also outside acute care hospital settings and rehabilitation centers. This article is being simultaneously published in Sarcoidosis Vasc Diffuse Lung Dis 2014, 31(Suppl. 1);3-21.  The aim of this study was to investigate relationships between acute exacerbation and Forced Expiratory Volume 1 second (FEV1) improvement after treatment with combined long-acting beta-agonist (LABA) and inhaled corticosteroid (ICS) in patients with chronic obstructive pulmonary disease (COPD). A total of 137 COPD patients were classified as responders or nonresponders according to FEV1 improvement after 3 months of LABA/ICS treatment in fourteen referral hospitals in Korea. Exacerbation occurrence in these two subgroups was compared over a period of 1 yr. Eighty of the 137 COPD patients (58.4%) were classified as responders and 57 (41.6%) as nonresponders. Acute exacerbations occurred in 25 patients (31.3%) in the responder group and in 26 patients (45.6%) in the nonresponder group (P=0.086). FEV1 improvement after LABA/ICS treatment was a significant prognostic factor for fewer acute exacerbations in a multivariate Cox proportional hazard model adjusted for age, sex, FEV1, smoking history, 6 min walk distance, body mass index, exacerbation history in the previous year, and dyspnea scale.Three-month treatment response to LABA/ICS might be a prognostic factor for the occurrence of acute exacerbation in COPD patients.  Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease (COPD). However, the benefit of inhaled glucocorticoids in addition to two long-acting bronchodilators has not been fully explored. In this 12-month, double-blind, parallel-group study, 2485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium (at a dose of 18 μg once daily), salmeterol (50 μg twice daily), and the inhaled glucocorticoid fluticasone propionate (500 μg twice daily) during a 6-week run-in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period. The primary end point was the time to the first moderate or severe COPD exacerbation. Spirometric findings, health status, and dyspnea were also monitored. As compared with continued glucocorticoid use, glucocorticoid withdrawal met the prespecified noninferiority criterion of 1.20 for the upper limit of the 95% confidence interval (CI) with respect to the first moderate or severe COPD exacerbation (hazard ratio, 1.06; 95% CI, 0.94 to 1.19). At week 18, when glucocorticoid withdrawal was complete, the adjusted mean reduction from baseline in the trough forced expiratory volume in 1 second was 38 ml greater in the glucocorticoid-withdrawal group than in the glucocorticoid-continuation group (P&lt;0.001); a similar between-group difference (43 ml) was seen at week 52 (P=0.001). No change in dyspnea and minor changes in health status occurred in the glucocorticoid-withdrawal group. In patients with severe COPD receiving tiotropium plus salmeterol, the risk of moderate or severe exacerbations was similar among those who discontinued inhaled glucocorticoids and those who continued glucocorticoid therapy. However, there was a greater decrease in lung function during the final step of glucocorticoid withdrawal. (Funded by Boehringer Ingelheim Pharma; WISDOM ClinicalTrials.gov number, NCT00975195.). Exacerbations are critical events in chronic pulmonary obstructive disease (COPD). The frequency of COPD exacerbations is associated with the prognosis, including mortality, but no useful biomarker has been established. The present retrospective study investigated 481 COPD patients. Clinical features in the stable period were compared between patients who experienced severe exacerbation (n = 88, 18.3%) and those who never experienced severe exacerbation (n = 393, 81.7%). In the patients who experienced exacerbations, clinical features were also compared between frequent exacerbators (exacerbation rate ≥ 2 times/year, n = 27, 30.7%) and infrequent exacerbators (1 time/year, n = 61, 69.3%). Compared to COPD patients who never experienced exacerbations, body mass index (BMI), serum albumin, and pulmonary functions were significantly lower, and the cardiovascular disease comorbidity rate, COPD assessment test score, modified Medical Research Council dyspnea scale, and use of long-term oxygen therapy, long-acting β<sub2</sub adrenergic agonist therapy, inhaled corticosteroid therapy, and macrolide therapy were significantly higher in COPD patients with exacerbations (all p &lt; 0.01). In patients who experienced exacerbations, frequent exacerbators had significantly lower % forced expiratory volume in 1.0 s and a higher risk of critical exacerbations, percentage of blood eosinophils, history of mechanical ventilation use, and use of long-term oxygen therapy and of macrolide therapy than infrequent exacerbators (all p &lt; 0.01). On multivariate analysis, the percentage of blood eosinophils was the parameter most correlated with exacerbation frequency (β value [95% confidence interval] 1.45 [1.12-1.88], p &lt; 0.01). Blood eosinophil in the stable period is the factor most correlated with the frequency of severe exacerbations. The patients in this study was registered retrospectively. Management of exacerbations People with COPD can experience exacerbations (flare-ups) that are commonly caused by respiratory tract infections. The symptoms that worsen are not specific to COPD and differential diagnoses need to be considered. Acute exacerbations are typically treated by increasing the use of short-acting bronchodilators including a combination of a short-acting inhaled beta agonist and short-acting anticholinergic. These medications can be given either via a metered-dose inhaler with a spacer or via a nebulizer, with both appearing to be equally effective. Nebulization may be easier for those who are more unwell. Oxygen supplementation can be useful. Excessive oxygen; however, can result in increased levels and a decreased level of consciousness. Corticosteroids given orally can improve lung function and shorten hospital stays but their use is recommended for only five to seven days; longer courses increase the risk of pneumonia and death. The diagnosis of COPD is established through spirometry although other pulmonary function tests can be helpful. A chest X-ray is often ordered to look for hyperinflation and rule out other lung conditions but the lung damage of COPD is not always visible on a chest x-ray. Emphysema, for example, can only be seen on CT scan. The main form of long term management involves the use of inhaled bronchodilators (specifically beta agonists and anticholinergics) and inhaled corticosteroids. Many patients eventually require oxygen supplementation at home. In severe cases that are difficult to control, chronic treatment with oral corticosteroids may be necessary, although this is fraught with significant side effects. The treatment of COPD (Chronic Obstructive Pulmonary Disease) aims to improve the patients's well-being and to reduce mortality, morbidity and the development of exacerbations. This study was thus designed to compare the efficacy and tolerability of salmeterol/fluticasone combination with tiotropium in patients with moderate COPD. This was an open, prospective, randomized trial in COPD patients whose FEV1 (forced expiratory volume in 1 second) levels were between 80% and 50% predicted. A total of 44 patients who met the inclusion and exlusion criteria and who gave written informed consent were included in the study. At the end of the two week wash-out period, the patients were randomized to receive either salmeterol 50 µg/fluticasone 500 µg combination as dry powder inhaler twice daily (SF Group) or tiotropium dry powder inhaler 18 µg once daily (T Group) for one year. These were equally distributed in the two groups (22 patients in each study group). At follow-up, the patients were required to come to the outpatient clinic at the third, sixth, ninth and twelfth months. There were no statistically significant difference between the two groups with regards to demographic features and baseline measurements. There were 1.2 ± 1.7 exacerbations in SF Group and 2.1 ± 2.2 exacerbations in T Group (p= 0.070). The time to the first exacerbation was 4.2 ± 4.0 and 4.2 ± 3.3 months, respectively (p= 0.697). The number of severe exacerbations that resulted in admission to the emergency department or hospital was 0.6 ± 1.0 and 1.1 ± 1.4, respectively (p= 0.245). Significant improvements were observed in CAT (CPOD Assessment Test) scores in both groups during the treatment period (p&lt; 0.0001); but there was no difference between the two groups. This study has shown that in patients with moderate COPD, treatment with combined corticosteroid and long-acting beta-2 agonist provides similar improvements in pulmonary function tests, patient-reported outcomes and exercise capacity as compared a long-acting anticholinergics. The efficacy of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease (COPD) remains controversial because of a lack of placebo-controlled studies. We compared the effect of inhaled fluticasone propionate with placebo in the treatment of patients with COPD. We used a randomised, double-blind, placebo-controlled design. We enrolled from 13 European countries, New Zealand, and South Africa, 281 outpatient current or ex-smokers, aged between 50 and 75 years. They had a forced expiratory volume in 1 s (FEV1) of between 35% and 90% of predicted normal values, a ratio of FEV1 to forced vital capacity of 70% or less and bronchodilator reversibility of less than 15%, as well as a history of chronic bronchitis. Patients were randomly assigned fluticasone propionate 500 microg (n=142) or placebo (n=139) twice daily via a metered-dose inhaler for 6 months. The main outcome measures were the number of patients who had at least one exacerbation by the end of treatment, the number and severity of exacerbations, clinic lung function, diary card symptoms and peak expiratory flow and 6 min walking distance. 51 (37%) patients in the placebo group compared with 45 (32%) in the fluticasone propionate group had had at least one exacerbation by the end of treatment (p=0.449). Significantly more patients had moderate or severe exacerbations in the placebo group than in the fluticasone propionate group (86% vs 60%, p&lt;0.001). Diary-card and clinic morning peak expiratory flows improved significantly in the fluticasone propionate group (p&lt;0.001, p=0.048, respectively), as did clinic FEV1 (p&lt;0.001), forced vital capacity (p&lt;0.001), and mid-expiratory flow (p=0.01). Symptom scores for median daily cough and sputum volume were significantly lower with fluticasone propionate treatment than with placebo (p=0.004 and p=0.016, respectively). At the end of treatment, patients on fluticasone propionate had increased their 6 min walking distance significantly more than those on placebo (p=0.032). Fluticasone propionate was tolerated as well as placebo, with few adverse effects and without a clinically important effect on mean serum cortisol concentration. Fluticasone propionate may be of clinical benefit in patients with COPD over at least 6 months. Inhaled corticosteroids may have an important role in the long-term treatment of COPD. Chronic obstructive pulmonary disease (COPD) is characterized by slow progressive deterioration of respiratory function with systemic effects which have a great impact on health-related quality of life (HRQoL). The severity of airflow limitation in COPD, as reflected by forced expiratory volume in one second (FEV1) does not represent the systemic consequences of COPD. Hence, a multidimensional grading system, BODE index (Body mass index, Airflow obstruction, Dyspnea and Exercise capacity) that assessed both the pulmonary and systemic manifestations has recently been proposed to provide useful prognostic information and predict the outcome in COPD patients. The objective of this study was to evaluate the relationship between BODE index and health-related quality of life (HRQOL) in stable COPD patients and its usefulness in predicting the disease exacerbations. Sixty stable COPD patients who presented in the out-patient departments of Medicine and Pulmonology were recruited over one year period. We evaluated them by body-mass index, forced expiratory volume in one second (FEV1), Modified Medical Research Council dyspnea scale and six minute walk test (6MWT). BODE index was calculated using these variables. Disease duration, number of exacerbations and hospitalization in the previous year were recorded. We also administered the St. George's Respiratory Questionnaire (SGRQ) to assess the health related quality of life (HRQoL) in these patients. BODE scores were categorized into four quartiles, quartile one to four with scores of 0-2, 3-4, 5-6 and 7-10, respectively. According to BODE score, (16) 26.7% of patients were BODE 1, (27) 45% BODE 2, (15) 25% BODE 3 and (2) 3.3% were BODE 4. Higher BODE quartiles were associated with higher total SGRQ scores and SGRQ subscale scores (symptom, activity and impact). Very strong correlations were found between BODE quartiles and total SGRQ scores (<iP</i &lt; 0.01). Among the components of BODE index, the decrease in the FEV1 (%predicted) and 6MWD, and the increase of MMRC dyspnea grade were associated with worsening of health status (increase in total SGRQ and SGRQ subscales). BODE index also correlated with the acute exacerbations (<iP</i &lt; 0.0012) during one year follow-up. BODE index strongly correlated with the HRQoL and also reliably predicted acute exacerbations in stable COPD patients.   The aim of this study was to describe the management and prognosis related to a hospital admission for acute exacerbation of chronic obstructive pulmonary disease and to compare results to an earlier study.   This is a retrospective study of 300 consecutively discharged patients admitted in 2006-2007 with an exacerbation of chronic obstructive pulmonary disease from three respiratory departments. Data were collected from patient charts and compared with a replicate study done in 2001.   The mean age was 72.1years; 61.7% were women. Mean forced expiratory volume in 1s was 37.6% of predicted. On admission, 11.3% were treated with non-invasive ventilation, and 84.3% were given systemic corticosteroids. In-hospital mortality was 4.7%. At discharge, treatment with inhaled corticosteroids or at least one long-acting bronchodilator was given to 86.7% and 89% of patients, respectively, which was significantly higher than for similarly sampled patients in 2001. Mortality in 30days and 1year after discharge was 4.5% and 25.5%, respectively, compared with 5.5% and 30.3% in 2001, the 12-month mortality being significantly lower (P=0.03). Readmission rate in the 12months following discharge was 42.3%. Long-term oxygen treatment, treatment with anti-dysrhythmic drugs and lack of outpatient follow-up were independent predictors of 1-year mortality. Risk of readmission was increased with dependence in self-care activities, previous admissions and treatment with strong analgesics.   Over a period of 6years, a significantly higher number of patients are being treated according to guidelines. Survival following discharge increased over the same period. In addition to smoking, acute exacerbations are considered to be a contributing factor to progression of chronic obstructive pulmonary disease (COPD). However, these findings come from studies including active smokers, while results in ex-smokers are scarce and contradictory. The purpose of this study was to evaluate if frequent acute moderate exacerbations are associated with an accelerated decline in forced expiratory volume in one second (FEV1) and impairment of functional and clinical outcomes in ex-smoking COPD patients. A cohort of 100 ex-smoking patients recruited for a 2-year follow-up study was evaluated at inclusion and at 6-monthly scheduled visits while in a stable condition. Evaluation included anthropometry, spirometry, inspiratory capacity, peripheral capillary oxygen saturation, severity of dyspnea, a 6-minute walking test, BODE (Body mass index, airflow Obstruction, Dyspnea, Exercise performance) index, and quality of life (St George's Respiratory Questionnaire and Chronic Respiratory Disease Questionnaire). Severity of exacerbation was graded as moderate or severe according to health care utilization. Patients were classified as infrequent exacerbators if they had no or one acute exacerbation/year and frequent exacerbators if they had two or more acute exacerbations/year. Random effects modeling, within hierarchical linear modeling, was used for analysis. During follow-up, 419 (96% moderate) acute exacerbations were registered. At baseline, frequent exacerbators had more severe disease than infrequent exacerbators according to their FEV1 and BODE index, and also showed greater impairment in inspiratory capacity, forced vital capacity, peripheral capillary oxygen saturation, 6-minute walking test, and quality of life. However, no significant difference in FEV1 decline over time was found between the two groups (54.7±13 mL/year versus 85.4±15.9 mL/year in frequent exacerbators and infrequent exacerbators, respectively). This was also the case for all other measurements. Our results suggest that frequent moderate exacerbations do not contribute to accelerated clinical and functional decline in COPD patients who are ex-smokers. Acute exacerbation of chronic obstructive pulmonary disease (COPD) is defined by modification of the usual COPD symptoms, dyspnea, coughing and sputum, beyond daily variations, with a sudden onset, and requiring modification of the usual treatment. Exacerbations stud the course of COPD. Their frequency is variable, averaging 1-2 per year. Their frequency generally increases with COPD severity. Exacerbations impair patients' quality of life and aggravate disease prognosis by accelerating the decline in FEV1, the primary indicator of respiratory function. The most frequent causes of exacerbations are viral and bacterial respiratory infections and pollution. No cause is identified for nearly one third of all exacerbations. Most exacerbations can be treated at home, if a careful search for signs of clinical severity is negative. Treatment combines inhaled bronchodilator agents (beta-2 agonists, combined if necessary with anticholinergics) and oral corticosteroid therapy (prednisone: 0.5 mg/kg/d for 1 week) when the COPD is severe or signs of severity accompany the exacerbation. Antibiotic therapy is justified when the sputum appears purulent. Severe exacerbation may require oxygen therapy in cases of severe hypoxemia (PaO(2)&lt;60 mm Hg) or mechanically assisted ventilation, essentially by noninvasive ventilation in cases of respiratory acidosis (pH&lt;7.35). Noninvasive ventilation improves dyspnea and respiratory acidosis, diminishes respiratory frequency, intubation, duration of hospitalization, nosocomial infections, and mortality. Pulmonary follow-up is necessary after an exacerbation, especially to prevent the recurrence of exacerbations by measures that have been demonstrated to be effective, including help in smoking cessation, adaptation of COPD treatment, vaccination against influenza and pneumonia (pneumococci), and respiratory rehabilitation. Early diagnosis and rapid treatment of exacerbations can limit their impact, improve quality of life, and reduce the risk of hospitalization.\nHere is the question:\nPNEUMOLOGY AND THORACIC SURGERY: A 67-year-old man, ex-smoker, with a diagnosis of severe COPD (multidimensional index BODE 5, FEVl 38%, body mass index 23, dyspnea index according to the mMRC 3 scale, distance covered in the 6-minute walk test 260 m) who has had 3 hospital admissions for exacerbation of his COPD in the last 7 months, comes to the consultation. She also has a history of hypertension, ischemic heart disease with AMI 5 years ago and intermittent claudication. In the clinical examination, there is a decrease in vesicular murmur with expiratory wheezing in both lung fields and an oximetry saturation of 88%. Which of the following therapeutic strategies would NOT be recommended for this patient?\nHere are the potential choices:\n1. Adjustment of inhaled therapy with long-acting bronchodilators combining anticholinergics and beta-2 adrenergics with inhaled glucocorticoids.\n2. Start oral glucocorticoids for 6 months to control exacerbations.\n3. Check that the patient performs the inhalation technique correctly.\n4. Initiate chronic home oxygen therapy regimen.\nThe correct answer is: 4. Initiate chronic home oxygen therapy regimen."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 71-year-old woman with a history of previous myocardial infarction was transferred to our hospital for evaluation of chest pain and ventricular tachycardia. On admission, a loud mid-systolic ejection murmur accompanied by a thrill was found at the left sternal border in the third intercostal space, and it was significantly accentuated in the post-extrasystolic beat. Abnormal Q waves and ST elevations were noted in leads I, aVL and V5,6 on electrocardiograms. Echocardiograms, confirmed a septal-to-apical aneurysm, and a thin interventricular septum (IVS) with paradoxical motion. Right ventricular (RV) catheterization showed a pressure gradient of 21 mmHg between the outflow tract (RVOT) and the apex, and a mid-systolic ejection murmur was recorded in the RVOT on an intracardiac phonocardiogram. Coronary arteriograms revealed total occlusion of the left anterior descending artery in its proximal portion, and a 90% stenosis of the circumflex artery. A left ventriculogram demonstrated a septal-to-apical aneurysm with a markedly reduced ejection fraction of 0.16. A right ventriculogram showed obstruction to RVOT caused by systolic ballooning of the IVS. In this patient, the mid-systolic ejection murmur was probably caused by the obstruction of the outflow tract secondary to septal aneurysm following old myocardial infarction. A 74-year-old female was admitted to our hospital due to prolonged chest pain that had lasted about 2 h. An electrocardiogram revealed ST-elevation in leads I, aVL, and V3-6, with an increase in myocardial necrosis markers. Emergency coronary angiography was performed, and left ventriculography showed the typical features of apical ballooning, and so a diagnosis of Takotsubo cardiomyopathy (TC) was made. On the 10th day after admission, the patient suddenly went into cardiopulmonary arrest because of a blow-out type left ventricular (LV) free wall rupture. Despite extensive cardiopulmonary resuscitation, the patient died. The autopsy revealed hemopericardium and a perforating wound located in the anterior wall of the LV. It was revealed that the diagonal branch of the coronary artery was occluded, and so a diagnosis of TC coexisting with acute myocardial infarction (AMI) was made. No previous case of TC accompanied by AMI has been reported. We present its clinical course during hospitalization and the result of a histopathologic examination. A 59-year-old woman was admitted to our hospital with acute pulmonary oedema and cardiogenic shock 35 days after anterior ST elevation myocardial infarction. She developed a new loud pan systolic murmur. Echocardiography revealed a ventricular septal rupture with a significant left to right shunt. She was immediately transferred to the local cardiothoracic unit where she underwent a successful ventricular septal defect (VSD) repair. Ventricular septal rupture often presents within the first 24 hours of acute myocardial infarction and is rare thereafter. It carries a poor mortality (41-80%) even when recognised. Timely recognition of this life-threatening complication can help reduce the resultant morbidity and mortality. Doctors should be aware that this well-recognised complication may present unusually late as in this case. We herein present an unusual case of a pseudoaneurysm of the left ventricular myocardium, which is a rare and fatal complication of myocardial infarction. A 64-year-old man with a history of bipolar disorder and arterial hypertension was hospitalized for delayed presentation ST-elevation myocardial infarction. He was admitted to our hospital 24 hours after symptom onset. Diagnostic coronary angiography revealed 95% stenosis at the distal third of the right coronary artery, and he underwent a primary percutaneous coronary intervention to the culprit lesion. Despite administration of a diuretic and optimization of other pharmaceutical treatment, his heart failure deteriorated. Electrocardiography showed a sinus rhythm with Q-wave formation in the inferior wall leads (II, III, aVF), T-wave inversion in the same leads, and borderline QT prolongation (QTc of 490 ms). No ST elevation suggestive of left ventricular aneurysm formation was noticed. Forty days later, cardiac ultrasound revealed a dyskinetic cavity (pseudoaneurysm) in continuity with the posterior-inferior wall of the myocardium, resulting in severe mitral valve regurgitation. Unfortunately, the patient died while awaiting surgical treatment. Although most patients with left ventricular pseudoaneurysm have a relatively benign outcome, those with symptoms of heart failure must be urgently diagnosed and treated. Four patients with acute myocardial infarction (MI) complicating double rupture; interventricular septum and ventricular free wall ruptures, were studied. All patients had histories of hypertension, and pre-infarction angina pectoris of short duration less than 8 days without previous MI. The sites of infarction were anteroseptal in 2 patients and inferoposterior in the other 2. Only one case was complicated with mild pump failure (Killip class II). Blood pressure was adequately controlled after the onset of MI in all patients. Interventricular septal rupture occurred between 2 and 10 days after the onset of MI. Free wall rupture occurred between 2 and 22 days after MI. Types of free wall ruptures were oozing in 2 patients and blow-out in the other 2. Surgical repair was performed in 2 patients with the oozing type rupture, who however died soon after surgery. The autopsy findings were as follows: 3 patients had left ventricular free wall ruptures and one had right ventricular free wall rupture. One of the patients with left ventricular free wall rupture showed a secondary rupture of a pseudo-ventricular aneurysm. Postmortem coronary angiograms revealed 3 patients with single-vessel disease and one patient with double-vessel disease, indicating that coronary arterial lesions and complicated heart failure were not severe in these 4 patients.(ABSTRACT TRUNCATED AT 250 WORDS) A 83-year-old man, who experienced a sudden severe malacia 13 days before, was admitted, complaining of dyspnea since 8 hours before. A loud systolic murmur of Levine IV/VI was audible on the left sternal border of the 4th intercostal space. The chest X-ray film demonstrated severe pulmonary congestion. The ECG showed abnormal Q waves in II, III, a VF and V1-5. The right heart catheterization revealed an intraventricular shunt from left to right and thus ventricular septal perforation (VSP) 13 days after acute anteroseptal-inferior myocardial infarction was diagnosed. Continuing an aggressive medical treatment with the intraaortic balloon pumping, an emergency operation for VSP was performed 2 days after the onset. A single Teflon patch was sutured on the left side of the septum around VSP (2.5 x 2.5 cm) and the ventricular free wall was closed including the patch with two felt strips. The patient survived through the operation and is doing well at the 11 months of follow-up. Twenty patients above 70 years old have been surgically treated with success for VSP after acute myocardial infarction in Japan. Our patient was the oldest. A 57-year-old woman presented with acute-onset dyspea with a duration of more than 2 days. Four days earlier, she had been thrombolyzed with streptokinase for inferior wall myocardial infarction in a nearby hospital. On examination, we found that the patient had elevated jugular venous pressure and systolic murmur in left lower parasternal region. In addition, there was a ventricular septal rupture in the posterobasal interventricular septum, with at least 2 exit points into the right ventricle. Timely identification of ventricular septal rupture before PCI is of paramount importance, as it has major implications in management of the patient. This is a report of the echocardiographic features of postinfarction perforation associated with dissection of the interventricular septum (IVS) in a 61-year-old woman. She had acute myocardial infarction and was admitted to a nearby hospital, and later admitted to our CCU because hemodynamic deterioration. On admission, she was somnolent and hypotensive (90/64 mmHg), with sinus tachycardia, marked cyanosis, and peripheral edema. On auscultation there were a harsh holosystolic murmur over the LLSB and moist rales in both lung fields. An ECG revealed extensive anterior and inferior infarctions. Catheterization data confirmed O2 step-up in the right ventricle. Two-dimensional echocardiograms demonstrated extensive dissection of the IVS characterized by an echo-free lumen extending from the apex to the cardiac base in the long-axis and partly reaching the left ventricular free wall in the short-axis with the concomitant paradoxical movement of the IVS. Autopsy disclosed marked hemorrhagic infarction and extensive dissection of the IVS forming a lumen (5 X 5.5 X 2 cm3) corresponding exactly to the echocardiographic free space. In addition, a shunt between the right and left ventricles was confirmed by the presence of two perforations near the apex on the right and left sides of the IVS, whose diameters were 6 and 10 mm, respectively. Ventricular septal defect (VSD) is a severe complication of acute myocardial infarction and has a high mortality rate. This complication appears to have declined in the reperfusion era. It has mostly been reported in elderly or female patients who suffer from anterior wall infarction, patients with multivessel coronary artery disease (CAD) or occluded infarct-related artery (IRA) without collateral circulation, or patients who have had delayed reperfusion therapy. Here, we report the case of a 60-year-old male patient who presented with persistent chest pain and Killip I ST-segment-elevation myocardial infarction. Thrombolytic therapy was started 3 hours after the onset of chest pain. Based on the subsidence of chest pain, resolution of the elevated ST segment, and early peak of cardiac enzymes, reperfusion was thought to be successful. However, on the third day of admission, the patient complained of dyspnea after defecation and was found to have new-onset grade 3 pansystolic murmur over the left sternal border. Cardiac echography showed an apical VSD. A Swan-Ganz catheter was inserted into the right side of the heart; analysis of blood oxygen saturation revealed a 6% step-up of oxygen in the right ventricle. Coronary angiography showed only one-vessel CAD and TIMI 3 flow in the IRA. The patient received intensive medical management and underwent VSD repair and internal mammary artery bypass grafting to the left anterior descending artery. His recovery was uneventful. This case illustrates that VSD can be found in patients receiving early successful reperfusion therapy, with one-vessel CAD, and TIMI 3 flow in the IRA. Takotsubo cardiomyopathy is characterized by transient dysfunction of the medial to apical segment of the left ventricle. Recurrence within a few months or years has been reported and serious complications, including arrhythmia, acute cardiac shock and cardiac rupture, can arise; however, recurrence is rare and takotsubo cardiomyopathy is typically a reversible functional disorder. A 91-year-old Japanese woman with a past medical history of angina pectoris, hypertension and uterine carcinoma noted bilateral axillary pain and presented herself to an emergency room. Although the pain improved and she went home, there were several subsequent episodes of recurrent chest pain. At approximately 1 week after the onset, she was hospitalized as her symptom worsened. Electrocardiography showed low voltage in limb and chest leads, and ST-segment elevation in leads II, III, aVF and V3 to V6. Echocardiography revealed medial to apical dyskinesia and basal hypercontractility of the left ventricle, and cardiac tamponade. Pericardiocentesis improved the symptom, but not her cardiac dysfunction. At 3 days after her admission, cardiopulmonary resuscitation was performed due to ventricular fibrillation. She died on the 5th day of admission (2 weeks after the onset). At autopsy, the left ventricle was dilatated and the apical ventricular wall was thin. On microscopy, remarkable wavy change and thinning of myocardium were diffusely observed, especially at the apex and the anterior to lateral wall of the left ventricle, interventricular septum and right ventricle, intermingled with interstitial fibrosis, hemorrhage and neutrophil infiltration. Contraction band necrosis was mainly observed on the posterior to inferior wall of the left ventricle. Our case showed severe morphological myocardial change after several chest pain episodes that were considered to be takotsubo cardiomyopathy. This notable case suggests that the frequent recurrence of serious takotsubo cardiomyopathy is life threatening and can lead to irreversible serious myocardial degeneration. A 58-year-old man presented to the chest pain unit with crescendo angina over 24 hours and worsening dyspnoea of 10 hours duration. He was a known diabetic and hypertensive on regular treatment for 10 years and a habitual smoker with over 15 pack-years smoking duration. Examination revealed a profusely diaphoretic and dyspnoeic (respiratory rate of 45/min) individual with a blood pressure of 100/60 mm Hg and heart rate of 124 beats/min. He was hypoxic and his oxygen saturation in the ambient air was 64%. His jugular venous pressure was elevated with a prominent V wave. Cardiovascular examination revealed a harsh grade IV/VI systolic murmur over the lower left parasternal border. There were bilateral extensive crepitations heard over the lung fields. ECG on admission revealed presence of Q wave and ST elevation in leads II and III, aVF with ST depression in I and aVL. X-ray chest showed normal cardiac shadow and features of grade III pulmonary venous hypertension. Transthoracic echocardiography is shown in figure 1.Figure 1Transthoracic echocardiogram short axis view at mid cavity level, 2D (A) and colour Doppler (B) image. <bWhat is the most likely diagnosis</b?A. Left ventricular (LV) true aneurysmB. LV pseudoaneurysmC. LV pseudo-pseudoaneurysmD. Ventricular septal rupture (VSR)E. LV free wall rupture. Dissection of the inferior wall of the right ventricle during the acute phase of myocardial infarction with right ventricular involvement is a mechanical complication which has been recently identified, the diagnosis being almost exclusively post-mortem. The authors report the clinical, echocardiographic and pathological features of myocardial dissection in four patients. Between 1985 and 1988, the diagnosis of myocardial dissection was made by echocardiography in 4 patients aged 77 to 80 years, admitted to hospital for an acute inferior wall myocardial infarction. All 4 patients had signs of acute right ventricular failure indicating right ventricular necrosis and a loud systolic murmur at the left sternal border; 2 patients were in shock. The ECG showed signs of inferior wall infarction with, in 2 patients, electrical changes suggestive of right ventricular involvement. Echocardiography showed dissection of the inferior wall of the right ventricle as a pulsatile, echo-free space in the diaphragmatic wall of the right ventricle which appeared to obstruct right ventricular ejection in end systole to a variable degree. The outcome was fatal in all cases with death resulting from refractory myocardial failure. Pathological analysis confirmed biventricular inferior wall infarction also involving the posterior part of the interventricular system, the site of a small tear on the left side which communicated with a neo-cavity dissecting the RV posterior wall. The right coronary artery was totally occluded in all cases. The anatomical lesions were fully concordant with the echocardiographic data: the dissection filled with blood from the left ventricle at each systole creating a pulsatile space in the diaphragmatic wall of the ventricle obstructing ejection. In this report, we present a case of interventricular septal dissection (IVSD) following inferior wall myocardial infarction (MI) in a 64-year-old patient; the patient ultimately recovered after prompt resuscitation and intervention, despite the high mortality associated with these cases. A 64-year-old male with a history of hypertension and obesity was brought to the hospital following an episode of syncope at home. He had been experiencing chest tightness over the past few days prior to the admission. On physical exam, he had a heart rate of 72 beats per minute and blood pressure of 73/52 mmHg. His electrocardiogram revealed ST-segment elevations in leads II, III, and aVF. Emergent coronary angiography revealed 100% occlusion of the right coronary artery (RCA) with no collateral supply and 95% stenosis of the left anterior descending (LAD) artery. Aspiration thrombectomy and balloon angioplasty and subsequent stenting of the RCA were performed. Transthoracic echocardiogram with color Doppler was performed, which confirmed the presence of a defect in the septum. Color Doppler demonstrated a clear jet entering the ventricular septum from the left ventricle (LV), with the jet traversing the entire length of the septum through a dissection and entering into the right ventricle (RV), consistent with complete IVSD. The patient subsequently underwent a successful bovine pericardial patch repair of the ventricular septum. IVSD is a rare anomaly of the IVS. An echocardiogram is a useful tool to establish the diagnosis. The mortality rate after ventricular septal rupture remains high. Fortunately, our patient had interventricular dissection without rupture. Prompt surgical repair remains the choice of treatment for this condition. Although left ventricular aneurysm (LVA) is the most common mechanical complication of myocardial infarction (MI), it rarely involves the inferior or posterior left ventricular wall. Ventricular septal rupture (VSR) may be a fatal mechanical complication of MI but rarely occurs in the posterior or inferior portion of the interventricular septum. Thus, LVA and VSR as two mechanical complications of MI in the same patient are extremely rare. A 65-year-old woman, who had inferior ST-segment elevation myocardial infarction 2 months before without reperfusion therapy, was admitted with exertional dyspnoea for 1 month. Echocardiography and computed tomography revealed true inferoposterior LVA and VSR as concurrent complications of MI. These imaging findings were confirmed during cardiac surgery. After successful coronary bypass grafting and ventriculoplasty, the patient recovered quickly and was discharged from the hospital. A rare case of post-infarction inferoposterior LVA with concurrent interventricular septal rupture was reported. Transthoracic and transoesophageal echocardiography and cardiac computed tomography were valuable tools for the diagnosis of this rare condition. Combined coronary bypass grafting and ventriculoplasty were effective in treating this often fatal complication of inferior MI. A 75-year-old woman was admitted complaining of anterior chest pains, and peripheral coldness. The 6th day after admission, a loud systolic murmur of Levine IV/VI was audible at the apex. The chest X-ray film demonstrated a cardiomegaly and ST elevation in the V1-V5 leads. UCG and right-heart catheterization revealed an intraventricular shunt from left to right, and the diagnosis of ventricular septal perforation after acute antero-septal myocardial infarction was confirmed. Although, we were continuing and aggressive medical treatment with the intraaortic balloon pumping, an emergency operation for ventricular septal perforation was performed, 15 days after onset. The direct closure of the septal perforation and the plication of the left ventricular free wall with two felt strips were performed. The postoperative course seemed well. But in the 3rd postoperative day, massive bleeding was recognized through the drainage tube. The left ventricular rupture was suggested, and a massive blood transfusion was done. An emergency operation was performed. Another left ventricular free wall was lacerated about 6 mm at the apex. The laceration was closed with teflon felt strips. The patient survived through the operation, and is doing well after 7 years since the operation. Left ventricular false aneurysms are rare. They are secondary to a myocardial rupture which is contained by adherent pericardium and scar tissue. LV pseudoaneurysm contains no endocardium or myocardium unlike left ventricular true aneurysm. Most cases of LV pseudoaneurysm are related to acute myocardial infarction in inferior or posterior wall. We report a case of a 56-year-old man with a medical history of chronic cigarette smoking, dyslipidemia, and obesity. The patient had no myocardial infarction before. He was admitted for evaluation of important shortness of breath at effort without chest pain for 5 months. Physical exam find an enlarged left ventricular. The electrocardiogram revealed Q waves and ST segment elevation in leads V1 to V6. Transthoracic echocardiogram showed a large thrombosed apical left ventricular false aneurysm, severe left ventricular dysfunction, which were confirmed by cardiac magnetic resonance imaging, this exam also showed no viability in the mid left anterior descending coronary artery territory. The coronary angiography showed an occlusion of the mid left anterior descending coronary artery and a stenosis of the first diagonal artery. The patient was offered a surgical aneurysectomy with coronary artery bypass. The surgery was successful with amelioration of symptoms. We present a rare case of a giant false left ventricular aneurysm complicating a silent myocardial infarction in the anterior wall. The diagnosis is made by cardiac echocardiogram and cardiac magnetic resonance imaging. Because of the important risk of rupture, the surgical treatment is required. Septal rupture (SR) during acute myocardial infarction (AMI) was found in 23 patients of 4 300 consecutive cases of AMI. In 55% the SR was diagnosed clinically by the appearance of a murmur, in 23% by shock and in 22% by heart failure. Eventually every patient developed a pan-systolic murmur. In 82% of the cases the murmur was best heard at the lower left sternal border. In half of the patients the location of the murmur suggested the possibility of papilary muscle rupture or dysfunction. In 68% of cases the rupture occurred during the first week after the onset of AMI. Cardiac catheterization was performed in 17 patients, pulmonary hypertension was found in all of them. Pulmonary blood flow was twice the systemic blood flow (P less than 0.005). Coronary angiograms performed in 6 patients showed three vessel disease in 5 cases. Five patients underwent surgery. Three of them survived. All of the 17 patients who had medical treatment died. Ten within the first week after AMI, 5 within the first month and 2 late deaths. Autopsy was performed in 15 cases. Eighty percent had coronary narrowing in several vessels. SR measured between 5 and 20 millimeters in 78% and was found in the anterior septum in 61%. In the cases who were in shock, the ventricular myocardium was extensively damaged. We conclude that once the diagnosis of SR is established, the patient should undergo surgical closure of the SR and coronary revascularization if necessary. Early surgical indication is particularly important in patients at risk of developing shock. A 50-year-old hypertensive smoker presented with a typical angina of 2 days duration. An urgent ECG revealed extensive anterior wall myocardial infarction. In view of the delayed presentation, the patient was conservatively managed with heparin. In-hospital echocardiogram showed akinesia of entire left anterior descending artery (LAD) territory with severe left ventricular (LV) dysfunction. He was discharged with a plan for early coronary intervention. However, he presented a fortnight later with acute pulmonary oedema. General appraisal revealed a restless individual who was dyspnoeic and diaphoretic at rest. On clinical examination, the patient was in hypotension with features of biventricular failure. A 12-lead ECG showed QS pattern with persistent ST segment elevation in precordial leads. The chest radiograph demonstrated features of pulmonary oedema, cardiomegaly and bilateral pleural effusion. Creatine Phosphokinase-MB (CPK-MB) was negative. A preliminary transthoracic echocardiography was done (figure 1 and see online supplementary video 1). What is the most likely diagnosis based on the echocardiogram? LV pseudo-aneurysm with contained ruptureDissecting intramural haematoma of LV apexVentricular apical aneurysm with thrombusLV non-compaction with prominent ventricular trabaculations. Cardiogenic shock caused by papillary muscle rupture in acute myocardial infarction is potentially reversible by surgical treatment. A case of posterior myocardial infarction in a 79-year-old woman is reported. She was admitted to the hospital in cardiogenic shock. She had been suffered from chest pain for three days before admission. On physical examination diffuse rales and a grade 4/6 holosystolic apical murmur were present. The diagnosis of an acute posterior myocardial infarction was based on the electrocardiographic findings and serum creatine kinase level. Coronary angiography visualized subtotal occlusion of the left circumflex coronary artery. Transesophageal echocardiography demonstrated severe mitral regurgitation and the ruptured anterior papillary muscle connected to normal chordae tendineae and posterior mitral leaflet. In systole, the head of the ruptured papillary muscle moved like a whip in the left atrium. At operation, the ruptured papillary muscle was confirmed. Mitral valve replacement with a 27 mm St. Jude Medical prosthesis and coronary artery bypass grafting to the left circumflex coronary artery was performed. Postoperatively she was weaned intraaortic balloon pumping after 4 days and recovered uneventfully. A rupture of the interventricular septum, as described in a case report, is found in 2% of myocardial infarctions. Clinical symptom loud systolic murmur audible at the left sternal border associated with a thrill and with signs of cardiogenic shock. The diagnosis is made by right heart catheterisation which shows a typical oxygen stepup between right atrium and right ventricle, by which the rupture of the interventricular septum can be differentiated from acute papillary muscle rupture. The therapy should be at first hemodynamic stabilisation by drugs and intraaortic balloon pump for 4 to 6 weeks and then closure of the ventricular septal defect by operation. Ventricular septal rupture is a potentially fatal complication of acute myocardial infarction. Its incidence has declined with modern reperfusion therapy. In the era of percutaneous coronary interventions, it occurs a median of 18-24 hours after myocardial infarction and is most commonly associated with anterior myocardial infarction. We present a case of delayed ventricular septal rupture complicating acute inferior wall myocardial infarction. A 53-year-old Caucasian male presented with epigastric pain for three days and electrocardiographic evidence for an acute inferior wall myocardial infarction. Coronary angiography revealed a total occlusion of the proximal right coronary artery. Reperfusion was achieved by balloon angioplasty followed by placement of a bare metal stent. On hospital day six, the patient developed acute respiratory distress, a new loud pansystolic murmur, and hemodynamic instability. Echocardiography revealed the presence of a large defect in the inferobasal interventricular septum with significant left-to-right shunt consistent with ventricular septal rupture. The patient underwent emergent surgical repair with a bovine pericardial patch. Ventricular septal rupture after myocardial infarction should be suspected in the presence of new physical findings and hemodynamic compromise regardless of revascularization therapy. The precise clinical features and etiologic basis of Takotsubo syndrome remain unclear, although an association with emotional or stressful triggers has been recognized. Ventricular septal perforation is a very rare life-threatening complication. A 77-year-old female patient presented to the hospital with unrelieved chest tightness and shortness of breath. Three months ago, the patient's electrocardiogram revealed ischemic T wave inversion of the anterior wall, along with an increase in myocardial injury markers. There was no evidence of a ventricular septal defect on echocardiography. The patient was admitted to the respiratory department to treat lung lesions. The electrocardiogram demonstrated dynamic changes following admission, and the myocardial markers returned to normal, but the echocardiography revealed a ventricular septal defect. The initial diagnosis was ventricular septal perforation because of myocardial infarction with acute anterior ST-segment elevation. Coronary angiography revealed no abnormalities, but left ventricular angiography revealed an enlarged apex and VSD, with a right ventricular shunt bundle. Later, cardiac MRI revealed an apical ventricular septal defect. Further inquiry of the patient's medical history revealed that her husband died unexpectedly three months ago, and her daughter was seriously injured in a car accident, causing the patient severe emotional distress. Takotsubo syndrome was then determined in conjunction with the patient's medical history, symptoms, signs, and pertinent examinations. Without using a catheter or a surgical procedure, we managed the patient's medical condition. Two weeks later, the patient was discharged with symptoms improved. Takotsubo syndrome is comparable to an acute myocardial infarction on clinical and electrocardiographic examination in the absence of significant coronary disease. Although ventricular septal perforation is most commonly associated with acute myocardial infarction, it can also happen following Takotsubo syndrome. Takotsubo syndrome complicated by ventricular septal perforation is easily misdiagnosed. The early recognition and management of this condition can avoid or reduce morbidity and mortality.\nHere is the question:\nCARDIOLOGY AND CARDIOVASCULAR SURGERY: An 87-year-old woman with a history of hypertension was admitted 48 hours ago to the coronary unit for acute myocardial infarction with ST-segment elevation of anterior location. She reported dyspnea. Examination revealed a systolic murmur with fremitus, radiating to the right sternal border, which was not present on admission. What complication do you suspect?\nHere are the potential choices:\n1. Heart failure due to extensive necrosis.\n2. Anterior aneurysm.\n3. Left ventricular free wall rupture.\n4. Rupture in the interventricular septum.\nThe correct answer is: ",
        "gold_answer": "4 Rupture in the interventricular septum.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 71-year-old woman with a history of previous myocardial infarction was transferred to our hospital for evaluation of chest pain and ventricular tachycardia. On admission, a loud mid-systolic ejection murmur accompanied by a thrill was found at the left sternal border in the third intercostal space, and it was significantly accentuated in the post-extrasystolic beat. Abnormal Q waves and ST elevations were noted in leads I, aVL and V5,6 on electrocardiograms. Echocardiograms, confirmed a septal-to-apical aneurysm, and a thin interventricular septum (IVS) with paradoxical motion. Right ventricular (RV) catheterization showed a pressure gradient of 21 mmHg between the outflow tract (RVOT) and the apex, and a mid-systolic ejection murmur was recorded in the RVOT on an intracardiac phonocardiogram. Coronary arteriograms revealed total occlusion of the left anterior descending artery in its proximal portion, and a 90% stenosis of the circumflex artery. A left ventriculogram demonstrated a septal-to-apical aneurysm with a markedly reduced ejection fraction of 0.16. A right ventriculogram showed obstruction to RVOT caused by systolic ballooning of the IVS. In this patient, the mid-systolic ejection murmur was probably caused by the obstruction of the outflow tract secondary to septal aneurysm following old myocardial infarction. A 74-year-old female was admitted to our hospital due to prolonged chest pain that had lasted about 2 h. An electrocardiogram revealed ST-elevation in leads I, aVL, and V3-6, with an increase in myocardial necrosis markers. Emergency coronary angiography was performed, and left ventriculography showed the typical features of apical ballooning, and so a diagnosis of Takotsubo cardiomyopathy (TC) was made. On the 10th day after admission, the patient suddenly went into cardiopulmonary arrest because of a blow-out type left ventricular (LV) free wall rupture. Despite extensive cardiopulmonary resuscitation, the patient died. The autopsy revealed hemopericardium and a perforating wound located in the anterior wall of the LV. It was revealed that the diagonal branch of the coronary artery was occluded, and so a diagnosis of TC coexisting with acute myocardial infarction (AMI) was made. No previous case of TC accompanied by AMI has been reported. We present its clinical course during hospitalization and the result of a histopathologic examination. A 59-year-old woman was admitted to our hospital with acute pulmonary oedema and cardiogenic shock 35 days after anterior ST elevation myocardial infarction. She developed a new loud pan systolic murmur. Echocardiography revealed a ventricular septal rupture with a significant left to right shunt. She was immediately transferred to the local cardiothoracic unit where she underwent a successful ventricular septal defect (VSD) repair. Ventricular septal rupture often presents within the first 24 hours of acute myocardial infarction and is rare thereafter. It carries a poor mortality (41-80%) even when recognised. Timely recognition of this life-threatening complication can help reduce the resultant morbidity and mortality. Doctors should be aware that this well-recognised complication may present unusually late as in this case. We herein present an unusual case of a pseudoaneurysm of the left ventricular myocardium, which is a rare and fatal complication of myocardial infarction. A 64-year-old man with a history of bipolar disorder and arterial hypertension was hospitalized for delayed presentation ST-elevation myocardial infarction. He was admitted to our hospital 24 hours after symptom onset. Diagnostic coronary angiography revealed 95% stenosis at the distal third of the right coronary artery, and he underwent a primary percutaneous coronary intervention to the culprit lesion. Despite administration of a diuretic and optimization of other pharmaceutical treatment, his heart failure deteriorated. Electrocardiography showed a sinus rhythm with Q-wave formation in the inferior wall leads (II, III, aVF), T-wave inversion in the same leads, and borderline QT prolongation (QTc of 490 ms). No ST elevation suggestive of left ventricular aneurysm formation was noticed. Forty days later, cardiac ultrasound revealed a dyskinetic cavity (pseudoaneurysm) in continuity with the posterior-inferior wall of the myocardium, resulting in severe mitral valve regurgitation. Unfortunately, the patient died while awaiting surgical treatment. Although most patients with left ventricular pseudoaneurysm have a relatively benign outcome, those with symptoms of heart failure must be urgently diagnosed and treated. Four patients with acute myocardial infarction (MI) complicating double rupture; interventricular septum and ventricular free wall ruptures, were studied. All patients had histories of hypertension, and pre-infarction angina pectoris of short duration less than 8 days without previous MI. The sites of infarction were anteroseptal in 2 patients and inferoposterior in the other 2. Only one case was complicated with mild pump failure (Killip class II). Blood pressure was adequately controlled after the onset of MI in all patients. Interventricular septal rupture occurred between 2 and 10 days after the onset of MI. Free wall rupture occurred between 2 and 22 days after MI. Types of free wall ruptures were oozing in 2 patients and blow-out in the other 2. Surgical repair was performed in 2 patients with the oozing type rupture, who however died soon after surgery. The autopsy findings were as follows: 3 patients had left ventricular free wall ruptures and one had right ventricular free wall rupture. One of the patients with left ventricular free wall rupture showed a secondary rupture of a pseudo-ventricular aneurysm. Postmortem coronary angiograms revealed 3 patients with single-vessel disease and one patient with double-vessel disease, indicating that coronary arterial lesions and complicated heart failure were not severe in these 4 patients.(ABSTRACT TRUNCATED AT 250 WORDS) A 83-year-old man, who experienced a sudden severe malacia 13 days before, was admitted, complaining of dyspnea since 8 hours before. A loud systolic murmur of Levine IV/VI was audible on the left sternal border of the 4th intercostal space. The chest X-ray film demonstrated severe pulmonary congestion. The ECG showed abnormal Q waves in II, III, a VF and V1-5. The right heart catheterization revealed an intraventricular shunt from left to right and thus ventricular septal perforation (VSP) 13 days after acute anteroseptal-inferior myocardial infarction was diagnosed. Continuing an aggressive medical treatment with the intraaortic balloon pumping, an emergency operation for VSP was performed 2 days after the onset. A single Teflon patch was sutured on the left side of the septum around VSP (2.5 x 2.5 cm) and the ventricular free wall was closed including the patch with two felt strips. The patient survived through the operation and is doing well at the 11 months of follow-up. Twenty patients above 70 years old have been surgically treated with success for VSP after acute myocardial infarction in Japan. Our patient was the oldest. A 57-year-old woman presented with acute-onset dyspea with a duration of more than 2 days. Four days earlier, she had been thrombolyzed with streptokinase for inferior wall myocardial infarction in a nearby hospital. On examination, we found that the patient had elevated jugular venous pressure and systolic murmur in left lower parasternal region. In addition, there was a ventricular septal rupture in the posterobasal interventricular septum, with at least 2 exit points into the right ventricle. Timely identification of ventricular septal rupture before PCI is of paramount importance, as it has major implications in management of the patient. This is a report of the echocardiographic features of postinfarction perforation associated with dissection of the interventricular septum (IVS) in a 61-year-old woman. She had acute myocardial infarction and was admitted to a nearby hospital, and later admitted to our CCU because hemodynamic deterioration. On admission, she was somnolent and hypotensive (90/64 mmHg), with sinus tachycardia, marked cyanosis, and peripheral edema. On auscultation there were a harsh holosystolic murmur over the LLSB and moist rales in both lung fields. An ECG revealed extensive anterior and inferior infarctions. Catheterization data confirmed O2 step-up in the right ventricle. Two-dimensional echocardiograms demonstrated extensive dissection of the IVS characterized by an echo-free lumen extending from the apex to the cardiac base in the long-axis and partly reaching the left ventricular free wall in the short-axis with the concomitant paradoxical movement of the IVS. Autopsy disclosed marked hemorrhagic infarction and extensive dissection of the IVS forming a lumen (5 X 5.5 X 2 cm3) corresponding exactly to the echocardiographic free space. In addition, a shunt between the right and left ventricles was confirmed by the presence of two perforations near the apex on the right and left sides of the IVS, whose diameters were 6 and 10 mm, respectively. Ventricular septal defect (VSD) is a severe complication of acute myocardial infarction and has a high mortality rate. This complication appears to have declined in the reperfusion era. It has mostly been reported in elderly or female patients who suffer from anterior wall infarction, patients with multivessel coronary artery disease (CAD) or occluded infarct-related artery (IRA) without collateral circulation, or patients who have had delayed reperfusion therapy. Here, we report the case of a 60-year-old male patient who presented with persistent chest pain and Killip I ST-segment-elevation myocardial infarction. Thrombolytic therapy was started 3 hours after the onset of chest pain. Based on the subsidence of chest pain, resolution of the elevated ST segment, and early peak of cardiac enzymes, reperfusion was thought to be successful. However, on the third day of admission, the patient complained of dyspnea after defecation and was found to have new-onset grade 3 pansystolic murmur over the left sternal border. Cardiac echography showed an apical VSD. A Swan-Ganz catheter was inserted into the right side of the heart; analysis of blood oxygen saturation revealed a 6% step-up of oxygen in the right ventricle. Coronary angiography showed only one-vessel CAD and TIMI 3 flow in the IRA. The patient received intensive medical management and underwent VSD repair and internal mammary artery bypass grafting to the left anterior descending artery. His recovery was uneventful. This case illustrates that VSD can be found in patients receiving early successful reperfusion therapy, with one-vessel CAD, and TIMI 3 flow in the IRA. Takotsubo cardiomyopathy is characterized by transient dysfunction of the medial to apical segment of the left ventricle. Recurrence within a few months or years has been reported and serious complications, including arrhythmia, acute cardiac shock and cardiac rupture, can arise; however, recurrence is rare and takotsubo cardiomyopathy is typically a reversible functional disorder. A 91-year-old Japanese woman with a past medical history of angina pectoris, hypertension and uterine carcinoma noted bilateral axillary pain and presented herself to an emergency room. Although the pain improved and she went home, there were several subsequent episodes of recurrent chest pain. At approximately 1 week after the onset, she was hospitalized as her symptom worsened. Electrocardiography showed low voltage in limb and chest leads, and ST-segment elevation in leads II, III, aVF and V3 to V6. Echocardiography revealed medial to apical dyskinesia and basal hypercontractility of the left ventricle, and cardiac tamponade. Pericardiocentesis improved the symptom, but not her cardiac dysfunction. At 3 days after her admission, cardiopulmonary resuscitation was performed due to ventricular fibrillation. She died on the 5th day of admission (2 weeks after the onset). At autopsy, the left ventricle was dilatated and the apical ventricular wall was thin. On microscopy, remarkable wavy change and thinning of myocardium were diffusely observed, especially at the apex and the anterior to lateral wall of the left ventricle, interventricular septum and right ventricle, intermingled with interstitial fibrosis, hemorrhage and neutrophil infiltration. Contraction band necrosis was mainly observed on the posterior to inferior wall of the left ventricle. Our case showed severe morphological myocardial change after several chest pain episodes that were considered to be takotsubo cardiomyopathy. This notable case suggests that the frequent recurrence of serious takotsubo cardiomyopathy is life threatening and can lead to irreversible serious myocardial degeneration. A 58-year-old man presented to the chest pain unit with crescendo angina over 24 hours and worsening dyspnoea of 10 hours duration. He was a known diabetic and hypertensive on regular treatment for 10 years and a habitual smoker with over 15 pack-years smoking duration. Examination revealed a profusely diaphoretic and dyspnoeic (respiratory rate of 45/min) individual with a blood pressure of 100/60 mm Hg and heart rate of 124 beats/min. He was hypoxic and his oxygen saturation in the ambient air was 64%. His jugular venous pressure was elevated with a prominent V wave. Cardiovascular examination revealed a harsh grade IV/VI systolic murmur over the lower left parasternal border. There were bilateral extensive crepitations heard over the lung fields. ECG on admission revealed presence of Q wave and ST elevation in leads II and III, aVF with ST depression in I and aVL. X-ray chest showed normal cardiac shadow and features of grade III pulmonary venous hypertension. Transthoracic echocardiography is shown in figure 1.Figure 1Transthoracic echocardiogram short axis view at mid cavity level, 2D (A) and colour Doppler (B) image. <bWhat is the most likely diagnosis</b?A. Left ventricular (LV) true aneurysmB. LV pseudoaneurysmC. LV pseudo-pseudoaneurysmD. Ventricular septal rupture (VSR)E. LV free wall rupture. Dissection of the inferior wall of the right ventricle during the acute phase of myocardial infarction with right ventricular involvement is a mechanical complication which has been recently identified, the diagnosis being almost exclusively post-mortem. The authors report the clinical, echocardiographic and pathological features of myocardial dissection in four patients. Between 1985 and 1988, the diagnosis of myocardial dissection was made by echocardiography in 4 patients aged 77 to 80 years, admitted to hospital for an acute inferior wall myocardial infarction. All 4 patients had signs of acute right ventricular failure indicating right ventricular necrosis and a loud systolic murmur at the left sternal border; 2 patients were in shock. The ECG showed signs of inferior wall infarction with, in 2 patients, electrical changes suggestive of right ventricular involvement. Echocardiography showed dissection of the inferior wall of the right ventricle as a pulsatile, echo-free space in the diaphragmatic wall of the right ventricle which appeared to obstruct right ventricular ejection in end systole to a variable degree. The outcome was fatal in all cases with death resulting from refractory myocardial failure. Pathological analysis confirmed biventricular inferior wall infarction also involving the posterior part of the interventricular system, the site of a small tear on the left side which communicated with a neo-cavity dissecting the RV posterior wall. The right coronary artery was totally occluded in all cases. The anatomical lesions were fully concordant with the echocardiographic data: the dissection filled with blood from the left ventricle at each systole creating a pulsatile space in the diaphragmatic wall of the ventricle obstructing ejection. In this report, we present a case of interventricular septal dissection (IVSD) following inferior wall myocardial infarction (MI) in a 64-year-old patient; the patient ultimately recovered after prompt resuscitation and intervention, despite the high mortality associated with these cases. A 64-year-old male with a history of hypertension and obesity was brought to the hospital following an episode of syncope at home. He had been experiencing chest tightness over the past few days prior to the admission. On physical exam, he had a heart rate of 72 beats per minute and blood pressure of 73/52 mmHg. His electrocardiogram revealed ST-segment elevations in leads II, III, and aVF. Emergent coronary angiography revealed 100% occlusion of the right coronary artery (RCA) with no collateral supply and 95% stenosis of the left anterior descending (LAD) artery. Aspiration thrombectomy and balloon angioplasty and subsequent stenting of the RCA were performed. Transthoracic echocardiogram with color Doppler was performed, which confirmed the presence of a defect in the septum. Color Doppler demonstrated a clear jet entering the ventricular septum from the left ventricle (LV), with the jet traversing the entire length of the septum through a dissection and entering into the right ventricle (RV), consistent with complete IVSD. The patient subsequently underwent a successful bovine pericardial patch repair of the ventricular septum. IVSD is a rare anomaly of the IVS. An echocardiogram is a useful tool to establish the diagnosis. The mortality rate after ventricular septal rupture remains high. Fortunately, our patient had interventricular dissection without rupture. Prompt surgical repair remains the choice of treatment for this condition. Although left ventricular aneurysm (LVA) is the most common mechanical complication of myocardial infarction (MI), it rarely involves the inferior or posterior left ventricular wall. Ventricular septal rupture (VSR) may be a fatal mechanical complication of MI but rarely occurs in the posterior or inferior portion of the interventricular septum. Thus, LVA and VSR as two mechanical complications of MI in the same patient are extremely rare. A 65-year-old woman, who had inferior ST-segment elevation myocardial infarction 2 months before without reperfusion therapy, was admitted with exertional dyspnoea for 1 month. Echocardiography and computed tomography revealed true inferoposterior LVA and VSR as concurrent complications of MI. These imaging findings were confirmed during cardiac surgery. After successful coronary bypass grafting and ventriculoplasty, the patient recovered quickly and was discharged from the hospital. A rare case of post-infarction inferoposterior LVA with concurrent interventricular septal rupture was reported. Transthoracic and transoesophageal echocardiography and cardiac computed tomography were valuable tools for the diagnosis of this rare condition. Combined coronary bypass grafting and ventriculoplasty were effective in treating this often fatal complication of inferior MI. A 75-year-old woman was admitted complaining of anterior chest pains, and peripheral coldness. The 6th day after admission, a loud systolic murmur of Levine IV/VI was audible at the apex. The chest X-ray film demonstrated a cardiomegaly and ST elevation in the V1-V5 leads. UCG and right-heart catheterization revealed an intraventricular shunt from left to right, and the diagnosis of ventricular septal perforation after acute antero-septal myocardial infarction was confirmed. Although, we were continuing and aggressive medical treatment with the intraaortic balloon pumping, an emergency operation for ventricular septal perforation was performed, 15 days after onset. The direct closure of the septal perforation and the plication of the left ventricular free wall with two felt strips were performed. The postoperative course seemed well. But in the 3rd postoperative day, massive bleeding was recognized through the drainage tube. The left ventricular rupture was suggested, and a massive blood transfusion was done. An emergency operation was performed. Another left ventricular free wall was lacerated about 6 mm at the apex. The laceration was closed with teflon felt strips. The patient survived through the operation, and is doing well after 7 years since the operation. Left ventricular false aneurysms are rare. They are secondary to a myocardial rupture which is contained by adherent pericardium and scar tissue. LV pseudoaneurysm contains no endocardium or myocardium unlike left ventricular true aneurysm. Most cases of LV pseudoaneurysm are related to acute myocardial infarction in inferior or posterior wall. We report a case of a 56-year-old man with a medical history of chronic cigarette smoking, dyslipidemia, and obesity. The patient had no myocardial infarction before. He was admitted for evaluation of important shortness of breath at effort without chest pain for 5 months. Physical exam find an enlarged left ventricular. The electrocardiogram revealed Q waves and ST segment elevation in leads V1 to V6. Transthoracic echocardiogram showed a large thrombosed apical left ventricular false aneurysm, severe left ventricular dysfunction, which were confirmed by cardiac magnetic resonance imaging, this exam also showed no viability in the mid left anterior descending coronary artery territory. The coronary angiography showed an occlusion of the mid left anterior descending coronary artery and a stenosis of the first diagonal artery. The patient was offered a surgical aneurysectomy with coronary artery bypass. The surgery was successful with amelioration of symptoms. We present a rare case of a giant false left ventricular aneurysm complicating a silent myocardial infarction in the anterior wall. The diagnosis is made by cardiac echocardiogram and cardiac magnetic resonance imaging. Because of the important risk of rupture, the surgical treatment is required. Septal rupture (SR) during acute myocardial infarction (AMI) was found in 23 patients of 4 300 consecutive cases of AMI. In 55% the SR was diagnosed clinically by the appearance of a murmur, in 23% by shock and in 22% by heart failure. Eventually every patient developed a pan-systolic murmur. In 82% of the cases the murmur was best heard at the lower left sternal border. In half of the patients the location of the murmur suggested the possibility of papilary muscle rupture or dysfunction. In 68% of cases the rupture occurred during the first week after the onset of AMI. Cardiac catheterization was performed in 17 patients, pulmonary hypertension was found in all of them. Pulmonary blood flow was twice the systemic blood flow (P less than 0.005). Coronary angiograms performed in 6 patients showed three vessel disease in 5 cases. Five patients underwent surgery. Three of them survived. All of the 17 patients who had medical treatment died. Ten within the first week after AMI, 5 within the first month and 2 late deaths. Autopsy was performed in 15 cases. Eighty percent had coronary narrowing in several vessels. SR measured between 5 and 20 millimeters in 78% and was found in the anterior septum in 61%. In the cases who were in shock, the ventricular myocardium was extensively damaged. We conclude that once the diagnosis of SR is established, the patient should undergo surgical closure of the SR and coronary revascularization if necessary. Early surgical indication is particularly important in patients at risk of developing shock. A 50-year-old hypertensive smoker presented with a typical angina of 2 days duration. An urgent ECG revealed extensive anterior wall myocardial infarction. In view of the delayed presentation, the patient was conservatively managed with heparin. In-hospital echocardiogram showed akinesia of entire left anterior descending artery (LAD) territory with severe left ventricular (LV) dysfunction. He was discharged with a plan for early coronary intervention. However, he presented a fortnight later with acute pulmonary oedema. General appraisal revealed a restless individual who was dyspnoeic and diaphoretic at rest. On clinical examination, the patient was in hypotension with features of biventricular failure. A 12-lead ECG showed QS pattern with persistent ST segment elevation in precordial leads. The chest radiograph demonstrated features of pulmonary oedema, cardiomegaly and bilateral pleural effusion. Creatine Phosphokinase-MB (CPK-MB) was negative. A preliminary transthoracic echocardiography was done (figure 1 and see online supplementary video 1). What is the most likely diagnosis based on the echocardiogram? LV pseudo-aneurysm with contained ruptureDissecting intramural haematoma of LV apexVentricular apical aneurysm with thrombusLV non-compaction with prominent ventricular trabaculations. Cardiogenic shock caused by papillary muscle rupture in acute myocardial infarction is potentially reversible by surgical treatment. A case of posterior myocardial infarction in a 79-year-old woman is reported. She was admitted to the hospital in cardiogenic shock. She had been suffered from chest pain for three days before admission. On physical examination diffuse rales and a grade 4/6 holosystolic apical murmur were present. The diagnosis of an acute posterior myocardial infarction was based on the electrocardiographic findings and serum creatine kinase level. Coronary angiography visualized subtotal occlusion of the left circumflex coronary artery. Transesophageal echocardiography demonstrated severe mitral regurgitation and the ruptured anterior papillary muscle connected to normal chordae tendineae and posterior mitral leaflet. In systole, the head of the ruptured papillary muscle moved like a whip in the left atrium. At operation, the ruptured papillary muscle was confirmed. Mitral valve replacement with a 27 mm St. Jude Medical prosthesis and coronary artery bypass grafting to the left circumflex coronary artery was performed. Postoperatively she was weaned intraaortic balloon pumping after 4 days and recovered uneventfully. A rupture of the interventricular septum, as described in a case report, is found in 2% of myocardial infarctions. Clinical symptom loud systolic murmur audible at the left sternal border associated with a thrill and with signs of cardiogenic shock. The diagnosis is made by right heart catheterisation which shows a typical oxygen stepup between right atrium and right ventricle, by which the rupture of the interventricular septum can be differentiated from acute papillary muscle rupture. The therapy should be at first hemodynamic stabilisation by drugs and intraaortic balloon pump for 4 to 6 weeks and then closure of the ventricular septal defect by operation. Ventricular septal rupture is a potentially fatal complication of acute myocardial infarction. Its incidence has declined with modern reperfusion therapy. In the era of percutaneous coronary interventions, it occurs a median of 18-24 hours after myocardial infarction and is most commonly associated with anterior myocardial infarction. We present a case of delayed ventricular septal rupture complicating acute inferior wall myocardial infarction. A 53-year-old Caucasian male presented with epigastric pain for three days and electrocardiographic evidence for an acute inferior wall myocardial infarction. Coronary angiography revealed a total occlusion of the proximal right coronary artery. Reperfusion was achieved by balloon angioplasty followed by placement of a bare metal stent. On hospital day six, the patient developed acute respiratory distress, a new loud pansystolic murmur, and hemodynamic instability. Echocardiography revealed the presence of a large defect in the inferobasal interventricular septum with significant left-to-right shunt consistent with ventricular septal rupture. The patient underwent emergent surgical repair with a bovine pericardial patch. Ventricular septal rupture after myocardial infarction should be suspected in the presence of new physical findings and hemodynamic compromise regardless of revascularization therapy. The precise clinical features and etiologic basis of Takotsubo syndrome remain unclear, although an association with emotional or stressful triggers has been recognized. Ventricular septal perforation is a very rare life-threatening complication. A 77-year-old female patient presented to the hospital with unrelieved chest tightness and shortness of breath. Three months ago, the patient's electrocardiogram revealed ischemic T wave inversion of the anterior wall, along with an increase in myocardial injury markers. There was no evidence of a ventricular septal defect on echocardiography. The patient was admitted to the respiratory department to treat lung lesions. The electrocardiogram demonstrated dynamic changes following admission, and the myocardial markers returned to normal, but the echocardiography revealed a ventricular septal defect. The initial diagnosis was ventricular septal perforation because of myocardial infarction with acute anterior ST-segment elevation. Coronary angiography revealed no abnormalities, but left ventricular angiography revealed an enlarged apex and VSD, with a right ventricular shunt bundle. Later, cardiac MRI revealed an apical ventricular septal defect. Further inquiry of the patient's medical history revealed that her husband died unexpectedly three months ago, and her daughter was seriously injured in a car accident, causing the patient severe emotional distress. Takotsubo syndrome was then determined in conjunction with the patient's medical history, symptoms, signs, and pertinent examinations. Without using a catheter or a surgical procedure, we managed the patient's medical condition. Two weeks later, the patient was discharged with symptoms improved. Takotsubo syndrome is comparable to an acute myocardial infarction on clinical and electrocardiographic examination in the absence of significant coronary disease. Although ventricular septal perforation is most commonly associated with acute myocardial infarction, it can also happen following Takotsubo syndrome. Takotsubo syndrome complicated by ventricular septal perforation is easily misdiagnosed. The early recognition and management of this condition can avoid or reduce morbidity and mortality.\nHere is the question:\nCARDIOLOGY AND CARDIOVASCULAR SURGERY: An 87-year-old woman with a history of hypertension was admitted 48 hours ago to the coronary unit for acute myocardial infarction with ST-segment elevation of anterior location. She reported dyspnea. Examination revealed a systolic murmur with fremitus, radiating to the right sternal border, which was not present on admission. What complication do you suspect?\nHere are the potential choices:\n1. Heart failure due to extensive necrosis.\n2. Anterior aneurysm.\n3. Left ventricular free wall rupture.\n4. Rupture in the interventricular septum.\nThe correct answer is: 4. Rupture in the interventricular septum."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Treatment Treatment options include medicines and surgery. Neuralgia is more difficult to treat than other types of pain because it does not respond well to normal pain medications. Special medications have become more specific to neuralgia and typically fall under the category of membrane stabilizing drugs or antidepressants such as Cymbalta. The antiepileptic medication(AED) Lyrica (pregabalin) was developed specifically for neuralgia and other neuropathic pain as a successor to Neurontin (gabapentin). High doses of anticonvulsant medicines—used to block nerve firing— and tricyclic antidepressants are generally effective in treating neuralgia. If medication fails to relieve pain or produces intolerable side effects, surgical treatment may be recommended. Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the nervous system. Opioid drugs, including morphine, are commonly used to treat neuropathic pain. Most reviews have examined all opioids together. This review sought evidence specifically for morphine; other opioids are considered in separate reviews. To assess the analgesic efficacy and adverse events of morphine for chronic neuropathic pain in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for randomised controlled trials from inception to February 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries. We included randomised, double-blind trials of two weeks' duration or longer, comparing morphine (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment. Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables. We identified five randomised, double-blind, cross-over studies with treatment periods of four to seven weeks, involving 236 participants in suitably characterised neuropathic pain; 152 (64%) participants completed all treatment periods. Oral morphine was titrated to maximum daily doses of 90 mg to 180 mg or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months. Included studies involved people with painful diabetic neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia criteria, phantom limb or postamputation pain, and lumbar radiculopathy. Exclusions were typically people with other significant comorbidity or pain from other causes.Overall, we judged the studies to be at low risk of bias, but there were concerns over small study size and the imputation method used for participants who withdrew from the studies, both of which could lead to overestimation of treatment benefits and underestimation of harm.There was insufficient or no evidence for the primary outcomes of interest for efficacy or harm. Four studies reported an approximation of moderate pain improvement (any pain-related outcome indicating some improvement) comparing morphine with placebo in different types of neuropathic pain. We pooled these data in an exploratory analysis. Moderate improvement was experienced by 63% (87/138) of participants with morphine and 36% (45/125) with placebo; the risk difference (RD) was 0.27 (95% confidence interval (CI) 0.16 to 0.38, fixed-effects analysis) and the NNT 3.7 (2.6 to 6.5). We assessed the quality of the evidence as very low because of the small number of events; available information did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different was very high. A similar exploratory analysis for substantial pain relief on three studies (177 participants) showed no difference between morphine and placebo.All-cause withdrawals in four studies occurred in 16% (24/152) of participants with morphine and 12% (16/137) with placebo. The RD was 0.04 (-0.04 to 0.12, random-effects analysis). Adverse events were inconsistently reported, more common with morphine than with placebo, and typical of opioids. There were two serious adverse events, one with morphine, and one with a combination of morphine and nortriptyline. No deaths were reported. These outcomes were assessed as very low quality because of the limited number of participants and events. There was insufficient evidence to support or refute the suggestion that morphine has any efficacy in any neuropathic pain condition. Medical The anticonvulsant carbamazepine is the first line treatment; second line medications include baclofen, lamotrigine, oxcarbazepine, phenytoin, gabapentin and pregabalin. Uncontrolled trials have suggested that clonazepam and lidocaine may be effective. Antidepressant medications, such as amitriptyline have shown good efficacy in treating trigeminal neuralgia, especially if combined with an anti-convulsant drug such as pregabalin. There is some evidence that duloxetine can also be used in some cases of neuropathic pain, especially in patients with major depressive disorder as it is an antidepressant. However, it should, by no means, be considered a first line therapy and should only be tried by specialist advice. There is controversy around opiate use such as morphine and oxycodone for treatment of TN, with varying evidence on its effectiveness for neuropathic pain. Generally, opioids are considered ineffective against TN and thus should not be prescribed. Neuropathic pain is difficult to diagnose and difficult to treat with certainty. So the aim of the study was to evaluate comparative clinical efficacy of pregabaline with amitriptyline and gabapentin in neuropathic cancer pain. A total of 120 patients with cancer having severe neuropathic cancer pain were enrolled in the study after taking approval from Institutional Ethics Committee and divided in to 4 groups: group AT-amitriptyline, group GB-gabapentin, group PG-pregabalin, and group PL-placebo. Oral morphine was used for rescue analgesic for continued pain. Pain score (Visual Analogue scale) and secondary outcome measures such as intensity of lancinating, dysesthesia, and burning on numerical rating scale, Global satisfaction score (GSS), Eastern Co-operative Oncology Group scoring (ECOG), and adverse effects were assessed. At the end of study there was significant decrease in pain score in group PG as compared to the other groups; group AT (P = .003), group GB (P = .042), and group PL (P = .024). Percentage of patients with lancinating pain and dysesthesia were significantly less in group PG as compared to groups GB and PL. All the patients in group PL needed rescue morphine. After 4 visits, maximum improvement in ECOG scoring and GSS scoring was observed in group PG patients. Our results suggested that all antineuropathic drugs are effective in relieving cancer-related neuropathic pain. There was statistically and clinically significant morphine sparing effect of pregabaline in relieving neuropathic cancer pain and neuropathic symptoms as compared to other antineuropathic drugs. The study presented here investigated the short-term effectiveness of one-off lumbar caudal epidural injection (EI) in sciatica in relationship to the reported duration of pain. This retrospective analysis involved 106 consecutive in-patients who received either conservative treatment (Group I) or an additional EI on the first day of their treatment (Group II). Both groups were divided according to the duration of symptoms at the time of admission (less than three months, or more than six months). Propensity score matching was performed for the whole collective and the resulting subgroups. This incorporated gender, age and pain intensity at the time of admission. The target parameter were changes on a visual analogue scale (VAS) of pain intensity on days D1, D3, and D10 depending on the respective treatment. A routine evaluation of the mental variables anxiety, depression and somatisation was performed as part of the examination upon admission and their relationship to the success of treatment was later assessed. The mean age of the patients was 61.7 (± 11.6) in Group I and 63.6 (± 13.6) in Group II. 59 % of the patients were female (n = 63). The Lasègue sign was prevalent in 45 % of Group I and 51 % of Group II. The intensity of pain on the day of admission was similar in both groups (7.0 ± 1.0 for Group I, 6.7 ± 1.8 for Group II). The length of stay on the ward was also similar in both groups (10.2 ± 3.9 and 9.4 ± 3.7 d, respectively). It was found that, independent of the duration of symptoms, injection treatment was significantly more effective than conservative treatment only in the early stages (D1 and D3, p &lt; 0.001). No differences could be found in the expression of these mental variables between treatment groups, as these factors showed no influence on the results of therapy. In the context of acute treatment a once only lumbar caudal epidural injection represents at most a short-term effectiveness for the therapy of sciatica. The results presented here indicate that neither the duration of symptoms nor the measured psychometric variables show any effect on the success of therapy. Gabapentin has shown efficacy in the treatment of chronic neuropathic or mixed pain in adults. Although pediatric pain specialists have extensive experience with gabapentin for the treatment of neuropathic pain, its use is off-label. Its efficacy and safety in this context have never been shown. The aim of this trial is to compare gabapentin with placebo as add-on to morphine for the treatment of severe chronic mixed or neuropathic pain in children. This trial is part of the European Union Seventh Framework Programme project Gabapentin in Paediatric Pain (GAPP) to develop a pediatric use marketing authorization for a new gabapentin suspension. The GAPP-2 study is a randomized, double-blind, placebo-controlled, multicenter superiority phase II study in children with severe chronic neuropathic or mixed pain. Its primary objective is to evaluate the efficacy of a gabapentin liquid formulation as adjunctive therapy to morphine. Sixty-six eligible children 3 months to 18 years of age with severe pain (pain scores ≥ 7), stratified in three age groups, will be randomized to receive gabapentin (to an accumulating dose of 45 to 63 mg/kg/day, dependent on age) or placebo, both in addition to morphine, for 12 weeks. Randomization will be preceded by a short washout period, and treatment will be initiated by a titration period of 3 weeks. After the treatment period, medication will be tapered during 4 weeks. The primary endpoint is the average pain scores in the two treatment groups (average of two measures each day for 3 days before the end-of-study visit [V10] assessed by age-appropriate pain scales (Face, Legs, Activity, Cry, Consolability scale; Faces Pain Scale-Revised; Numeric Rating Scale). Secondary outcomes include percentage responders to treatment (subjects with 30% reduction in pain scale), number of episodes of breakthrough pain, number of rescue interventions, number of pain-free days, participant dropouts, quality of life (Pediatric Quality of Life Inventory), and acceptability of treatment. Outcomes will be measured at the end-of-study visit after 12 weeks of treatment at the optimal gabapentin dose. Groups will be compared on an intention-to-treat basis. We hope to provide evidence that the combination of morphine and gabapentin will provide better analgesia than morphine alone and will be safe. We also aim to obtain confirmation of the recommended pediatric dose. EudractCT, 2014-004897-40 . Registered on 7 September 2017. ClinicalTrials.gov, NCT03275012 . Registered on 7 September 2017. The data from a previously published 12-week randomised, double-blind, placebo-controlled multicentre study on the efficacy and safety of pregabalin were analyzed for time to onset of analgesic action with neuropathic pain. A total of 338 patients with postherpetic neuralgia or painful diabetic peripheral neuropathy were treated with flexible or fixed regimens of pregabalin at daily doses of up to 600 mg/day (n=141 and 132, respectively) or placebo (n=65). Under fixed dose treatment, a decrease of one full point on the 11-point numerical rating pain scale was reached on day 1, two full points on day 13, and three full points on day 23 (under flexible dose pregabalin: on days 6, 17 and 30). In both treatment arms, pain reduction was statistically significant (P=0.001, P=0.002 vs placebo, respectively). In patients with chronic neuropathic pain, the analgesic effect of both pregabalin treatment regimens was high and associated with a rapid time to onset. Neurologic and psychiatric disorders Patients who experience frequent attacks can develop chronic neuropathic pain in extremities as well as chronic pain in the abdomen. Intestinal pseudo-obstruction, ileus, intussusception, hypoganglionosis, and encopresis in children have been associated with porphyrias. This is thought to be due to axonal nerve deterioration in affected areas of the nervous system and vagal nerve dysfunction. Pain treatment with long-acting opioids, such as morphine, is often indicated, and, in cases where seizure or neuropathy is present, gabapentin is known to improve outcome. Patients operated because of lumbar disc herniations (104 patients) were included in a randomized double-blind study analyzing the influence of dexamethasone versus placebo on postoperative drug requirements and the pain score on the visual analogue scale. High doses of dexamethasone had been administered: 40 mg i.v. on the night before the operation; 8 mg intraoperatively topical perineural application; 8 mg i.v. in the evening of the day of operation; 2x8 mg i.m. on days 1 and 2 postoperatively; 2x4 mg i.m. on days 3 and 4; 4 mg po on day 5 and 6 postoperatively. A significant decrease in the requirement for analgesics was found in the drug-treated group, particularly male patients, and also an impressive reduction in the lumbar pain score. In conclusion, there was good alleviation of sciatic pain in the dexamethasone-treated group of females during the 1st week after operation, but we found no evidence that the agent tested had an influence on the clinical outcome 1 month following the operation. Extended-release There are extended-release formulations of orally administered morphine whose effect last longer, which can be given once per day. Brand names for this formulation of morphine include Avinza, Kadian, MS Contin and Dolcontin. For constant pain, the relieving effect of extended-release morphine given once (for Kadian) or twice (for MS Contin) every 24 hours is roughly the same as multiple administrations of immediate release (or \"regular\") morphine. Extended-release morphine can be administered together with \"rescue doses\" of immediate-release morphine as needed in case of breakthrough pain, each generally consisting of 5% to 15% of the 24-hour extended-release dosage. Despite the progress in understanding acute pain physiology during recent decade, eighty percent of patients still suffer from post-operative discomfort. Pregabalin is an anticonvulsant agent that is approved for painful neuropathies in diabetic patients and post herpetic neuralgia. The main objective of the present study was to compare the improvement in post-operative pain management and patient lifestyle in 3 groups, as first group received placebo, second who received Pregabalin for one day and the last group those who received it for 14 days. This was a prospective single center, randomized, triple-blind, 3-arm, parallel group study. In this triple-blind study, patients were randomized to 1 of 3 groups using computer-generated random number table. 1) The first group received placebo for 14 days, the second group received Pregabalin 300mg 8h preoperatively and 150mg 12 and 24h postoperatively and for the rest of 13days received placebo and the third group received Pregabalin 300mg eight hours preoperatively and 15mg every 12h postoperatively for 14 days. Name, age, gender, height, weight, education, duration of pain, past medical history, drug history,total morphine requirement at the time of discharge and MRI findings of all the patients were recorded, also they Numerical scale system (NRS) and Oswestry low back pain disability index (ODI) questionnaire were completed for them. All the patients were operated based on standard surgery techniques, bilateral foramenotomy and interlaminar discectomy. Of the 105 patients who entered the run-in period, 47 patients (44.8%) were female and 58 (55.2%) were male. The Patients radicular pain mean score based on NRS estimated before surgery was 7.22±1.95 in pregabalin14, 7.71±1.84 in pregabalin1 and 7.45±1.9 in control group. There were no statically significant differences between three groups (P-Value&gt;0.05). The Patients back pain mean score based on NRS was 5.2±2.87 in pregabalin14, 5.11±3.23 in pregabalin1 and 6.4±3.06 in control group. This means that there were no significant differences in the overall score among those three groups (P-Value&gt;0.05). In comparison to their preoperative pain, the average radicular pain in each group of patients improved significantly 4, 8, 12 and 24h after the operation (P-Value&lt;0.001), but there were no significant differences in radicular pain improvements comparing three groups. The results of this study indicate that 1day and 2 weeks post-operative 300mg pregabalin administration may not improve acute pain, morphine consumption and quality of life of patients after surgery. It seems that the diseases cause chronic pain that requires long-term treatment with higher doses. Its analgesic effects take about one hour to come into effect and 2 to 4 h to peak after oral administration with an immediate-release formulation. On a dose-by-dose basis, tramadol has about one-tenth the potency of morphine (thus 100 mg is commensurate with 10 mg morphine but may vary) and is practically equally potent when compared with pethidine and codeine. For pain moderate in severity, its effectiveness is equivalent to that of codeine at low doses, and hydrocodone at very high doses; for severe pain it is less effective than morphine. These painkilling effects last about 6 h. The potency of analgesia varies considerably as it depends on an individual's genetics. People with specific variants of CYP2D6 enzymes may not produce adequate amounts of the active metabolite (desmetramadol) for effective pain control. To investigate the short-term clinical effect of lumbar nerve root canal injection under X-ray angiography in the treatment of sciatica. The clincal data of 78 patients with sciatica underwent lumbar nerve root canal injection under X-ray angiography from December 2017 to February 2020 was retrospectively analyzed. Including 31 males and 47 females, aged from 22 to 88 years old with a median of 65 years. There were 55 cases of lumbar disc herniation and 23 cases of lumbar spinal stenosis, the course of disease ranged from 1 to 8 weeks with a median of 3 weeks. There were 71 cases of single segment disc herniation or stenosis, including L<sub3,4</sub of 5 cases, L<sub4,5</sub of 61 cases, L<sub5</subS<sub1</sub of 5 cases, and 7 cases of multisegment herniation or stenosis. The pain visual analogue scale (VAS) was recorded and Macnab was used to evaluate the clinical effect. All patients completed standardized treatment without serious adverse reactions. VAS were (3.21±0.76) scores immediately after treatment, (2.89±0.33) scores 1 hour after treatment, (1.80±0.27) scores 6 hours after treatment, (1.10±0.20) scores 24 hours after treatment, (2.53±0.35) scores 1 week after treatment and (4.27±0.36) scores 1 month after treatment. There were significant differences in VAS between before treatment(7.83±0.56) and each time period after treatment(<iP</i&lt;0.05). According to Macnab low back pain evaluation standard, 42 cases were effective, 34 cases were markedly effective and 2 cases were ineffective within 24 hours after treatment, with an effective rate of 97.4%;38 cases were effective, 25 cases were markedly effective, 15 cases were ineffective within one week after treatment, the effective rate was 80.0%;32 cases were effective, 22 cases were markedly effective, 24 cases were ineffective within one month after treatment, the effective rate was 69.2%. The short-term clinical effect of nerve root canal injection under X-ray radiography in the treatment of sciatica is good and it is an effective method to relieve sciatica. Amitriptyline is the most common analgesic adjuvant used in cancer patients with neuropathic pain, even though no specific studies have demonstrated a benefit. A randomized placebo-controlled, double-blind crossover study was designed to evidence the effects of amitriptyline in patients with neuropathic cancer pain. Sixteen advanced cancer patients with neuropathic pain on systemic morphine therapy, no longer receiving oncologic treatment, presenting moderate pain (about 4 or more, but less than 7, on a numerical scale of 0-10) in the last week, and given a stable morphine dose in the last 2 days were admitted to the study. During the first week of study, patients were administered 25 mg of amitriptyline or equivalent drops of placebo at night for 3 days and 50 mg for the following 4 days. Doses for patients aged more than 65 years were 15 mg (first 3 days) and 30 mg (3 days after). After a week, a crossover took place for the second week, with the other treatment at an inverse sequence. Opioid consumption, pain intensity, symptoms and adverse effects, mood, sleep, patient's preference, quality of life before starting the study, the first week after and the second week after were recorded. No significant benefits in analgesia were found in the global pain intensity of the previous week of treatment, the least pain intensity or the pain evaluated just after a week of treatment, at the moment of the visit, when amitriptyline was compared with placebo. A significant difference was evidenced for the worst pain (P &lt; 0.035). No differences in opioid doses during the period of study were found. Drowsiness, confusion and dry mouth were significantly more intense with amitriptyline than with placebo (P &lt; 0.036, 0.003, and 0.034, respectively). There were no substantial differences between the two treatments in Spitzer's quality of life score and for each item. No differences in patients' preference for the two treatment periods were found. The analgesic effects of amitriptyline were slight and associated with adverse effects. In light of the results obtained in the study, the extensive use of the drug for cancer pain should be questioned. Neuropathic pain (NP), in view of its non-nociceptive component, is not caused by physiological lesions but by problems in the nervous system itself, whether in the central nervous system (CNS) or peripheral nervous system (PNS). This particular action mechanism makes NP a very difficult-to-treat condition, resistant to most of the commonly used analgesic drugs. A recent study stated that NP has an incidence of 1.24% over the general population, and this percentage increases if we consider acute radiculopathies and some recurrent neuropathies, frequently considered not only neuropathic pain but also nociceptive. Thus, the improvement of NP treatment has become a public health necessity. While WHO recommendations include a three-lined scale in pain treatment -including NSAIDs as the first-line drugs, soft opioids (tramadol or codein) as the second-line, and strong opioids (morphine, oxycodone, and phentanyl) as the third-line- some studies have found this rationale not useful in NP treatment. Based on several studies as STEP, Spanish Pain Society recommendations included antidepressant and anticonvulsant drugs as the first line treatment. Pregabalin, a new neuromodulators class drug, provides a pharmacokinetic profile than its predecessors (phenytoin, carbamazepine, gabapentin, topiramate, oxcarbazepine, and lamotrigine), and showed effectiveness controlling peripheral neuropathic pain. Thus, pregabalin opened the door to a new approach to NP. Other pain societies, such as the Canada Pain Society, have also included pregabalin in the first line treatment of NP. In fact, gabapentin and pregabalin are the current standard care in most of NP-associated diseases. Dosage comparison For constant pain, the relieving effect of extended-release morphine given once (for Kadian) or twice (for MS Contin) every 24 hours is roughly the same as multiple administrations of immediate release (or \"regular\") morphine. Morphine sulfate pentahydrade (trade names including Dolcontin) has a higher molecular mass than morphine base, and therefore 10 mg morphine sulfate pentahydrate contains approximatively 7.5 mg of morphine free base. Extended-release morphine can be administered together with \"rescue doses\" of immediate-release morphine pro re nata in case of breakthrough pain, each generally consisting of 5% to 15% of the 24-hour extended-release dosage. Lidocaine infusion therapy (LIT) is an effective treatment for relieving neuropathic pain (NeP). However, it remains unclear whether pain relief can be sustained through repeated lidocaine infusions. This study aimed to determine whether repeated intravenous administration of low-dose lidocaine could provide prolonged pain relief in patients with specific NeP conditions. This is a prospective, randomized, double-blind, placebo-controlled, parallel study. We compared the efficacy and safety of lidocaine infusions (3 mg/kg) in the LIT group and normal saline infusions in the control group once a week for 4 consecutive weeks in patients with postherpetic neuralgia or complex regional pain syndrome type II. The primary outcome was the difference in the percentage change in the 11-point numerical rating scale (NRS) pain score from baseline to after the final infusion. Secondary outcomes included pain scores during 4 weeks of follow-up and any complications. Forty-two patients completed this study protocol. The percentage reduction in NRS pain scores after the final infusion was significantly greater in the LIT group compared with the control group (P = 0.011). However, this pain reduction was not detectable at the 4-week follow-up. The difference in the percentage change in NRS pain scores was especially prominent in the LIT group after the third and fourth infusions. None of the study participants experienced serious complications from the treatment. Lidocaine infusion therapy (3 mg/kg of lidocaine administered over 1 hour) provided effective short-term pain relief, which was substantially prominent after repeated infusions were administered to patients with refractory NeP. This study was registered at ClinicalTrials.gov, identifier NCT02597257. Few controlled trials have been carried out with non-steroidal antiinflammatory drugs in this indication, mainly as a result of methodological difficulties. A prerequisite for correct evaluation is compliance with certain fundamental principles. The study must be controlled (i.e. comparative, prospective randomized, double-blind, with data quality control and statistical analysis). The sample size must be consistent with the objectives (at least 40 patients per group). The selection criteria must be well specified and the comparability of baseline data assessed. The most appropriate study design for assessing clinical efficacy is to compare two parallel groups of out patients treated during five to fifteen days. The main criterion of efficacy should be based on the judgments of both patients and physician. Time course of pain, improvement in the patient's functional capacity, improvement in physical findings (Schober, Lasègue), dosage of concomitant analgesic treatments when these are allowed, and evaluation at three and six months can also be used as efficacy criteria. Assessment of clinical and biological tolerance is mandatory. Considering the frequent use of non-steroidal antiinflammatory drugs in treating sciatica, there is a strong need for rigorous investigations.\nHere is the question:\nONCOLOGY: A 66-year-old patient diagnosed with stage IV pancreatic adenocarcinoma 8 months ago. He follows treatment with delayed release morphine 200 mg/12 hours orally, kerosene and lactulose. For the last 15 days he has reported paresthesias and occasional lancinating pain in the right lumbar and periumbilical area that does not subside with rescue morphine. The neurological examination is normal. Indicate the most appropriate management:\nHere are the potential choices:\n1. Perform computed axial tomography and evaluate nerve compression since it is neuropathic pain.\n2. Evaluate neurolytic treatment since neuropathic pain is difficult to control.\n3. Decrease the dose of morphine as it is ineffective in this type of pain.\n4. Administer amitriptyline or gabapentin, dexamethasone and increase the dose of morphine.\nThe correct answer is: ",
        "gold_answer": "4 Administer amitriptyline or gabapentin, dexamethasone and increase the dose of morphine.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Treatment Treatment options include medicines and surgery. Neuralgia is more difficult to treat than other types of pain because it does not respond well to normal pain medications. Special medications have become more specific to neuralgia and typically fall under the category of membrane stabilizing drugs or antidepressants such as Cymbalta. The antiepileptic medication(AED) Lyrica (pregabalin) was developed specifically for neuralgia and other neuropathic pain as a successor to Neurontin (gabapentin). High doses of anticonvulsant medicines—used to block nerve firing— and tricyclic antidepressants are generally effective in treating neuralgia. If medication fails to relieve pain or produces intolerable side effects, surgical treatment may be recommended. Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the nervous system. Opioid drugs, including morphine, are commonly used to treat neuropathic pain. Most reviews have examined all opioids together. This review sought evidence specifically for morphine; other opioids are considered in separate reviews. To assess the analgesic efficacy and adverse events of morphine for chronic neuropathic pain in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for randomised controlled trials from inception to February 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries. We included randomised, double-blind trials of two weeks' duration or longer, comparing morphine (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment. Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables. We identified five randomised, double-blind, cross-over studies with treatment periods of four to seven weeks, involving 236 participants in suitably characterised neuropathic pain; 152 (64%) participants completed all treatment periods. Oral morphine was titrated to maximum daily doses of 90 mg to 180 mg or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months. Included studies involved people with painful diabetic neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia criteria, phantom limb or postamputation pain, and lumbar radiculopathy. Exclusions were typically people with other significant comorbidity or pain from other causes.Overall, we judged the studies to be at low risk of bias, but there were concerns over small study size and the imputation method used for participants who withdrew from the studies, both of which could lead to overestimation of treatment benefits and underestimation of harm.There was insufficient or no evidence for the primary outcomes of interest for efficacy or harm. Four studies reported an approximation of moderate pain improvement (any pain-related outcome indicating some improvement) comparing morphine with placebo in different types of neuropathic pain. We pooled these data in an exploratory analysis. Moderate improvement was experienced by 63% (87/138) of participants with morphine and 36% (45/125) with placebo; the risk difference (RD) was 0.27 (95% confidence interval (CI) 0.16 to 0.38, fixed-effects analysis) and the NNT 3.7 (2.6 to 6.5). We assessed the quality of the evidence as very low because of the small number of events; available information did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different was very high. A similar exploratory analysis for substantial pain relief on three studies (177 participants) showed no difference between morphine and placebo.All-cause withdrawals in four studies occurred in 16% (24/152) of participants with morphine and 12% (16/137) with placebo. The RD was 0.04 (-0.04 to 0.12, random-effects analysis). Adverse events were inconsistently reported, more common with morphine than with placebo, and typical of opioids. There were two serious adverse events, one with morphine, and one with a combination of morphine and nortriptyline. No deaths were reported. These outcomes were assessed as very low quality because of the limited number of participants and events. There was insufficient evidence to support or refute the suggestion that morphine has any efficacy in any neuropathic pain condition. Medical The anticonvulsant carbamazepine is the first line treatment; second line medications include baclofen, lamotrigine, oxcarbazepine, phenytoin, gabapentin and pregabalin. Uncontrolled trials have suggested that clonazepam and lidocaine may be effective. Antidepressant medications, such as amitriptyline have shown good efficacy in treating trigeminal neuralgia, especially if combined with an anti-convulsant drug such as pregabalin. There is some evidence that duloxetine can also be used in some cases of neuropathic pain, especially in patients with major depressive disorder as it is an antidepressant. However, it should, by no means, be considered a first line therapy and should only be tried by specialist advice. There is controversy around opiate use such as morphine and oxycodone for treatment of TN, with varying evidence on its effectiveness for neuropathic pain. Generally, opioids are considered ineffective against TN and thus should not be prescribed. Neuropathic pain is difficult to diagnose and difficult to treat with certainty. So the aim of the study was to evaluate comparative clinical efficacy of pregabaline with amitriptyline and gabapentin in neuropathic cancer pain. A total of 120 patients with cancer having severe neuropathic cancer pain were enrolled in the study after taking approval from Institutional Ethics Committee and divided in to 4 groups: group AT-amitriptyline, group GB-gabapentin, group PG-pregabalin, and group PL-placebo. Oral morphine was used for rescue analgesic for continued pain. Pain score (Visual Analogue scale) and secondary outcome measures such as intensity of lancinating, dysesthesia, and burning on numerical rating scale, Global satisfaction score (GSS), Eastern Co-operative Oncology Group scoring (ECOG), and adverse effects were assessed. At the end of study there was significant decrease in pain score in group PG as compared to the other groups; group AT (P = .003), group GB (P = .042), and group PL (P = .024). Percentage of patients with lancinating pain and dysesthesia were significantly less in group PG as compared to groups GB and PL. All the patients in group PL needed rescue morphine. After 4 visits, maximum improvement in ECOG scoring and GSS scoring was observed in group PG patients. Our results suggested that all antineuropathic drugs are effective in relieving cancer-related neuropathic pain. There was statistically and clinically significant morphine sparing effect of pregabaline in relieving neuropathic cancer pain and neuropathic symptoms as compared to other antineuropathic drugs. The study presented here investigated the short-term effectiveness of one-off lumbar caudal epidural injection (EI) in sciatica in relationship to the reported duration of pain. This retrospective analysis involved 106 consecutive in-patients who received either conservative treatment (Group I) or an additional EI on the first day of their treatment (Group II). Both groups were divided according to the duration of symptoms at the time of admission (less than three months, or more than six months). Propensity score matching was performed for the whole collective and the resulting subgroups. This incorporated gender, age and pain intensity at the time of admission. The target parameter were changes on a visual analogue scale (VAS) of pain intensity on days D1, D3, and D10 depending on the respective treatment. A routine evaluation of the mental variables anxiety, depression and somatisation was performed as part of the examination upon admission and their relationship to the success of treatment was later assessed. The mean age of the patients was 61.7 (± 11.6) in Group I and 63.6 (± 13.6) in Group II. 59 % of the patients were female (n = 63). The Lasègue sign was prevalent in 45 % of Group I and 51 % of Group II. The intensity of pain on the day of admission was similar in both groups (7.0 ± 1.0 for Group I, 6.7 ± 1.8 for Group II). The length of stay on the ward was also similar in both groups (10.2 ± 3.9 and 9.4 ± 3.7 d, respectively). It was found that, independent of the duration of symptoms, injection treatment was significantly more effective than conservative treatment only in the early stages (D1 and D3, p &lt; 0.001). No differences could be found in the expression of these mental variables between treatment groups, as these factors showed no influence on the results of therapy. In the context of acute treatment a once only lumbar caudal epidural injection represents at most a short-term effectiveness for the therapy of sciatica. The results presented here indicate that neither the duration of symptoms nor the measured psychometric variables show any effect on the success of therapy. Gabapentin has shown efficacy in the treatment of chronic neuropathic or mixed pain in adults. Although pediatric pain specialists have extensive experience with gabapentin for the treatment of neuropathic pain, its use is off-label. Its efficacy and safety in this context have never been shown. The aim of this trial is to compare gabapentin with placebo as add-on to morphine for the treatment of severe chronic mixed or neuropathic pain in children. This trial is part of the European Union Seventh Framework Programme project Gabapentin in Paediatric Pain (GAPP) to develop a pediatric use marketing authorization for a new gabapentin suspension. The GAPP-2 study is a randomized, double-blind, placebo-controlled, multicenter superiority phase II study in children with severe chronic neuropathic or mixed pain. Its primary objective is to evaluate the efficacy of a gabapentin liquid formulation as adjunctive therapy to morphine. Sixty-six eligible children 3 months to 18 years of age with severe pain (pain scores ≥ 7), stratified in three age groups, will be randomized to receive gabapentin (to an accumulating dose of 45 to 63 mg/kg/day, dependent on age) or placebo, both in addition to morphine, for 12 weeks. Randomization will be preceded by a short washout period, and treatment will be initiated by a titration period of 3 weeks. After the treatment period, medication will be tapered during 4 weeks. The primary endpoint is the average pain scores in the two treatment groups (average of two measures each day for 3 days before the end-of-study visit [V10] assessed by age-appropriate pain scales (Face, Legs, Activity, Cry, Consolability scale; Faces Pain Scale-Revised; Numeric Rating Scale). Secondary outcomes include percentage responders to treatment (subjects with 30% reduction in pain scale), number of episodes of breakthrough pain, number of rescue interventions, number of pain-free days, participant dropouts, quality of life (Pediatric Quality of Life Inventory), and acceptability of treatment. Outcomes will be measured at the end-of-study visit after 12 weeks of treatment at the optimal gabapentin dose. Groups will be compared on an intention-to-treat basis. We hope to provide evidence that the combination of morphine and gabapentin will provide better analgesia than morphine alone and will be safe. We also aim to obtain confirmation of the recommended pediatric dose. EudractCT, 2014-004897-40 . Registered on 7 September 2017. ClinicalTrials.gov, NCT03275012 . Registered on 7 September 2017. The data from a previously published 12-week randomised, double-blind, placebo-controlled multicentre study on the efficacy and safety of pregabalin were analyzed for time to onset of analgesic action with neuropathic pain. A total of 338 patients with postherpetic neuralgia or painful diabetic peripheral neuropathy were treated with flexible or fixed regimens of pregabalin at daily doses of up to 600 mg/day (n=141 and 132, respectively) or placebo (n=65). Under fixed dose treatment, a decrease of one full point on the 11-point numerical rating pain scale was reached on day 1, two full points on day 13, and three full points on day 23 (under flexible dose pregabalin: on days 6, 17 and 30). In both treatment arms, pain reduction was statistically significant (P=0.001, P=0.002 vs placebo, respectively). In patients with chronic neuropathic pain, the analgesic effect of both pregabalin treatment regimens was high and associated with a rapid time to onset. Neurologic and psychiatric disorders Patients who experience frequent attacks can develop chronic neuropathic pain in extremities as well as chronic pain in the abdomen. Intestinal pseudo-obstruction, ileus, intussusception, hypoganglionosis, and encopresis in children have been associated with porphyrias. This is thought to be due to axonal nerve deterioration in affected areas of the nervous system and vagal nerve dysfunction. Pain treatment with long-acting opioids, such as morphine, is often indicated, and, in cases where seizure or neuropathy is present, gabapentin is known to improve outcome. Patients operated because of lumbar disc herniations (104 patients) were included in a randomized double-blind study analyzing the influence of dexamethasone versus placebo on postoperative drug requirements and the pain score on the visual analogue scale. High doses of dexamethasone had been administered: 40 mg i.v. on the night before the operation; 8 mg intraoperatively topical perineural application; 8 mg i.v. in the evening of the day of operation; 2x8 mg i.m. on days 1 and 2 postoperatively; 2x4 mg i.m. on days 3 and 4; 4 mg po on day 5 and 6 postoperatively. A significant decrease in the requirement for analgesics was found in the drug-treated group, particularly male patients, and also an impressive reduction in the lumbar pain score. In conclusion, there was good alleviation of sciatic pain in the dexamethasone-treated group of females during the 1st week after operation, but we found no evidence that the agent tested had an influence on the clinical outcome 1 month following the operation. Extended-release There are extended-release formulations of orally administered morphine whose effect last longer, which can be given once per day. Brand names for this formulation of morphine include Avinza, Kadian, MS Contin and Dolcontin. For constant pain, the relieving effect of extended-release morphine given once (for Kadian) or twice (for MS Contin) every 24 hours is roughly the same as multiple administrations of immediate release (or \"regular\") morphine. Extended-release morphine can be administered together with \"rescue doses\" of immediate-release morphine as needed in case of breakthrough pain, each generally consisting of 5% to 15% of the 24-hour extended-release dosage. Despite the progress in understanding acute pain physiology during recent decade, eighty percent of patients still suffer from post-operative discomfort. Pregabalin is an anticonvulsant agent that is approved for painful neuropathies in diabetic patients and post herpetic neuralgia. The main objective of the present study was to compare the improvement in post-operative pain management and patient lifestyle in 3 groups, as first group received placebo, second who received Pregabalin for one day and the last group those who received it for 14 days. This was a prospective single center, randomized, triple-blind, 3-arm, parallel group study. In this triple-blind study, patients were randomized to 1 of 3 groups using computer-generated random number table. 1) The first group received placebo for 14 days, the second group received Pregabalin 300mg 8h preoperatively and 150mg 12 and 24h postoperatively and for the rest of 13days received placebo and the third group received Pregabalin 300mg eight hours preoperatively and 15mg every 12h postoperatively for 14 days. Name, age, gender, height, weight, education, duration of pain, past medical history, drug history,total morphine requirement at the time of discharge and MRI findings of all the patients were recorded, also they Numerical scale system (NRS) and Oswestry low back pain disability index (ODI) questionnaire were completed for them. All the patients were operated based on standard surgery techniques, bilateral foramenotomy and interlaminar discectomy. Of the 105 patients who entered the run-in period, 47 patients (44.8%) were female and 58 (55.2%) were male. The Patients radicular pain mean score based on NRS estimated before surgery was 7.22±1.95 in pregabalin14, 7.71±1.84 in pregabalin1 and 7.45±1.9 in control group. There were no statically significant differences between three groups (P-Value&gt;0.05). The Patients back pain mean score based on NRS was 5.2±2.87 in pregabalin14, 5.11±3.23 in pregabalin1 and 6.4±3.06 in control group. This means that there were no significant differences in the overall score among those three groups (P-Value&gt;0.05). In comparison to their preoperative pain, the average radicular pain in each group of patients improved significantly 4, 8, 12 and 24h after the operation (P-Value&lt;0.001), but there were no significant differences in radicular pain improvements comparing three groups. The results of this study indicate that 1day and 2 weeks post-operative 300mg pregabalin administration may not improve acute pain, morphine consumption and quality of life of patients after surgery. It seems that the diseases cause chronic pain that requires long-term treatment with higher doses. Its analgesic effects take about one hour to come into effect and 2 to 4 h to peak after oral administration with an immediate-release formulation. On a dose-by-dose basis, tramadol has about one-tenth the potency of morphine (thus 100 mg is commensurate with 10 mg morphine but may vary) and is practically equally potent when compared with pethidine and codeine. For pain moderate in severity, its effectiveness is equivalent to that of codeine at low doses, and hydrocodone at very high doses; for severe pain it is less effective than morphine. These painkilling effects last about 6 h. The potency of analgesia varies considerably as it depends on an individual's genetics. People with specific variants of CYP2D6 enzymes may not produce adequate amounts of the active metabolite (desmetramadol) for effective pain control. To investigate the short-term clinical effect of lumbar nerve root canal injection under X-ray angiography in the treatment of sciatica. The clincal data of 78 patients with sciatica underwent lumbar nerve root canal injection under X-ray angiography from December 2017 to February 2020 was retrospectively analyzed. Including 31 males and 47 females, aged from 22 to 88 years old with a median of 65 years. There were 55 cases of lumbar disc herniation and 23 cases of lumbar spinal stenosis, the course of disease ranged from 1 to 8 weeks with a median of 3 weeks. There were 71 cases of single segment disc herniation or stenosis, including L<sub3,4</sub of 5 cases, L<sub4,5</sub of 61 cases, L<sub5</subS<sub1</sub of 5 cases, and 7 cases of multisegment herniation or stenosis. The pain visual analogue scale (VAS) was recorded and Macnab was used to evaluate the clinical effect. All patients completed standardized treatment without serious adverse reactions. VAS were (3.21±0.76) scores immediately after treatment, (2.89±0.33) scores 1 hour after treatment, (1.80±0.27) scores 6 hours after treatment, (1.10±0.20) scores 24 hours after treatment, (2.53±0.35) scores 1 week after treatment and (4.27±0.36) scores 1 month after treatment. There were significant differences in VAS between before treatment(7.83±0.56) and each time period after treatment(<iP</i&lt;0.05). According to Macnab low back pain evaluation standard, 42 cases were effective, 34 cases were markedly effective and 2 cases were ineffective within 24 hours after treatment, with an effective rate of 97.4%;38 cases were effective, 25 cases were markedly effective, 15 cases were ineffective within one week after treatment, the effective rate was 80.0%;32 cases were effective, 22 cases were markedly effective, 24 cases were ineffective within one month after treatment, the effective rate was 69.2%. The short-term clinical effect of nerve root canal injection under X-ray radiography in the treatment of sciatica is good and it is an effective method to relieve sciatica. Amitriptyline is the most common analgesic adjuvant used in cancer patients with neuropathic pain, even though no specific studies have demonstrated a benefit. A randomized placebo-controlled, double-blind crossover study was designed to evidence the effects of amitriptyline in patients with neuropathic cancer pain. Sixteen advanced cancer patients with neuropathic pain on systemic morphine therapy, no longer receiving oncologic treatment, presenting moderate pain (about 4 or more, but less than 7, on a numerical scale of 0-10) in the last week, and given a stable morphine dose in the last 2 days were admitted to the study. During the first week of study, patients were administered 25 mg of amitriptyline or equivalent drops of placebo at night for 3 days and 50 mg for the following 4 days. Doses for patients aged more than 65 years were 15 mg (first 3 days) and 30 mg (3 days after). After a week, a crossover took place for the second week, with the other treatment at an inverse sequence. Opioid consumption, pain intensity, symptoms and adverse effects, mood, sleep, patient's preference, quality of life before starting the study, the first week after and the second week after were recorded. No significant benefits in analgesia were found in the global pain intensity of the previous week of treatment, the least pain intensity or the pain evaluated just after a week of treatment, at the moment of the visit, when amitriptyline was compared with placebo. A significant difference was evidenced for the worst pain (P &lt; 0.035). No differences in opioid doses during the period of study were found. Drowsiness, confusion and dry mouth were significantly more intense with amitriptyline than with placebo (P &lt; 0.036, 0.003, and 0.034, respectively). There were no substantial differences between the two treatments in Spitzer's quality of life score and for each item. No differences in patients' preference for the two treatment periods were found. The analgesic effects of amitriptyline were slight and associated with adverse effects. In light of the results obtained in the study, the extensive use of the drug for cancer pain should be questioned. Neuropathic pain (NP), in view of its non-nociceptive component, is not caused by physiological lesions but by problems in the nervous system itself, whether in the central nervous system (CNS) or peripheral nervous system (PNS). This particular action mechanism makes NP a very difficult-to-treat condition, resistant to most of the commonly used analgesic drugs. A recent study stated that NP has an incidence of 1.24% over the general population, and this percentage increases if we consider acute radiculopathies and some recurrent neuropathies, frequently considered not only neuropathic pain but also nociceptive. Thus, the improvement of NP treatment has become a public health necessity. While WHO recommendations include a three-lined scale in pain treatment -including NSAIDs as the first-line drugs, soft opioids (tramadol or codein) as the second-line, and strong opioids (morphine, oxycodone, and phentanyl) as the third-line- some studies have found this rationale not useful in NP treatment. Based on several studies as STEP, Spanish Pain Society recommendations included antidepressant and anticonvulsant drugs as the first line treatment. Pregabalin, a new neuromodulators class drug, provides a pharmacokinetic profile than its predecessors (phenytoin, carbamazepine, gabapentin, topiramate, oxcarbazepine, and lamotrigine), and showed effectiveness controlling peripheral neuropathic pain. Thus, pregabalin opened the door to a new approach to NP. Other pain societies, such as the Canada Pain Society, have also included pregabalin in the first line treatment of NP. In fact, gabapentin and pregabalin are the current standard care in most of NP-associated diseases. Dosage comparison For constant pain, the relieving effect of extended-release morphine given once (for Kadian) or twice (for MS Contin) every 24 hours is roughly the same as multiple administrations of immediate release (or \"regular\") morphine. Morphine sulfate pentahydrade (trade names including Dolcontin) has a higher molecular mass than morphine base, and therefore 10 mg morphine sulfate pentahydrate contains approximatively 7.5 mg of morphine free base. Extended-release morphine can be administered together with \"rescue doses\" of immediate-release morphine pro re nata in case of breakthrough pain, each generally consisting of 5% to 15% of the 24-hour extended-release dosage. Lidocaine infusion therapy (LIT) is an effective treatment for relieving neuropathic pain (NeP). However, it remains unclear whether pain relief can be sustained through repeated lidocaine infusions. This study aimed to determine whether repeated intravenous administration of low-dose lidocaine could provide prolonged pain relief in patients with specific NeP conditions. This is a prospective, randomized, double-blind, placebo-controlled, parallel study. We compared the efficacy and safety of lidocaine infusions (3 mg/kg) in the LIT group and normal saline infusions in the control group once a week for 4 consecutive weeks in patients with postherpetic neuralgia or complex regional pain syndrome type II. The primary outcome was the difference in the percentage change in the 11-point numerical rating scale (NRS) pain score from baseline to after the final infusion. Secondary outcomes included pain scores during 4 weeks of follow-up and any complications. Forty-two patients completed this study protocol. The percentage reduction in NRS pain scores after the final infusion was significantly greater in the LIT group compared with the control group (P = 0.011). However, this pain reduction was not detectable at the 4-week follow-up. The difference in the percentage change in NRS pain scores was especially prominent in the LIT group after the third and fourth infusions. None of the study participants experienced serious complications from the treatment. Lidocaine infusion therapy (3 mg/kg of lidocaine administered over 1 hour) provided effective short-term pain relief, which was substantially prominent after repeated infusions were administered to patients with refractory NeP. This study was registered at ClinicalTrials.gov, identifier NCT02597257. Few controlled trials have been carried out with non-steroidal antiinflammatory drugs in this indication, mainly as a result of methodological difficulties. A prerequisite for correct evaluation is compliance with certain fundamental principles. The study must be controlled (i.e. comparative, prospective randomized, double-blind, with data quality control and statistical analysis). The sample size must be consistent with the objectives (at least 40 patients per group). The selection criteria must be well specified and the comparability of baseline data assessed. The most appropriate study design for assessing clinical efficacy is to compare two parallel groups of out patients treated during five to fifteen days. The main criterion of efficacy should be based on the judgments of both patients and physician. Time course of pain, improvement in the patient's functional capacity, improvement in physical findings (Schober, Lasègue), dosage of concomitant analgesic treatments when these are allowed, and evaluation at three and six months can also be used as efficacy criteria. Assessment of clinical and biological tolerance is mandatory. Considering the frequent use of non-steroidal antiinflammatory drugs in treating sciatica, there is a strong need for rigorous investigations.\nHere is the question:\nONCOLOGY: A 66-year-old patient diagnosed with stage IV pancreatic adenocarcinoma 8 months ago. He follows treatment with delayed release morphine 200 mg/12 hours orally, kerosene and lactulose. For the last 15 days he has reported paresthesias and occasional lancinating pain in the right lumbar and periumbilical area that does not subside with rescue morphine. The neurological examination is normal. Indicate the most appropriate management:\nHere are the potential choices:\n1. Perform computed axial tomography and evaluate nerve compression since it is neuropathic pain.\n2. Evaluate neurolytic treatment since neuropathic pain is difficult to control.\n3. Decrease the dose of morphine as it is ineffective in this type of pain.\n4. Administer amitriptyline or gabapentin, dexamethasone and increase the dose of morphine.\nThe correct answer is: 4. Administer amitriptyline or gabapentin, dexamethasone and increase the dose of morphine."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n All these branches enter the muscles on their ocular surfaces, with the exception of the nerve to the inferior oblique, which enters the muscle at its posterior border. Nuclei The oculomotor nerve (CN III) arises from the anterior aspect of mesencephalon (midbrain). There are two nuclei for the oculomotor nerve: The oculomotor nucleus originates at the level of the superior colliculus. The muscles it controls are the striated muscle in levator palpebrae superioris and other extraocular muscles except for the superior oblique muscle and the lateral rectus muscle. The Edinger-Westphal nucleus supplies parasympathetic fibers to the eye via the ciliary ganglion, and thus controls the sphincter pupillae muscle (affecting pupil constriction) and the ciliary muscle (affecting accommodation). Schematic Referring to the neural pathway schematic diagram, the entire pupillary light reflex system can be visualized as having eight neural segments, numbered 1 through 8. Odd-numbered segments 1, 3, 5, and 7 are on the left. Even-numbered segments 2, 4, 6, and 8 are on the right. Segments 1 and 2 each includes both the retina and the optic nerve (cranial Nerve #2). Segments 3 and 4 are nerve fibers that cross from the pretectal nucleus on one side to the Edinger-Westphal nucleus on the contralateral side. Segments 5 and 6 are fibers that connect the pretectal nucleus on one side to the Edinger-Westphal nucleus on the same side. Segments 3, 4, 5, and 6 are all located within a compact region within the midbrain. Segments 7 and 8 each contains parasympathetic fibers that courses from the Edinger-Westphal nucleus, through the ciliary ganglion, along the oculomotor nerve (cranial nerve #3), to the ciliary sphincter, the muscular structure within the iris. The oculomotor nerve is responsible for a number of parasympathetic functions related to the eye. The oculomotor PNS fibers originate in the Edinger-Westphal nucleus in the central nervous system and travel through the superior orbital fissure to synapse in the ciliary ganglion located just behind the orbit (eye). From the ciliary ganglion the postganglionic parasympathetic fibers leave via short ciliary nerve fibers, a continuation of the nasociliary nerve (a branch of ophthalmic division of the trigeminal nerve (CN V1)). The short ciliary nerves innervate the orbit to control the ciliary muscle (responsible for accommodation) and the iris sphincter muscle, which is responsible for miosis or constriction of the pupil (in response to light or accommodation). There are two motors that are part of the oculomotor nerve known as the somatic motor and visceral motor. The somatic motor is responsible for moving the eye in precise motions and for keeping the eye fixated on an object. The The Oculomotor nerve (cranial nerve III) – Arises from the oculomotor sulcus on the medial portion of the crus cerebri. It is a motor nerve that receives inputs from two nuclei. The first nucleus is the oculomotor nucleus; it serves as its main motor nucleus and is in the anterior midline of the periaqueductal grey at the level of the superior colliculus. The second nucleus is the Edinger-Westphal nucleus, which provides parasympathetic motor inputs. The somatic motor fibers from the oculomotor nucleus provide innervation to all the extraocular muscles, with the exceptions of the superior oblique and lateral rectus muscles. The parasympathetic motor fibers of the Edinger-Westphal nucleus provide innervation to the ciliary muscles and constrictor pupillae after passing through the ciliary ganglion. CN III, IV, and VI nerves innervate the six extraocular muscles that control eye movements in response to head movements. When the head turns to the left, vestibular information initiates its journey from the left semicircular canal via vestibular nerve fibers and proceeds to the ipsilateral medial and superior vestibular nuclei. Then, excited neurons in the left superior and medial vestibular nuclei send signals to the right CN VI nucleus. The right CN VI innervates the right lateral rectus muscle to contract and direct the gaze to the right. Another nerve fiber projects from the CN VI nucleus and ascends via the MLF toward the left CN III nucleus. When stimulated, the oculomotor nerve results in the medial rectus muscle contraction and allows the left eye to gaze to the right. Inhibitory nerve fibers also proceed from the medial vestibular nucleus to the left CN VI nucleus, rendering the left lateral rectus and right medial rectus muscles to relax. The result of these combined counteracting effects is a smooth, coordinated eye movement toward the opposite direction, and thus a steady visual field with head-turning. The trochlear nerves innervate the contralateral superior oblique muscle and stimulate the muscle to contract and make eye movements via lateral rotation, intorsion, and depression. [8] [24] The parasympathetic nervous system causes pupillary constriction through a process called miosis. The parasympathetic nerve fibers start at the first neuron called the Edinger-Westphal nucleus. This neuron's nerve fibers span to the ciliary ganglion by traveling on the oculomotor nerve. After the ciliary ganglion, the second neuron is from the short ciliary nerves to the sphincter pupillae muscles. When the sphincter pupillae muscle contract, it will cause the constriction of the pupils. [7] Nerve supply The parasympathetic innervation of the ciliary body is the most clearly understood. Presynaptic parasympathetic signals that originate in the Edinger-Westphal nucleus are carried by cranial nerve III (the oculomotor nerve) and travel through the ciliary ganglion. Postsynaptic fibers from the ciliary ganglion form the short ciliary nerves. Parasympathetic activation of the M3 muscarinic receptors causes ciliary muscle contraction, the effect of contraction is to decrease the diameter of the ring of ciliary muscle. The parasympathetic tone is dominant when a higher degree of accommodation of the lens is required, such as reading a book. The ciliary body is also known to receive sympathetic innervation via long ciliary nerves. When test subjects are startled, their eyes automatically adjust for distance vision. Presynaptic parasympathetic fibers originate in the Edinger-Westphal nucleus, the parasympathetic motor nucleus associated with the oculomotor nucleus in the brainstem. Axons from the Edinger-Westphal nucleus and the oculomotor nucleus run together in the brainstem and exit together as the oculomotor nerve. The oculomotor nerve passes through the lateral wall of the cavernous sinus and enters the orbit through the superior orbital fissure. It divides into branches that innervate the levator palpebrae superioris and four of the six extraocular muscles. Parasympathetic fibers initially run in the inferior division of the oculomotor nerve. They exit as one or two short “motor roots” that synapse in the ciliary ganglion. Light travels through the cornea, anterior chamber, pupil, lens, and the posterior chamber, eventually reaching the retina. Photoreceptor cells in the outer layers of the retina, which are called rods and cones, convert light stimuli into neuronal impulses. These signals are then relayed to the bipolar cells, which interact with ganglion cells, which in turn coalesce to form the optic disc and optic nerve (CN II). The optic nerve sends impulses to the brain for further processing and image recognition. [1] These are the first steps of the pupillary light reflex afferent pathway. The optic nerve then forms the optic chiasm, which diverges into a left and right optic tract. At the optic chiasm, nasal retinal fibers will cross to the contralateral side of the optic tract, and the temporal retinal fibers continue on the ipsilateral side. Thus, the right optic tract will contain temporal retinal fibers from the right eye, as well as nasal retinal fibers from the left eye. The optic tracts join the brachium of the superior colliculus, and then signals travel to the pretectal area of the midbrain. Each pretectal area sends bilateral signals to the preganglionic parasympathetic nuclei in the midbrain called Edinger-Westphal nuclei. [2] [3] There are a minority of axons that go to the hypothalamus and the olivary pretectal nucleus (OPN). [4] Efferent parasympathetic preganglionic fibers travel on the oculomotor nerve and synapse with the ciliary ganglion, which sends postganglionic axons to directly innervate the iris sphincter muscles. The contraction of the iris sphincter muscles leads to pupillary constriction (miosis). [3] This extensive pathway is being tested when a light is shined in the eyes. And, because of the crossing fibers, there is not only a direct pupillary reflex but also a consensual pupillary light reflex. Of note, the pupillary dark reflex involves a separate pathway, which ends with sympathetic fibers from long ciliary nerves innervating the dilator pupillae muscle. Horner syndrome refers to a set of clinical presentations resulting from disruption of sympathetic innervation to the eye and adnexa. Classically, the clinical triad consists of ipsilateral blepharoptosis, pupillary miosis, and facial anhidrosis. Ocular sympathetic denervation may signify life-threatening causes. Timely investigation and accurate diagnosis are essential in patients with oculosympathetic denervation. A 33-year-old Asian man with a heavy smoking habit presented with a 3-week history of left ptosis and no other complaints. His visual acuity was 20/20 bilaterally. An ophthalmic examination was significant for mild ptosis of his left eyelid and anisocoria (smaller left pupil), which was greater in the dark. Both pupils reacted to light briskly without an afferent pupillary defect. Anhidrosis was found on the medial side of the left forehead. A 10% cocaine test was positive. At his first visit, neurologic examination was unremarkable. Comprehensive radiological investigations were scheduled for a left-sided isolated Horner syndrome. Two weeks after his first visit, he experienced a left-sided headache along with ipsilateral Horner syndrome. Neurologic examination revealed hypoesthesia in the left cranial nerve V<sub1-3</sub territories. Emergent computed tomography angiography was suspected for petrous part of the left internal carotid artery (ICA) dissection. Magnetic resonance imaging demonstrated an enhancing infiltrative lesion with its epicenter at the left sphenoid bone. The lesion encased the left ICA and invaded the left Meckel cave. Rhinoscopy with incisional biopsy revealed squamous cell nasopharyngeal carcinoma. This case involved an unusual initial presentation of nasopharyngeal carcinoma: isolated Horner syndrome with clinical progression to adjacent structures. Infiltration involving the Meckel cave and ICA at the foramen lacerum can present as postganglionic Horner syndrome associated with trigeminal pain and hypoesthesia. These clinical findings may mimic carotid artery dissection on computed tomography angiography. Detailed magnetic resonance imaging with careful attention to the skull base should be performed. The third cranial nerve is also known as oculomotor nerve and has 2 major components: Outer parasympathetic fibers that supply the ciliary muscles and the sphincter pupillae Inner somatic fibers that supply the levator palpebrae superioris in the eyelid (which retracts the upper eyelid) and the 4 extraocular muscles (superior, middle, inferior recti, and inferior oblique). LR6(SO4)3 is a simple mnemonic representing the innervation of the extraocular muscles. It stands for: LR6: Lateral rectus muscle which is supplied by the sixth cranial nerve SO4: Superior oblique muscle which is supplied by the fourth cranial nerve 3: The third cranial nerve supplies other extraocular muscles We report a 55-year-old man with papilledema and multiple cranial nerve palsies. He was well until 52 years of age when there was an onset of progressive difficulty in initiating urination; he visited the urology service of our hospital where a diagnosis of prostate cancer was made; the cancer was invading the bladder and was metastasizing to lymph nodes and bones. He was treated with oochiectomy and estrogen preparations with some improvement in his symptoms. Two years later, he developed difficulty in urination again, and transurethral resection of the tumor was performed in 1991. In December 1991, he noted tingling and numb sensation in his left face, which had become progressive worse within the next one month, and he developed blepharoptosis and deafness all on the left side. He was admitted to the urology service on February 4, 1992, and a neurological consultation was asked. On physical examination, general findings were unremarkable, except for lymph node enlargements of about 0.5 to 1.0 mm in size in cervical and inguinal regions. On neurologic examination, he was alert with normal mental activities; higher cerebral functions were intact. He had normal vision and visual fields, however, papilledema was present bilaterally; pupils and light reactions were normal. Extraocular muscles were intact on the right side, however, moderate restriction was noted in the left eye in that all the extraocular muscles except for the medial rectus were weak; blepharoptosis was noted on the left; no nystagmus was present. The sensation was diminished in the left face, and left facial paresis of the peripheral type was also noted; the taste sensation was also diminished in the left anterior two thirds of the tongue. He had sensorineural deafness on the left side. The other cranial nerves appeared intact. He walked normally; no weakness or muscle atrophy was noted; muscle tone was normal and no ataxia was observed. Deep reflexes were normally elicited and symmetric; the plantar response was flexor. No meningeal signs were present. Laboratory examination revealed following abnormalities: Hb 7.1 g/dl, platelet 47,000/cmm, WBC3,800/cmm, LDH 950IU/l, PAP232ng/ml (normal less than 1.6), PA2.631ng/ml (normal less than 7.4); a small amount of effusion was noted in the left pleural cavity; cytological examination of the fluid was class V. A cranial CT scan as well as MRI were entirely normal, as was the spinal tap. He was treated with glycerol, however, there was progressive increase in the pleural effusion, and he developed dyspnea; moist rale had become audible in the end of February.(ABSTRACT TRUNCATED AT 400 WORDS) There are six cranial nerves and nerve fibers from the autonomic nervous system. Optic nerve Oculomotor nerve Short ciliary nerve (parasympathetic nervous system) Trochlear nerve Trigeminal nerve (ophthalmic branch) Abducens nerve Facial nerve Long ciliary nerve (sympathetic nervous system) Fig. 11.1 ). Hence, this part of the autonomic nervous system is sometimes called the craniosacral division. The cranial nerve nuclei that contain parasympathetic preganglionic neurons are the Edinger-Westphal nucleus (cranial nerve III), the superior (cranial nerve VII) and inferior (cranial nerve IX) salivatory nuclei, and the dorsal motor nucleus of the vagus and nucleus ambiguus (cranial nerve X). Postganglionic parasympathetic cells are located in cranial ganglia, including the ciliary ganglion (preganglionic input is from the Edinger-Westphal nucleus), the pterygopalatine and submandibular ganglia (input is from the superior salivatory nucleus), and the otic ganglion (input is from the inferior salivatory nucleus). The ciliary ganglion innervates the pupillary sphincter and ciliary muscles in the eye. The pterygopalatine ganglion supplies the lacrimal gland, as well as glands in the nasal and oral pharynx. The submandibular ganglion projects to the submandibular and sublingual The pupillary light reflex neural pathway on each side has an afferent limb and two efferent limbs. The afferent limb has nerve fibers running within the optic nerve (CN II). Each efferent limb has nerve fibers running along the oculomotor nerve (CN III). The afferent limb carries sensory input. Anatomically, the afferent limb consists of the retina, the optic nerve, and the pretectal nucleus in the midbrain, at level of superior colliculus. Ganglion cells of the retina project fibers through the optic nerve to the ipsilateral pretectal nucleus. The efferent limb is the pupillary motor output from the pretectal nucleus to the ciliary sphincter muscle of the iris. The pretectal nucleus projects crossed and uncrossed fibers to the ipsilateral and contralateral Edinger-Westphal nuclei, which are also located in the midbrain. Each Edinger-Westphal nucleus gives rise to preganglionic parasympathetic fibers which exit with CN III and synapse with postganglionic parasympathetic neurons in Poisoning with organophosphate pesticides can cause sensory and motor neuropathy with permanent paralysis. Paralysis at the site of dermal exposure has not been reported. A 61-year-old carpenter sprayed a nest of termites with an insecticide containing chlorpyrifos without protective equipment and with direct contact of pesticide solution to hands, lower arms, feet, and lower legs, as well as inhalation of vapors from spraying. After 30 min he became ill with nausea, abdominal cramping, arm and leg weakness, bilateral shoulder pain, chest pain, and numbness in the left hand and arm. At a hospital, he was treated with atropine 1 mg IV and pralidoxime Cl 2 g IV There was 0/5 strength in the hands and wrists and 3/5 elsewhere, a left peritoneal palsy, and urinary retention. He was transferred to a tertiary care hospital where paralysis persisted. Electromyogram studies documented widespread peripheral neuropathy. With continued progression of neuropathy, pralidoxime was repeated on the third day. By day 12, motor strength improved except for the hands and left lower leg. Right interosseous muscle strength was 1/5 and left was 0/5. Right-hand grip was 2/5, and left-hand grip was 0/5. He was transferred to a rehabilitation center. He never regained use of his hands and was disabled from employment as a carpenter. There was a disturbed gait, with inability to clear his left foot with walking. Urinary retention persisted and required self-catherization. Dermal exposure of the hands and feet to chlorpyrifos was associated with atrophy and permanent paralysis of exposed areas. The importance of protective equipment is emphasized. The abducens nerve innerves only one muscle in the eye. This muscle is the lateral rectus muscle. When this muscle contracts, it causes the eye to abduct. [5] We report a 56-year-old man who developed progressive paraparesis. He was apparently well, except for left Bell's palsy which developed on May 9 of 1994, for which he received stellate ganglion block on the left side more than ten times until July 2nd of 1994, when he noted pain in his left shoulder and in his lumbar region. On July 5th, he noted some difficulty in urination. On July 6th, he noted tingling sensation in his four extremities and difficulty in gait. He was admitted to another hospital where he was treated with intravenous infusion of glycerol. After this treatment, his gait and sensory disturbance showed some improvement, however, on July 7th, his shoulder and lumbar pain worsened, and he became unable to stand. His temperature went up to 39 degrees C on the next day. Lumbar CSF on that day contained 119 cells/microliters, 112 mg/dl of protein, and 53 mg/dl of sugar. He was transferred to our hospital on July 14th. His past medical history revealed that he had suffered from frequent bouts of osteomyelitis since the age of 13 years. He was operated on several times on osteomyelitis. He had been treated on his tooth ache until shortly before the onset of the present illness. He also received steroid hormone for his Bell's palsy. On admission, his consciousness varied from alert to stupor. His BP was 150/100 mmHg, HR 98/min and regular, BT 39.4 degrees C. The bulbar conjunctiva appeared somewhat icteric. Otherwise, general physical examination was unremarkable. On neurologic examination, there was no apparent dementia. Higher cerebral functions appeared intact. The optic discs were flat. Pupils were round and isocoric reacting to light and accommodation promptly. Ocular movements were full without nystagmus. Some exophthalmos was noted bilaterally. The sensation of the face and facial muscles were intact. The remaining cranial nerves also appeared intact. Nuchal rigidity was present. He was unable to stand or walk. Muscle strength was markedly diminished in all four limbs; manual muscle testing revealed 1 to 2/5 weakness in both upper and lower extremities bilaterally. Muscle stretch reflexes were decreased or lost in both upper and lower limbs, but the plantar response was extensor on the right. Sensation appeared to be diminished in legs, but detail was not clear because of disturbance of consciousness. Pertinent laboratory findings were as follows: WBC 12,800/microliter, GPT 58 IU/l, total bilirubin 2.65 mg/dl, and CRP 16.8 mg/dl. Cerebrospinal fluid contained 34 cells/microliter (approximately two thirds were neutrophils), RBC 1,110/microliter, 2,949 mg/dl of protein, and 119 mg/dl of glucose; stapylococcus aureus was cultured from the CSF. Myelogram showed a filling defect in the anterior epidural space between the low thoracic and the upper lumbar region. The patient was treated with cephotaxim, aminobenzyl penicillin, and chloramphenicol. On the second hospital day, his BT was still 39 degrees C and he was agitated His weakness was worse than the previous day. Spinal MRI was attempted; as he was agitated 5 mg of diazepam was given intravenously at 4 PM. His respiration was rapid and somewhat shallow. At 6 PM, gadolinium DTPA was injected intravenously; at that time, he was breathing and pupils were 3 mm on both sides. At 6:35 PM, an examiner noted that he stopped breathing; the left pupil was dilated to 5 mm. Cardiopulmonary resuscitation was initiated immediately, and intubation was performed. He was placed on a respirator. His blood pressure did not reach 100 mmHg; he was in deep coma. Cardiac arrest occurred at 8:53 AM on the next morning. The patient was discussed in a neurological CPC. Most of the participants thought that the patient had either spinal epidural empyema or spinal subdural abscess. The question was what might be the original focus of infection. Three possibilities were considered, i.e., stellate ganglion block, teeth infection, and osteomyelitis... Six extrinsic eye muscles that move each eye: (1) superior rectus, (2) inferior rectus, (3) lateral rectus, (4) medial rectus, (5) superior oblique, and (6) inferior oblique. Lateral rectus is innervated by trochlear and superior oblique is innervated by abducens nerve; The oculomotor nerve innervates the remaining four muscles. The motor units in these muscles tend to be small with neurons serving only two or three muscle fibers at times. Such small motor units allow precise and rapid eye movement. Portions of the brainstem and cerebellum coordinate eye movements. Bickerstaff brainstem encephalitis (BBE) is a rare demyelinating disease of the central nervous system (CNS) that is caused by a direct viral infection or secondary autoimmune responses. BBE secondary to Herpes zoster has rarely been reported. A 68-year-old man developed a painful vesicular rash and drooping eyelid on the left side of his face for 20 days. Physical examination revealed left-sided blepharoptosis and crusted erythema on the left front side of his face, left upper eyelid, and left nasal tip. Neurological examination showed impaired sensation over the left side of his face and cheek. His left pupil was dilated (4mm compared to 2mm on the right side), and the Pupillary light reflection (PLR) was absent, with an ocular movement disorder (limited adduction) and diplopia. Brain imaging did not reveal abnormalities. Cerebrospinal fluid (CSF) examination showed leukocytosis and increased protein levels. He was treated with intravenous acyclovir for 7 days, but developed disturbance of consciousness and right limb weakness. Neurological examination revealed right lower limb hypoesthesia. The Heel-Knee-Shin test was positive on the left side, and Babinski's sign was present on the right side. He was diagnosed with Bickerstaff brainstem encephalitis caused by herpes zoster. After 2 days of intravenous acyclovir combined with intravenous immune globulin (IVIG), the patient developed acute kidney injury (AKI). Then, his treatment was changed to systemic steroids. At the 3-month follow-up, his pupils were bilaterally equal and reactive to light, and there was a significant improvement in ocular motility and ptosis. At the 6-month follow-up, his diplopia had completely resolved. BBE associated with herpes zoster is very rare and can be overlooked. Dermatologists should be aware of the expanding spectrum of neurological complications caused by varicella zoster virus (VZV) infections to aid early diagnosis and treatment. The inferior division of cranial nerve III, also known as the oculomotor nerve, runs inferolaterally along the inferior rectus to innervate the inferior oblique muscle. The nerve is approximately 27 mm long, running from orbital apex to the inferior oblique muscle. [6] The nerve to the inferior oblique is the longest branch of the inferior division of the oculomotor nerve. It enters the muscle through its orbital surface. [2] The nerve has been measured to be approximately 1.04mm on the right and 1.07 mm on the left. [2] Ptosis caused by oculomotor palsy can be unilateral or bilateral, as the subnucleus to the levator muscle is a shared, midline structure in the brainstem. In cases in which the palsy is caused by the compression of the nerve by a tumor or aneurysm, it is highly likely to result in an abnormal ipsilateral papillary response and a larger pupil. Surgical third nerve palsy is characterized by a sudden onset of unilateral ptosis and an enlarged or sluggish pupil to the light. In this case, imaging tests such as CTs or MRIs should be considered. Medical third nerve palsy, contrary to surgical third nerve palsy, usually does not affect the pupil and it tends to slowly improve in several weeks. Surgery to correct ptosis due to medical third nerve palsy is normally considered only if the improvement of ptosis and ocular motility are unsatisfactory after half a year. Patients with third nerve palsy tend to have diminished or absent function of the levator.\nHere is the question:\nPNEUMOLOGY: Juan is 60 years old, has been smoking 2 packs/day for years and has reported a persistent cough for the last 6 months. He notes that his left eyelid is more droopy and that the pupil of this eye is smaller. John reports that the medial side of his left hand is numb and with less strength. His physician checks for palpebral ptosis and left miosis; he checks that he can close both eyelids symmetrically and that both pupils respond correctly to light. In addition, he checks that there is no sweating from the left hemiface, that he feels less prickling on the inner surface of the left hand and that he has less strength in the grip of the left hand. Regarding the ocular symptomatology, where is the lesion located?\nHere are the potential choices:\n1. Sympathetic fibers, at some level that would span from the hypothalamus to the interinedio-lateral Clark's column of the dorsal medulla.\n2. Left common ocular motor nerve in the midbrain.\n3. Edinger-Westphal nucleus above the left common ocular motor nerve nucleus.\n4. Parasympathetic fibers, at some level ranging from the Edinger-Westphal nucleus to the constrictor muscle of the left pupil.\n5. Tarsal muscle exclusively.\nThe correct answer is: ",
        "gold_answer": "1 Sympathetic fibers, at some level that would span from the hypothalamus to the interinedio-lateral Clark's column of the dorsal medulla.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n All these branches enter the muscles on their ocular surfaces, with the exception of the nerve to the inferior oblique, which enters the muscle at its posterior border. Nuclei The oculomotor nerve (CN III) arises from the anterior aspect of mesencephalon (midbrain). There are two nuclei for the oculomotor nerve: The oculomotor nucleus originates at the level of the superior colliculus. The muscles it controls are the striated muscle in levator palpebrae superioris and other extraocular muscles except for the superior oblique muscle and the lateral rectus muscle. The Edinger-Westphal nucleus supplies parasympathetic fibers to the eye via the ciliary ganglion, and thus controls the sphincter pupillae muscle (affecting pupil constriction) and the ciliary muscle (affecting accommodation). Schematic Referring to the neural pathway schematic diagram, the entire pupillary light reflex system can be visualized as having eight neural segments, numbered 1 through 8. Odd-numbered segments 1, 3, 5, and 7 are on the left. Even-numbered segments 2, 4, 6, and 8 are on the right. Segments 1 and 2 each includes both the retina and the optic nerve (cranial Nerve #2). Segments 3 and 4 are nerve fibers that cross from the pretectal nucleus on one side to the Edinger-Westphal nucleus on the contralateral side. Segments 5 and 6 are fibers that connect the pretectal nucleus on one side to the Edinger-Westphal nucleus on the same side. Segments 3, 4, 5, and 6 are all located within a compact region within the midbrain. Segments 7 and 8 each contains parasympathetic fibers that courses from the Edinger-Westphal nucleus, through the ciliary ganglion, along the oculomotor nerve (cranial nerve #3), to the ciliary sphincter, the muscular structure within the iris. The oculomotor nerve is responsible for a number of parasympathetic functions related to the eye. The oculomotor PNS fibers originate in the Edinger-Westphal nucleus in the central nervous system and travel through the superior orbital fissure to synapse in the ciliary ganglion located just behind the orbit (eye). From the ciliary ganglion the postganglionic parasympathetic fibers leave via short ciliary nerve fibers, a continuation of the nasociliary nerve (a branch of ophthalmic division of the trigeminal nerve (CN V1)). The short ciliary nerves innervate the orbit to control the ciliary muscle (responsible for accommodation) and the iris sphincter muscle, which is responsible for miosis or constriction of the pupil (in response to light or accommodation). There are two motors that are part of the oculomotor nerve known as the somatic motor and visceral motor. The somatic motor is responsible for moving the eye in precise motions and for keeping the eye fixated on an object. The The Oculomotor nerve (cranial nerve III) – Arises from the oculomotor sulcus on the medial portion of the crus cerebri. It is a motor nerve that receives inputs from two nuclei. The first nucleus is the oculomotor nucleus; it serves as its main motor nucleus and is in the anterior midline of the periaqueductal grey at the level of the superior colliculus. The second nucleus is the Edinger-Westphal nucleus, which provides parasympathetic motor inputs. The somatic motor fibers from the oculomotor nucleus provide innervation to all the extraocular muscles, with the exceptions of the superior oblique and lateral rectus muscles. The parasympathetic motor fibers of the Edinger-Westphal nucleus provide innervation to the ciliary muscles and constrictor pupillae after passing through the ciliary ganglion. CN III, IV, and VI nerves innervate the six extraocular muscles that control eye movements in response to head movements. When the head turns to the left, vestibular information initiates its journey from the left semicircular canal via vestibular nerve fibers and proceeds to the ipsilateral medial and superior vestibular nuclei. Then, excited neurons in the left superior and medial vestibular nuclei send signals to the right CN VI nucleus. The right CN VI innervates the right lateral rectus muscle to contract and direct the gaze to the right. Another nerve fiber projects from the CN VI nucleus and ascends via the MLF toward the left CN III nucleus. When stimulated, the oculomotor nerve results in the medial rectus muscle contraction and allows the left eye to gaze to the right. Inhibitory nerve fibers also proceed from the medial vestibular nucleus to the left CN VI nucleus, rendering the left lateral rectus and right medial rectus muscles to relax. The result of these combined counteracting effects is a smooth, coordinated eye movement toward the opposite direction, and thus a steady visual field with head-turning. The trochlear nerves innervate the contralateral superior oblique muscle and stimulate the muscle to contract and make eye movements via lateral rotation, intorsion, and depression. [8] [24] The parasympathetic nervous system causes pupillary constriction through a process called miosis. The parasympathetic nerve fibers start at the first neuron called the Edinger-Westphal nucleus. This neuron's nerve fibers span to the ciliary ganglion by traveling on the oculomotor nerve. After the ciliary ganglion, the second neuron is from the short ciliary nerves to the sphincter pupillae muscles. When the sphincter pupillae muscle contract, it will cause the constriction of the pupils. [7] Nerve supply The parasympathetic innervation of the ciliary body is the most clearly understood. Presynaptic parasympathetic signals that originate in the Edinger-Westphal nucleus are carried by cranial nerve III (the oculomotor nerve) and travel through the ciliary ganglion. Postsynaptic fibers from the ciliary ganglion form the short ciliary nerves. Parasympathetic activation of the M3 muscarinic receptors causes ciliary muscle contraction, the effect of contraction is to decrease the diameter of the ring of ciliary muscle. The parasympathetic tone is dominant when a higher degree of accommodation of the lens is required, such as reading a book. The ciliary body is also known to receive sympathetic innervation via long ciliary nerves. When test subjects are startled, their eyes automatically adjust for distance vision. Presynaptic parasympathetic fibers originate in the Edinger-Westphal nucleus, the parasympathetic motor nucleus associated with the oculomotor nucleus in the brainstem. Axons from the Edinger-Westphal nucleus and the oculomotor nucleus run together in the brainstem and exit together as the oculomotor nerve. The oculomotor nerve passes through the lateral wall of the cavernous sinus and enters the orbit through the superior orbital fissure. It divides into branches that innervate the levator palpebrae superioris and four of the six extraocular muscles. Parasympathetic fibers initially run in the inferior division of the oculomotor nerve. They exit as one or two short “motor roots” that synapse in the ciliary ganglion. Light travels through the cornea, anterior chamber, pupil, lens, and the posterior chamber, eventually reaching the retina. Photoreceptor cells in the outer layers of the retina, which are called rods and cones, convert light stimuli into neuronal impulses. These signals are then relayed to the bipolar cells, which interact with ganglion cells, which in turn coalesce to form the optic disc and optic nerve (CN II). The optic nerve sends impulses to the brain for further processing and image recognition. [1] These are the first steps of the pupillary light reflex afferent pathway. The optic nerve then forms the optic chiasm, which diverges into a left and right optic tract. At the optic chiasm, nasal retinal fibers will cross to the contralateral side of the optic tract, and the temporal retinal fibers continue on the ipsilateral side. Thus, the right optic tract will contain temporal retinal fibers from the right eye, as well as nasal retinal fibers from the left eye. The optic tracts join the brachium of the superior colliculus, and then signals travel to the pretectal area of the midbrain. Each pretectal area sends bilateral signals to the preganglionic parasympathetic nuclei in the midbrain called Edinger-Westphal nuclei. [2] [3] There are a minority of axons that go to the hypothalamus and the olivary pretectal nucleus (OPN). [4] Efferent parasympathetic preganglionic fibers travel on the oculomotor nerve and synapse with the ciliary ganglion, which sends postganglionic axons to directly innervate the iris sphincter muscles. The contraction of the iris sphincter muscles leads to pupillary constriction (miosis). [3] This extensive pathway is being tested when a light is shined in the eyes. And, because of the crossing fibers, there is not only a direct pupillary reflex but also a consensual pupillary light reflex. Of note, the pupillary dark reflex involves a separate pathway, which ends with sympathetic fibers from long ciliary nerves innervating the dilator pupillae muscle. Horner syndrome refers to a set of clinical presentations resulting from disruption of sympathetic innervation to the eye and adnexa. Classically, the clinical triad consists of ipsilateral blepharoptosis, pupillary miosis, and facial anhidrosis. Ocular sympathetic denervation may signify life-threatening causes. Timely investigation and accurate diagnosis are essential in patients with oculosympathetic denervation. A 33-year-old Asian man with a heavy smoking habit presented with a 3-week history of left ptosis and no other complaints. His visual acuity was 20/20 bilaterally. An ophthalmic examination was significant for mild ptosis of his left eyelid and anisocoria (smaller left pupil), which was greater in the dark. Both pupils reacted to light briskly without an afferent pupillary defect. Anhidrosis was found on the medial side of the left forehead. A 10% cocaine test was positive. At his first visit, neurologic examination was unremarkable. Comprehensive radiological investigations were scheduled for a left-sided isolated Horner syndrome. Two weeks after his first visit, he experienced a left-sided headache along with ipsilateral Horner syndrome. Neurologic examination revealed hypoesthesia in the left cranial nerve V<sub1-3</sub territories. Emergent computed tomography angiography was suspected for petrous part of the left internal carotid artery (ICA) dissection. Magnetic resonance imaging demonstrated an enhancing infiltrative lesion with its epicenter at the left sphenoid bone. The lesion encased the left ICA and invaded the left Meckel cave. Rhinoscopy with incisional biopsy revealed squamous cell nasopharyngeal carcinoma. This case involved an unusual initial presentation of nasopharyngeal carcinoma: isolated Horner syndrome with clinical progression to adjacent structures. Infiltration involving the Meckel cave and ICA at the foramen lacerum can present as postganglionic Horner syndrome associated with trigeminal pain and hypoesthesia. These clinical findings may mimic carotid artery dissection on computed tomography angiography. Detailed magnetic resonance imaging with careful attention to the skull base should be performed. The third cranial nerve is also known as oculomotor nerve and has 2 major components: Outer parasympathetic fibers that supply the ciliary muscles and the sphincter pupillae Inner somatic fibers that supply the levator palpebrae superioris in the eyelid (which retracts the upper eyelid) and the 4 extraocular muscles (superior, middle, inferior recti, and inferior oblique). LR6(SO4)3 is a simple mnemonic representing the innervation of the extraocular muscles. It stands for: LR6: Lateral rectus muscle which is supplied by the sixth cranial nerve SO4: Superior oblique muscle which is supplied by the fourth cranial nerve 3: The third cranial nerve supplies other extraocular muscles We report a 55-year-old man with papilledema and multiple cranial nerve palsies. He was well until 52 years of age when there was an onset of progressive difficulty in initiating urination; he visited the urology service of our hospital where a diagnosis of prostate cancer was made; the cancer was invading the bladder and was metastasizing to lymph nodes and bones. He was treated with oochiectomy and estrogen preparations with some improvement in his symptoms. Two years later, he developed difficulty in urination again, and transurethral resection of the tumor was performed in 1991. In December 1991, he noted tingling and numb sensation in his left face, which had become progressive worse within the next one month, and he developed blepharoptosis and deafness all on the left side. He was admitted to the urology service on February 4, 1992, and a neurological consultation was asked. On physical examination, general findings were unremarkable, except for lymph node enlargements of about 0.5 to 1.0 mm in size in cervical and inguinal regions. On neurologic examination, he was alert with normal mental activities; higher cerebral functions were intact. He had normal vision and visual fields, however, papilledema was present bilaterally; pupils and light reactions were normal. Extraocular muscles were intact on the right side, however, moderate restriction was noted in the left eye in that all the extraocular muscles except for the medial rectus were weak; blepharoptosis was noted on the left; no nystagmus was present. The sensation was diminished in the left face, and left facial paresis of the peripheral type was also noted; the taste sensation was also diminished in the left anterior two thirds of the tongue. He had sensorineural deafness on the left side. The other cranial nerves appeared intact. He walked normally; no weakness or muscle atrophy was noted; muscle tone was normal and no ataxia was observed. Deep reflexes were normally elicited and symmetric; the plantar response was flexor. No meningeal signs were present. Laboratory examination revealed following abnormalities: Hb 7.1 g/dl, platelet 47,000/cmm, WBC3,800/cmm, LDH 950IU/l, PAP232ng/ml (normal less than 1.6), PA2.631ng/ml (normal less than 7.4); a small amount of effusion was noted in the left pleural cavity; cytological examination of the fluid was class V. A cranial CT scan as well as MRI were entirely normal, as was the spinal tap. He was treated with glycerol, however, there was progressive increase in the pleural effusion, and he developed dyspnea; moist rale had become audible in the end of February.(ABSTRACT TRUNCATED AT 400 WORDS) There are six cranial nerves and nerve fibers from the autonomic nervous system. Optic nerve Oculomotor nerve Short ciliary nerve (parasympathetic nervous system) Trochlear nerve Trigeminal nerve (ophthalmic branch) Abducens nerve Facial nerve Long ciliary nerve (sympathetic nervous system) Fig. 11.1 ). Hence, this part of the autonomic nervous system is sometimes called the craniosacral division. The cranial nerve nuclei that contain parasympathetic preganglionic neurons are the Edinger-Westphal nucleus (cranial nerve III), the superior (cranial nerve VII) and inferior (cranial nerve IX) salivatory nuclei, and the dorsal motor nucleus of the vagus and nucleus ambiguus (cranial nerve X). Postganglionic parasympathetic cells are located in cranial ganglia, including the ciliary ganglion (preganglionic input is from the Edinger-Westphal nucleus), the pterygopalatine and submandibular ganglia (input is from the superior salivatory nucleus), and the otic ganglion (input is from the inferior salivatory nucleus). The ciliary ganglion innervates the pupillary sphincter and ciliary muscles in the eye. The pterygopalatine ganglion supplies the lacrimal gland, as well as glands in the nasal and oral pharynx. The submandibular ganglion projects to the submandibular and sublingual The pupillary light reflex neural pathway on each side has an afferent limb and two efferent limbs. The afferent limb has nerve fibers running within the optic nerve (CN II). Each efferent limb has nerve fibers running along the oculomotor nerve (CN III). The afferent limb carries sensory input. Anatomically, the afferent limb consists of the retina, the optic nerve, and the pretectal nucleus in the midbrain, at level of superior colliculus. Ganglion cells of the retina project fibers through the optic nerve to the ipsilateral pretectal nucleus. The efferent limb is the pupillary motor output from the pretectal nucleus to the ciliary sphincter muscle of the iris. The pretectal nucleus projects crossed and uncrossed fibers to the ipsilateral and contralateral Edinger-Westphal nuclei, which are also located in the midbrain. Each Edinger-Westphal nucleus gives rise to preganglionic parasympathetic fibers which exit with CN III and synapse with postganglionic parasympathetic neurons in Poisoning with organophosphate pesticides can cause sensory and motor neuropathy with permanent paralysis. Paralysis at the site of dermal exposure has not been reported. A 61-year-old carpenter sprayed a nest of termites with an insecticide containing chlorpyrifos without protective equipment and with direct contact of pesticide solution to hands, lower arms, feet, and lower legs, as well as inhalation of vapors from spraying. After 30 min he became ill with nausea, abdominal cramping, arm and leg weakness, bilateral shoulder pain, chest pain, and numbness in the left hand and arm. At a hospital, he was treated with atropine 1 mg IV and pralidoxime Cl 2 g IV There was 0/5 strength in the hands and wrists and 3/5 elsewhere, a left peritoneal palsy, and urinary retention. He was transferred to a tertiary care hospital where paralysis persisted. Electromyogram studies documented widespread peripheral neuropathy. With continued progression of neuropathy, pralidoxime was repeated on the third day. By day 12, motor strength improved except for the hands and left lower leg. Right interosseous muscle strength was 1/5 and left was 0/5. Right-hand grip was 2/5, and left-hand grip was 0/5. He was transferred to a rehabilitation center. He never regained use of his hands and was disabled from employment as a carpenter. There was a disturbed gait, with inability to clear his left foot with walking. Urinary retention persisted and required self-catherization. Dermal exposure of the hands and feet to chlorpyrifos was associated with atrophy and permanent paralysis of exposed areas. The importance of protective equipment is emphasized. The abducens nerve innerves only one muscle in the eye. This muscle is the lateral rectus muscle. When this muscle contracts, it causes the eye to abduct. [5] We report a 56-year-old man who developed progressive paraparesis. He was apparently well, except for left Bell's palsy which developed on May 9 of 1994, for which he received stellate ganglion block on the left side more than ten times until July 2nd of 1994, when he noted pain in his left shoulder and in his lumbar region. On July 5th, he noted some difficulty in urination. On July 6th, he noted tingling sensation in his four extremities and difficulty in gait. He was admitted to another hospital where he was treated with intravenous infusion of glycerol. After this treatment, his gait and sensory disturbance showed some improvement, however, on July 7th, his shoulder and lumbar pain worsened, and he became unable to stand. His temperature went up to 39 degrees C on the next day. Lumbar CSF on that day contained 119 cells/microliters, 112 mg/dl of protein, and 53 mg/dl of sugar. He was transferred to our hospital on July 14th. His past medical history revealed that he had suffered from frequent bouts of osteomyelitis since the age of 13 years. He was operated on several times on osteomyelitis. He had been treated on his tooth ache until shortly before the onset of the present illness. He also received steroid hormone for his Bell's palsy. On admission, his consciousness varied from alert to stupor. His BP was 150/100 mmHg, HR 98/min and regular, BT 39.4 degrees C. The bulbar conjunctiva appeared somewhat icteric. Otherwise, general physical examination was unremarkable. On neurologic examination, there was no apparent dementia. Higher cerebral functions appeared intact. The optic discs were flat. Pupils were round and isocoric reacting to light and accommodation promptly. Ocular movements were full without nystagmus. Some exophthalmos was noted bilaterally. The sensation of the face and facial muscles were intact. The remaining cranial nerves also appeared intact. Nuchal rigidity was present. He was unable to stand or walk. Muscle strength was markedly diminished in all four limbs; manual muscle testing revealed 1 to 2/5 weakness in both upper and lower extremities bilaterally. Muscle stretch reflexes were decreased or lost in both upper and lower limbs, but the plantar response was extensor on the right. Sensation appeared to be diminished in legs, but detail was not clear because of disturbance of consciousness. Pertinent laboratory findings were as follows: WBC 12,800/microliter, GPT 58 IU/l, total bilirubin 2.65 mg/dl, and CRP 16.8 mg/dl. Cerebrospinal fluid contained 34 cells/microliter (approximately two thirds were neutrophils), RBC 1,110/microliter, 2,949 mg/dl of protein, and 119 mg/dl of glucose; stapylococcus aureus was cultured from the CSF. Myelogram showed a filling defect in the anterior epidural space between the low thoracic and the upper lumbar region. The patient was treated with cephotaxim, aminobenzyl penicillin, and chloramphenicol. On the second hospital day, his BT was still 39 degrees C and he was agitated His weakness was worse than the previous day. Spinal MRI was attempted; as he was agitated 5 mg of diazepam was given intravenously at 4 PM. His respiration was rapid and somewhat shallow. At 6 PM, gadolinium DTPA was injected intravenously; at that time, he was breathing and pupils were 3 mm on both sides. At 6:35 PM, an examiner noted that he stopped breathing; the left pupil was dilated to 5 mm. Cardiopulmonary resuscitation was initiated immediately, and intubation was performed. He was placed on a respirator. His blood pressure did not reach 100 mmHg; he was in deep coma. Cardiac arrest occurred at 8:53 AM on the next morning. The patient was discussed in a neurological CPC. Most of the participants thought that the patient had either spinal epidural empyema or spinal subdural abscess. The question was what might be the original focus of infection. Three possibilities were considered, i.e., stellate ganglion block, teeth infection, and osteomyelitis... Six extrinsic eye muscles that move each eye: (1) superior rectus, (2) inferior rectus, (3) lateral rectus, (4) medial rectus, (5) superior oblique, and (6) inferior oblique. Lateral rectus is innervated by trochlear and superior oblique is innervated by abducens nerve; The oculomotor nerve innervates the remaining four muscles. The motor units in these muscles tend to be small with neurons serving only two or three muscle fibers at times. Such small motor units allow precise and rapid eye movement. Portions of the brainstem and cerebellum coordinate eye movements. Bickerstaff brainstem encephalitis (BBE) is a rare demyelinating disease of the central nervous system (CNS) that is caused by a direct viral infection or secondary autoimmune responses. BBE secondary to Herpes zoster has rarely been reported. A 68-year-old man developed a painful vesicular rash and drooping eyelid on the left side of his face for 20 days. Physical examination revealed left-sided blepharoptosis and crusted erythema on the left front side of his face, left upper eyelid, and left nasal tip. Neurological examination showed impaired sensation over the left side of his face and cheek. His left pupil was dilated (4mm compared to 2mm on the right side), and the Pupillary light reflection (PLR) was absent, with an ocular movement disorder (limited adduction) and diplopia. Brain imaging did not reveal abnormalities. Cerebrospinal fluid (CSF) examination showed leukocytosis and increased protein levels. He was treated with intravenous acyclovir for 7 days, but developed disturbance of consciousness and right limb weakness. Neurological examination revealed right lower limb hypoesthesia. The Heel-Knee-Shin test was positive on the left side, and Babinski's sign was present on the right side. He was diagnosed with Bickerstaff brainstem encephalitis caused by herpes zoster. After 2 days of intravenous acyclovir combined with intravenous immune globulin (IVIG), the patient developed acute kidney injury (AKI). Then, his treatment was changed to systemic steroids. At the 3-month follow-up, his pupils were bilaterally equal and reactive to light, and there was a significant improvement in ocular motility and ptosis. At the 6-month follow-up, his diplopia had completely resolved. BBE associated with herpes zoster is very rare and can be overlooked. Dermatologists should be aware of the expanding spectrum of neurological complications caused by varicella zoster virus (VZV) infections to aid early diagnosis and treatment. The inferior division of cranial nerve III, also known as the oculomotor nerve, runs inferolaterally along the inferior rectus to innervate the inferior oblique muscle. The nerve is approximately 27 mm long, running from orbital apex to the inferior oblique muscle. [6] The nerve to the inferior oblique is the longest branch of the inferior division of the oculomotor nerve. It enters the muscle through its orbital surface. [2] The nerve has been measured to be approximately 1.04mm on the right and 1.07 mm on the left. [2] Ptosis caused by oculomotor palsy can be unilateral or bilateral, as the subnucleus to the levator muscle is a shared, midline structure in the brainstem. In cases in which the palsy is caused by the compression of the nerve by a tumor or aneurysm, it is highly likely to result in an abnormal ipsilateral papillary response and a larger pupil. Surgical third nerve palsy is characterized by a sudden onset of unilateral ptosis and an enlarged or sluggish pupil to the light. In this case, imaging tests such as CTs or MRIs should be considered. Medical third nerve palsy, contrary to surgical third nerve palsy, usually does not affect the pupil and it tends to slowly improve in several weeks. Surgery to correct ptosis due to medical third nerve palsy is normally considered only if the improvement of ptosis and ocular motility are unsatisfactory after half a year. Patients with third nerve palsy tend to have diminished or absent function of the levator.\nHere is the question:\nPNEUMOLOGY: Juan is 60 years old, has been smoking 2 packs/day for years and has reported a persistent cough for the last 6 months. He notes that his left eyelid is more droopy and that the pupil of this eye is smaller. John reports that the medial side of his left hand is numb and with less strength. His physician checks for palpebral ptosis and left miosis; he checks that he can close both eyelids symmetrically and that both pupils respond correctly to light. In addition, he checks that there is no sweating from the left hemiface, that he feels less prickling on the inner surface of the left hand and that he has less strength in the grip of the left hand. Regarding the ocular symptomatology, where is the lesion located?\nHere are the potential choices:\n1. Sympathetic fibers, at some level that would span from the hypothalamus to the interinedio-lateral Clark's column of the dorsal medulla.\n2. Left common ocular motor nerve in the midbrain.\n3. Edinger-Westphal nucleus above the left common ocular motor nerve nucleus.\n4. Parasympathetic fibers, at some level ranging from the Edinger-Westphal nucleus to the constrictor muscle of the left pupil.\n5. Tarsal muscle exclusively.\nThe correct answer is: 4. Parasympathetic fibers, at some level ranging from the Edinger-Westphal nucleus to the constrictor muscle of the left pupil."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n In the past, it was seen as important not to get pregnant straight away after a GTD. Specialists recommended a waiting period of 6 months after the hCG levels become normal. Recently, this standpoint has been questioned. New medical data suggest that a significantly shorter waiting period after the hCG levels become normal is reasonable for approximately 97% of the patients with hydatidiform mole. Risk of a repeat GTD The risk of a repeat GTD is approximately 1 in 100, compared with approximately 1 in 1000 risk in the general population. Especially women whose hCG levels remain significantly elevated are at risk of developing a repeat GTD. Persistent trophoblastic disease The term «persistent trophoblastic disease» (PTD) is used when after treatment of a molar pregnancy, some molar tissue is left behind and again starts growing into a tumour. Although PTD can spread within the body like a malignant cancer, the overall cure rate is nearly 100%. A spontaneous fall in the radioimmunoassay for the beta subunit of hCG to less than 2 mIU/mL documents regression of hydatidiform mole following evacuation of a molar pregnancy. Continued negative hCG levels for the year after evacuation indicates the absence of risk for persistent gestational trophoblastic disease. This report describes an unusual case of recurrent nonmetastatic gestational trophoblastic disease 16 months after initial evacuation. A 29-year-old woman presented at 19 weeks' gestation with severe preeclampsia and vaginal bleeding. Pelvic ultrasonography demonstrated a molar pregnancy. Pathology following uterine evacuation confirmed a hydatidiform mole. Serial hCG levels fell progressively to less than 2 mIU/mL over the following 25 weeks. She remained compliant with oral contraceptive pills despite having no sexual activity. Sixteen months after uterine evacuation, recurrence of gestational trophoblastic disease was documented by a rising beta-hCG, negative pelvic ultrasound, normal liver function tests, and normal computed tomography of the head. Endometrial curettage showed no chorionic villi or molar tissue. She was treated with five courses of actinomycin D and has remained disease-free for the following 5 years. This late recurrence of gestational trophoblastic disease suggests that those with a molar pregnancy may benefit from surveillance beyond 1 year after uterine evacuation. Recent clinical advances in the field of gestational trophoblastic diseases are described. WHO modified its risk factor scoring system. This change was proposed to combine both the basic FIGO anatomic staging with the modified WHO risk factor scoring system. Patients who score as low-risk are treated with single agent chemotherapy, such as methotrexate (MTX), and patients refractory to MTX are treated with a combination chemotherapy, EMA/CO. Patients who score as high-risk are treated with EMA/CO, and patients refractory to the first line chemotherapy may be successfully treated with EP/EMA. Recent epidemiological data showed that women with complete hydatidiform moles could anticipate normal reproduction in the future. Studies found that pregnancies after treatment of molar pregnancy resulted in 69% full-term, live births; 8% premature deliveries; 1% ectopic pregnancies, and 0.5% stillbirths. First-trimester spontaneous abortions occurred in 17% of pregnancies, and major and minor malformations were detected in 0.4% of infants. Patients with hydatidiform mole were at increased risk of developing molar pregnancy in subsequent conceptions. After having one molar pregnancy, the risk of having molar disease in a future gestation was about 1%. The risk of persistent gestational trophoblastic tumors was increased by long-term oral contraceptive use before conception. In a large, multicenter, case-control study, the risk was shown to be increased in women who had ever used oral contraceptives, but was highest for women taking oral contraceptives during the cycle in which they became pregnant. Partial hydatidiform moles were never previously proven to transform into choriocarcinoma; however, a recent study with molecular techniques clearly showed that partial moles could transform into choriocarcinoma. All patients with suspected partial moles should be reviewed centrally and require hCG follow-up. Complete hydatidiform molar pregnancies occur in approximately 1 of 1,000 conceptions. After uterine evacuation of the trophoblastic tissue, women are followed up with serial serum human chorionic gonadotropin (hCG) measurements. Patients are considered to have attained remission when their hCG level spontaneously declines to an undetectable level and remains there during a 6-month follow-up period. This standard effectively detects all disease recurrence; however, it is resource intensive, delays child bearing, and is subject to significant noncompliance. Our objective was to determine the risk of disease recurrence after hCG spontaneously declines to undetectable levels. We used a database from the New England Trophoblastic Disease Center to analyze hCG levels in patients with complete molar pregnancies. Among 1,029 women with complete molar pregnancy and complete data, 15% developed persistent gestational trophoblastic neoplasia. The rate of persistent neoplasm among those whose hCG level fell spontaneously to undetectable levels was 0.2% (2/876, 95% confidence interval 0-0.8%). No women developed persistent gestational trophoblastic neoplasia after their hCG level fell to undetectable levels using an assay with a sensitivity of 5 mIU/mL (n = 82, 95% confidence interval 0-4.5%). Based on our experience with women with complete hydatidiform molar pregnancies whose hCG values spontaneously fell to undetectable levels after molar evacuation, we conclude that the risk of recurrent neoplasm after hCG levels fall to less than 5 mIU/mL approaches zero. Placental site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic disease. Little is known about its pathogenesis and natural history. This report describes two cases that arose in patients with documented complete hydatidiform moles and summarizes the antecedent prenatal histories of PSTTs based on a detailed Medline literature analysis. A 28-year-old, G(2)P(2) female had a live, 12-week gestation fetus and a coexisting molar pregnancy. Her hCG levels dropped promptly from 1.5 million to 23,273 IU/ml after termination, but rose shortly thereafter together with the onset of recurrent vaginal bleeding. Curettage revealed persistent mole. Persistently elevated hCG led to hysterectomy disclosing a fundal PSTT. The second case was that of a 48-year-old, G(2) woman who presented with symptoms of preeclampsia, hyperthyroidism, and elevated hCG. Curettage yielded a complete hydatidiform mole. Although the hCG level decreased for a short period, it soon increased despite treatment with methotrexate. A second curettage revealed a PSTT. A Medline literature analysis of PSTT, which consists almost entirely of individual cases and several small series, disclosed that PSTT is preceded in 61% of cases by normal term pregnancy, 12% molar pregnancy, 9% spontaneous abortion, 8% therapeutic abortion, and 3% with ectopic pregnancy, stillbirths or preterm delivery. No information is known in 7%. This report describes two additional cases of PSTT preceded by complete molar pregnancy. PSTT is a well recognized, but uncommon form of gestational trophoblastic disease. Although little is known about its pathogenesis, it is preceded not uncommonly by an abnormal pregnancy, including a molar pregnancy. Although normal value of hCG (LH level) does not necessarily indicate eradication of viable trophoblast, its confirmation has been demonstrated as a clinically useful guide for the probable prevention of choriocarcinoma after hydatidiform mole by Takeuchi et al. Choriocarcinoma preceded by other pregnancies than hydatidiform mole which has the highest risk for choriocarcinoma has drawn more attention than before in connection with the decrease of postmolar choriocarcinoma. So that I have studied the regression rate of urinary gonadotropin (hCG) after the termination of various kinds of pregnancies. In 2,433 cases of induced abortion, 695 cases of spontaneous abortion, 1,724 cases of term delivery and 43 cases of hydatidiform mole, their urinary hCG were determined to the level of physiological range of LH. The rate of hCG regression was in the order of term delivery, spontaneous abortion, induced abortion and hydatidiform mole. The younger was the gestational age of trophoblast, the slower was the regression of hCG. At one month after the termination of pregnancy, 80.1%, 11%, 0.3%, 8% and 4.1%, and at two month 55.8%, 1.6%, 0.5%, 4% and 0.5% for hydatidiform mole, induced abortion of less than 12 week of gestation, spontaneous abortion of less than 12 week of gestation, spontaneous abortion of between 13 and 20 week of gestation respectively still showed abnormal hCG value. One percent of induced abortion at 5 month, 4% of spontaneous abortion at 3 month, 0.3% of term delivery at 4 month still maintained abnormal titer. No malignant sequelae in patients under the investigation have ever been observed in the follow up period between 3 and 8 years. Women diagnosed with complete hydatidiform molar pregnancy are at 15% to 28% risk of developing persistent gestational trophoblastic neoplasia (GTN) requiring further management with chemotherapy. Our objective was to develop human chorionic gonadotropin (hCG) criteria that establish a patient's risk of developing persistent GTN or achieving remission from their baseline risk within a few weeks of molar evacuation. We used a database from the New England Trophoblastic Disease Center to analyze hCG levels from 1,029 women with complete molar pregnancies. We conducted a retrospective cohort study using data from 1973 to 2001. Women whose hCG level declined below 50 mIU/mL during their follow-up were found to be at no more than 1.1% risk for developing persistent GTN, irrespective of when this level was reached. Women whose hCG levels was below 200 mIU/mL in the fourth week after evacuation (59.8% of all women), or below 100 mIU/mL in the sixth week after evacuation (65.8% of all women), had a risk of persistence below 9%. hCG levels above 2,000 mIU/mL in the fourth week after evacuation (13.3% of women) were associated with a 63.8% risk of developing persistent disease. These data may allow clinicians to evaluate the risk of persistence that their patients with complete molar pregnancy have based on early hCG results after molar evacuation. In the fourth week after molar evacuation, 59.8% of women may be counseled that their risk of developing persistent GTN is substantially reduced from their baseline, whereas 13.3% of women may be warned that their risk of developing persistent GTN is greater than 50%. II-2. To approach the efficiency and feasibility of preserving the fertility for patients with placental site trophoblastic tumor (PSTT). Totally 2 086 cases of gestational trophoblastic neoplasm (GTN) patients registered in Peking Union Medical College Hospital between 1998 and 2013. Fifty-seven of them were PSTT patients, 40 cases of which suffered hysterectomy, the rest 17 PSTT patients who preserved their fertility were analyzed retrospectively. The computerized database of clinical and pathological reports was reviewed in this cohort. The clinical manifestation of PSTT was not specific compared to other types of GTN. The average age of the 17 patients was 29.5 years old (range 22-39 years). The most common antecedent pregnancy was term birth (8 cases), the others were spontaneous abortion in 4 case, artificial abortion in 3 cases and molar pregnancy in 2 cases. The baseline serum β-hCG was slightly elevated and 12 patients (12/15) were less than 1 000 U/L. In this cohort, nine of the patients were in stage I, while the other eight cases were in stage III . The patients suffered conservative surgery, including dilation and curettage of uterus in 7 cases, open abdomen uterine lesion excision in 4 cases, laparoscopic uterine lesion excision in 3 cases, hysteroscopic uterine lesion excision in 1 case, and pulmonary lobectomy in 2 cases. Two of the patients didn't received chemotherapy, while the other 15 cases suffered combination chemotherapy. Compared with 40 patients who suffered hysterectomy during the same interval, fertility preservation group did not result in poor outcomes or high risk of relapse rate. Six subsequent pregnancies happened after the therapy, two of them were during their second-trimester, while four patients had healthy babies by vaginal delivery in two and cesarean section in two. The scar of the uterus was fairly well during the cesarean sections. Reservation of fertility therapy could be considered in highly-selected patients for young women who strongly desired to preserve their fertility and with localized lesion. Exactitude follow-up after therapy should be recommended. Contraception should also be recommended for at least one year after the chemotherapy. Vaginal delivery could be an option for the future pregnancies. The aim of this study was to explore the risk of pregnancy of patients who conceived within 1 year after successful chemotherapy for gestational trophoblastic tumor (GTT). From 1966 to 1996, 22 patients who conceived within 1 year after chemotherapy were followed up and analyzed retrospectively. Among 22 patients, 9 had term deliveries and 1 had a premature birth, 6 had induced abortion at the patient's request, and 6 had therapeutic abortion because of various indications such as repeated hydatidiform mole (1 case), intrauterine death (1 case), inevitable abortion (1 case), and threatened abortion (3 cases). The fetal loss rate was 27.1% (6/22). The incidence rate of gestational trophoblastic disease (GTD) was 9.1% (2/22). The incidence rate of GTT was 4.5% (1/22). The average interval between completion of chemotherapy and pregnancy was 10.25 months in the group of term pregnancies and 5.86 months in that of fetal loss (P &lt; 0.05), indicating that the longer the interval, the lesser the risk of GTD. The results suggest that contraception for 1 year is necessary in patients with GTT after successful chemotherapy. However, in the case of a patient who conceives within 1 year, it is not necessary to terminate pregnancy, but the pregnancy must be carefully watched. The use of a reliable contraception method is very important during the entire follow up period, as patients are strongly advised against pregnancy at that time. If a reliable contraception method is not used during the follow-up, it could be initially unclear to clinicians as to whether a rising hCG level is caused by the patient becoming pregnant again, or by the continued presence of GTD. In women who have a malignant form of GTD, hCG concentrations stay the same (plateau) or they rise. Persistent elevation of serum hCG levels after a non molar pregnancy (i.e., normal pregnancy [term pregnancy], or preterm pregnancy, or ectopic pregnancy [pregnancy taking place in the wrong place, usually in the fallopian tube], or abortion) always indicate persistent GTD (very frequently due to choriocarcinoma or placental site trophoblastic tumour), but this is not common, because treatment mostly is successful. Hydatidiform mole is treated with surgical uterine evacuation with suction and blunt curettage (D). Medical uterine evacuation should not be used (C). On clinical suspicion of hydatidiform mole, one representative sample of the evacuated tissue is fixed for histopathologic investigation and one is forwarded unfixed for genetic analysis (D). Serum hCG is measured on suspicion of hydatidiform mole. At the time of the uterine evacuation, the initial hCG is measured (A). After a hydatidiform mole that is both triploid and partial, serum hCG is measured weekly until there are two consecutive undetectable values (&lt; 1 or &lt; 2), after which the patient can be discharged from follow-up (C). After a diploid hydatidiform mole, a complete mole, or a hydatidiform mole without valid ploidy determination, serum hCG is measured weekly until the value is undetectable (&lt; 1 or &lt; 2). If serum hCG is undetectable within 56 days after evacuation, the patient can be discharged from follow-up after an additional four monthly measurements. If serum hCG is first normalised after 56 days, the patient is follow-up with monthly serum hCG measurement for six months. Safe contraception should be used during the follow-up period (A). If hCG stagnates (less than 10% fall over three measurements), increases, or if hCG can be demonstrated for longer than 6 months, the patient by definition has persistent trophoblastic disease (PTD). A chest X-ray should be taken and a gynaecologic ultrasound scanning performed. The patient is referred to oncologic treatment (A). Uterine re-evacuation as a treatment for PTD can, in general, not be recommended because the rate of remission is low, and there is the risk of perforation of the uterus (C). In all following pregnancies, the woman is offered an early ultrasound scan, e.g. in gestational week eight (D). Eight weeks after termination of all future pregnancies, serum hCG is measured (D). In PTD and invasive hydatidiform mole, the primary treatment is MTX, either orally every third week or IV every week (B). In MTX-resistant PTD, IV act D is added (or replaces the MTX) (B). Third line chemotherapy is BEP or EP, alternatively EMA-CO (B). Choriocarcinoma is primarily treated with chemotherapy. Hysterectomy and/or resection of metastases are possible treatments (A). Placental site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT) are primarily treated with hysterectomy. In the case of disseminated disease, chemotherapy is considered (A). The risk of reoccurrence after trophoblastic disease treated with chemotherapy is approximately 3%. Most reoccurrences are seen within 12 months, and for this reason monitoring of hCG is recommended for one year, the first third months once or twice a month, thereafter every second to third month. Patients with PSTT and ETT are monitored with measurement of hCG throughout their lifetimes (C). In genetically verified twin pregnancy with hydatidiform mole and a living foetus, the pregnancy can continue if serum hCG is monitored and ultrasound scans regularly performed, and possible obstetric complications dealt with (C). In the case of recurrent hydatidiform mole and/or familial hydatidiform mole, patients should be referred to genetic workup and counselling (C). Women with a hereditary disposition to hydatidiform mole because of a mutation in NLRP7 should be informed of the possibility of becoming pregnant via egg donation (C).  Gestational trophoblastic neoplasia is an uncommon disease, whose clinical manifestations are similar to ectopic pregnancy, thus some rare pelvic lesion can be misdiagnosed as ectopic pregnancy. This study was presented to investigate the characteristics of gestational trophoblastic neoplasia misdiagnosed as ectopic pregnancy and reduce the misdiagnosis. The clinicopathological data for 14 cases of gestational trophoblastic neoplasia misdiagnosed as ectopic pregnancy at West China Second Hospital Sichuan University from January 2006 to December 2020 were retrospectively analyzed. The main clinical manifestations were amenorrhea, abnormal vaginal bleeding, and abdominal pain. At initial diagnosis, the serum hCG level was &gt;10,000 mIU/mL in 5 patients and &lt;10,000 mIU/mL in 7 patients, and a positive urine pregnancy test alone was found in 2 patients. Vaginal ultrasonography showed no abnormalities in 7 cases, adnexal mass in 5 cases, and tubal thickening in 2 cases. The patient's previous pregnancy was an abortion in 7 cases, full-term in 4 cases, and a hydatidiform mole in 3 cases. Clinical stage: 3 cases were stage I, 3 were stage II, 7 were stage III, and 1 case was stage IV (liver and spleen metastases). The median FIGO prognostic score was 13.5 points (12-21 points), with 9 cases having a score &gt;13 points (very high risk). From 14 patients, only 3 had molar pregnancy previously. Only 3 patients had no metastasis at GTN diagnosis (from these 3, only one after molar pregnancy). After chemotherapy alone or in combination with surgery, all patients survived, with a median follow-up of 84 months (23-102 months). If we have positive hCG, without a sonographic topic gestation confirmation, associated with metastatic lesions, the GTN diagnosis should be considered instead of ectopic pregnancy, if the patient have had a pregnancy once during her life. This study analysed subsequent pregnancy outcome in patients treated for persistent gestational trophoblastic tumour (GTT). Between 1974 and 1999, a total of 378 patients with GTT (83 patients with high-risk and 295 patients with low-risk GTT) were treated at Chiba University Hospital, Japan. Of these 378 patients, 363 (96.0%) achieved primary remission and 315 survivors have been followed at our hospital. To date, 129 patients have had 243 subsequent conceptions. While pregnancy outcome was comparable with that of the general Japanese population, the incidence of repeat molar pregnancy (2.1%) was approximately seven times higher than that of the general population. During the mandatory HCG follow-up period of 1 year, 15 patients conceived within 6 months of completion of chemotherapy. The incidence of spontaneous abortion in these 15 patients was significantly higher than that in patients who conceived after a waiting period of &gt;6 months (P = 0.0053). Patients treated for GTT may anticipate a normal future reproductive outcome, although it would be better to avoid pregnancy for at least 6 months after completion of chemotherapy. Clinical data of molar pregnancies found in women undergoing elective abortion (group 1, n = 39) were compared to those of molar pregnancies in women who experienced spontaneous abortions (group 2, n = 157) and women in whom molar pregnancy was discovered before symptoms of spontaneous abortion were evident (group 3, n = 209). Group 1 women were younger and experienced uterine evacuation at an earlier stage of amenorrhea than groups 2 and 3. Group 3 had larger uteri at evacuation and longer intervals of positive tests for the beta-subunit of human chorionic gonadotropin during the postmolar phase as compared with groups 1 and 2. On the basis of available provincial data for the number of elective abortions, the estimated incidence of molar pregnancies in this population was 1:2,699. The presence of malignant gestational trophoblastic neoplasia was documented in a single patient in group 1. The incidence of malignant gestational trophoblastic neoplasia in this group was not significantly different from that in groups 2 and 3. Routine pathologic examination of the products of conception in women undergoing elective abortion coupled with routine assays of the beta-subunit of human chorionic gonadotropin when molar pregnancy is found can identify both noninvasive and invasive trophoblastic disease in these women. However, the incidence of rare diseases (such as GTD) is difficult to measure, because epidemiologic data on rare diseases is limited. Not all cases will be reported, and some cases will not be recognised. In addition, in GTD, this is especially difficult, because one would need to know all gestational events in the total population. Yet, it seems very likely that the estimated number of births that occur at home or outside of a hospital has been inflated in some reports. Terminology Gestational trophoblastic disease (GTD) may also be called gestational trophoblastic tumour (GTT). Hydatidiform mole (one type of GTD) may also be called molar pregnancy. Persistent disease; persistent GTD: If there is any evidence of persistence of GTD, usually defined as persistent elevation of beta hCG (see «Diagnosis» below), the condition may also be referred to as gestational trophoblastic neoplasia (GTN). See also Trophoblastic neoplasms References External links To study the clinical presentations of gestational trophoblastic neoplasia and its response to chemotherapy. This is a retrospective study of 28 women of gestational trophoblastic neoplasia evaluated over a period of 6 years from January 2004 to December 2009. Patients were evaluated on the basis of their age, number of deliveries, history of abortion or molar pregnancy, and the treatment received. All patients were scored on the basis of WHO scoring system. Patients with low risk (score &lt;/=6) received single agent chemotherapy with methotrexate or actinomycin D. Patients with high risk (score &gt;/=7) received multiple agent chemotherapy with EMACO regimen. After completion of chemotherapy patients were followed for a minimum of 2 years. The response to treatment was evaluated during follow-up by clinical examination, beta hCG levels and imaging as and when required. Out of 28 women only 27 could be evaluated, because 1 patient was lost to follow-up. Out of 27 patients, 18 patients (66.67%) achieved complete remission with the first-line chemotherapy and additional 25.92% (7/27) achieved complete remission with second line chemotherapy resulting in complete remission of 92.5% (25/27). Gestational trophoblastic neoplasia is curable if patient is properly evaluated and scored. It shows good response to chemotherapy. To evaluate the risk of gestational trophoblastic neoplasia (GTN) after spontaneous human chorionic gonadotropin normalization in postmolar follow-up. Retrospective chart review of 2284 consecutive cases of hydatidiform mole with spontaneous normalization of hCG following uterine evacuation treated at one of five Brazilian reference centers from January 2002 to June 2013. After hCG normalization, GTN occurred in 10/2284 patients (0.4%; 95% CI 0.2%-0.8%). GTN developed in 9/1424 patients (0.6%; 95% CI 0.3%-1.2%) after a complete hydatidiform mole, in 1/849 patients (0.1%; 95% CI&lt;0.01%-0.7%) after a partial hydatidiform mole, and in 0/13 patients (0%; 95% CI 0%-27%) after a twin molar pregnancy. The median time to GTN diagnosis after hCG normalization was 18months, and no diagnoses were made before six months of postmolar surveillance. Patients who required more than 56days to achieve a normal hCG value had a ten-fold increased risk of developing GTN after hCG normalization (9/1074; 0.8%; 95% CI 0.4%-1.6%) compared to those who reached a normal hCG level in fewer than 56days (1/1210;0.08%; 95% CI&lt;0.01%-0.5%; p=0.008). All patients presented with symptoms at the time of GTN diagnosis. GTN after spontaneous hCG normalization following molar pregnancy is exceedingly rare, and the few patients who do develop GTN after achieving a normal hCG value are likely to be diagnosed after completing the commonly recommended six months of postmolar surveillance. Current recommendations for surveillance after hCG normalization should be revisited. Management of GTN requires pathology review, treatment options and monitoring of hCG. Therefore, it can be treated with curettage, hysterectomy and single agent or multi agent chemotherapy. Although this group of diseases are highly susceptible to chemotherapy, prognosis depends on the type of GTN and whether the tumor has spread to other areas of the body. Cause and Risk factors The exact cause of gestational trophoblastic neoplasia (GTN) is unknown. GTN often arises after molar pregnancies but can also occur after any gestation including miscarriages and term pregnancies. Although risk factors may impact on the development of the tumor, most do not directly cause of disease. According to the some studies, the risk of complete molar pregnancy is highest in women over age 35 and younger than 20. The risk is even higher for women over age 45. Signs and Symptoms The symptoms of GTN will vary from person to person. People with the same disease may not have all the symptoms listed. In this scoring system, women with a score of 7 or greater are considered at high risk. It is very important for malignant forms of GTD to be discovered in time. In Western countries, women with molar pregnancies are followed carefully; for instance, in the UK, all women who have had a molar pregnancy are registered at the National Trophoblastic Screening Centre. There are efforts in this direction in the developing countries too, and there have been improvements in these countries in the early detection of choriocarcinoma, thereby significantly reducing the mortality rate also in developing countries. Becoming pregnant again Most women with GTD can become pregnant again and can have children again. The risk of a further molar pregnancy is low. More than 98% of women who become pregnant following a molar pregnancy will not have a further hydatidiform mole or be at increased risk of complications.\nHere is the question:\nGYNECOLOGY AND OBSTETRICS: A 24-year-old woman, primigestation, suffers a spontaneous abortion at 7 weeks gestation. The anatomopathological study of the abortive remains indicates molar disease. We should inform you that:\nHere are the potential choices:\n1. The risk of a new molar gestation in a future pregnancy is 50%.\n2. She should not become pregnant until periodic check-ups and after one year with negative BHCG levels.\n3. Subsequent controls are not necessary if the evacuation of the trophoblastic tissue was complete.\n4. Periodic check-ups are necessary since 40% of cases will develop gestational trophoblastic neoplasia.\nThe correct answer is: ",
        "gold_answer": "2 She should not become pregnant until periodic check-ups and after one year with negative BHCG levels.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n In the past, it was seen as important not to get pregnant straight away after a GTD. Specialists recommended a waiting period of 6 months after the hCG levels become normal. Recently, this standpoint has been questioned. New medical data suggest that a significantly shorter waiting period after the hCG levels become normal is reasonable for approximately 97% of the patients with hydatidiform mole. Risk of a repeat GTD The risk of a repeat GTD is approximately 1 in 100, compared with approximately 1 in 1000 risk in the general population. Especially women whose hCG levels remain significantly elevated are at risk of developing a repeat GTD. Persistent trophoblastic disease The term «persistent trophoblastic disease» (PTD) is used when after treatment of a molar pregnancy, some molar tissue is left behind and again starts growing into a tumour. Although PTD can spread within the body like a malignant cancer, the overall cure rate is nearly 100%. A spontaneous fall in the radioimmunoassay for the beta subunit of hCG to less than 2 mIU/mL documents regression of hydatidiform mole following evacuation of a molar pregnancy. Continued negative hCG levels for the year after evacuation indicates the absence of risk for persistent gestational trophoblastic disease. This report describes an unusual case of recurrent nonmetastatic gestational trophoblastic disease 16 months after initial evacuation. A 29-year-old woman presented at 19 weeks' gestation with severe preeclampsia and vaginal bleeding. Pelvic ultrasonography demonstrated a molar pregnancy. Pathology following uterine evacuation confirmed a hydatidiform mole. Serial hCG levels fell progressively to less than 2 mIU/mL over the following 25 weeks. She remained compliant with oral contraceptive pills despite having no sexual activity. Sixteen months after uterine evacuation, recurrence of gestational trophoblastic disease was documented by a rising beta-hCG, negative pelvic ultrasound, normal liver function tests, and normal computed tomography of the head. Endometrial curettage showed no chorionic villi or molar tissue. She was treated with five courses of actinomycin D and has remained disease-free for the following 5 years. This late recurrence of gestational trophoblastic disease suggests that those with a molar pregnancy may benefit from surveillance beyond 1 year after uterine evacuation. Recent clinical advances in the field of gestational trophoblastic diseases are described. WHO modified its risk factor scoring system. This change was proposed to combine both the basic FIGO anatomic staging with the modified WHO risk factor scoring system. Patients who score as low-risk are treated with single agent chemotherapy, such as methotrexate (MTX), and patients refractory to MTX are treated with a combination chemotherapy, EMA/CO. Patients who score as high-risk are treated with EMA/CO, and patients refractory to the first line chemotherapy may be successfully treated with EP/EMA. Recent epidemiological data showed that women with complete hydatidiform moles could anticipate normal reproduction in the future. Studies found that pregnancies after treatment of molar pregnancy resulted in 69% full-term, live births; 8% premature deliveries; 1% ectopic pregnancies, and 0.5% stillbirths. First-trimester spontaneous abortions occurred in 17% of pregnancies, and major and minor malformations were detected in 0.4% of infants. Patients with hydatidiform mole were at increased risk of developing molar pregnancy in subsequent conceptions. After having one molar pregnancy, the risk of having molar disease in a future gestation was about 1%. The risk of persistent gestational trophoblastic tumors was increased by long-term oral contraceptive use before conception. In a large, multicenter, case-control study, the risk was shown to be increased in women who had ever used oral contraceptives, but was highest for women taking oral contraceptives during the cycle in which they became pregnant. Partial hydatidiform moles were never previously proven to transform into choriocarcinoma; however, a recent study with molecular techniques clearly showed that partial moles could transform into choriocarcinoma. All patients with suspected partial moles should be reviewed centrally and require hCG follow-up. Complete hydatidiform molar pregnancies occur in approximately 1 of 1,000 conceptions. After uterine evacuation of the trophoblastic tissue, women are followed up with serial serum human chorionic gonadotropin (hCG) measurements. Patients are considered to have attained remission when their hCG level spontaneously declines to an undetectable level and remains there during a 6-month follow-up period. This standard effectively detects all disease recurrence; however, it is resource intensive, delays child bearing, and is subject to significant noncompliance. Our objective was to determine the risk of disease recurrence after hCG spontaneously declines to undetectable levels. We used a database from the New England Trophoblastic Disease Center to analyze hCG levels in patients with complete molar pregnancies. Among 1,029 women with complete molar pregnancy and complete data, 15% developed persistent gestational trophoblastic neoplasia. The rate of persistent neoplasm among those whose hCG level fell spontaneously to undetectable levels was 0.2% (2/876, 95% confidence interval 0-0.8%). No women developed persistent gestational trophoblastic neoplasia after their hCG level fell to undetectable levels using an assay with a sensitivity of 5 mIU/mL (n = 82, 95% confidence interval 0-4.5%). Based on our experience with women with complete hydatidiform molar pregnancies whose hCG values spontaneously fell to undetectable levels after molar evacuation, we conclude that the risk of recurrent neoplasm after hCG levels fall to less than 5 mIU/mL approaches zero. Placental site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic disease. Little is known about its pathogenesis and natural history. This report describes two cases that arose in patients with documented complete hydatidiform moles and summarizes the antecedent prenatal histories of PSTTs based on a detailed Medline literature analysis. A 28-year-old, G(2)P(2) female had a live, 12-week gestation fetus and a coexisting molar pregnancy. Her hCG levels dropped promptly from 1.5 million to 23,273 IU/ml after termination, but rose shortly thereafter together with the onset of recurrent vaginal bleeding. Curettage revealed persistent mole. Persistently elevated hCG led to hysterectomy disclosing a fundal PSTT. The second case was that of a 48-year-old, G(2) woman who presented with symptoms of preeclampsia, hyperthyroidism, and elevated hCG. Curettage yielded a complete hydatidiform mole. Although the hCG level decreased for a short period, it soon increased despite treatment with methotrexate. A second curettage revealed a PSTT. A Medline literature analysis of PSTT, which consists almost entirely of individual cases and several small series, disclosed that PSTT is preceded in 61% of cases by normal term pregnancy, 12% molar pregnancy, 9% spontaneous abortion, 8% therapeutic abortion, and 3% with ectopic pregnancy, stillbirths or preterm delivery. No information is known in 7%. This report describes two additional cases of PSTT preceded by complete molar pregnancy. PSTT is a well recognized, but uncommon form of gestational trophoblastic disease. Although little is known about its pathogenesis, it is preceded not uncommonly by an abnormal pregnancy, including a molar pregnancy. Although normal value of hCG (LH level) does not necessarily indicate eradication of viable trophoblast, its confirmation has been demonstrated as a clinically useful guide for the probable prevention of choriocarcinoma after hydatidiform mole by Takeuchi et al. Choriocarcinoma preceded by other pregnancies than hydatidiform mole which has the highest risk for choriocarcinoma has drawn more attention than before in connection with the decrease of postmolar choriocarcinoma. So that I have studied the regression rate of urinary gonadotropin (hCG) after the termination of various kinds of pregnancies. In 2,433 cases of induced abortion, 695 cases of spontaneous abortion, 1,724 cases of term delivery and 43 cases of hydatidiform mole, their urinary hCG were determined to the level of physiological range of LH. The rate of hCG regression was in the order of term delivery, spontaneous abortion, induced abortion and hydatidiform mole. The younger was the gestational age of trophoblast, the slower was the regression of hCG. At one month after the termination of pregnancy, 80.1%, 11%, 0.3%, 8% and 4.1%, and at two month 55.8%, 1.6%, 0.5%, 4% and 0.5% for hydatidiform mole, induced abortion of less than 12 week of gestation, spontaneous abortion of less than 12 week of gestation, spontaneous abortion of between 13 and 20 week of gestation respectively still showed abnormal hCG value. One percent of induced abortion at 5 month, 4% of spontaneous abortion at 3 month, 0.3% of term delivery at 4 month still maintained abnormal titer. No malignant sequelae in patients under the investigation have ever been observed in the follow up period between 3 and 8 years. Women diagnosed with complete hydatidiform molar pregnancy are at 15% to 28% risk of developing persistent gestational trophoblastic neoplasia (GTN) requiring further management with chemotherapy. Our objective was to develop human chorionic gonadotropin (hCG) criteria that establish a patient's risk of developing persistent GTN or achieving remission from their baseline risk within a few weeks of molar evacuation. We used a database from the New England Trophoblastic Disease Center to analyze hCG levels from 1,029 women with complete molar pregnancies. We conducted a retrospective cohort study using data from 1973 to 2001. Women whose hCG level declined below 50 mIU/mL during their follow-up were found to be at no more than 1.1% risk for developing persistent GTN, irrespective of when this level was reached. Women whose hCG levels was below 200 mIU/mL in the fourth week after evacuation (59.8% of all women), or below 100 mIU/mL in the sixth week after evacuation (65.8% of all women), had a risk of persistence below 9%. hCG levels above 2,000 mIU/mL in the fourth week after evacuation (13.3% of women) were associated with a 63.8% risk of developing persistent disease. These data may allow clinicians to evaluate the risk of persistence that their patients with complete molar pregnancy have based on early hCG results after molar evacuation. In the fourth week after molar evacuation, 59.8% of women may be counseled that their risk of developing persistent GTN is substantially reduced from their baseline, whereas 13.3% of women may be warned that their risk of developing persistent GTN is greater than 50%. II-2. To approach the efficiency and feasibility of preserving the fertility for patients with placental site trophoblastic tumor (PSTT). Totally 2 086 cases of gestational trophoblastic neoplasm (GTN) patients registered in Peking Union Medical College Hospital between 1998 and 2013. Fifty-seven of them were PSTT patients, 40 cases of which suffered hysterectomy, the rest 17 PSTT patients who preserved their fertility were analyzed retrospectively. The computerized database of clinical and pathological reports was reviewed in this cohort. The clinical manifestation of PSTT was not specific compared to other types of GTN. The average age of the 17 patients was 29.5 years old (range 22-39 years). The most common antecedent pregnancy was term birth (8 cases), the others were spontaneous abortion in 4 case, artificial abortion in 3 cases and molar pregnancy in 2 cases. The baseline serum β-hCG was slightly elevated and 12 patients (12/15) were less than 1 000 U/L. In this cohort, nine of the patients were in stage I, while the other eight cases were in stage III . The patients suffered conservative surgery, including dilation and curettage of uterus in 7 cases, open abdomen uterine lesion excision in 4 cases, laparoscopic uterine lesion excision in 3 cases, hysteroscopic uterine lesion excision in 1 case, and pulmonary lobectomy in 2 cases. Two of the patients didn't received chemotherapy, while the other 15 cases suffered combination chemotherapy. Compared with 40 patients who suffered hysterectomy during the same interval, fertility preservation group did not result in poor outcomes or high risk of relapse rate. Six subsequent pregnancies happened after the therapy, two of them were during their second-trimester, while four patients had healthy babies by vaginal delivery in two and cesarean section in two. The scar of the uterus was fairly well during the cesarean sections. Reservation of fertility therapy could be considered in highly-selected patients for young women who strongly desired to preserve their fertility and with localized lesion. Exactitude follow-up after therapy should be recommended. Contraception should also be recommended for at least one year after the chemotherapy. Vaginal delivery could be an option for the future pregnancies. The aim of this study was to explore the risk of pregnancy of patients who conceived within 1 year after successful chemotherapy for gestational trophoblastic tumor (GTT). From 1966 to 1996, 22 patients who conceived within 1 year after chemotherapy were followed up and analyzed retrospectively. Among 22 patients, 9 had term deliveries and 1 had a premature birth, 6 had induced abortion at the patient's request, and 6 had therapeutic abortion because of various indications such as repeated hydatidiform mole (1 case), intrauterine death (1 case), inevitable abortion (1 case), and threatened abortion (3 cases). The fetal loss rate was 27.1% (6/22). The incidence rate of gestational trophoblastic disease (GTD) was 9.1% (2/22). The incidence rate of GTT was 4.5% (1/22). The average interval between completion of chemotherapy and pregnancy was 10.25 months in the group of term pregnancies and 5.86 months in that of fetal loss (P &lt; 0.05), indicating that the longer the interval, the lesser the risk of GTD. The results suggest that contraception for 1 year is necessary in patients with GTT after successful chemotherapy. However, in the case of a patient who conceives within 1 year, it is not necessary to terminate pregnancy, but the pregnancy must be carefully watched. The use of a reliable contraception method is very important during the entire follow up period, as patients are strongly advised against pregnancy at that time. If a reliable contraception method is not used during the follow-up, it could be initially unclear to clinicians as to whether a rising hCG level is caused by the patient becoming pregnant again, or by the continued presence of GTD. In women who have a malignant form of GTD, hCG concentrations stay the same (plateau) or they rise. Persistent elevation of serum hCG levels after a non molar pregnancy (i.e., normal pregnancy [term pregnancy], or preterm pregnancy, or ectopic pregnancy [pregnancy taking place in the wrong place, usually in the fallopian tube], or abortion) always indicate persistent GTD (very frequently due to choriocarcinoma or placental site trophoblastic tumour), but this is not common, because treatment mostly is successful. Hydatidiform mole is treated with surgical uterine evacuation with suction and blunt curettage (D). Medical uterine evacuation should not be used (C). On clinical suspicion of hydatidiform mole, one representative sample of the evacuated tissue is fixed for histopathologic investigation and one is forwarded unfixed for genetic analysis (D). Serum hCG is measured on suspicion of hydatidiform mole. At the time of the uterine evacuation, the initial hCG is measured (A). After a hydatidiform mole that is both triploid and partial, serum hCG is measured weekly until there are two consecutive undetectable values (&lt; 1 or &lt; 2), after which the patient can be discharged from follow-up (C). After a diploid hydatidiform mole, a complete mole, or a hydatidiform mole without valid ploidy determination, serum hCG is measured weekly until the value is undetectable (&lt; 1 or &lt; 2). If serum hCG is undetectable within 56 days after evacuation, the patient can be discharged from follow-up after an additional four monthly measurements. If serum hCG is first normalised after 56 days, the patient is follow-up with monthly serum hCG measurement for six months. Safe contraception should be used during the follow-up period (A). If hCG stagnates (less than 10% fall over three measurements), increases, or if hCG can be demonstrated for longer than 6 months, the patient by definition has persistent trophoblastic disease (PTD). A chest X-ray should be taken and a gynaecologic ultrasound scanning performed. The patient is referred to oncologic treatment (A). Uterine re-evacuation as a treatment for PTD can, in general, not be recommended because the rate of remission is low, and there is the risk of perforation of the uterus (C). In all following pregnancies, the woman is offered an early ultrasound scan, e.g. in gestational week eight (D). Eight weeks after termination of all future pregnancies, serum hCG is measured (D). In PTD and invasive hydatidiform mole, the primary treatment is MTX, either orally every third week or IV every week (B). In MTX-resistant PTD, IV act D is added (or replaces the MTX) (B). Third line chemotherapy is BEP or EP, alternatively EMA-CO (B). Choriocarcinoma is primarily treated with chemotherapy. Hysterectomy and/or resection of metastases are possible treatments (A). Placental site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT) are primarily treated with hysterectomy. In the case of disseminated disease, chemotherapy is considered (A). The risk of reoccurrence after trophoblastic disease treated with chemotherapy is approximately 3%. Most reoccurrences are seen within 12 months, and for this reason monitoring of hCG is recommended for one year, the first third months once or twice a month, thereafter every second to third month. Patients with PSTT and ETT are monitored with measurement of hCG throughout their lifetimes (C). In genetically verified twin pregnancy with hydatidiform mole and a living foetus, the pregnancy can continue if serum hCG is monitored and ultrasound scans regularly performed, and possible obstetric complications dealt with (C). In the case of recurrent hydatidiform mole and/or familial hydatidiform mole, patients should be referred to genetic workup and counselling (C). Women with a hereditary disposition to hydatidiform mole because of a mutation in NLRP7 should be informed of the possibility of becoming pregnant via egg donation (C).  Gestational trophoblastic neoplasia is an uncommon disease, whose clinical manifestations are similar to ectopic pregnancy, thus some rare pelvic lesion can be misdiagnosed as ectopic pregnancy. This study was presented to investigate the characteristics of gestational trophoblastic neoplasia misdiagnosed as ectopic pregnancy and reduce the misdiagnosis. The clinicopathological data for 14 cases of gestational trophoblastic neoplasia misdiagnosed as ectopic pregnancy at West China Second Hospital Sichuan University from January 2006 to December 2020 were retrospectively analyzed. The main clinical manifestations were amenorrhea, abnormal vaginal bleeding, and abdominal pain. At initial diagnosis, the serum hCG level was &gt;10,000 mIU/mL in 5 patients and &lt;10,000 mIU/mL in 7 patients, and a positive urine pregnancy test alone was found in 2 patients. Vaginal ultrasonography showed no abnormalities in 7 cases, adnexal mass in 5 cases, and tubal thickening in 2 cases. The patient's previous pregnancy was an abortion in 7 cases, full-term in 4 cases, and a hydatidiform mole in 3 cases. Clinical stage: 3 cases were stage I, 3 were stage II, 7 were stage III, and 1 case was stage IV (liver and spleen metastases). The median FIGO prognostic score was 13.5 points (12-21 points), with 9 cases having a score &gt;13 points (very high risk). From 14 patients, only 3 had molar pregnancy previously. Only 3 patients had no metastasis at GTN diagnosis (from these 3, only one after molar pregnancy). After chemotherapy alone or in combination with surgery, all patients survived, with a median follow-up of 84 months (23-102 months). If we have positive hCG, without a sonographic topic gestation confirmation, associated with metastatic lesions, the GTN diagnosis should be considered instead of ectopic pregnancy, if the patient have had a pregnancy once during her life. This study analysed subsequent pregnancy outcome in patients treated for persistent gestational trophoblastic tumour (GTT). Between 1974 and 1999, a total of 378 patients with GTT (83 patients with high-risk and 295 patients with low-risk GTT) were treated at Chiba University Hospital, Japan. Of these 378 patients, 363 (96.0%) achieved primary remission and 315 survivors have been followed at our hospital. To date, 129 patients have had 243 subsequent conceptions. While pregnancy outcome was comparable with that of the general Japanese population, the incidence of repeat molar pregnancy (2.1%) was approximately seven times higher than that of the general population. During the mandatory HCG follow-up period of 1 year, 15 patients conceived within 6 months of completion of chemotherapy. The incidence of spontaneous abortion in these 15 patients was significantly higher than that in patients who conceived after a waiting period of &gt;6 months (P = 0.0053). Patients treated for GTT may anticipate a normal future reproductive outcome, although it would be better to avoid pregnancy for at least 6 months after completion of chemotherapy. Clinical data of molar pregnancies found in women undergoing elective abortion (group 1, n = 39) were compared to those of molar pregnancies in women who experienced spontaneous abortions (group 2, n = 157) and women in whom molar pregnancy was discovered before symptoms of spontaneous abortion were evident (group 3, n = 209). Group 1 women were younger and experienced uterine evacuation at an earlier stage of amenorrhea than groups 2 and 3. Group 3 had larger uteri at evacuation and longer intervals of positive tests for the beta-subunit of human chorionic gonadotropin during the postmolar phase as compared with groups 1 and 2. On the basis of available provincial data for the number of elective abortions, the estimated incidence of molar pregnancies in this population was 1:2,699. The presence of malignant gestational trophoblastic neoplasia was documented in a single patient in group 1. The incidence of malignant gestational trophoblastic neoplasia in this group was not significantly different from that in groups 2 and 3. Routine pathologic examination of the products of conception in women undergoing elective abortion coupled with routine assays of the beta-subunit of human chorionic gonadotropin when molar pregnancy is found can identify both noninvasive and invasive trophoblastic disease in these women. However, the incidence of rare diseases (such as GTD) is difficult to measure, because epidemiologic data on rare diseases is limited. Not all cases will be reported, and some cases will not be recognised. In addition, in GTD, this is especially difficult, because one would need to know all gestational events in the total population. Yet, it seems very likely that the estimated number of births that occur at home or outside of a hospital has been inflated in some reports. Terminology Gestational trophoblastic disease (GTD) may also be called gestational trophoblastic tumour (GTT). Hydatidiform mole (one type of GTD) may also be called molar pregnancy. Persistent disease; persistent GTD: If there is any evidence of persistence of GTD, usually defined as persistent elevation of beta hCG (see «Diagnosis» below), the condition may also be referred to as gestational trophoblastic neoplasia (GTN). See also Trophoblastic neoplasms References External links To study the clinical presentations of gestational trophoblastic neoplasia and its response to chemotherapy. This is a retrospective study of 28 women of gestational trophoblastic neoplasia evaluated over a period of 6 years from January 2004 to December 2009. Patients were evaluated on the basis of their age, number of deliveries, history of abortion or molar pregnancy, and the treatment received. All patients were scored on the basis of WHO scoring system. Patients with low risk (score &lt;/=6) received single agent chemotherapy with methotrexate or actinomycin D. Patients with high risk (score &gt;/=7) received multiple agent chemotherapy with EMACO regimen. After completion of chemotherapy patients were followed for a minimum of 2 years. The response to treatment was evaluated during follow-up by clinical examination, beta hCG levels and imaging as and when required. Out of 28 women only 27 could be evaluated, because 1 patient was lost to follow-up. Out of 27 patients, 18 patients (66.67%) achieved complete remission with the first-line chemotherapy and additional 25.92% (7/27) achieved complete remission with second line chemotherapy resulting in complete remission of 92.5% (25/27). Gestational trophoblastic neoplasia is curable if patient is properly evaluated and scored. It shows good response to chemotherapy. To evaluate the risk of gestational trophoblastic neoplasia (GTN) after spontaneous human chorionic gonadotropin normalization in postmolar follow-up. Retrospective chart review of 2284 consecutive cases of hydatidiform mole with spontaneous normalization of hCG following uterine evacuation treated at one of five Brazilian reference centers from January 2002 to June 2013. After hCG normalization, GTN occurred in 10/2284 patients (0.4%; 95% CI 0.2%-0.8%). GTN developed in 9/1424 patients (0.6%; 95% CI 0.3%-1.2%) after a complete hydatidiform mole, in 1/849 patients (0.1%; 95% CI&lt;0.01%-0.7%) after a partial hydatidiform mole, and in 0/13 patients (0%; 95% CI 0%-27%) after a twin molar pregnancy. The median time to GTN diagnosis after hCG normalization was 18months, and no diagnoses were made before six months of postmolar surveillance. Patients who required more than 56days to achieve a normal hCG value had a ten-fold increased risk of developing GTN after hCG normalization (9/1074; 0.8%; 95% CI 0.4%-1.6%) compared to those who reached a normal hCG level in fewer than 56days (1/1210;0.08%; 95% CI&lt;0.01%-0.5%; p=0.008). All patients presented with symptoms at the time of GTN diagnosis. GTN after spontaneous hCG normalization following molar pregnancy is exceedingly rare, and the few patients who do develop GTN after achieving a normal hCG value are likely to be diagnosed after completing the commonly recommended six months of postmolar surveillance. Current recommendations for surveillance after hCG normalization should be revisited. Management of GTN requires pathology review, treatment options and monitoring of hCG. Therefore, it can be treated with curettage, hysterectomy and single agent or multi agent chemotherapy. Although this group of diseases are highly susceptible to chemotherapy, prognosis depends on the type of GTN and whether the tumor has spread to other areas of the body. Cause and Risk factors The exact cause of gestational trophoblastic neoplasia (GTN) is unknown. GTN often arises after molar pregnancies but can also occur after any gestation including miscarriages and term pregnancies. Although risk factors may impact on the development of the tumor, most do not directly cause of disease. According to the some studies, the risk of complete molar pregnancy is highest in women over age 35 and younger than 20. The risk is even higher for women over age 45. Signs and Symptoms The symptoms of GTN will vary from person to person. People with the same disease may not have all the symptoms listed. In this scoring system, women with a score of 7 or greater are considered at high risk. It is very important for malignant forms of GTD to be discovered in time. In Western countries, women with molar pregnancies are followed carefully; for instance, in the UK, all women who have had a molar pregnancy are registered at the National Trophoblastic Screening Centre. There are efforts in this direction in the developing countries too, and there have been improvements in these countries in the early detection of choriocarcinoma, thereby significantly reducing the mortality rate also in developing countries. Becoming pregnant again Most women with GTD can become pregnant again and can have children again. The risk of a further molar pregnancy is low. More than 98% of women who become pregnant following a molar pregnancy will not have a further hydatidiform mole or be at increased risk of complications.\nHere is the question:\nGYNECOLOGY AND OBSTETRICS: A 24-year-old woman, primigestation, suffers a spontaneous abortion at 7 weeks gestation. The anatomopathological study of the abortive remains indicates molar disease. We should inform you that:\nHere are the potential choices:\n1. The risk of a new molar gestation in a future pregnancy is 50%.\n2. She should not become pregnant until periodic check-ups and after one year with negative BHCG levels.\n3. Subsequent controls are not necessary if the evacuation of the trophoblastic tissue was complete.\n4. Periodic check-ups are necessary since 40% of cases will develop gestational trophoblastic neoplasia.\nThe correct answer is: 2. She should not become pregnant until periodic check-ups and after one year with negative BHCG levels."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Acute tubulointerstitial nephritis (ATIN) is a rare renal disorder in children. Patients usually present non-specific symptoms and signs so that the diagnosis of ATIN is often delayed. The disease may be infection- or drug-induced or it may occur without a known cause. Early recognition and appropriated therapy usually lead to an excellent prognosis. The aim of the study was to describe clinical and laboratory findings and the course of ATIN in 21 patients, that are typical enough to enable early recognition of the disease as it is potentially reversible. Between 1986 and 1997 we observed 21 patients, aged 7-16 years (mean, 12.8), with acute tubulointerstitial nephritis, including eight with tubulointerstitial nephritis and uveitis (TINU syndrome). Laboratory studies included urinalysis, complete blood count, erytrocyte sedimentation rate (ESR), plasma creatinine, glomerular filtration rate (GFR), electrolytes, proteins, IgG, C3, C4 antinuclear-antibodies (ANA), antistreptolysin-O and antibodies to hantaviruses. Renal ultrasound was done in all patients. Renal biopsy was performed in 5 children. All children had previously been healthy. The symptoms of ATIN developed within a few days (Table 1). The most common initial symptoms were fatigue, fever, gastrointestinal disturbances, anorexia and weight loss. Less common complaints included headache, arthralgias and maculopapular rash. On addmition no patient had hypertension, oedema or evidence of acute infection. ESR, plasma urea and creatinine concentrations were increased in all, plasma proteins and IgG levels in the majority of patients. ANA were negative in 15 pts in whom this analysis was performed; C3 and C4 levels were normal. In two children recent strepococcal and in the other 6 hantavirus infection was serologicaly proved. All patients had non-oliguric acute renal failure (ARF): GFR was 21.7 +/- 8 9 in 14 pts and 67 +/- 9.7 in 7 pts. Low urine specific gravity (1003-1014), mild proteinuria (0.3-0.4 g/24 h), leukocyturia and/or haematuria were found in all patients; glycosuria, aminoaciduria and decreased tubular reaposrption of phosphate (TRP) were found in 12/21, 9/21 and 9/14 patients, respectively. Urine cultures were negative in all children. Renal US demonstrated enlarged hyperechoic kidneys in 11 pts, in remaining 10 pts no abnormalities were found. Renal biopsy, performed in 5 children, confirmed the diagnosis of ATIN. Eight patients subsequently developed anterior uveitis as part of TINU syndrome. Treatment included supportive therapy in all and six patients received prednisolone for 4-8 weeks (40-60 mg/m2/24 h for 10-14 days with subsequent reduction of dose over several weeks). Anterior uveitis was successfully treated with topical steroids. Renal function completely recovered in all patients: GFR (109 +/- 22.6 ml/min) within a mean interval of 47 +/- 33 days, concentration ability within 2-12 (mean 4.5) months. Common clinical features of ATIN are non-oliguric acute renal failure of various degrees, signs of tubular dysfunction, proteinuria, haematuria, leukocyturia and absence of hypertension. All our patients had normal blood pressure, non-oliguric renal failure, proteinuria, hypostenuria and abnormal urinary sediment; about half of them had glycosuria and/or other signs of proximal tubular dysfunction. The most important causes of ATIN in children reported in literature are systemic infections and drugs. However, the cause of ATIN in our patients was assessed as being related to infection only in 8 patients and to diclofenac in one. No infection, drug, toxin or other cause could be identified in 4, as well as in 8 pts with TINU syndrome. The prognosis of ATIN in children is considered to be favourable, but some patients may develop chronic renal failure. Renal function completely recovered in all our patients; that is consistent with outcome data from the most reports. Acute tubulointerstitial nephritis is an important cause of ARF in children, its aetiology may be different and it carries an excellent prognosis. ATIN should be suspected in a child who presents typical, although non-specific symptoms and signs, associated with lukocyturia and/or microhaematuria, signs of tubular dysfunction and unexplained renal failure. The diagnosis can be verified at renal biopsy. Early recognition of the disease is important to remove possible aetiologic agents and to treat them before chronic lesions are present to avoid long-term renal damage. A 47-year-old Taiwanese man with no notable medical history was admitted with low-grade fevers and night sweats that had persisted for 5 to 6 weeks. An extensive investigation at another hospital could not determine the cause of the fevers, but documented acute renal failure with a blood urea nitrogen level of 60 mg/dL and a serum creatinine level of 5.6 mg/dL. He was admitted to the Johns Hopkins Hospital for further evaluation.The patient, who had been living in the United States for the past 20 years, reported no recent travel and no behaviors that are associated with transmission of human immunodeficiency virus. He was not taking any medications, and he denied using herbal or nutritional supplements. He had no recent weight loss. There were no specific complaints on review of systems. On physical examination, he was a thin, middle-aged man in no distress. Vital signs included a temperature of 37.5 degrees C, a blood pressure of 166/86 mm Hg, a pulse of 70 beats per minute, a respiratory rate of 16 breaths per minute, and 99% oxygen saturation on room air. Sclera were anicteric, and he had no palpable adenopathy. His lungs were clear, and his heart rate was regular without extra sounds. His abdomen was thin, nontender, and without masses or organomegaly. There was no edema or signs of embolism in the extremities. Laboratory studies revealed a white blood cell count of 14,200/mL(3), a hematocrit of 23.1%, and a platelet count of 456,000/mL(3). Blood chemistries were notable for a blood urea nitrogen level of 61 mg/dL and a serum creatinine level of 7.6 mg/dL. Levels of aminotransferases, total bilirubin, and alkaline phosphatase were within normal limits. Urinalysis revealed large hemoglobin, 1+ protein, numerous red blood cells, and 3 to 5 white blood cells. Numerous red blood cell casts were seen on microscopic examination of the urine sediment. The patient's erythrocyte sedimentation rate was &gt;130 mm/h, and his C-reactive protein level was elevated at 12.6 mg/dL. Serologies were negative for antinuclear antibodies and antineutrophil cytoplasmic antibodies; serum complement levels were normal. What is the diagnosis? Little is known concerning renal or urological risk factors for osteoporosis. The aim of this study was to explore an association between urinalysis and bone mineral density (BMD) in 4,835 Japanese adults. Participants were 4,835 individuals (female 3,683; male 1,152) aged 50 years and over who received a health check-up between January 1995 and March 2006 in Japan. BMD of the distal radius and ulna of the non-dominant forearm was measured by the dual-energy X-ray absorptiometry (DXA) method using a DTX-200 Dexacare osteometer (Osteometer MediTech A/S, Rødovre, Denmark). Urine variables were protein, and red blood cells (RBCs) and white blood cells (WBCs) in urine sediment (categorized as &lt;1, 1-4, 5-9, or &gt;or=10 cells per high-power microscopic field). Average age was 58.9 years (SD 5.6) in women, and 60.5 years (SD 6.2) in men. Simple linear regression analysis showed that urinary RBCs were associated with BMD in women (beta = or-5.88 x 10(-3), R (2) = 0.004, p &lt; 0.0001) and men (beta = or-1.34 x 10(-2), R (2) = 0.013, p = 0.0001). These associations held when possible confounders were adjusted (beta = or-2.05 x 10(-3), R (2) = 0.001, p = 0.0338 for women and beta =or -5.67 x 10(-3), R (2) = 0.006, p = 0.0163 for men). Microscopic hematuria is associated with forearm BMD in women and men aged 50 years and over. Further studies should be conducted to determine the mechanisms underlying this association. The purpose was to determine the value of the standard laboratory and radiologic evaluation of microscopic hematuria in children, and to determine the prevalence of idiopathic hypercalciuria in those children referred for evaluation of unexplained microscopic hematuria. This was a retrospective study of 325 children referred from 1985 to 1994 for the evaluation of asymptomatic microscopic hematuria. The diagnostic studies reviewed included serum creatinine, blood urea nitrogen, serum electrolyte studies, serum complement concentration, antinuclear antibody, urinalysis, urine calcium to creatinine ratios, urinary protein to creatinine ratio and/or 24-hour urinary protein excretion, renal ultrasounds, intravenous pyelograms, voiding cystourethrograms, and historical information. All creatinine and electrolyte values were normal for age, and none of the biochemical tests obtained in the children with hypercalciuria was abnormal. Of the 325 patients with idiopathic microscopic hematuria, only 18 had abnormal renal ultrasound examinations and 9 voiding cystourethrograms showed low-grade reflux. Hypercalciuria was found in 29 patients. The family history was positive for urolithiasis in 16% of patients without hypercalciuria compared with 14% of patients with hypercalciuria. A positive family history of hematuria was reported in 25% of patients; 62 patients did not have hypercalciuria and 4 of the patients had hypercalciuria. Microscopic hematuria in children is a benign finding in the vast majority of children. Our data demonstrate that a renal ultrasound, voiding cystourethrogram, cystoscopy, and renal biopsy are not indicated in the work-up of microscopic hematuria, and microhematuria in the otherwise healthy child is a minimal health threat, rarely indicative of serious illness. A 58-year-old female was referred to our department with intermittent suffocation for 1.5 years, aggravated for a month. 1.5 years before she developed oral ulcer, raynaud phenomenon, proteinuria, bilateral pleural effusion, ANA and anti-dsDNA positive. This patient was diagnosed with systemic lupus erythematosus (SLE). After given hormones, hydroxychloroquine sulfate (HCQ), her symptom relieved soon. The patient stopped her pills 1 year ago. One month ago, she had chest tightness, increased urine foam, and suffered from oliguria. Her admission medical examination: blood pressure (BP) 130/80 mmHg, conjunctiva pale, and lower lung breath sounds reduced. There was no tenderness, rebound pain and abdominal muscle tension in the abdomen. Liver and spleen rib inferior, mobile dullness negative, and lower extremity edema. Blood routine tests were performed with hemoglobin (HGB) 57 g/L. Urine routine: BLD (3+). 24-hour urinary protein 3.2 g. serum albumin 20.5 g/L, C-reactive protein (CRP) 12.85 mg/L, erythrocyte sedimentation rate (ESR) 140 mm/h. Antinuclear antibody (ANA) (H)1:10 000, anti-dsDNA antibody 1:3 200; anti-Smith antibody, anti-U1-snRNP/Sm antibody were positive, blood complement 3(C3) 0.43 g/L, complement 4(C4) 0.07 g /L. Anticardiolipin antibody (ACL), anti-β2-GP1, lupus anticoagulant (LA) were negative; HRCT suggested bilateral medial pleural cavity product liquid. Admission diagnosis: SLE lupus nephritis, anemia, pleural effusion, and hypoproteinemia. We treated her with methylprednisolone 1 000 mg×3 d, late to 48 mg/d and cyclophosphamide 1.0 g, HCQ 0.2 g bid, gamma globulin 10 g×5 d. Day 2 of treatment, this patient developed acute right upper quadrant pain, not accompanied by nausea, vomiting, blood stool and diarrhea. Antipyretic antispasmodic treatment was invalid, after the morning to ease their own abdominal pain. Day 4 of treatment, daytime blood HGB 77 g/L. Bilateral renal vascular ultrasound: bilateral renal artery blood flow velocity was reduced. The abdominal pain of the above symptoms recurred at night, BP was 120/80 mmHg, and no positive signs were found on abdominal examination. No abnormality was found in the vertical abdominal plain film. Blood routine examination: HGB 53 g/L, Plasma D dimer 2 515 μg/L, amylase in hematuria was normal, the stool occult blood was negative. Abdominal computed tomography (CT): normal structure of right adrenal gland disappeared, irregular mass shadow could be seen in adrenal region, CT value was about 50 HU. Morphological density of left adrenal gland was not abnormal. The retroperitoneum descended along the inferior vena cava to the right iliac blood vessel and showed a bolus shadow. The density of some segments increased. The lesion involved the right renal periphery and reached the left side of abdominal aorta. Most lesions surrounded the inferior vena cava, the right renal vein and part of the small intestine. The boundary between the upper lesion and the vena cava was unclear. Iodinecontaining contrast agent was taken orally. No sign of contrast agent overflowing was found in the abdominal cavity. Hematoma and exudative changes were considered in retroperitoneum. CONCLUSION of contrast-enhanced ultrasound of blood vessels: The retroperitoneal inferior vena cava (volume 3.5 cm×3.5 cm×1.5 cm) was hypoechoic and had no blood flow lesion. The adrenal gland had a high possibility of origin. Left renal vein thrombosis extended to inferior vena cava. According to the above data, it was analyzed that the cause of retroperitoneal hematoma of the patient was left adrenal vein thrombosis caused by hypercoagulable state, which led to vascular rupture and hemorrhage caused by increased vascular pressure in adrenal gland. Therefore, on the basis of continuing to actively treat the primary disease, and on the basis of dynamic observation of no active hemorrhage for 3 days, the anticoagulant therapy was continued with 10 mg/d of apixaban. Clinical symptoms were gradually eased, HGB did not decrease. Two weeks later, the ultrasonic examination showed that the irregular cluster hypoechoic range behind the inferior vena cava was significantly smaller than that before (1.8 cm×1.2 cm×0.7 cm). Abdominal CT examination after 1 month showed that there was no abnormal morphological density of bilateral adrenal glands and basic absorption of retroperitoneal exudation. Adrenal hemorrhage is uncommon. SLE with adrenal hemorrhage is rarer. In SLE patients, especially those complicated with APS, if abdominal pain accompanied by HGB decrease occurs, except after gastrointestinal hemorrhage, the possibility of adrenal hemorrhage should be warned. The patient, a 78-year-old Asian male, was brought to the hospital because of acute shortness of breath that had progressively worsened over the course of the day. He complained of a nonproductive cough and claudication after walking 1 block. His past medical history was significant for mild renal insufficiency (serum creatinine 1.5--2.0 mg/dl), the etiology of which was never explored. Although there was a recent history of mild to moderate hypertension, at presentation his blood pressure was noted to be 240/118 mm Hg in both arms. His physical exam at the time of admission was remarkable for grade II hypertensive retinopathy, an S4 gallop, periumbilical systolic bruits, audible femoral arterial bruits and absent distal lower extremity pulses. Initial complete blood count, serum electrolytes and cardiac enzymes (including lactate dehydrogenase) were normal. His blood urea nitrogen and serum creatinine concentrations were 51 and 3.6 mg/dl, respectively, and his urinalysis showed 1+ protein (both by dipstick and sulfasalicylic acid) with a \"benign\" sediment (0--1 WBC/HPE, 1--2 RBCs/HPF) with occasional granular casts. His electrocardiogram, apart from demonstrating left ventricular hypertrophy with secondary ST-T wave abnormalities, showed no acute changes; his chest X-ray demonstrated cardiomegaly and pulmonary vascular congestion. He was intubated and subsequently treated with increasing parenteral doses of furosemide (40--240 mg) and a nitroglycerine drip (up to 15 mcg/min). Over the course of the first 48 h, his blood pressure was gradually lowered to 170/100 mm Hg. His urine output increased from 20 ml/h to 125/ml/h, and his respiratory status improved, allowing him to be extubated. In spite of adequate control of his blood pressure in the ensuing days (150--170/80--90 mm Hg), his renal function continued to deteriorate. Renal sonography (without Doppler) demonstrated a right kidney of 9.6 cm and a left kidney of 9.3 cm in length without evidence of hydronephrosis. Both kidneys were noted to be echogenic. Assays for antinuclear antibodies and antineutrophilic cytoplasmic antibodies were negative, and the patient's serum complement levels were normal. For several days after his admission, his serum creatinine gradually rose to 10.7 mg/dl, and hemodialysis was initiated for uremic encephalopathy. Because of the high index of suspicion for renal artery stenosis as the case of both his hypertension and renal failure, a renal angiogram was performed. It revealed a 90% occlusion of the right renal artery with ostial involvement and a 70% occlusion of the left renal artery; both kidneys had poor distal renal vasculature and there was marked atherosclerotic disease of the aorta. After being hemodialyzed for 3 treatments, his renal function began to improve spontaneously. His serum creatinine returned to 3.4 mg/dl, and a subsequent 24-hour urine demonstrated a creatinine clearance of 20 ml/min and an excretion of 1.2 g of protein. Following his discharge from the hospital, his renal function remained unchanged for 3 years, and his blood pressure was easily controlled on monotherapy with a long-acting calcium channel blocker. He recently died from pneumonia. A complete blood count showing possible anemia and low platelet count followed by renal function tests with elevated serum creatinine (0.4 mg/dl above the upper limit), blood urea nitrogen levels, and urine analysis positive for urine sediments: red blood cells and casts, white blood cells, granular casts are indicative of a glomerular pathology. For further confirmation, a 24 hours urine protein to creatinine ratio and 24 hours urine sample for protein levels can be done. A protein count of greater than 3.5 g/day is suggestive of nephrotic range proteinuria, which is associated with a worse prognosis. A 24-hour urine sample can be used to calculate creatinine clearance to estimate the eGFR. Renal ultrasound can be done to see the size and confirm the presence of two kidneys and the absence of any obstructive pathology resulting in hydronephrosis. Serum complement (C3 and C4) levels help determine the etiology; low levels are associated with the presence of SLE, cryoglobulinemia, and infectious etiology. [12] During a 5-year study period, 109 patients were referred to a large children's hospital for evaluation of prolonged fever of unknown origin, defined as temperature greater than or equal to 38 degrees C (100.4 degrees F) for 3 weeks or longer and negative findings on initial examination. A two-phase protocol of outpatient followed by inpatient diagnostic studies was instituted for most patients. Confirmed diagnoses were achieved in just 36 of these children (33%) in the following disease categories: infectious, 24 (22%); autoimmune, 7 (6%); and neoplastic, 2 (2%). Scanning or special procedures and the number with positive results (in parentheses) were as follows: abdominal ultrasonography, 43 (8); abdominal computed tomography, 14 (3); indium scan 11 (5); gallium scanning, 4 (1), upper gastrointestinal tract series, 13 (2); technetium bone scanning 15 (2); bone marrow examination, 16 (1); and cranial computed tomography, 7 (0). These studies rarely led to an unsuspected diagnosis. It appears most appropriate in evaluating fever of unknown origin in children to obtain only basic laboratory studies such as a complete blood cell count, urinalysis and culture, chest radiograph, tuberculin skin test, and, in the older child, an antinuclear antibody titer. When these test results are negative, almost all children can be observed clinically for progression of illness or a focus that might then direct specific diagnostic procedures. Japan Society of Clinical Pathology has formed a committee dealing with \"lab. tests in primary care medicine\". As the first step, they made \"Essential Lab. Tests\" which were composed of simple qualitative bed-side tests such as urinalysis, Complete blood count (CBC: Hb, Ht, WBC, RBC), CRP, or ESR (Erythrocyte sedimental rate), A/G ratio and biochemical tests if necessary (Table 1). We have performed \"Essential Lab. Tests\" on 1,026 outpatients who visited General Medicine Clinic for the first time. They consisted of 456 male (age 13-81), and 526 female (age 10-85). This report is the result of urinalysis from \"Essential Lab. Tests\" of 1,026 patients. 1) The result showed that overall positivity of the urinalysis was 21.3% (when more than one item of the qualitative tests was positive). 2) There was distinctive difference in the positivity of the urinalysis between the sex; i.e. protein and glucose were about twice frequently positive in male, where as occult blood and WBC (Esterase reaction) were 2-3 times more positive in female. 3) Urine protein shows positive in the individual 10-20 yrs old and more than 50 yrs old in both sexes. 4) Glucose was positive in over 40 yrs in male, and occult blood, 40-50 yrs or older in male. 5) WBC shows positive in all age groups in female and 50 yrs or older in male. 6) Positive WBC patients did not necessarily reflect urinary infection in female but nitrites roughly corresponded with urinary WBC in male of 50 yrs or older, meaning probable urinary infection associated with prostatic hypertrophy. 7) Abnormality of urinary sediment corresponded to the positive occult blood and WBC Erastase. 8) Urinalysis is an useful method of screening in primary care medicine. Blood and urine test While there is no laboratory test specific for appendicitis, a complete blood count (CBC) is done to check for signs of infection. Although 70–90 percent of people with appendicitis may have an elevated white blood cell (WBC) count, there are many other abdominal and pelvic conditions that can cause the WBC count to be elevated. Due to its low sensitivity and specificity, on its own, WBC is not seen as a good indicator of appendicitis. A urinalysis generally does not show infection, but it is important for determining pregnancy status, especially the possibility of an ectopic pregnancy in women of childbearing age. The urinalysis is also important for ruling out a urinary tract infection as the cause of abdominal pain. The presence of more than 20 WBC per high-power field in the urine is more suggestive of a urinary tract disorder. The first step in evaluation of red or brown colored urine is to confirm true hematuria with urinalysis and urine microscopy, where hematuria is defined by three of more red blood cells per high power field. Although a urine dipstick test may be used, it can give false positive or false negative results. In gathering information, it is important to inquire about recent trauma, urologic procedures, menses, and culture-documented urinary tract infection. If any of these are present, it is appropriate to repeat a urinalysis with urine microscopy in 1 to 2 weeks or after treatment of the infection. If the results of the urinalysis and urine microscopy reveal a glomerular origin of hematuria (indicated by proteinuria or red blood cell casts), consultation of a nephrologist should be made. If the results of the urinalysis indicate a non-glomerular origin, a microbiological culture of the urine should be performed, if it has not been done already. If the culture is positive, treatment of the a female less than 50 years old or a male less than 40 years old; has 3-10 red blood cells per high power field; has not had microscopic hematuria before; and has no other risk factors for urothelial cancer. To be in the intermediate risk category, one must satisfy any of the following criteria: Has smoked 10-30 pack-years; is a female 50-59 years old or a male aged 40-59 years old; has 11-25 red blood cells per high power field; or was previously a low-risk patient with persistent microscopic hematuria and has 3-25 red blood cells per high power field. To be in the high risk category, one must satisfy any of the following criteria: Has smoked more than 30 pack-years; is older than 60 years of age; or has above 25 red blood cells per high power field on any urinalysis. For the low risk category, the next step is to either repeat a urinalysis with urine microscopy in 6 months or perform a cystoscopy and renal ultrasound. For the intermediate risk category, the next step is to perform a Blood urea nitrogen (BUN) - Also measured using a BMP or CMP, blood urea nitrogen is an indicator of how much nitrogen is in the blood at the time of the phlebotomy. The kidney is responsible for excreting nitrogenous substances in the urine, so an elevated BUN usually indicates that the kidney is not functioning appropriately. Urine Analysis (Urinalysis) - After the patient provides a urine specimen, it is sent to the lab for analysis using a variety of methods including urine dipstick testing and microscopic examination. Because the kidney is responsible for making urine, analyzing the urine directly can provide crucial data that can help the physician diagnose nephritic syndrome. Some findings on urinalysis that are consistent with nephritic syndrome include red blood cells (hematuria), red blood cell casts, proteinuria, and possibly white blood cells (pyuria).\nHere is the question:\nPEDIATRICS: A 10-year-old girl comes for a health check-up. Physical examination is normal with weight and height in the 50th percentile and BP 109/65. A routine urinalysis shows a specific gravity of 1035 pH6 blood 2+ with no protein. Urine sediment shows 5-10 red blood cells per field. What would be the most appropriate course of action?\nHere are the potential choices:\n1. Determination of creatinine and nitrogen in blood.\n2. Refer the child for cystoscopy.\n3. Determine antinuclear antibodies and complement.\n4. Repeat urine sediment in 15 days.\n5. Abdominal computed axial tomography.\nThe correct answer is: ",
        "gold_answer": "4 Repeat urine sediment in 15 days.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Acute tubulointerstitial nephritis (ATIN) is a rare renal disorder in children. Patients usually present non-specific symptoms and signs so that the diagnosis of ATIN is often delayed. The disease may be infection- or drug-induced or it may occur without a known cause. Early recognition and appropriated therapy usually lead to an excellent prognosis. The aim of the study was to describe clinical and laboratory findings and the course of ATIN in 21 patients, that are typical enough to enable early recognition of the disease as it is potentially reversible. Between 1986 and 1997 we observed 21 patients, aged 7-16 years (mean, 12.8), with acute tubulointerstitial nephritis, including eight with tubulointerstitial nephritis and uveitis (TINU syndrome). Laboratory studies included urinalysis, complete blood count, erytrocyte sedimentation rate (ESR), plasma creatinine, glomerular filtration rate (GFR), electrolytes, proteins, IgG, C3, C4 antinuclear-antibodies (ANA), antistreptolysin-O and antibodies to hantaviruses. Renal ultrasound was done in all patients. Renal biopsy was performed in 5 children. All children had previously been healthy. The symptoms of ATIN developed within a few days (Table 1). The most common initial symptoms were fatigue, fever, gastrointestinal disturbances, anorexia and weight loss. Less common complaints included headache, arthralgias and maculopapular rash. On addmition no patient had hypertension, oedema or evidence of acute infection. ESR, plasma urea and creatinine concentrations were increased in all, plasma proteins and IgG levels in the majority of patients. ANA were negative in 15 pts in whom this analysis was performed; C3 and C4 levels were normal. In two children recent strepococcal and in the other 6 hantavirus infection was serologicaly proved. All patients had non-oliguric acute renal failure (ARF): GFR was 21.7 +/- 8 9 in 14 pts and 67 +/- 9.7 in 7 pts. Low urine specific gravity (1003-1014), mild proteinuria (0.3-0.4 g/24 h), leukocyturia and/or haematuria were found in all patients; glycosuria, aminoaciduria and decreased tubular reaposrption of phosphate (TRP) were found in 12/21, 9/21 and 9/14 patients, respectively. Urine cultures were negative in all children. Renal US demonstrated enlarged hyperechoic kidneys in 11 pts, in remaining 10 pts no abnormalities were found. Renal biopsy, performed in 5 children, confirmed the diagnosis of ATIN. Eight patients subsequently developed anterior uveitis as part of TINU syndrome. Treatment included supportive therapy in all and six patients received prednisolone for 4-8 weeks (40-60 mg/m2/24 h for 10-14 days with subsequent reduction of dose over several weeks). Anterior uveitis was successfully treated with topical steroids. Renal function completely recovered in all patients: GFR (109 +/- 22.6 ml/min) within a mean interval of 47 +/- 33 days, concentration ability within 2-12 (mean 4.5) months. Common clinical features of ATIN are non-oliguric acute renal failure of various degrees, signs of tubular dysfunction, proteinuria, haematuria, leukocyturia and absence of hypertension. All our patients had normal blood pressure, non-oliguric renal failure, proteinuria, hypostenuria and abnormal urinary sediment; about half of them had glycosuria and/or other signs of proximal tubular dysfunction. The most important causes of ATIN in children reported in literature are systemic infections and drugs. However, the cause of ATIN in our patients was assessed as being related to infection only in 8 patients and to diclofenac in one. No infection, drug, toxin or other cause could be identified in 4, as well as in 8 pts with TINU syndrome. The prognosis of ATIN in children is considered to be favourable, but some patients may develop chronic renal failure. Renal function completely recovered in all our patients; that is consistent with outcome data from the most reports. Acute tubulointerstitial nephritis is an important cause of ARF in children, its aetiology may be different and it carries an excellent prognosis. ATIN should be suspected in a child who presents typical, although non-specific symptoms and signs, associated with lukocyturia and/or microhaematuria, signs of tubular dysfunction and unexplained renal failure. The diagnosis can be verified at renal biopsy. Early recognition of the disease is important to remove possible aetiologic agents and to treat them before chronic lesions are present to avoid long-term renal damage. A 47-year-old Taiwanese man with no notable medical history was admitted with low-grade fevers and night sweats that had persisted for 5 to 6 weeks. An extensive investigation at another hospital could not determine the cause of the fevers, but documented acute renal failure with a blood urea nitrogen level of 60 mg/dL and a serum creatinine level of 5.6 mg/dL. He was admitted to the Johns Hopkins Hospital for further evaluation.The patient, who had been living in the United States for the past 20 years, reported no recent travel and no behaviors that are associated with transmission of human immunodeficiency virus. He was not taking any medications, and he denied using herbal or nutritional supplements. He had no recent weight loss. There were no specific complaints on review of systems. On physical examination, he was a thin, middle-aged man in no distress. Vital signs included a temperature of 37.5 degrees C, a blood pressure of 166/86 mm Hg, a pulse of 70 beats per minute, a respiratory rate of 16 breaths per minute, and 99% oxygen saturation on room air. Sclera were anicteric, and he had no palpable adenopathy. His lungs were clear, and his heart rate was regular without extra sounds. His abdomen was thin, nontender, and without masses or organomegaly. There was no edema or signs of embolism in the extremities. Laboratory studies revealed a white blood cell count of 14,200/mL(3), a hematocrit of 23.1%, and a platelet count of 456,000/mL(3). Blood chemistries were notable for a blood urea nitrogen level of 61 mg/dL and a serum creatinine level of 7.6 mg/dL. Levels of aminotransferases, total bilirubin, and alkaline phosphatase were within normal limits. Urinalysis revealed large hemoglobin, 1+ protein, numerous red blood cells, and 3 to 5 white blood cells. Numerous red blood cell casts were seen on microscopic examination of the urine sediment. The patient's erythrocyte sedimentation rate was &gt;130 mm/h, and his C-reactive protein level was elevated at 12.6 mg/dL. Serologies were negative for antinuclear antibodies and antineutrophil cytoplasmic antibodies; serum complement levels were normal. What is the diagnosis? Little is known concerning renal or urological risk factors for osteoporosis. The aim of this study was to explore an association between urinalysis and bone mineral density (BMD) in 4,835 Japanese adults. Participants were 4,835 individuals (female 3,683; male 1,152) aged 50 years and over who received a health check-up between January 1995 and March 2006 in Japan. BMD of the distal radius and ulna of the non-dominant forearm was measured by the dual-energy X-ray absorptiometry (DXA) method using a DTX-200 Dexacare osteometer (Osteometer MediTech A/S, Rødovre, Denmark). Urine variables were protein, and red blood cells (RBCs) and white blood cells (WBCs) in urine sediment (categorized as &lt;1, 1-4, 5-9, or &gt;or=10 cells per high-power microscopic field). Average age was 58.9 years (SD 5.6) in women, and 60.5 years (SD 6.2) in men. Simple linear regression analysis showed that urinary RBCs were associated with BMD in women (beta = or-5.88 x 10(-3), R (2) = 0.004, p &lt; 0.0001) and men (beta = or-1.34 x 10(-2), R (2) = 0.013, p = 0.0001). These associations held when possible confounders were adjusted (beta = or-2.05 x 10(-3), R (2) = 0.001, p = 0.0338 for women and beta =or -5.67 x 10(-3), R (2) = 0.006, p = 0.0163 for men). Microscopic hematuria is associated with forearm BMD in women and men aged 50 years and over. Further studies should be conducted to determine the mechanisms underlying this association. The purpose was to determine the value of the standard laboratory and radiologic evaluation of microscopic hematuria in children, and to determine the prevalence of idiopathic hypercalciuria in those children referred for evaluation of unexplained microscopic hematuria. This was a retrospective study of 325 children referred from 1985 to 1994 for the evaluation of asymptomatic microscopic hematuria. The diagnostic studies reviewed included serum creatinine, blood urea nitrogen, serum electrolyte studies, serum complement concentration, antinuclear antibody, urinalysis, urine calcium to creatinine ratios, urinary protein to creatinine ratio and/or 24-hour urinary protein excretion, renal ultrasounds, intravenous pyelograms, voiding cystourethrograms, and historical information. All creatinine and electrolyte values were normal for age, and none of the biochemical tests obtained in the children with hypercalciuria was abnormal. Of the 325 patients with idiopathic microscopic hematuria, only 18 had abnormal renal ultrasound examinations and 9 voiding cystourethrograms showed low-grade reflux. Hypercalciuria was found in 29 patients. The family history was positive for urolithiasis in 16% of patients without hypercalciuria compared with 14% of patients with hypercalciuria. A positive family history of hematuria was reported in 25% of patients; 62 patients did not have hypercalciuria and 4 of the patients had hypercalciuria. Microscopic hematuria in children is a benign finding in the vast majority of children. Our data demonstrate that a renal ultrasound, voiding cystourethrogram, cystoscopy, and renal biopsy are not indicated in the work-up of microscopic hematuria, and microhematuria in the otherwise healthy child is a minimal health threat, rarely indicative of serious illness. A 58-year-old female was referred to our department with intermittent suffocation for 1.5 years, aggravated for a month. 1.5 years before she developed oral ulcer, raynaud phenomenon, proteinuria, bilateral pleural effusion, ANA and anti-dsDNA positive. This patient was diagnosed with systemic lupus erythematosus (SLE). After given hormones, hydroxychloroquine sulfate (HCQ), her symptom relieved soon. The patient stopped her pills 1 year ago. One month ago, she had chest tightness, increased urine foam, and suffered from oliguria. Her admission medical examination: blood pressure (BP) 130/80 mmHg, conjunctiva pale, and lower lung breath sounds reduced. There was no tenderness, rebound pain and abdominal muscle tension in the abdomen. Liver and spleen rib inferior, mobile dullness negative, and lower extremity edema. Blood routine tests were performed with hemoglobin (HGB) 57 g/L. Urine routine: BLD (3+). 24-hour urinary protein 3.2 g. serum albumin 20.5 g/L, C-reactive protein (CRP) 12.85 mg/L, erythrocyte sedimentation rate (ESR) 140 mm/h. Antinuclear antibody (ANA) (H)1:10 000, anti-dsDNA antibody 1:3 200; anti-Smith antibody, anti-U1-snRNP/Sm antibody were positive, blood complement 3(C3) 0.43 g/L, complement 4(C4) 0.07 g /L. Anticardiolipin antibody (ACL), anti-β2-GP1, lupus anticoagulant (LA) were negative; HRCT suggested bilateral medial pleural cavity product liquid. Admission diagnosis: SLE lupus nephritis, anemia, pleural effusion, and hypoproteinemia. We treated her with methylprednisolone 1 000 mg×3 d, late to 48 mg/d and cyclophosphamide 1.0 g, HCQ 0.2 g bid, gamma globulin 10 g×5 d. Day 2 of treatment, this patient developed acute right upper quadrant pain, not accompanied by nausea, vomiting, blood stool and diarrhea. Antipyretic antispasmodic treatment was invalid, after the morning to ease their own abdominal pain. Day 4 of treatment, daytime blood HGB 77 g/L. Bilateral renal vascular ultrasound: bilateral renal artery blood flow velocity was reduced. The abdominal pain of the above symptoms recurred at night, BP was 120/80 mmHg, and no positive signs were found on abdominal examination. No abnormality was found in the vertical abdominal plain film. Blood routine examination: HGB 53 g/L, Plasma D dimer 2 515 μg/L, amylase in hematuria was normal, the stool occult blood was negative. Abdominal computed tomography (CT): normal structure of right adrenal gland disappeared, irregular mass shadow could be seen in adrenal region, CT value was about 50 HU. Morphological density of left adrenal gland was not abnormal. The retroperitoneum descended along the inferior vena cava to the right iliac blood vessel and showed a bolus shadow. The density of some segments increased. The lesion involved the right renal periphery and reached the left side of abdominal aorta. Most lesions surrounded the inferior vena cava, the right renal vein and part of the small intestine. The boundary between the upper lesion and the vena cava was unclear. Iodinecontaining contrast agent was taken orally. No sign of contrast agent overflowing was found in the abdominal cavity. Hematoma and exudative changes were considered in retroperitoneum. CONCLUSION of contrast-enhanced ultrasound of blood vessels: The retroperitoneal inferior vena cava (volume 3.5 cm×3.5 cm×1.5 cm) was hypoechoic and had no blood flow lesion. The adrenal gland had a high possibility of origin. Left renal vein thrombosis extended to inferior vena cava. According to the above data, it was analyzed that the cause of retroperitoneal hematoma of the patient was left adrenal vein thrombosis caused by hypercoagulable state, which led to vascular rupture and hemorrhage caused by increased vascular pressure in adrenal gland. Therefore, on the basis of continuing to actively treat the primary disease, and on the basis of dynamic observation of no active hemorrhage for 3 days, the anticoagulant therapy was continued with 10 mg/d of apixaban. Clinical symptoms were gradually eased, HGB did not decrease. Two weeks later, the ultrasonic examination showed that the irregular cluster hypoechoic range behind the inferior vena cava was significantly smaller than that before (1.8 cm×1.2 cm×0.7 cm). Abdominal CT examination after 1 month showed that there was no abnormal morphological density of bilateral adrenal glands and basic absorption of retroperitoneal exudation. Adrenal hemorrhage is uncommon. SLE with adrenal hemorrhage is rarer. In SLE patients, especially those complicated with APS, if abdominal pain accompanied by HGB decrease occurs, except after gastrointestinal hemorrhage, the possibility of adrenal hemorrhage should be warned. The patient, a 78-year-old Asian male, was brought to the hospital because of acute shortness of breath that had progressively worsened over the course of the day. He complained of a nonproductive cough and claudication after walking 1 block. His past medical history was significant for mild renal insufficiency (serum creatinine 1.5--2.0 mg/dl), the etiology of which was never explored. Although there was a recent history of mild to moderate hypertension, at presentation his blood pressure was noted to be 240/118 mm Hg in both arms. His physical exam at the time of admission was remarkable for grade II hypertensive retinopathy, an S4 gallop, periumbilical systolic bruits, audible femoral arterial bruits and absent distal lower extremity pulses. Initial complete blood count, serum electrolytes and cardiac enzymes (including lactate dehydrogenase) were normal. His blood urea nitrogen and serum creatinine concentrations were 51 and 3.6 mg/dl, respectively, and his urinalysis showed 1+ protein (both by dipstick and sulfasalicylic acid) with a \"benign\" sediment (0--1 WBC/HPE, 1--2 RBCs/HPF) with occasional granular casts. His electrocardiogram, apart from demonstrating left ventricular hypertrophy with secondary ST-T wave abnormalities, showed no acute changes; his chest X-ray demonstrated cardiomegaly and pulmonary vascular congestion. He was intubated and subsequently treated with increasing parenteral doses of furosemide (40--240 mg) and a nitroglycerine drip (up to 15 mcg/min). Over the course of the first 48 h, his blood pressure was gradually lowered to 170/100 mm Hg. His urine output increased from 20 ml/h to 125/ml/h, and his respiratory status improved, allowing him to be extubated. In spite of adequate control of his blood pressure in the ensuing days (150--170/80--90 mm Hg), his renal function continued to deteriorate. Renal sonography (without Doppler) demonstrated a right kidney of 9.6 cm and a left kidney of 9.3 cm in length without evidence of hydronephrosis. Both kidneys were noted to be echogenic. Assays for antinuclear antibodies and antineutrophilic cytoplasmic antibodies were negative, and the patient's serum complement levels were normal. For several days after his admission, his serum creatinine gradually rose to 10.7 mg/dl, and hemodialysis was initiated for uremic encephalopathy. Because of the high index of suspicion for renal artery stenosis as the case of both his hypertension and renal failure, a renal angiogram was performed. It revealed a 90% occlusion of the right renal artery with ostial involvement and a 70% occlusion of the left renal artery; both kidneys had poor distal renal vasculature and there was marked atherosclerotic disease of the aorta. After being hemodialyzed for 3 treatments, his renal function began to improve spontaneously. His serum creatinine returned to 3.4 mg/dl, and a subsequent 24-hour urine demonstrated a creatinine clearance of 20 ml/min and an excretion of 1.2 g of protein. Following his discharge from the hospital, his renal function remained unchanged for 3 years, and his blood pressure was easily controlled on monotherapy with a long-acting calcium channel blocker. He recently died from pneumonia. A complete blood count showing possible anemia and low platelet count followed by renal function tests with elevated serum creatinine (0.4 mg/dl above the upper limit), blood urea nitrogen levels, and urine analysis positive for urine sediments: red blood cells and casts, white blood cells, granular casts are indicative of a glomerular pathology. For further confirmation, a 24 hours urine protein to creatinine ratio and 24 hours urine sample for protein levels can be done. A protein count of greater than 3.5 g/day is suggestive of nephrotic range proteinuria, which is associated with a worse prognosis. A 24-hour urine sample can be used to calculate creatinine clearance to estimate the eGFR. Renal ultrasound can be done to see the size and confirm the presence of two kidneys and the absence of any obstructive pathology resulting in hydronephrosis. Serum complement (C3 and C4) levels help determine the etiology; low levels are associated with the presence of SLE, cryoglobulinemia, and infectious etiology. [12] During a 5-year study period, 109 patients were referred to a large children's hospital for evaluation of prolonged fever of unknown origin, defined as temperature greater than or equal to 38 degrees C (100.4 degrees F) for 3 weeks or longer and negative findings on initial examination. A two-phase protocol of outpatient followed by inpatient diagnostic studies was instituted for most patients. Confirmed diagnoses were achieved in just 36 of these children (33%) in the following disease categories: infectious, 24 (22%); autoimmune, 7 (6%); and neoplastic, 2 (2%). Scanning or special procedures and the number with positive results (in parentheses) were as follows: abdominal ultrasonography, 43 (8); abdominal computed tomography, 14 (3); indium scan 11 (5); gallium scanning, 4 (1), upper gastrointestinal tract series, 13 (2); technetium bone scanning 15 (2); bone marrow examination, 16 (1); and cranial computed tomography, 7 (0). These studies rarely led to an unsuspected diagnosis. It appears most appropriate in evaluating fever of unknown origin in children to obtain only basic laboratory studies such as a complete blood cell count, urinalysis and culture, chest radiograph, tuberculin skin test, and, in the older child, an antinuclear antibody titer. When these test results are negative, almost all children can be observed clinically for progression of illness or a focus that might then direct specific diagnostic procedures. Japan Society of Clinical Pathology has formed a committee dealing with \"lab. tests in primary care medicine\". As the first step, they made \"Essential Lab. Tests\" which were composed of simple qualitative bed-side tests such as urinalysis, Complete blood count (CBC: Hb, Ht, WBC, RBC), CRP, or ESR (Erythrocyte sedimental rate), A/G ratio and biochemical tests if necessary (Table 1). We have performed \"Essential Lab. Tests\" on 1,026 outpatients who visited General Medicine Clinic for the first time. They consisted of 456 male (age 13-81), and 526 female (age 10-85). This report is the result of urinalysis from \"Essential Lab. Tests\" of 1,026 patients. 1) The result showed that overall positivity of the urinalysis was 21.3% (when more than one item of the qualitative tests was positive). 2) There was distinctive difference in the positivity of the urinalysis between the sex; i.e. protein and glucose were about twice frequently positive in male, where as occult blood and WBC (Esterase reaction) were 2-3 times more positive in female. 3) Urine protein shows positive in the individual 10-20 yrs old and more than 50 yrs old in both sexes. 4) Glucose was positive in over 40 yrs in male, and occult blood, 40-50 yrs or older in male. 5) WBC shows positive in all age groups in female and 50 yrs or older in male. 6) Positive WBC patients did not necessarily reflect urinary infection in female but nitrites roughly corresponded with urinary WBC in male of 50 yrs or older, meaning probable urinary infection associated with prostatic hypertrophy. 7) Abnormality of urinary sediment corresponded to the positive occult blood and WBC Erastase. 8) Urinalysis is an useful method of screening in primary care medicine. Blood and urine test While there is no laboratory test specific for appendicitis, a complete blood count (CBC) is done to check for signs of infection. Although 70–90 percent of people with appendicitis may have an elevated white blood cell (WBC) count, there are many other abdominal and pelvic conditions that can cause the WBC count to be elevated. Due to its low sensitivity and specificity, on its own, WBC is not seen as a good indicator of appendicitis. A urinalysis generally does not show infection, but it is important for determining pregnancy status, especially the possibility of an ectopic pregnancy in women of childbearing age. The urinalysis is also important for ruling out a urinary tract infection as the cause of abdominal pain. The presence of more than 20 WBC per high-power field in the urine is more suggestive of a urinary tract disorder. The first step in evaluation of red or brown colored urine is to confirm true hematuria with urinalysis and urine microscopy, where hematuria is defined by three of more red blood cells per high power field. Although a urine dipstick test may be used, it can give false positive or false negative results. In gathering information, it is important to inquire about recent trauma, urologic procedures, menses, and culture-documented urinary tract infection. If any of these are present, it is appropriate to repeat a urinalysis with urine microscopy in 1 to 2 weeks or after treatment of the infection. If the results of the urinalysis and urine microscopy reveal a glomerular origin of hematuria (indicated by proteinuria or red blood cell casts), consultation of a nephrologist should be made. If the results of the urinalysis indicate a non-glomerular origin, a microbiological culture of the urine should be performed, if it has not been done already. If the culture is positive, treatment of the a female less than 50 years old or a male less than 40 years old; has 3-10 red blood cells per high power field; has not had microscopic hematuria before; and has no other risk factors for urothelial cancer. To be in the intermediate risk category, one must satisfy any of the following criteria: Has smoked 10-30 pack-years; is a female 50-59 years old or a male aged 40-59 years old; has 11-25 red blood cells per high power field; or was previously a low-risk patient with persistent microscopic hematuria and has 3-25 red blood cells per high power field. To be in the high risk category, one must satisfy any of the following criteria: Has smoked more than 30 pack-years; is older than 60 years of age; or has above 25 red blood cells per high power field on any urinalysis. For the low risk category, the next step is to either repeat a urinalysis with urine microscopy in 6 months or perform a cystoscopy and renal ultrasound. For the intermediate risk category, the next step is to perform a Blood urea nitrogen (BUN) - Also measured using a BMP or CMP, blood urea nitrogen is an indicator of how much nitrogen is in the blood at the time of the phlebotomy. The kidney is responsible for excreting nitrogenous substances in the urine, so an elevated BUN usually indicates that the kidney is not functioning appropriately. Urine Analysis (Urinalysis) - After the patient provides a urine specimen, it is sent to the lab for analysis using a variety of methods including urine dipstick testing and microscopic examination. Because the kidney is responsible for making urine, analyzing the urine directly can provide crucial data that can help the physician diagnose nephritic syndrome. Some findings on urinalysis that are consistent with nephritic syndrome include red blood cells (hematuria), red blood cell casts, proteinuria, and possibly white blood cells (pyuria).\nHere is the question:\nPEDIATRICS: A 10-year-old girl comes for a health check-up. Physical examination is normal with weight and height in the 50th percentile and BP 109/65. A routine urinalysis shows a specific gravity of 1035 pH6 blood 2+ with no protein. Urine sediment shows 5-10 red blood cells per field. What would be the most appropriate course of action?\nHere are the potential choices:\n1. Determination of creatinine and nitrogen in blood.\n2. Refer the child for cystoscopy.\n3. Determine antinuclear antibodies and complement.\n4. Repeat urine sediment in 15 days.\n5. Abdominal computed axial tomography.\nThe correct answer is: 4. Repeat urine sediment in 15 days."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Background. The natural history of idiopathic scoliosis is a crucial issue in the planning and assessment of different treatment methods. This article presents the evaluation of scoliotic deformity in immature patients who have been in observation without any treatment. Material and methods. 159 patients (128 girls, 31 boys) were examined between 1971 and 2002. Skoliosis was diagnosed at a mean age of 6 years 4 months (range 2.1-8.10), and observation was concluded at a mean age of 16 years 11 months (range 14.6-20.3). The mean follow-up was 10 years 5 months. The prognostic factors analyzed were: age, sex, Cobb angle, Mehta angle, apical vertebral rotation, specific rotation, Risser test. The progression and regression of curvature was analyzed in different biological age periods, and was measured by calculating the difference in the Cobb angle on successive x-rays divided by the interval between x-rays. Results. The mean progression of curvature before age 5 was 5.7 degrees per year; in the 6-10 age bracket, 2.3 degrees per year; in the 11-15 age bracket, 7.4 degrees per year; in the &gt;15 age bracket, 0.3 degrees per year. The mean progression for patients with Risser 1 was 8.8 degrees per year; Risser 2, 7.3 degrees per year; Risser 3, 5.1 per year; Risser 4, 2.1 degrees per year; Risser 5, 0.3 degrees per year. Conclusions. The progression of curvature in idiopathic scoliosis is variable, and is influenced by age. Knowledge of the natural history of idiopathic scoliosis is a crucial tool in predicting the development of spinal curvature. The Risser test and biological age are the only effective predictors of progression. Effectiveness of brace treatment for adolescent idiopathic scoliosis (AIS) was demonstrated by the BrAIST study in 2013. Objectives of this study were to confirm its effectiveness by analyzing our results and to clarify the factors affecting the results of the treatment. According to the Scoliosis Research Society AIS brace studies standardization criteria, patients with age 10 years or older, Risser 0 to II, less than 1 year post-menarche, curve magnitude 25 to 40 degrees before brace treatment and who received no prior treatment were included in the study. At skeletal maturity, the rate of the patients whose curve was stabilized, exceeded 45 degrees, and who were recommended or underwent surgery were investigated. Additionally, initial correction rate by the brace and factors affecting the results were investigated. A total of 33 patients (27 females and 6 males) could be followed-up until their skeletal maturity and included in the analysis. An average age was 11.9 years, average Cobb angle was 30.8°, and Risser sign was 0 in 13 patients, I in 5, and II in 15 patients before treatment. There were 13 thoracic curves, 14 thoracolumbar or lumbar curves, and 6 double curves. Initial correction rate by the brace was 53.8% for the total curves. In terms of curve pattern, 34.4% for thoracic curve, 73.9% for thoracolumbar or lumbar curve, and 48.8% for double curve. After an average follow-up period of 33 months, 8 patients improved in more than 6 degrees, change of 17 patients were within 6 degrees, and 8 progressed in more than 6 degrees. Therefore, totally, 76% (25/33) of the curves were stabilized by the treatment. Four curves (12%) exceeded 45 degrees and one patient (3%) underwent surgery. Our results were better than the reported natural history. Factors that affected the results were hump degree before treatment and initial correction rate by the brace. 76% of the curve with AIS could be stabilized by brace treatment. Brace treatment was effective for treatment of AIS. Factors affecting the results were hump degrees and initial correction rate. The prospective study reported here was instituted in 1987 to obtain more detailed data on the efficacy of scoliosis-specific spinal rehabilitation after Schroth. Inclusion criteria were 1) idiopathic scoliosis, 2) Risser stage &lt; 4, 3) no treatment with corset or electrical stimulation, 4) first examination between 1 and 3 years postoperatively, 5) usable total X-rays taken with the patient standing not more than 6 months prior to admission. A total of 181 scoliosis patients with an average age of 12.76 years and an average Cobb angle of 27 degrees were included in the study. The average Risser's sign was 1.4 and the average follow-up period was 33 months. No cases of relative progression (annual increase in curvature of 5 degrees or more) were observed. For the purpose of comparison with the spontaneous course, the patients were grouped by age and severity of scoliosis. Both the absence of any relative progression as well as direct comparison of the development of scoliosis under therapy with the spontaneous course confirmed the efficacy of the stationary rehabilitation programme notably in cases with poor prognosis, i.e. with large scoliosis angles and unfavourable curvatures. Part-time or night-time bracing has been introduced to address the poor compliance and psychological burden of full-time bracing. The results of various bracing methods vary, however, due to a lack of consistent inclusion criteria and definitions of brace effectiveness. We have evaluated the effectiveness of the Charleston night-time bending brace in the treatment of adolescent idiopathic scoliosis based on the new standardized criteria proposed by the Scoliosis Research Society. To be included in this study, patients met the following criteria proposed by the Scoliosis Research Society: diagnosis of adolescent idiopathic scoliosis, age 10 years and older when the orthosis was prescribed, Risser 0-2, a primary curve magnitude of 25 to 40 degrees, and no prior treatment. A total of 95 patients (87 girls, 8 boys) were included. At skeletal maturity, 80 patients (84.2%) had 5 degrees or less curve progression and 15 (15.8%) had 6 degrees or more progression. Seven patients (7.8%) were recommended to undergo or underwent surgery before skeletal maturity. Eleven patients (12.6%) progressed beyond 45 degrees. According to these 3 criteria, the Charleston night-time brace was successful in 74 patients (77.9%). Depending on curve type, we observed success rates of 78.3% (47/60) for double, 71.4% (15/21) for thoracic, 83.3% (5/6) for thoracolumbar, and 87.5% (7/8) for lumbar curves. Success rates of 80.0% (36/45) and 76.0% (38/50) were observed in patients with curve magnitudes at bracing of 25 to 30 degrees and 31 to 40 degrees, respectively. Patients with high apex curves had a 67.6% (23/34) success rate, and those with low apex curves had 83.0% (39/47) success rate. Brace success rates among patients with initial Risser signs of 0, 1, and 2 were 68.8% (22/32), 80.6% (25/31), and 84.4% (27/32), respectively. Compared with the results of previous natural history and conventional brace study, the Charleston night-time bending brace is effective for the treatment of adolescent idiopathic scoliosis. Level VI. The purpose of this study was to assess the effectiveness of a scoliosis-specific rehabilitation programme as it is carried out in the Katharina Schroth Spinal Deformities Rehabilitation Center. Physiotherapy in the treatment of scoliosis patients is still regarded as ineffective since the study by the American Orthopedic Association in 1941, which showed that general exercises could not influence the natural history of scoliosis. However, specific exercise programmes were not known in the USA at that time. This preliminary study started in 1989 with the following inclusion criteria: (1) diagnosis of idiopathic scoliosis; (2) risser sign &lt; 4; (3) no treatment other than physiotherapy; (4) first control after 1-3 years during repeated in patient treatment; (5) standing AP radiograph taken not more than 6 months before the first in patient treatment. A total of 181 scoliosis patients, with an average age of 12.7 years and an average angle of curvature of 27% according to Cobb, were included in this study. The average risser sign was 1.4, the average follow-up 33 months. The Cobb angle of the major curve was measured in a standardized way. The results of our preliminary study were compared to natural history as known from literature. For the worst-case analysis additionally a questionnaire was sent to the non-repeaters treated at our centre at the same time (1989 and 1990) as the patient sample described above, taking into account the same inclusion criteria for this patient sample except point 4. Results showed that progression as usually defined (increase in curvature of 5 degrees or more per year) has not been found in the preliminary study. The patient sample of this study was divided into different age groups and different groups of curve magnitude, for comparison with other studies. Additional to the patient sample of the preliminary study, 116 of the patients from the years 1989 and 1990 fulfilled the inclusion criteria of the preliminary study with the exception of point 4. These patients formed the questionnaire sample for the worst-case analysis showing that the progression rate of the 181 patients from the preliminary study and the 116 patients of the questionnaire sample together was still better than natural history even if all drop-outs were considered to be failures. The fact that there was no relative progression in our patients sample treated solely by physiotherapy (preliminary study), seems to show the effectiveness of the inpatient rehabilitation programme even in cases with a bad prognosis, severe angles of curvature and unfavourable curvature patterns. A worst-case analysis does not prevent this conclusion, even if all dropouts from the non-repeaters group were considered as failures. Physiotherapy for stabilization of idiopathic scoliosis angle in growing children remains controversial. Notably, little data on effectiveness of physiotherapy in children with Early Onset Idiopathic Scoliosis (EOIS) has been published.The aim of this study was to check results of FITS physiotherapy in a group of children with EOIS.The charts of the patients archived in a prospectively collected database were retrospectively reviewed. The inclusion criteria were:diagnosis of EOIS based on spine radiography, age below 10 years, both girls and boys, Cobb angle between 118 and 308, Risser zero, FITS therapy, no other treatment (bracing), and a follow-up at least 2 years from the initiation of the treatment. The criterion for curve progression were as follows: the Cobb angle increase of 68 or more, for curve stabilization; the Cobb angle was 58 comparing to the initial radiograph,for curve correction; and the Cobb angle decrease of 68 or more at the final follow-up radiograph.There were 41 children with EOIS, 36 girls and 5 boys, mean age 7.71.3 years (range 4 to 9 years) who started FITS therapy. The curve pattern was single thoracic (5 children), single thoracolumbar (22 children) or double thoracic/thoracolumbar (14 children), totally 55 structural curvatures. The minimum follow-up was 2 years after initiation of the FITS treatment, maximum was 16 years, mean 4.8 years). At follow-up the mean age was 12.53.4 years. Out of 41 children, 10 passed pubertal growth spurt at the final follow-up and 31 were still immature and continued FITS therapy. Out of 41 children, 27 improved, 13 were stable, and one progressed. Out of 55 structural curves, 32 improved, 22 were stable and one progressed. For the 55 structural curves, the Cobb angle significantly decreased from 18.085.48 at first assessment to 12.586.38 at last evaluation,p&lt;0.0001, paired t-test. The angle of trunk rotation decreased significantly from 4.782.98 to 3.282.58 at last evaluation, p&lt;0.0001,paired t-test.FITS physiotherapy was effective in preventing curve progression in children with EOIS. Final postpubertal follow-up data is needed. As part of our study, the effectiveness and patient's acceptance of the Wilmington-brace is to be evaluated. The effectiveness can be documented with the help of the primary correction achieved, especially in light of the fact, that the primary correction and the long-term results are directly dependant upon one another. We examined a total of 52 patients with an idiopathic scoliosis treated in a thermoplast brace. The group consisted of 38 female and 14 male patients (average age 11.6 years). The angulation was measured with the help of the Cobb-angle and the rotation with the method described by Nash and Moe. The skeletal age was classified according to Risser's-sign. The angle determinations were carried out at three separate points in time--at first presentation, prior to bracing and four to six weeks following bracing. The patients presented with an average angulation of 31 degrees. The average correction achieved in the Wilmington-brace was 41%. This corresponds to a correction of 13 degrees. The best primary correction (45%) was obtained in the thoracolumbar spine. Those patients with the smallest deformity at the onset of treatment showed the best results. The scoliosis with a large primary deformity and a marked rotation of the vertebral bodies responded poorly to correction. Advanced age or skeletal maturity were also limiting factors. Physical therapy had a positive influence on the amount of primary correction obtained. The Wilmington-brace (thermoplast) allows for a good primary correction of idiopathic scoliosis. The simplicity of application and the low production costs are also positive attributes. The SRS criteria give the methodological reference framework for the presentation of bracing results, while the SOSORT criteria give the clinical reference framework for an appropriate bracing treatment. The two have not been combined in a study until now. Our aim was to verify the efficacy of a complete, conservative treatment of Adolescent Idiopathic Scoliosis (AIS)according to the best methodological and management criteria defined in the literature. Study Design. Retrospective study. Population. We included all AIS patients respecting the SRS inclusion criteria (age 10 years or older; Risser test 0-2; Cobb degrees 25-40 degrees ; no prior treatment; less than one year post-menarchal) who had reached the end of treatment since our institute database start in 2003. Thus we had 44 females and four males, with an age of 12.8 +/- 1.6 at the commencement of the study. Methods. According to individual needs, two patients have been treated with Risser casts followed by Lyon brace, 40 with Lyon or SPoRT braces (14 for 23 hours per day, 23 for 21 h/d, and seven for 18 h/d at start), and two with exercises only (1 male, 1 female): these were excluded from further analysis. Outcome criteria. SRS (unchanged; worsened 6 degrees or more; over 45 degrees at the end of treatment; surgically treated; two years' follow-up); clinical (ATR, Aesthetic Index, plumbline distances); radiographic (Cobb degrees); and ISICO (optimal; minimal). Statistics. Paired ANOVA and t-test, Tukey-Kramer and chi-square test. Median reported compliance during the 4.2 +/- 1.4 treatment years was 90% (range 5-106%). No patient progressed beyond 45 degrees , nor was any patient fused, and this remained true at the two-year follow-up for the 85% that reached it. Only two patients (4%) worsened, both with single thoracic curve, 25-30 degrees Cobb and Risser 0 at the start. We found statistically significant reductions of the scoliosis curvatures (-7.1 degrees ): thoracic (-7.3 degrees ), thoracolumbar (-8.4 degrees ) and lumbar (-7.8 degrees ), but not double major. Statistically significant improvements have also been found for aesthetics and ATR. Respecting also SOSORT management criteria and thus increasing compliance, the results of conservative treatment were much better than what had previously been reported in the literature using SRS criteria only. The main distinctive aspect of Juvenile Idiopathic Scoliosis (JIS) with respect to Adolescent Idiopathic Scoliosis (AIS) is the high risk of severe deformity and surgery. Approximately 70% of curves in patients with JIS progress and ultimately require surgery. There are presently very few studies with long-term follow-up of JIS and even fewer looking specifically at bracing Purpose To verify the effectiveness of a complete conservative treatment, including bracing and exercises, for JIS. Retrospective cohort observational study nested in a clinical prospective database of consecutive outpatients. Patient Sample Inclusion criteria: JIS, no previous treatment, all consecutive radiographies available from treatment start to end of growth (Risser sign 3). We found 30 patients, 27 females, 10 JIS type 1; mean age at first diagnosis was 7.8 +/-1.5 and mean treatment lasted 5.8 years. Cobb degrees 24.4+/-10 degrees, with 7 cases &gt;30 degrees, and 2 &gt; 45degrees. Outcome Measures Physiological measures. Radiographic and clinical data. Treatment (exercises alone, or elastic-rigid-highly rigid braces plus exercises) was tailored and continuously changed according to Cobb degrees, individual preferences, anthropometric characteristics, pubertal spurt, remaining growth, rotation, hump, lumbar curve take-off, and imbalance. The SOSORT Guidelines for patients' management have been followed. Funding and Conflict of Interest: no. 33.3% (95% Confidence Interval 16.4-50.2%) of patients worsened over the years. At the end of growth, 6.6% (0-15.5%) had surgical deformities (&gt;45degrees). We observed a good correction in the first years of treatment until pubertal growth spurt, when progression was usually noted and treatment changed increasing corrective forces (hours or rigidity of bracing). 23 cases were followed up until they had two consecutive radiographies showing Risser sign 5 and showed stability. Conservative treatment initiated already in childhood may favorably change the natural history of JIS with the aim of reaching a curve as far as possible from surgical thresholds. Observation, physical exercises, braces can be useful tools in the hand of physicians, but they must be carefully utilized by a deep knowledge of JIS. SpineCor is a relatively new bracing system that uses dynamic bracing concepts in the treatment of adolescent idiopathic scoliosis (AIS). Limited data are available regarding its effectiveness. This study compared treatment outcomes of 2 groups of AIS patients treated via either a conventional rigid thoracolumbosacral orthoses (TLSO) or a SpineCor nonrigid orthosis. We identified 2 scoliosis patient cohorts: 35 patients treated with a TLSO and 32 patients treated with a SpineCor orthosis. All patients included in these groups conformed with the Scoliosis Research Society (SRS) standardized criteria for AIS bracing: (1) Risser &lt; or =2, (2) curve magnitude 25 to 40 degrees, (3) age &gt; or =10 years. Outcomes were SRS standardized with failure being defined as curve progression &gt; or =6 degrees, or ever exceeding 45 degrees, or having surgery recommended before skeletal maturity. All patients were followed through the completion of brace treatment or attainment of other treatment end points. The Yates corrected chi test and unpaired t test were used for data analysis. The 35 patients (32 girls, 3 boys) in the TLSO group had an average age of 13 years (range: 11.1-16.8) and an average primary curve magnitude of 33 degrees (range: 25-40 degrees). Follow-up averaged 2 years (range: 8-61 m) from the beginning of brace treatment. The 32 patients (28 girls, 4 boys) in the SpineCor group had an average age of 13 years (range: 11-15.2) and an average primary curve magnitude of 31 degrees (range: 25-40 degrees). Follow-up for this group averaged 2 years and 6 months (range: 13-73 mo) from the beginning of brace treatment. No significant difference (P=0.75) was found using the more strict outcome measure (&lt; or =5-degree curve progression) as the success rates were 60% (21/35) for TLSO and 53% (17/32) for SpineCor. Similarly, no significant difference (P=0.62) was found using the more liberal outcome measure (never reached 45 degrees) as the success rates were 80% (28/35) for TLSO and 72% (23/32) for SpineCor. We were unable to identify any significant differences in brace treatment outcomes when comparing TLSO and SpineCor treated patients. Surgery is indicated by the Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT) at 45 degrees to 50 degrees and by the Scoliosis Research Society (SRS) at a Cobb angle of 45 degrees. SOSORT uses the 45-degree to 50-degree threshold as a result of the well-documented, plus or minus five degrees measurement error that can occur while measuring Cobb angles. Scoliosis braces are usually comfortable for the patient, especially when it is well designed and fit; also after the 7- to 10-day break-in period. A well fit and functioning scoliosis brace provides comfort when it is supporting the deformity and redirecting the body into a more corrected and normal physiological position. The Scoliosis Research Society's recommendations for bracing include curves progressing to larger than 25°, curves presenting between 30 and 45°, Risser sign 0, 1, or 2 (an X-ray measurement of a pelvic growth area), and less than six months from the onset of menses in girls. The results of the brace treatment (Milwaukee brace, Thoraco-Lumbo-Sacral-Orthosis, Boston-Milwaukee brace) were studied in 509 patients with idiopathic scoliosis, who were braces for an average of 3 years and 3 months ranging from 2 to 10 years. Of these patients, 60 were followed up for about 24 months after the brace was discontinued. The distribution of these patients according to curve pattern was as follows: 319 had thoracic curve; 78 had lumbar curve (combining lumbar and thoracolumbar curves together as one group); and 112 had double major curve. The findings are summarized and conclusions were drawn as follows. 1. The best correction was obtained within a year after the initiation of bracing, followed by a gradual loss of correction. 2. There was a significant difference between the final correction rate and the best correction rate in the brace. 3. In the patients with ages ranging from 11 to 14 years and with curves of 30 degrees or less at the beginning of brace treatment, the curves were maintained within 30 degrees at the final stage. 4. Those patients who cooperated well in wearing their braces had a smaller loss of correction at the final stage. 5. In 63 per cent of the cases who showed progression in the brace, iliac apophysis did not appear at the beginning of brace treatment. 6. Moiré topography was used for the analysis of cosmesis and it was shown to be a valuable method of three dimensional evaluation. 7. In 60 patients who were followed up for 24 months on average after the brace was discontinued, the curves had improved an average of 1.6 degrees at the time of their last check up. Recently it has been shown that idiopathic scoliosis (IS) curves can be reduced with bracing, and it has been proposed that this could be useful in non-surgically treated high degree curves even after Risser 3. Moreover, bracing has been shown to be able to improve aesthetics, and this could be another reason to treat some patients with cosmetic needs. Our aim is to preliminary check if results can be obtained in IS patients after Risser 3. Design. Retrospective uncontrolled cohort study. Inclusion criteria. All IS patients treated on a voluntary basis for aesthetic reasons and/or for curve reduction; Risser 4-5 at start; end of treatment reached. Population. 34 females and 2 males, age 16.2±1.6 years, Cobb angle 27.6°±8.9°. Treatment. Lyon or SPoRT braces 18 to 24 hours/day, specific SEAS exercises, rapid weaning (2-3 hours every 6 months). Outcome criteria: SRS (unchanged; worsened over 6°; over 45° at the end of treatment; surgically treated), radiographic and clinical. Statistics. ANOVA and chi-test. The reported compliance during the 2.8 ± 1.1 treatment years was 95.1%, while residual growth was 0.9 ± 1.1 cm. Improvements were found in 39% of this cohort, (46% in curves over 30°). Only 1 patient progressed 6°. We found highly statistically significant reductions of maximal (-4.4°), thoracic (-6.0°) and thoracolumbar (-6.6°) curves. Statistically significant improvements were found for Aesthetic Index. Before 20 years of age, even in skeletally mature patients, it is possible to reach radiographic and aesthetic improvements, although not as good as during growth. Correction is based on bone growth, but ligaments and neuromuscular control of posture can also be involved. The effectiveness of conservative treatment of scoliosis is controversial. Some studies suggest that brace is effective in stopping curve progression, whilst others did not report such an effect.The purpose of the present study was to effectiveness of Progressive Action Short Brace (PASB) in the correction of thoraco-lumbar curves, in agreement with the Scoliosis Research Society (SRS) Committee on Bracing and Nonoperative Management Standardisation Criteria. Fifty adolescent females (mean age 11.8 +/- 0.5 years) with thoraco-lumbar curve and a pre-treatment Risser score ranging from 0 to 2 have been enrolled. The minimum duration of follow-up was 24 months (mean: 55.4 +/- 44.5 months). Antero-posterior radiographs were used to estimate the curve magnitude (CM) and the torsion of the apical vertebra (TA) at 5 time points: beginning of treatment (t1), one year after the beginning of treatment (t2), intermediate time between t1 and t4 (t3), end of weaning (t4), 2-year minimum follow-up from t4 (t5). Three situations were distinguished: curve correction, curve stabilisation and curve progression.The Kruskal Wallis and Spearman Rank Correlation tests have been used as statistical tests. CM mean value was 29,30 +/- 5,16 SD at t1 and 14,67 +/- 7,65 SD at t5. TA was 12.70 +/- 6,14 SD at t1 and 8,95 +/- 5,82 at t5. The variation between measures of Cobb and Perdriolle degrees at t1,2,3,4,5 and between CM t5-t1 and TA t5-t1 were significantly different.Curve correction was accomplished in 94% of patients, whereas a curve stabilisation was obtained in 6% of patients. The PASB, due to its peculiar biomechanical action on vertebral modelling, is highly effective in correcting thoraco-lumbar curves. Early diagnosis of idiopathic scoliosis allows for observation and timely initiation of brace treatment in order to halt progression. School scoliosis screening programs were abolished in Norway in 1994 for lack of evidence that the programs improved outcome and for the costs involved. The consequences of this decision are discussed. To describe the detection, patient characteristics, referral patterns and treatment of idiopathic scoliosis at a scoliosis clinic during the period 2003-2011, when there was no screening and to compare treatment modalities to the period 1976-1988 when screening was performed. Patient demographics, age at detection, family history, clinical and radiological charts of consecutive patients referred for scoliosis evaluation during the period 2003-2011, were prospectively registered. Patients were recruited from a catchment area of about 500000 teenagers. Maturity was estimated according to Risser sign and menarcheal status. Severity of pain was recorded by a verbal 5-point scale from no pain to pain at all times. Physical and neurological examinations were conducted. The detector and patient characteristics were recorded. Referral patterns of orthopedic surgeons at local hospitals and other health care providers were recorded. Patient data was obtained by spine surgeons. Treatment modalities in the current period were compared to the period 1976-1988. We registered 752 patients with late onset juvenile and adolescent idiopathic scoliosis from 2003-2011. There were 644 (86%) girls and 108 (14%) boys. Mean age at detection was 14.6 (7-19) years. Sixty percent had Risser sign ≥ 3, whilst 74% were post menarche with a mean age at menarche of 13.2 years. Thirty-one percent had a family history of scoliosis. The mean major curve at first consultation at our clinic was 38° (10°-95°). About 40% had a major curve &gt;40°. Seventy-one percent were detected by patients, close relatives, and friends. Orthopaedic surgeons referred 61% of the patients. The mean duration from detection to the first consultation was 20(0-27) months. The proportion of the average number of patients braced each year was 68% during the period with screening compared to 38% in the period without screening, while the proportion for those operated was 32% and 62%, respectively ( p=0.002, OR 3.5, (95%CI 1.6 to 7.5). In the absence of scoliosis screening, lay persons most often detect scoliosis. Many patients presented with a mean Cobb angle approaching the upper limit for brace treatment indications. The frequency of brace treatment has been reduced and surgery is increased during the recent period without screening compared with the period in the past when screening was still conducted.\nHere is the question:\nTRAUMATOLOGY: A 13-year-old female, with no relevant history, with menarche 3 months ago, followed since the age of 10 years by idiopathic scoliosis that has worsened. In the physical examination she presents a hump of 7 degrees in the Adams test and in the scoliogram a thoracolumbar curve T4-L1 of 35 degrees of Cobb and a Risser 0. The correct attitude to take will be:\nHere are the potential choices:\n1. Recommend swimming and revision in three months.\n2. Prescribe a corset-type orthosis.\n3. Refer to physiotherapy for spine elastification.\n4. Review in 6 months with a new X-ray.\nThe correct answer is: ",
        "gold_answer": "2 Prescribe a corset-type orthosis.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Background. The natural history of idiopathic scoliosis is a crucial issue in the planning and assessment of different treatment methods. This article presents the evaluation of scoliotic deformity in immature patients who have been in observation without any treatment. Material and methods. 159 patients (128 girls, 31 boys) were examined between 1971 and 2002. Skoliosis was diagnosed at a mean age of 6 years 4 months (range 2.1-8.10), and observation was concluded at a mean age of 16 years 11 months (range 14.6-20.3). The mean follow-up was 10 years 5 months. The prognostic factors analyzed were: age, sex, Cobb angle, Mehta angle, apical vertebral rotation, specific rotation, Risser test. The progression and regression of curvature was analyzed in different biological age periods, and was measured by calculating the difference in the Cobb angle on successive x-rays divided by the interval between x-rays. Results. The mean progression of curvature before age 5 was 5.7 degrees per year; in the 6-10 age bracket, 2.3 degrees per year; in the 11-15 age bracket, 7.4 degrees per year; in the &gt;15 age bracket, 0.3 degrees per year. The mean progression for patients with Risser 1 was 8.8 degrees per year; Risser 2, 7.3 degrees per year; Risser 3, 5.1 per year; Risser 4, 2.1 degrees per year; Risser 5, 0.3 degrees per year. Conclusions. The progression of curvature in idiopathic scoliosis is variable, and is influenced by age. Knowledge of the natural history of idiopathic scoliosis is a crucial tool in predicting the development of spinal curvature. The Risser test and biological age are the only effective predictors of progression. Effectiveness of brace treatment for adolescent idiopathic scoliosis (AIS) was demonstrated by the BrAIST study in 2013. Objectives of this study were to confirm its effectiveness by analyzing our results and to clarify the factors affecting the results of the treatment. According to the Scoliosis Research Society AIS brace studies standardization criteria, patients with age 10 years or older, Risser 0 to II, less than 1 year post-menarche, curve magnitude 25 to 40 degrees before brace treatment and who received no prior treatment were included in the study. At skeletal maturity, the rate of the patients whose curve was stabilized, exceeded 45 degrees, and who were recommended or underwent surgery were investigated. Additionally, initial correction rate by the brace and factors affecting the results were investigated. A total of 33 patients (27 females and 6 males) could be followed-up until their skeletal maturity and included in the analysis. An average age was 11.9 years, average Cobb angle was 30.8°, and Risser sign was 0 in 13 patients, I in 5, and II in 15 patients before treatment. There were 13 thoracic curves, 14 thoracolumbar or lumbar curves, and 6 double curves. Initial correction rate by the brace was 53.8% for the total curves. In terms of curve pattern, 34.4% for thoracic curve, 73.9% for thoracolumbar or lumbar curve, and 48.8% for double curve. After an average follow-up period of 33 months, 8 patients improved in more than 6 degrees, change of 17 patients were within 6 degrees, and 8 progressed in more than 6 degrees. Therefore, totally, 76% (25/33) of the curves were stabilized by the treatment. Four curves (12%) exceeded 45 degrees and one patient (3%) underwent surgery. Our results were better than the reported natural history. Factors that affected the results were hump degree before treatment and initial correction rate by the brace. 76% of the curve with AIS could be stabilized by brace treatment. Brace treatment was effective for treatment of AIS. Factors affecting the results were hump degrees and initial correction rate. The prospective study reported here was instituted in 1987 to obtain more detailed data on the efficacy of scoliosis-specific spinal rehabilitation after Schroth. Inclusion criteria were 1) idiopathic scoliosis, 2) Risser stage &lt; 4, 3) no treatment with corset or electrical stimulation, 4) first examination between 1 and 3 years postoperatively, 5) usable total X-rays taken with the patient standing not more than 6 months prior to admission. A total of 181 scoliosis patients with an average age of 12.76 years and an average Cobb angle of 27 degrees were included in the study. The average Risser's sign was 1.4 and the average follow-up period was 33 months. No cases of relative progression (annual increase in curvature of 5 degrees or more) were observed. For the purpose of comparison with the spontaneous course, the patients were grouped by age and severity of scoliosis. Both the absence of any relative progression as well as direct comparison of the development of scoliosis under therapy with the spontaneous course confirmed the efficacy of the stationary rehabilitation programme notably in cases with poor prognosis, i.e. with large scoliosis angles and unfavourable curvatures. Part-time or night-time bracing has been introduced to address the poor compliance and psychological burden of full-time bracing. The results of various bracing methods vary, however, due to a lack of consistent inclusion criteria and definitions of brace effectiveness. We have evaluated the effectiveness of the Charleston night-time bending brace in the treatment of adolescent idiopathic scoliosis based on the new standardized criteria proposed by the Scoliosis Research Society. To be included in this study, patients met the following criteria proposed by the Scoliosis Research Society: diagnosis of adolescent idiopathic scoliosis, age 10 years and older when the orthosis was prescribed, Risser 0-2, a primary curve magnitude of 25 to 40 degrees, and no prior treatment. A total of 95 patients (87 girls, 8 boys) were included. At skeletal maturity, 80 patients (84.2%) had 5 degrees or less curve progression and 15 (15.8%) had 6 degrees or more progression. Seven patients (7.8%) were recommended to undergo or underwent surgery before skeletal maturity. Eleven patients (12.6%) progressed beyond 45 degrees. According to these 3 criteria, the Charleston night-time brace was successful in 74 patients (77.9%). Depending on curve type, we observed success rates of 78.3% (47/60) for double, 71.4% (15/21) for thoracic, 83.3% (5/6) for thoracolumbar, and 87.5% (7/8) for lumbar curves. Success rates of 80.0% (36/45) and 76.0% (38/50) were observed in patients with curve magnitudes at bracing of 25 to 30 degrees and 31 to 40 degrees, respectively. Patients with high apex curves had a 67.6% (23/34) success rate, and those with low apex curves had 83.0% (39/47) success rate. Brace success rates among patients with initial Risser signs of 0, 1, and 2 were 68.8% (22/32), 80.6% (25/31), and 84.4% (27/32), respectively. Compared with the results of previous natural history and conventional brace study, the Charleston night-time bending brace is effective for the treatment of adolescent idiopathic scoliosis. Level VI. The purpose of this study was to assess the effectiveness of a scoliosis-specific rehabilitation programme as it is carried out in the Katharina Schroth Spinal Deformities Rehabilitation Center. Physiotherapy in the treatment of scoliosis patients is still regarded as ineffective since the study by the American Orthopedic Association in 1941, which showed that general exercises could not influence the natural history of scoliosis. However, specific exercise programmes were not known in the USA at that time. This preliminary study started in 1989 with the following inclusion criteria: (1) diagnosis of idiopathic scoliosis; (2) risser sign &lt; 4; (3) no treatment other than physiotherapy; (4) first control after 1-3 years during repeated in patient treatment; (5) standing AP radiograph taken not more than 6 months before the first in patient treatment. A total of 181 scoliosis patients, with an average age of 12.7 years and an average angle of curvature of 27% according to Cobb, were included in this study. The average risser sign was 1.4, the average follow-up 33 months. The Cobb angle of the major curve was measured in a standardized way. The results of our preliminary study were compared to natural history as known from literature. For the worst-case analysis additionally a questionnaire was sent to the non-repeaters treated at our centre at the same time (1989 and 1990) as the patient sample described above, taking into account the same inclusion criteria for this patient sample except point 4. Results showed that progression as usually defined (increase in curvature of 5 degrees or more per year) has not been found in the preliminary study. The patient sample of this study was divided into different age groups and different groups of curve magnitude, for comparison with other studies. Additional to the patient sample of the preliminary study, 116 of the patients from the years 1989 and 1990 fulfilled the inclusion criteria of the preliminary study with the exception of point 4. These patients formed the questionnaire sample for the worst-case analysis showing that the progression rate of the 181 patients from the preliminary study and the 116 patients of the questionnaire sample together was still better than natural history even if all drop-outs were considered to be failures. The fact that there was no relative progression in our patients sample treated solely by physiotherapy (preliminary study), seems to show the effectiveness of the inpatient rehabilitation programme even in cases with a bad prognosis, severe angles of curvature and unfavourable curvature patterns. A worst-case analysis does not prevent this conclusion, even if all dropouts from the non-repeaters group were considered as failures. Physiotherapy for stabilization of idiopathic scoliosis angle in growing children remains controversial. Notably, little data on effectiveness of physiotherapy in children with Early Onset Idiopathic Scoliosis (EOIS) has been published.The aim of this study was to check results of FITS physiotherapy in a group of children with EOIS.The charts of the patients archived in a prospectively collected database were retrospectively reviewed. The inclusion criteria were:diagnosis of EOIS based on spine radiography, age below 10 years, both girls and boys, Cobb angle between 118 and 308, Risser zero, FITS therapy, no other treatment (bracing), and a follow-up at least 2 years from the initiation of the treatment. The criterion for curve progression were as follows: the Cobb angle increase of 68 or more, for curve stabilization; the Cobb angle was 58 comparing to the initial radiograph,for curve correction; and the Cobb angle decrease of 68 or more at the final follow-up radiograph.There were 41 children with EOIS, 36 girls and 5 boys, mean age 7.71.3 years (range 4 to 9 years) who started FITS therapy. The curve pattern was single thoracic (5 children), single thoracolumbar (22 children) or double thoracic/thoracolumbar (14 children), totally 55 structural curvatures. The minimum follow-up was 2 years after initiation of the FITS treatment, maximum was 16 years, mean 4.8 years). At follow-up the mean age was 12.53.4 years. Out of 41 children, 10 passed pubertal growth spurt at the final follow-up and 31 were still immature and continued FITS therapy. Out of 41 children, 27 improved, 13 were stable, and one progressed. Out of 55 structural curves, 32 improved, 22 were stable and one progressed. For the 55 structural curves, the Cobb angle significantly decreased from 18.085.48 at first assessment to 12.586.38 at last evaluation,p&lt;0.0001, paired t-test. The angle of trunk rotation decreased significantly from 4.782.98 to 3.282.58 at last evaluation, p&lt;0.0001,paired t-test.FITS physiotherapy was effective in preventing curve progression in children with EOIS. Final postpubertal follow-up data is needed. As part of our study, the effectiveness and patient's acceptance of the Wilmington-brace is to be evaluated. The effectiveness can be documented with the help of the primary correction achieved, especially in light of the fact, that the primary correction and the long-term results are directly dependant upon one another. We examined a total of 52 patients with an idiopathic scoliosis treated in a thermoplast brace. The group consisted of 38 female and 14 male patients (average age 11.6 years). The angulation was measured with the help of the Cobb-angle and the rotation with the method described by Nash and Moe. The skeletal age was classified according to Risser's-sign. The angle determinations were carried out at three separate points in time--at first presentation, prior to bracing and four to six weeks following bracing. The patients presented with an average angulation of 31 degrees. The average correction achieved in the Wilmington-brace was 41%. This corresponds to a correction of 13 degrees. The best primary correction (45%) was obtained in the thoracolumbar spine. Those patients with the smallest deformity at the onset of treatment showed the best results. The scoliosis with a large primary deformity and a marked rotation of the vertebral bodies responded poorly to correction. Advanced age or skeletal maturity were also limiting factors. Physical therapy had a positive influence on the amount of primary correction obtained. The Wilmington-brace (thermoplast) allows for a good primary correction of idiopathic scoliosis. The simplicity of application and the low production costs are also positive attributes. The SRS criteria give the methodological reference framework for the presentation of bracing results, while the SOSORT criteria give the clinical reference framework for an appropriate bracing treatment. The two have not been combined in a study until now. Our aim was to verify the efficacy of a complete, conservative treatment of Adolescent Idiopathic Scoliosis (AIS)according to the best methodological and management criteria defined in the literature. Study Design. Retrospective study. Population. We included all AIS patients respecting the SRS inclusion criteria (age 10 years or older; Risser test 0-2; Cobb degrees 25-40 degrees ; no prior treatment; less than one year post-menarchal) who had reached the end of treatment since our institute database start in 2003. Thus we had 44 females and four males, with an age of 12.8 +/- 1.6 at the commencement of the study. Methods. According to individual needs, two patients have been treated with Risser casts followed by Lyon brace, 40 with Lyon or SPoRT braces (14 for 23 hours per day, 23 for 21 h/d, and seven for 18 h/d at start), and two with exercises only (1 male, 1 female): these were excluded from further analysis. Outcome criteria. SRS (unchanged; worsened 6 degrees or more; over 45 degrees at the end of treatment; surgically treated; two years' follow-up); clinical (ATR, Aesthetic Index, plumbline distances); radiographic (Cobb degrees); and ISICO (optimal; minimal). Statistics. Paired ANOVA and t-test, Tukey-Kramer and chi-square test. Median reported compliance during the 4.2 +/- 1.4 treatment years was 90% (range 5-106%). No patient progressed beyond 45 degrees , nor was any patient fused, and this remained true at the two-year follow-up for the 85% that reached it. Only two patients (4%) worsened, both with single thoracic curve, 25-30 degrees Cobb and Risser 0 at the start. We found statistically significant reductions of the scoliosis curvatures (-7.1 degrees ): thoracic (-7.3 degrees ), thoracolumbar (-8.4 degrees ) and lumbar (-7.8 degrees ), but not double major. Statistically significant improvements have also been found for aesthetics and ATR. Respecting also SOSORT management criteria and thus increasing compliance, the results of conservative treatment were much better than what had previously been reported in the literature using SRS criteria only. The main distinctive aspect of Juvenile Idiopathic Scoliosis (JIS) with respect to Adolescent Idiopathic Scoliosis (AIS) is the high risk of severe deformity and surgery. Approximately 70% of curves in patients with JIS progress and ultimately require surgery. There are presently very few studies with long-term follow-up of JIS and even fewer looking specifically at bracing Purpose To verify the effectiveness of a complete conservative treatment, including bracing and exercises, for JIS. Retrospective cohort observational study nested in a clinical prospective database of consecutive outpatients. Patient Sample Inclusion criteria: JIS, no previous treatment, all consecutive radiographies available from treatment start to end of growth (Risser sign 3). We found 30 patients, 27 females, 10 JIS type 1; mean age at first diagnosis was 7.8 +/-1.5 and mean treatment lasted 5.8 years. Cobb degrees 24.4+/-10 degrees, with 7 cases &gt;30 degrees, and 2 &gt; 45degrees. Outcome Measures Physiological measures. Radiographic and clinical data. Treatment (exercises alone, or elastic-rigid-highly rigid braces plus exercises) was tailored and continuously changed according to Cobb degrees, individual preferences, anthropometric characteristics, pubertal spurt, remaining growth, rotation, hump, lumbar curve take-off, and imbalance. The SOSORT Guidelines for patients' management have been followed. Funding and Conflict of Interest: no. 33.3% (95% Confidence Interval 16.4-50.2%) of patients worsened over the years. At the end of growth, 6.6% (0-15.5%) had surgical deformities (&gt;45degrees). We observed a good correction in the first years of treatment until pubertal growth spurt, when progression was usually noted and treatment changed increasing corrective forces (hours or rigidity of bracing). 23 cases were followed up until they had two consecutive radiographies showing Risser sign 5 and showed stability. Conservative treatment initiated already in childhood may favorably change the natural history of JIS with the aim of reaching a curve as far as possible from surgical thresholds. Observation, physical exercises, braces can be useful tools in the hand of physicians, but they must be carefully utilized by a deep knowledge of JIS. SpineCor is a relatively new bracing system that uses dynamic bracing concepts in the treatment of adolescent idiopathic scoliosis (AIS). Limited data are available regarding its effectiveness. This study compared treatment outcomes of 2 groups of AIS patients treated via either a conventional rigid thoracolumbosacral orthoses (TLSO) or a SpineCor nonrigid orthosis. We identified 2 scoliosis patient cohorts: 35 patients treated with a TLSO and 32 patients treated with a SpineCor orthosis. All patients included in these groups conformed with the Scoliosis Research Society (SRS) standardized criteria for AIS bracing: (1) Risser &lt; or =2, (2) curve magnitude 25 to 40 degrees, (3) age &gt; or =10 years. Outcomes were SRS standardized with failure being defined as curve progression &gt; or =6 degrees, or ever exceeding 45 degrees, or having surgery recommended before skeletal maturity. All patients were followed through the completion of brace treatment or attainment of other treatment end points. The Yates corrected chi test and unpaired t test were used for data analysis. The 35 patients (32 girls, 3 boys) in the TLSO group had an average age of 13 years (range: 11.1-16.8) and an average primary curve magnitude of 33 degrees (range: 25-40 degrees). Follow-up averaged 2 years (range: 8-61 m) from the beginning of brace treatment. The 32 patients (28 girls, 4 boys) in the SpineCor group had an average age of 13 years (range: 11-15.2) and an average primary curve magnitude of 31 degrees (range: 25-40 degrees). Follow-up for this group averaged 2 years and 6 months (range: 13-73 mo) from the beginning of brace treatment. No significant difference (P=0.75) was found using the more strict outcome measure (&lt; or =5-degree curve progression) as the success rates were 60% (21/35) for TLSO and 53% (17/32) for SpineCor. Similarly, no significant difference (P=0.62) was found using the more liberal outcome measure (never reached 45 degrees) as the success rates were 80% (28/35) for TLSO and 72% (23/32) for SpineCor. We were unable to identify any significant differences in brace treatment outcomes when comparing TLSO and SpineCor treated patients. Surgery is indicated by the Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT) at 45 degrees to 50 degrees and by the Scoliosis Research Society (SRS) at a Cobb angle of 45 degrees. SOSORT uses the 45-degree to 50-degree threshold as a result of the well-documented, plus or minus five degrees measurement error that can occur while measuring Cobb angles. Scoliosis braces are usually comfortable for the patient, especially when it is well designed and fit; also after the 7- to 10-day break-in period. A well fit and functioning scoliosis brace provides comfort when it is supporting the deformity and redirecting the body into a more corrected and normal physiological position. The Scoliosis Research Society's recommendations for bracing include curves progressing to larger than 25°, curves presenting between 30 and 45°, Risser sign 0, 1, or 2 (an X-ray measurement of a pelvic growth area), and less than six months from the onset of menses in girls. The results of the brace treatment (Milwaukee brace, Thoraco-Lumbo-Sacral-Orthosis, Boston-Milwaukee brace) were studied in 509 patients with idiopathic scoliosis, who were braces for an average of 3 years and 3 months ranging from 2 to 10 years. Of these patients, 60 were followed up for about 24 months after the brace was discontinued. The distribution of these patients according to curve pattern was as follows: 319 had thoracic curve; 78 had lumbar curve (combining lumbar and thoracolumbar curves together as one group); and 112 had double major curve. The findings are summarized and conclusions were drawn as follows. 1. The best correction was obtained within a year after the initiation of bracing, followed by a gradual loss of correction. 2. There was a significant difference between the final correction rate and the best correction rate in the brace. 3. In the patients with ages ranging from 11 to 14 years and with curves of 30 degrees or less at the beginning of brace treatment, the curves were maintained within 30 degrees at the final stage. 4. Those patients who cooperated well in wearing their braces had a smaller loss of correction at the final stage. 5. In 63 per cent of the cases who showed progression in the brace, iliac apophysis did not appear at the beginning of brace treatment. 6. Moiré topography was used for the analysis of cosmesis and it was shown to be a valuable method of three dimensional evaluation. 7. In 60 patients who were followed up for 24 months on average after the brace was discontinued, the curves had improved an average of 1.6 degrees at the time of their last check up. Recently it has been shown that idiopathic scoliosis (IS) curves can be reduced with bracing, and it has been proposed that this could be useful in non-surgically treated high degree curves even after Risser 3. Moreover, bracing has been shown to be able to improve aesthetics, and this could be another reason to treat some patients with cosmetic needs. Our aim is to preliminary check if results can be obtained in IS patients after Risser 3. Design. Retrospective uncontrolled cohort study. Inclusion criteria. All IS patients treated on a voluntary basis for aesthetic reasons and/or for curve reduction; Risser 4-5 at start; end of treatment reached. Population. 34 females and 2 males, age 16.2±1.6 years, Cobb angle 27.6°±8.9°. Treatment. Lyon or SPoRT braces 18 to 24 hours/day, specific SEAS exercises, rapid weaning (2-3 hours every 6 months). Outcome criteria: SRS (unchanged; worsened over 6°; over 45° at the end of treatment; surgically treated), radiographic and clinical. Statistics. ANOVA and chi-test. The reported compliance during the 2.8 ± 1.1 treatment years was 95.1%, while residual growth was 0.9 ± 1.1 cm. Improvements were found in 39% of this cohort, (46% in curves over 30°). Only 1 patient progressed 6°. We found highly statistically significant reductions of maximal (-4.4°), thoracic (-6.0°) and thoracolumbar (-6.6°) curves. Statistically significant improvements were found for Aesthetic Index. Before 20 years of age, even in skeletally mature patients, it is possible to reach radiographic and aesthetic improvements, although not as good as during growth. Correction is based on bone growth, but ligaments and neuromuscular control of posture can also be involved. The effectiveness of conservative treatment of scoliosis is controversial. Some studies suggest that brace is effective in stopping curve progression, whilst others did not report such an effect.The purpose of the present study was to effectiveness of Progressive Action Short Brace (PASB) in the correction of thoraco-lumbar curves, in agreement with the Scoliosis Research Society (SRS) Committee on Bracing and Nonoperative Management Standardisation Criteria. Fifty adolescent females (mean age 11.8 +/- 0.5 years) with thoraco-lumbar curve and a pre-treatment Risser score ranging from 0 to 2 have been enrolled. The minimum duration of follow-up was 24 months (mean: 55.4 +/- 44.5 months). Antero-posterior radiographs were used to estimate the curve magnitude (CM) and the torsion of the apical vertebra (TA) at 5 time points: beginning of treatment (t1), one year after the beginning of treatment (t2), intermediate time between t1 and t4 (t3), end of weaning (t4), 2-year minimum follow-up from t4 (t5). Three situations were distinguished: curve correction, curve stabilisation and curve progression.The Kruskal Wallis and Spearman Rank Correlation tests have been used as statistical tests. CM mean value was 29,30 +/- 5,16 SD at t1 and 14,67 +/- 7,65 SD at t5. TA was 12.70 +/- 6,14 SD at t1 and 8,95 +/- 5,82 at t5. The variation between measures of Cobb and Perdriolle degrees at t1,2,3,4,5 and between CM t5-t1 and TA t5-t1 were significantly different.Curve correction was accomplished in 94% of patients, whereas a curve stabilisation was obtained in 6% of patients. The PASB, due to its peculiar biomechanical action on vertebral modelling, is highly effective in correcting thoraco-lumbar curves. Early diagnosis of idiopathic scoliosis allows for observation and timely initiation of brace treatment in order to halt progression. School scoliosis screening programs were abolished in Norway in 1994 for lack of evidence that the programs improved outcome and for the costs involved. The consequences of this decision are discussed. To describe the detection, patient characteristics, referral patterns and treatment of idiopathic scoliosis at a scoliosis clinic during the period 2003-2011, when there was no screening and to compare treatment modalities to the period 1976-1988 when screening was performed. Patient demographics, age at detection, family history, clinical and radiological charts of consecutive patients referred for scoliosis evaluation during the period 2003-2011, were prospectively registered. Patients were recruited from a catchment area of about 500000 teenagers. Maturity was estimated according to Risser sign and menarcheal status. Severity of pain was recorded by a verbal 5-point scale from no pain to pain at all times. Physical and neurological examinations were conducted. The detector and patient characteristics were recorded. Referral patterns of orthopedic surgeons at local hospitals and other health care providers were recorded. Patient data was obtained by spine surgeons. Treatment modalities in the current period were compared to the period 1976-1988. We registered 752 patients with late onset juvenile and adolescent idiopathic scoliosis from 2003-2011. There were 644 (86%) girls and 108 (14%) boys. Mean age at detection was 14.6 (7-19) years. Sixty percent had Risser sign ≥ 3, whilst 74% were post menarche with a mean age at menarche of 13.2 years. Thirty-one percent had a family history of scoliosis. The mean major curve at first consultation at our clinic was 38° (10°-95°). About 40% had a major curve &gt;40°. Seventy-one percent were detected by patients, close relatives, and friends. Orthopaedic surgeons referred 61% of the patients. The mean duration from detection to the first consultation was 20(0-27) months. The proportion of the average number of patients braced each year was 68% during the period with screening compared to 38% in the period without screening, while the proportion for those operated was 32% and 62%, respectively ( p=0.002, OR 3.5, (95%CI 1.6 to 7.5). In the absence of scoliosis screening, lay persons most often detect scoliosis. Many patients presented with a mean Cobb angle approaching the upper limit for brace treatment indications. The frequency of brace treatment has been reduced and surgery is increased during the recent period without screening compared with the period in the past when screening was still conducted.\nHere is the question:\nTRAUMATOLOGY: A 13-year-old female, with no relevant history, with menarche 3 months ago, followed since the age of 10 years by idiopathic scoliosis that has worsened. In the physical examination she presents a hump of 7 degrees in the Adams test and in the scoliogram a thoracolumbar curve T4-L1 of 35 degrees of Cobb and a Risser 0. The correct attitude to take will be:\nHere are the potential choices:\n1. Recommend swimming and revision in three months.\n2. Prescribe a corset-type orthosis.\n3. Refer to physiotherapy for spine elastification.\n4. Review in 6 months with a new X-ray.\nThe correct answer is: 2. Prescribe a corset-type orthosis."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder that accounts for approximately 30 % of adult leukemias and 25 % of Non-Hodgkin lymphomas (NHL). It is the most common form of leukemia in the western world (incidence 3-5/100 000). Elderly people are mainly affected, median age at diagnosis is around 70 years and there is a slight predominance in men. The etiology of the disease is unknown. The initial symptoms are nonspecific. Cervical lymphadenopathy and splenomegaly followed by general fatigue are seen most commonly. Other possible symptoms include night sweats, fever, loss of weight (so-called B symptoms) and frequent infections. Several patients develop autoimmune complications as autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP). To confirm the diagnosis more than 5000 B-lymphocytes/µl need to be present. The expression of the typical surface markers CD5, CD19, and CD23 has to be confirmed by flow cytometry. Imaging studies as X-ray of the chest, ultrasound of the abdomen, or CT scan are used to assess the degree of lymphadenopathy or organomegaly. A bone marrow biopsy is not mandatory for the diagnosis. According to the European Binet staging system, CLL is divided into 3 stages (A, B and C). Patients in Binet stage A have 0 to 2 areas of node or organ enlargement with normal levels of hemoglobin and platelets. Binet stage B patients have 3 to 5 areas of node or organ enlargement and normal or slightly decreased levels of hemoglobin and platelets. Binet stage C patients have anemia (hemoglobin &lt; 10 g/dl) and/or thrombocytopenia (platelet counts &lt; 100 000/µl), with or without lymphadenopathy or organomegaly. As there is no survival benefit associated with early intervention, asymptomatic patients with early stage CLL (Binet stage A and B) are usually not treated but are followed on a \"watch and wait\" principle. Treatment indications include stage Binet C or signs of an active disease as rapidly progressive lymphadenopathy or organomegaly together with physical limitation, B symptoms that cannot be tolerated, rapidly deteriorating blood values, or rapidly increasing leukocyte counts. The patient's physical condition has major impact on the treatment decision. Currently immunochemotherapy with fludarabine, cyclophosphamide and the CD20-antibody rituximab (FCR) is the standard of care in previously untreated and physically fit CLL-patients. An alternative regimen is the combination of bendamustine and rituximab (BR). Physically compromised patients can be treated with the oral drug chlorambucil or with bendamustine with or without rituximab. Due to high morbidity and mortality, allogeneic stem cell transplantation is limited to a small group of patients and should be discussed in a high-risk situation, such as 17p deletion, lack of response to standard therapy or early relapse. Chronic Lymphocytic Leukemia (CLL) is the most frequent lymphoproliferative disease and leukaemia in western countries. CLL occurs more frequently in men than women, the median age at diagnosis is 65 years. CLL is defined as a persisting chronic lymphocytosis &gt; 5 G/l with classical morphological features (small lymphocytic cells with round nuclei, dense chromatin and small cytoplasmic rim) and a classical immunophenotype (CD5+, CD19+, CD20+, CD23+); however, deviations from classical morphology are frequent. In cases with classical diagnostic features in the peripheral blood, a bone marrow biopsy is not necessary for diagnosis. Prognostic features comprise the stage of the disease according to the Rai or Binet systems, laboratory markers such as LDH, beta-2-microglobulin, lymphocyte doubling time and CD38 expression by flow cytometry (and ZAP-70 expression if available) as well as the status on IgV(H) hypermutations and cytogenetic analysis. Up to 2/3 of patients do not need treatment at the time of diagnosis and can initially be followed using a watch and wait strategy. If therapy becomes necessary, initial standard treatment still is chlorambucil. Later, purine analogues and Alemtuzumab are treatment options for refractory or relapsing disease. Therapies with antibodies such as Alemtuzumab and Rituximab in combination with purine analogues are currently under clinical investigation. With recurrent or atypical infections, hypogammaglobulinemia should be searched for and immunoglobulins should be substituted if necessary. However, their prophylactic use is not recommended. Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. Median age at diagnosis is around 70 years. To confirm the diagnosis more than 5000 B-lymphocytes/µl need to be present. The expression of the typical surface markers CD5, CD19, CD20 and CD23 has to be confirmed by flow cytometry. A bone marrow biopsy is not mandatory for the diagnosis. Before start of treatment the assessment of 17 p deletion and/or TP53-mutational status is recommended. Treatment indications include stage Binet C or signs of an active disease as rapidly progressive lymphadenopathy or organomegaly together with physical limitation, B symptoms that cannot be tolerated, rapidly deteriorating blood values, or rapidly increasing leukocyte counts (Lymphocyte doubling time less than 6 months). The patient's physical condition has major impact on the treatment decision. Currently immunochemotherapy with fludarabine, cyclophosphamide and the CD20-antibody rituximab (FCR) is the standard of care in previously untreated and physically fit patients. An alternative regimen is the combination of bendamustine and rituximab (BR) or ofatumumab. Physically compromised patients can be treated with the oral drug chlorambucil in combination with an anti-CD20 antibody. Due to high morbidity and mortality, allogeneic stem cell transplantation is limited to a small group of patients and should be discussed in a high-risk situation, such as 17 p deletion and/or TP53-mutation, lack of response to standard therapy or early relapse. Recently several new chemo-free treatment options have been introduced within clinical trials. Among them are monoclonal antibodies, most of them targeting the CD20 molecule: besides the licensed drugs rituximab and ofatumumab, obinutuzumab, in combination with chemotherapy, has recently shown high clinical efficacy in front-line treatment of elderly patients with CLL. Novel agents have been designed to block aberrant signaling from the B-cell receptor. Ibrutinib acts by inhibiting the Bruton's tyrosine kinase (BTK) while idelalisib represents a first-in-class specific inhibitor of the phosphoinositol-3 kinase (PI3K) delta isoform. Another class of drugs with potential impact for chemo-free treatment strategies in CLL is the BH3-mimetic inhibitor of the Bcl-2 family of pro-survival proteins, ABT-199. Given all these novel agents and targets, chemo-free or at least chemo-reduced concepts may become reality in the near future for our patients suffering from CLL.  CD43 (other names: sialophorin, leukosialin, sialoglycoprotein of white blood cells) is an integral cell membrane mucin. In population of peripheral B cells CD43 occurs only on activated B cells and CD5 positive B cells. These last cells create neoplasm population in patients with B-cell chronic lymphocytic leukemia (B-CLL). Anti-CD43 monoclonal antibodies are used routinely in investigations of tissue fragments in cases of non-Hodgkin's lymphoma, whereas we did not find publication on theme of CD43 expression on peripheral blood B cells in patients with B-cell chronic lymphocytic leukemia. Wherefore advisable appeared estimation CD43 expression on B-CLL cells and comparison it with expression of typical B-CLL markers--such as CD5 and CD6. Immunological phenotype of peripheral blood and bone marrow lymphocytes has been evaluated using flow cytometry (Cytoron Absolute Ortho-Diagnostic Systems) and two-color staining. Twenty six untreated patients with B-CLL were studied. Because on well-known correlations between CD43 expression and metastasis potential of tumor, patients were divided on two groups differing score of total tumor mass (score TTM). Score TTM was evaluated according to criterion of Jaksic and Vitale. Twelve patients whose TTM score was equal or lower than 9 and median lymphocytosis was 24.6 x 10(9) in microliter were included in group I. 14 patients whose TTM score was higher than 9 were included in group II. Median lymphocytosis in these patients was 152.6 x 10(9) in microliter. The median percentage of CD43+/CD19+ cells in peripheral blood was 62.6% in the group I, and 75% in the group II (p &lt; 0.05). Median fluorescence intensity (MFI) of CD43 antigen was 87.7 in the I group comparing to 77.4 in the group II. So one observed tendency to lowering MFI during tumor growing but the difference was not significant (p = 0.25). In peripheral blood during progression of disease more clearly than CD43+ cells increased percentage of CD5+ and CD6+ cells. The median percentage of CD19+/CD5+ cells was 62.7% in the group I, 82.4% in the group II and the difference was significant (p &lt; 0.002). The difference in the median percentages CD6+/CD19+ cell 71.8% in group I and 84.3% in the II one were also significant (p &lt; 0.03). MFI of CD5 and also CD6 antigens did not change in course of disease. Moreover, examination of CD43 and CD5 expression in marrow additionally to blood study were performed in 12 cases (6 from group I, 2 from group II and 4 new not included). The median percentage of CD43+/CD19+ cell was 35.1% in blood and 43.7% In marrow, in contrast to these results was the median percentage of CD19+/CD5+ cell, which was higher in peripheral blood (70.4%) than in bone marrow (60.9%). The results of this study indicate that CD43 is present on peripheral blood B-CLL cells. Moreover, percentage of these cell increases during progression of disease however more weakly than percentage of CD5 and CD6 positive cells. Expression of CD43 is independent from expression CD5 and CD6 and diminishes during tumor mass increasing, what can depended from releases exocellular domains of CD43. CD43+ cell from B-CLL patients have a tendency to accumulation in tissues what is illustrated by higher percentage of CD43+ cell in bone marrow than in peripheral blood. The genetic characterization of chronic lymphocytic leukemia (CLL) has made significant progress over the past few years. Chromosomal abnormalities are detected in up to 80% of patients. Determination of new chromosomal disorders is important in the pathogenesis and treatment facilities. A patient was diagnosed with CLL Stage 2 on 2012 and followed since then by hematology clinic. She was 63 years old. Mature, small lymphocytes, and smudge cell was found in the patient's peripheral blood smear. Bone marrow (BM) biopsy made and hypercellularity showing infiltration of atypical cells with CD5+, CD20+, and CD23+ were determined. Hypoplasia is detected in myeloid/erythroid series, and Stage 2 reticular fibers proliferation were detected. The patient was followed up without medication. While follow-up of patient's white blood cell: 57300, hemoglobin: 5.36, and PLT: 99700 are determined in May 2014. According to the patient's flow results, CD5+, CD23+, and FMC7+ were detected. Mature, small lymphocytes and smudge cell was found in the patient's peripheral blood smear. In ultrasonography imaging, multiple laps were found in the abdomen and multiple neck lymph nodes were detected. The patient BM aspiration was performed in 2014, and hypercellularity was found to contain 54% of atypical lymphocytes in the BM. Fluorescence in situ hybridization (FISH) analysis made two times in 2014. At first, FISH analysis patient's rate of 18% in RB1/13q14.2/13qter revealed a deletion of the gene regions. Patient's FISH result was reported as normal (for RB1/13q14.2/13qter) after 5 months at second analysis. Cytogenetic analysis is made from the patient's BM at the same time. According to the results of karyotyping and FISH, 47, XX, isochromosome 4q (+i4q) is determined. According to literature, extra isochromosome 4q is reported by our case for the first time in CLL. She was diagnosed with Stage 4 CLL and FISH treatment was initiated. Our patient showed disease progression compared to previous results. Hence, we offer that this evidence can be considered regarding triggering the disease's progression or as a result of disease progression i4q was occurred. Diagnosis and staging Diagnostic and staging investigations depend on the size and type of malignancy. Blood cancer Blood investigations including hemoglobin, total leukocyte count, platelet count, peripheral smear, red cell indices. Bone marrow studies including aspiration, flow cytometry, cytogenetics, fluorescent in situ hybridisation and molecular studies. Lymphoma Excision biopsy of lymph node for histopathological examination, immunohistochemistry, and molecular studies. Blood investigations include lactate dehydrogenase (LDH), serum uric acid, and kidney function tests. Imaging tests such as computerised tomography (CT scan), positron emission tomography (PET CT). Bone marrow biopsy. Solid tumors Biopsy for histopathology and immunohistochemistry. Imaging tests like X-ray, ultrasonography, computerised tomography (CT), magnetic resonance imaging (MRI) and PET CT. We report 26 elderly patients (median age 68.3 years) who met diagnostic criteria for B-cell chronic lymphocytic leukaemia (B-CLL) but whose lymphocytes lacked CD5 expression. Haematological and clinical features of this CD5- series were compared with those of 333 CD5+ B-CLL patients from the same institute. No significant differences were observed regarding peripheral blood (PB) and bone marrow (BM) lymphocytosis, Hb level, platelet count, incidence of adenomegaly, hepatomegaly or splenomegaly or diffuse BM pattern. Due to an absence of nodal enlargements or to general clinical condition, lymph node biopsy was performed in only three patients, while spleen histology was examined in two cases following splenectomy. All histological results confirmed the clinical diagnosis of CLL. The distribution of the CD5- subjects according to the different staging categories proposed by Rai, Binet and Mandelli was similar to that of CD5+ subjects. Ten patients received standard chemotherapy with Chlorambucil (CHL) and Prednisone (PDN). All achieved partial remission, although one of these patients later died of disease progression; 80 months after diagnosis. We conclude that rare cases of CD5- lymphocytosis fulfilling all criteria for B-CLL may occur. Haematological and clinical features at presentation and the response to conventional treatment with Chlorambucil support our hypothesis of considering this disease as a less frequent subgroup of B-CLL. A 61-year-old man with no subjective symptom was admitted to our hospital for further examination of the causes of anemia (hemoglobin, 9.5 g/dL) and thrombocytopenia (platelets, 9.2 x 10(4)/microL), which had been pointed out in a medical checkup half a year previously. A bone marrow examination showed 73% lymphoid cells. Immunophenotyping of these cells were CD19+CD20+CD3-CD5-CD10-CD23-, and light chain restriction (kappa) was positive by fluorescence-activated cell sorting analysis. A computed tomography scan showed mild splenomegaly. To confirm the diagnosis histologically, we performed a splenectomy. Finally, we diagnosed the patient's disease as nonvillous splenic marginal zone lymphoma (SMZL). A month after the splenectomy, the white blood cell count was remarkably increased to 7 x 10(4)/microL with the blastic transformation of lymphoid cells. We first treated the patient with fludarabine and then with the CHOP regimen (cyclophosphamide, hydroxydaunomycin, vincristine [Oncovin], and prednisone), but the disease was so refractory that the patient died of the disease 13 months after the splenectomy. Immunohistochemical staining and a molecular examination for p53 were carried out with specimens from the splenectomy. We found overexpression of the p53 protein in lymphoid cells and a point missense mutation in codon 280 at exon 8 that changed AGA (Arg) to AGT (Ser). This case may indicate the existence of a more aggressive subset of SMZL, suggesting a reconsideration of the roles of splenectomy and p53 overexpression in the diagnostic and therapeutic approaches to patients with SMZL. We have investigated the value of both conventional and quantitative flow cytometry to detect minimal residual disease in 21 CLL patients in remission including bone marrow histology: eight in complete remission (CR), 11 in nodular partial remission (nPR) and two in PR. The techniques used were double immunostaining with CD5 and CD19 and quantitative estimation of the number of both antigens with standard microbeads. Reference values were established on normal peripheral blood and bone marrow controls. Patients were considered in 'immunological' remission when the percentage of CD5+ CD19+/total CD19+ cells was &lt;25% in PB and &lt;15% in BM. In six of the eight patients in CR, CLL cells were still detectable by flow cytometry. Only two patients, that underwent allogeneic bone marrow transplant, achieved immunological remission. CLL samples showed significantly higher CD5 and lower CD19 antigen density than normal controls (P &lt; 0.001). Persistence of residual disease was a predictor of time to progression. None of the two patients in immunological remission relapsed within a period of 13 and 33 months, whilst two of the six patients in CR with positive flow cytometry relapsed 3 and 6 months after achieving CR. This study demonstrates that flow cytometry contributes to increase the sensitivity of the clinicohematological criteria to detect residual malignant cells in CLL patients and may be useful to monitor disease status following treatment. Monoclonal B-cell lymphocytosis (MBL) is defined as an asymptomatic condition characterized by the presence of less than 5,000 monoclonal B-cells per microliter and the absence of clinical signs or symptoms of a B-cell lymphoproliferative disorder. Most MBL cases involve B cells presenting an identical phenotype to CLL (CLL-like MBL) with a Catovsky-Matutes score of 3 to 5 and share the same chromosomal abnormalities than CLL. Depending on the absolute B cell count, one may distinguish low-count CLL-like MBL (&lt;500 B cells/μL) which have no evidence of progression, no reduction in overall survival, no increase in infection risk and do not require any specific follow-up. Patients with clinical CLL-like MBL (&gt;500 B cells/μL) have a 1% to 2% per year risk of progression to CLL requiring therapy, a higher risk of infectious complications and mortality implicating an annual follow-up by hematologist. MBL may also express other less common phenotypes and are named atypical MBL in case of CD5 antigen expression (Catovsky-Matutes score: 1-2) and non-CLL-like MBL for CD5 negative cases (Catovsky-Matutes score: 0-2). Their poorer prognosis implicates imaging studies, bone marrow biopsy and cytogenetic analysis in addition to physical examination in order to rule out non-hodgkinien lymphoma, and require a more frequent follow-up. This review focuses on key concepts in the classification, diagnosis, monitoring and biology of MBL in laboratory practice.  Chronic-lymphocytic-leukemia (CLL) is the most prevalent leukemia in developed countries, caused by monoclonal proliferation of CD5+ B-cells and accumulation of mature-appearing-neoplastic lymphocytes in blood, bone marrow, and secondary lymphoid organs. Oral manifestations of CLL are infrequent and rarely reported in literature. We report a new case of a 67-year old man who presented with the complaints of tooth mobility and gingival swelling. Extra-oral examination was remarkable for cutaneous pallor and bilateral cervical lymphadenopathy involving the submandibular, and deep cervical lymph nodes on both sides of the neck. Complete blood count revealed normal red blood cell count (4.25 × 106/μl), normal platelet count (136 × 103/μl) and increased white blood cell count (25.3 × 103/μl). Differential white blood cell count showed marked lymphocytosis (88%), and blood film revealed the presence of leukocytosis, with small mature-looking lymphocytes, and mild thrombocytopenia. A flow cytometry immune-phenotyping revealed that 55% of peripheral blood cells were monoclonal B-lymphocytes expressing CD19, CD20, CD23, CD200, CD22, CD5, CD38, CD11c, sIgD and Kappa light chain confirming the diagnosis of CLL. Oral healthcare professionals should consider systemic causes, such as CLL, in the differential diagnosis of generalized tooth mobility and gingival swelling, particularly in patients with associated symptoms such as lymphadenopathy, fever, weight loss, and general fatigue. Additional testing: Flow Cytometry: Peripheral blood flow cytometry is essential to determine the proliferation of monoclonal cells. It is a costly test and should not be ordered routinely on all patients with lymphocytosis. Certain features on peripheral blood smear or on review of CBC which prompt a physician to order flow cytometry include: The presence of lymphoblasts on the peripheral blood smear, suggesting ALL- This should also prompt a referral to a tertiary care center to obtain further workup. The presence of other abnormal lymphocyte morphology on PBS as detailed above ALC more than 30000 cells/microL Persistent unexplained lymphocytosis for more than one month Abnormalities in other cell lines including anemia and thrombocytopenia Presence of lymphadenopathy and/or hepatosplenomegaly in the right clinical context where reactive causes have been ruled out Flow cytometry patterns are beneficial in delineating clonality and differentiating clonal disorders as follows: CLL: lymphocytes are CD5+, CD23+, CD20 (dim), CD10-, cyclin D1-, weak sIg (surface immunoglobulin), FMC -, CD200 + MCL: lymphocytes are CD5+, CD23-, CD10-, CD20+, sIg +, cyclin D1 +, FMC +, CD200- FL: lymphocytes are CD5-, CD10+, CD20+, sIg+ and often BCL2+, BCL6+ MZL: lymphocytes are CD5-, CD10-, CD20+, sIg+, cyclin D1- HCL: lymphocytes are CD5-, CD10-, CD20+, sIg+, CD11c+, CD25+, CD103+ T-LGL: lymphocytes are CD3+, CD8+, CD16+, CD56+ Fluorescence in situ hybridization (FISH), karyotype, and mutation analysis: FISH, karyotype, and certain mutation analysis help diagnose and risk stratification of hematologic malignancies, especially CLL and lymphomas. The FISH can not only help to ascertain the clonal nature of lymphocytosis but also helps to confirm the diagnosis of certain lymphomas. Examples include: FL: characterized by t(14,18) MCL: characterized by t(11,14) HCL: characterized by the presence of BRAF mutation CLL: different karyotypic abnormalities including del 17p, del 11q, trisomy 12, and del 13q14. A 74 years old male patient, presented with history of generalized weakness, fatigue, loss of appetite and breathlessness on exertion for past one and a half months. On examination, he was found to have significant pallor and generalized lymphadenopathy (cervical, axillary and inguinal). The skeletal survey showed punched out lytic lesions in skull and pelvic bones. The peripheral smear examination showed lymphocytosis with absolute lymphocyte count of 25,000/μL. The bone marrow aspirates revealed a hypercellular marrow with 74 % lymphocytes &amp; 14 % plasma cells, suggestive of chronic lymphoplasmacytic disorder. The bone marrow biopsy had two morphologically distinct populations of lymphocytes &amp; plasma cells. The immunohistochemical markers on bone marrow biopsy showed hat plasma cells were positive for CD138 with kappa light chain restriction. Flow cytometry showed B cell population with CD19/CD5 co expression, CD5/CD23 coexpression, were positive for CD22, CD20 and negative for FMC-7 and lambda light chain. In addition, plasma cells were also identified as CD45 negative cells and showed CD38/CD138 co-expression with variable CD19 and CD56 positivity. Serum protein electrophoresis revealed M band, serum immunofixation electrophoresis corresponded to IgA -Kappa. The final diagnosis of chronic lymphocytic leukemia with concomittant presence of plasma cell myeloma was concluded. This case imparts an important message to look for presence of coexisting entities in a single specimen and highlights the benefits of testing both plasma cell and B-cell compartments when the clinical features are not entirely consistent Flow cytometry together with protein electrophoresis can help to clinch difficult and rare dual diagnosis. These cases are rare and pose therapeutic challenge.  To analyze the expression of various antigens on the leukemic blasts and to determine the hematological parameters, in Acute Lymphoblastic Leukemia (ALL) patients at presentation. Observational study. King Edward Medical University, Lahore and Hameed Latif Hospital, Lahore, from February 2013 to March 2014. A total of 50 newly diagnosed and untreated patients of ALL were selected from Mayo Hospital and Hameed Latif Hospital. These patients included both genders and all age groups. Hemoglobin, total leukocyte count and platelet count were determined on hematology analyser-Sysmex-Kx-2I. Blast cell percentage was estimated on Giemsa stained blood smears. Immunophenotyping was done on bone marrow samples by 5 colour flowcytometery on Beckman Coulter Navious Flowcytometer. An acute leukemia panel of 23 antibodies was used. The data was entered and analyzed in SPSS version 22. Of the 50 ALL patients, 36 (72%) were B-ALL and 14 (28%) T-ALL. There were 18 (36%) children and 32 (64%) adults. T-ALL included 22% of the childhood and 31% of the adult cases. Immunophenotypic analysis showed that CD19, CD79a and CD20 were B-lineage specific markers whereas cCD3, CD3 and CD5 were T-lineage specific. CD10 was the most sensitive marker for B-ALL and CD7 was the most sensitive marker of T-ALL. TdT was expressed in 92% B-ALL and 71% T-ALL cases, CD34 in 58% and 43% cases and CD45 in 83% and 100% respectively. High leukocyte count (&gt; 50 x 109/L) was present in 58% cases. Hemoglobin was &lt; 10 g/dl in 74% patients and platelet count was below 20 x 109/Lin 12% patients. Leukocyte count, hemoglobin, platelet count and blast cell % did not show a significant difference in the two ALL immunotypes. The frequency of T-ALL is higher in childhood as well as adult ALL in our population compared to the Western literature. Antigenic expression of the blast cells also shows some interesting differences. A large number of our patients present with high leukocyte count which is a known factor associated with poor prognosis.\nHere is the question:\nHEMATOLOGY: A 67-year-old patient who in the last 6 months, in two routine analyses, presents progressive lymphocytosis. In the last one, hemoglobin 15.4 g/dL; leukocytes 18.5 x103/μL with 82 % of mature lymphocytes that by flow cytometry express CD5/CD19/CD23 antigens and platelets 240 x103/μL. What do you think is the correct approach?\nHere are the potential choices:\n1. Study of TP53 mutations to establish prognosis.\n2. Bone aspirate/biopsy to confirm diagnosis.\n3. PET/CT to establish the therapeutic attitude.\n4. New clinical and analytical control in 6 months.\nThe correct answer is: ",
        "gold_answer": "4 New clinical and analytical control in 6 months.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder that accounts for approximately 30 % of adult leukemias and 25 % of Non-Hodgkin lymphomas (NHL). It is the most common form of leukemia in the western world (incidence 3-5/100 000). Elderly people are mainly affected, median age at diagnosis is around 70 years and there is a slight predominance in men. The etiology of the disease is unknown. The initial symptoms are nonspecific. Cervical lymphadenopathy and splenomegaly followed by general fatigue are seen most commonly. Other possible symptoms include night sweats, fever, loss of weight (so-called B symptoms) and frequent infections. Several patients develop autoimmune complications as autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP). To confirm the diagnosis more than 5000 B-lymphocytes/µl need to be present. The expression of the typical surface markers CD5, CD19, and CD23 has to be confirmed by flow cytometry. Imaging studies as X-ray of the chest, ultrasound of the abdomen, or CT scan are used to assess the degree of lymphadenopathy or organomegaly. A bone marrow biopsy is not mandatory for the diagnosis. According to the European Binet staging system, CLL is divided into 3 stages (A, B and C). Patients in Binet stage A have 0 to 2 areas of node or organ enlargement with normal levels of hemoglobin and platelets. Binet stage B patients have 3 to 5 areas of node or organ enlargement and normal or slightly decreased levels of hemoglobin and platelets. Binet stage C patients have anemia (hemoglobin &lt; 10 g/dl) and/or thrombocytopenia (platelet counts &lt; 100 000/µl), with or without lymphadenopathy or organomegaly. As there is no survival benefit associated with early intervention, asymptomatic patients with early stage CLL (Binet stage A and B) are usually not treated but are followed on a \"watch and wait\" principle. Treatment indications include stage Binet C or signs of an active disease as rapidly progressive lymphadenopathy or organomegaly together with physical limitation, B symptoms that cannot be tolerated, rapidly deteriorating blood values, or rapidly increasing leukocyte counts. The patient's physical condition has major impact on the treatment decision. Currently immunochemotherapy with fludarabine, cyclophosphamide and the CD20-antibody rituximab (FCR) is the standard of care in previously untreated and physically fit CLL-patients. An alternative regimen is the combination of bendamustine and rituximab (BR). Physically compromised patients can be treated with the oral drug chlorambucil or with bendamustine with or without rituximab. Due to high morbidity and mortality, allogeneic stem cell transplantation is limited to a small group of patients and should be discussed in a high-risk situation, such as 17p deletion, lack of response to standard therapy or early relapse. Chronic Lymphocytic Leukemia (CLL) is the most frequent lymphoproliferative disease and leukaemia in western countries. CLL occurs more frequently in men than women, the median age at diagnosis is 65 years. CLL is defined as a persisting chronic lymphocytosis &gt; 5 G/l with classical morphological features (small lymphocytic cells with round nuclei, dense chromatin and small cytoplasmic rim) and a classical immunophenotype (CD5+, CD19+, CD20+, CD23+); however, deviations from classical morphology are frequent. In cases with classical diagnostic features in the peripheral blood, a bone marrow biopsy is not necessary for diagnosis. Prognostic features comprise the stage of the disease according to the Rai or Binet systems, laboratory markers such as LDH, beta-2-microglobulin, lymphocyte doubling time and CD38 expression by flow cytometry (and ZAP-70 expression if available) as well as the status on IgV(H) hypermutations and cytogenetic analysis. Up to 2/3 of patients do not need treatment at the time of diagnosis and can initially be followed using a watch and wait strategy. If therapy becomes necessary, initial standard treatment still is chlorambucil. Later, purine analogues and Alemtuzumab are treatment options for refractory or relapsing disease. Therapies with antibodies such as Alemtuzumab and Rituximab in combination with purine analogues are currently under clinical investigation. With recurrent or atypical infections, hypogammaglobulinemia should be searched for and immunoglobulins should be substituted if necessary. However, their prophylactic use is not recommended. Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. Median age at diagnosis is around 70 years. To confirm the diagnosis more than 5000 B-lymphocytes/µl need to be present. The expression of the typical surface markers CD5, CD19, CD20 and CD23 has to be confirmed by flow cytometry. A bone marrow biopsy is not mandatory for the diagnosis. Before start of treatment the assessment of 17 p deletion and/or TP53-mutational status is recommended. Treatment indications include stage Binet C or signs of an active disease as rapidly progressive lymphadenopathy or organomegaly together with physical limitation, B symptoms that cannot be tolerated, rapidly deteriorating blood values, or rapidly increasing leukocyte counts (Lymphocyte doubling time less than 6 months). The patient's physical condition has major impact on the treatment decision. Currently immunochemotherapy with fludarabine, cyclophosphamide and the CD20-antibody rituximab (FCR) is the standard of care in previously untreated and physically fit patients. An alternative regimen is the combination of bendamustine and rituximab (BR) or ofatumumab. Physically compromised patients can be treated with the oral drug chlorambucil in combination with an anti-CD20 antibody. Due to high morbidity and mortality, allogeneic stem cell transplantation is limited to a small group of patients and should be discussed in a high-risk situation, such as 17 p deletion and/or TP53-mutation, lack of response to standard therapy or early relapse. Recently several new chemo-free treatment options have been introduced within clinical trials. Among them are monoclonal antibodies, most of them targeting the CD20 molecule: besides the licensed drugs rituximab and ofatumumab, obinutuzumab, in combination with chemotherapy, has recently shown high clinical efficacy in front-line treatment of elderly patients with CLL. Novel agents have been designed to block aberrant signaling from the B-cell receptor. Ibrutinib acts by inhibiting the Bruton's tyrosine kinase (BTK) while idelalisib represents a first-in-class specific inhibitor of the phosphoinositol-3 kinase (PI3K) delta isoform. Another class of drugs with potential impact for chemo-free treatment strategies in CLL is the BH3-mimetic inhibitor of the Bcl-2 family of pro-survival proteins, ABT-199. Given all these novel agents and targets, chemo-free or at least chemo-reduced concepts may become reality in the near future for our patients suffering from CLL.  CD43 (other names: sialophorin, leukosialin, sialoglycoprotein of white blood cells) is an integral cell membrane mucin. In population of peripheral B cells CD43 occurs only on activated B cells and CD5 positive B cells. These last cells create neoplasm population in patients with B-cell chronic lymphocytic leukemia (B-CLL). Anti-CD43 monoclonal antibodies are used routinely in investigations of tissue fragments in cases of non-Hodgkin's lymphoma, whereas we did not find publication on theme of CD43 expression on peripheral blood B cells in patients with B-cell chronic lymphocytic leukemia. Wherefore advisable appeared estimation CD43 expression on B-CLL cells and comparison it with expression of typical B-CLL markers--such as CD5 and CD6. Immunological phenotype of peripheral blood and bone marrow lymphocytes has been evaluated using flow cytometry (Cytoron Absolute Ortho-Diagnostic Systems) and two-color staining. Twenty six untreated patients with B-CLL were studied. Because on well-known correlations between CD43 expression and metastasis potential of tumor, patients were divided on two groups differing score of total tumor mass (score TTM). Score TTM was evaluated according to criterion of Jaksic and Vitale. Twelve patients whose TTM score was equal or lower than 9 and median lymphocytosis was 24.6 x 10(9) in microliter were included in group I. 14 patients whose TTM score was higher than 9 were included in group II. Median lymphocytosis in these patients was 152.6 x 10(9) in microliter. The median percentage of CD43+/CD19+ cells in peripheral blood was 62.6% in the group I, and 75% in the group II (p &lt; 0.05). Median fluorescence intensity (MFI) of CD43 antigen was 87.7 in the I group comparing to 77.4 in the group II. So one observed tendency to lowering MFI during tumor growing but the difference was not significant (p = 0.25). In peripheral blood during progression of disease more clearly than CD43+ cells increased percentage of CD5+ and CD6+ cells. The median percentage of CD19+/CD5+ cells was 62.7% in the group I, 82.4% in the group II and the difference was significant (p &lt; 0.002). The difference in the median percentages CD6+/CD19+ cell 71.8% in group I and 84.3% in the II one were also significant (p &lt; 0.03). MFI of CD5 and also CD6 antigens did not change in course of disease. Moreover, examination of CD43 and CD5 expression in marrow additionally to blood study were performed in 12 cases (6 from group I, 2 from group II and 4 new not included). The median percentage of CD43+/CD19+ cell was 35.1% in blood and 43.7% In marrow, in contrast to these results was the median percentage of CD19+/CD5+ cell, which was higher in peripheral blood (70.4%) than in bone marrow (60.9%). The results of this study indicate that CD43 is present on peripheral blood B-CLL cells. Moreover, percentage of these cell increases during progression of disease however more weakly than percentage of CD5 and CD6 positive cells. Expression of CD43 is independent from expression CD5 and CD6 and diminishes during tumor mass increasing, what can depended from releases exocellular domains of CD43. CD43+ cell from B-CLL patients have a tendency to accumulation in tissues what is illustrated by higher percentage of CD43+ cell in bone marrow than in peripheral blood. The genetic characterization of chronic lymphocytic leukemia (CLL) has made significant progress over the past few years. Chromosomal abnormalities are detected in up to 80% of patients. Determination of new chromosomal disorders is important in the pathogenesis and treatment facilities. A patient was diagnosed with CLL Stage 2 on 2012 and followed since then by hematology clinic. She was 63 years old. Mature, small lymphocytes, and smudge cell was found in the patient's peripheral blood smear. Bone marrow (BM) biopsy made and hypercellularity showing infiltration of atypical cells with CD5+, CD20+, and CD23+ were determined. Hypoplasia is detected in myeloid/erythroid series, and Stage 2 reticular fibers proliferation were detected. The patient was followed up without medication. While follow-up of patient's white blood cell: 57300, hemoglobin: 5.36, and PLT: 99700 are determined in May 2014. According to the patient's flow results, CD5+, CD23+, and FMC7+ were detected. Mature, small lymphocytes and smudge cell was found in the patient's peripheral blood smear. In ultrasonography imaging, multiple laps were found in the abdomen and multiple neck lymph nodes were detected. The patient BM aspiration was performed in 2014, and hypercellularity was found to contain 54% of atypical lymphocytes in the BM. Fluorescence in situ hybridization (FISH) analysis made two times in 2014. At first, FISH analysis patient's rate of 18% in RB1/13q14.2/13qter revealed a deletion of the gene regions. Patient's FISH result was reported as normal (for RB1/13q14.2/13qter) after 5 months at second analysis. Cytogenetic analysis is made from the patient's BM at the same time. According to the results of karyotyping and FISH, 47, XX, isochromosome 4q (+i4q) is determined. According to literature, extra isochromosome 4q is reported by our case for the first time in CLL. She was diagnosed with Stage 4 CLL and FISH treatment was initiated. Our patient showed disease progression compared to previous results. Hence, we offer that this evidence can be considered regarding triggering the disease's progression or as a result of disease progression i4q was occurred. Diagnosis and staging Diagnostic and staging investigations depend on the size and type of malignancy. Blood cancer Blood investigations including hemoglobin, total leukocyte count, platelet count, peripheral smear, red cell indices. Bone marrow studies including aspiration, flow cytometry, cytogenetics, fluorescent in situ hybridisation and molecular studies. Lymphoma Excision biopsy of lymph node for histopathological examination, immunohistochemistry, and molecular studies. Blood investigations include lactate dehydrogenase (LDH), serum uric acid, and kidney function tests. Imaging tests such as computerised tomography (CT scan), positron emission tomography (PET CT). Bone marrow biopsy. Solid tumors Biopsy for histopathology and immunohistochemistry. Imaging tests like X-ray, ultrasonography, computerised tomography (CT), magnetic resonance imaging (MRI) and PET CT. We report 26 elderly patients (median age 68.3 years) who met diagnostic criteria for B-cell chronic lymphocytic leukaemia (B-CLL) but whose lymphocytes lacked CD5 expression. Haematological and clinical features of this CD5- series were compared with those of 333 CD5+ B-CLL patients from the same institute. No significant differences were observed regarding peripheral blood (PB) and bone marrow (BM) lymphocytosis, Hb level, platelet count, incidence of adenomegaly, hepatomegaly or splenomegaly or diffuse BM pattern. Due to an absence of nodal enlargements or to general clinical condition, lymph node biopsy was performed in only three patients, while spleen histology was examined in two cases following splenectomy. All histological results confirmed the clinical diagnosis of CLL. The distribution of the CD5- subjects according to the different staging categories proposed by Rai, Binet and Mandelli was similar to that of CD5+ subjects. Ten patients received standard chemotherapy with Chlorambucil (CHL) and Prednisone (PDN). All achieved partial remission, although one of these patients later died of disease progression; 80 months after diagnosis. We conclude that rare cases of CD5- lymphocytosis fulfilling all criteria for B-CLL may occur. Haematological and clinical features at presentation and the response to conventional treatment with Chlorambucil support our hypothesis of considering this disease as a less frequent subgroup of B-CLL. A 61-year-old man with no subjective symptom was admitted to our hospital for further examination of the causes of anemia (hemoglobin, 9.5 g/dL) and thrombocytopenia (platelets, 9.2 x 10(4)/microL), which had been pointed out in a medical checkup half a year previously. A bone marrow examination showed 73% lymphoid cells. Immunophenotyping of these cells were CD19+CD20+CD3-CD5-CD10-CD23-, and light chain restriction (kappa) was positive by fluorescence-activated cell sorting analysis. A computed tomography scan showed mild splenomegaly. To confirm the diagnosis histologically, we performed a splenectomy. Finally, we diagnosed the patient's disease as nonvillous splenic marginal zone lymphoma (SMZL). A month after the splenectomy, the white blood cell count was remarkably increased to 7 x 10(4)/microL with the blastic transformation of lymphoid cells. We first treated the patient with fludarabine and then with the CHOP regimen (cyclophosphamide, hydroxydaunomycin, vincristine [Oncovin], and prednisone), but the disease was so refractory that the patient died of the disease 13 months after the splenectomy. Immunohistochemical staining and a molecular examination for p53 were carried out with specimens from the splenectomy. We found overexpression of the p53 protein in lymphoid cells and a point missense mutation in codon 280 at exon 8 that changed AGA (Arg) to AGT (Ser). This case may indicate the existence of a more aggressive subset of SMZL, suggesting a reconsideration of the roles of splenectomy and p53 overexpression in the diagnostic and therapeutic approaches to patients with SMZL. We have investigated the value of both conventional and quantitative flow cytometry to detect minimal residual disease in 21 CLL patients in remission including bone marrow histology: eight in complete remission (CR), 11 in nodular partial remission (nPR) and two in PR. The techniques used were double immunostaining with CD5 and CD19 and quantitative estimation of the number of both antigens with standard microbeads. Reference values were established on normal peripheral blood and bone marrow controls. Patients were considered in 'immunological' remission when the percentage of CD5+ CD19+/total CD19+ cells was &lt;25% in PB and &lt;15% in BM. In six of the eight patients in CR, CLL cells were still detectable by flow cytometry. Only two patients, that underwent allogeneic bone marrow transplant, achieved immunological remission. CLL samples showed significantly higher CD5 and lower CD19 antigen density than normal controls (P &lt; 0.001). Persistence of residual disease was a predictor of time to progression. None of the two patients in immunological remission relapsed within a period of 13 and 33 months, whilst two of the six patients in CR with positive flow cytometry relapsed 3 and 6 months after achieving CR. This study demonstrates that flow cytometry contributes to increase the sensitivity of the clinicohematological criteria to detect residual malignant cells in CLL patients and may be useful to monitor disease status following treatment. Monoclonal B-cell lymphocytosis (MBL) is defined as an asymptomatic condition characterized by the presence of less than 5,000 monoclonal B-cells per microliter and the absence of clinical signs or symptoms of a B-cell lymphoproliferative disorder. Most MBL cases involve B cells presenting an identical phenotype to CLL (CLL-like MBL) with a Catovsky-Matutes score of 3 to 5 and share the same chromosomal abnormalities than CLL. Depending on the absolute B cell count, one may distinguish low-count CLL-like MBL (&lt;500 B cells/μL) which have no evidence of progression, no reduction in overall survival, no increase in infection risk and do not require any specific follow-up. Patients with clinical CLL-like MBL (&gt;500 B cells/μL) have a 1% to 2% per year risk of progression to CLL requiring therapy, a higher risk of infectious complications and mortality implicating an annual follow-up by hematologist. MBL may also express other less common phenotypes and are named atypical MBL in case of CD5 antigen expression (Catovsky-Matutes score: 1-2) and non-CLL-like MBL for CD5 negative cases (Catovsky-Matutes score: 0-2). Their poorer prognosis implicates imaging studies, bone marrow biopsy and cytogenetic analysis in addition to physical examination in order to rule out non-hodgkinien lymphoma, and require a more frequent follow-up. This review focuses on key concepts in the classification, diagnosis, monitoring and biology of MBL in laboratory practice.  Chronic-lymphocytic-leukemia (CLL) is the most prevalent leukemia in developed countries, caused by monoclonal proliferation of CD5+ B-cells and accumulation of mature-appearing-neoplastic lymphocytes in blood, bone marrow, and secondary lymphoid organs. Oral manifestations of CLL are infrequent and rarely reported in literature. We report a new case of a 67-year old man who presented with the complaints of tooth mobility and gingival swelling. Extra-oral examination was remarkable for cutaneous pallor and bilateral cervical lymphadenopathy involving the submandibular, and deep cervical lymph nodes on both sides of the neck. Complete blood count revealed normal red blood cell count (4.25 × 106/μl), normal platelet count (136 × 103/μl) and increased white blood cell count (25.3 × 103/μl). Differential white blood cell count showed marked lymphocytosis (88%), and blood film revealed the presence of leukocytosis, with small mature-looking lymphocytes, and mild thrombocytopenia. A flow cytometry immune-phenotyping revealed that 55% of peripheral blood cells were monoclonal B-lymphocytes expressing CD19, CD20, CD23, CD200, CD22, CD5, CD38, CD11c, sIgD and Kappa light chain confirming the diagnosis of CLL. Oral healthcare professionals should consider systemic causes, such as CLL, in the differential diagnosis of generalized tooth mobility and gingival swelling, particularly in patients with associated symptoms such as lymphadenopathy, fever, weight loss, and general fatigue. Additional testing: Flow Cytometry: Peripheral blood flow cytometry is essential to determine the proliferation of monoclonal cells. It is a costly test and should not be ordered routinely on all patients with lymphocytosis. Certain features on peripheral blood smear or on review of CBC which prompt a physician to order flow cytometry include: The presence of lymphoblasts on the peripheral blood smear, suggesting ALL- This should also prompt a referral to a tertiary care center to obtain further workup. The presence of other abnormal lymphocyte morphology on PBS as detailed above ALC more than 30000 cells/microL Persistent unexplained lymphocytosis for more than one month Abnormalities in other cell lines including anemia and thrombocytopenia Presence of lymphadenopathy and/or hepatosplenomegaly in the right clinical context where reactive causes have been ruled out Flow cytometry patterns are beneficial in delineating clonality and differentiating clonal disorders as follows: CLL: lymphocytes are CD5+, CD23+, CD20 (dim), CD10-, cyclin D1-, weak sIg (surface immunoglobulin), FMC -, CD200 + MCL: lymphocytes are CD5+, CD23-, CD10-, CD20+, sIg +, cyclin D1 +, FMC +, CD200- FL: lymphocytes are CD5-, CD10+, CD20+, sIg+ and often BCL2+, BCL6+ MZL: lymphocytes are CD5-, CD10-, CD20+, sIg+, cyclin D1- HCL: lymphocytes are CD5-, CD10-, CD20+, sIg+, CD11c+, CD25+, CD103+ T-LGL: lymphocytes are CD3+, CD8+, CD16+, CD56+ Fluorescence in situ hybridization (FISH), karyotype, and mutation analysis: FISH, karyotype, and certain mutation analysis help diagnose and risk stratification of hematologic malignancies, especially CLL and lymphomas. The FISH can not only help to ascertain the clonal nature of lymphocytosis but also helps to confirm the diagnosis of certain lymphomas. Examples include: FL: characterized by t(14,18) MCL: characterized by t(11,14) HCL: characterized by the presence of BRAF mutation CLL: different karyotypic abnormalities including del 17p, del 11q, trisomy 12, and del 13q14. A 74 years old male patient, presented with history of generalized weakness, fatigue, loss of appetite and breathlessness on exertion for past one and a half months. On examination, he was found to have significant pallor and generalized lymphadenopathy (cervical, axillary and inguinal). The skeletal survey showed punched out lytic lesions in skull and pelvic bones. The peripheral smear examination showed lymphocytosis with absolute lymphocyte count of 25,000/μL. The bone marrow aspirates revealed a hypercellular marrow with 74 % lymphocytes &amp; 14 % plasma cells, suggestive of chronic lymphoplasmacytic disorder. The bone marrow biopsy had two morphologically distinct populations of lymphocytes &amp; plasma cells. The immunohistochemical markers on bone marrow biopsy showed hat plasma cells were positive for CD138 with kappa light chain restriction. Flow cytometry showed B cell population with CD19/CD5 co expression, CD5/CD23 coexpression, were positive for CD22, CD20 and negative for FMC-7 and lambda light chain. In addition, plasma cells were also identified as CD45 negative cells and showed CD38/CD138 co-expression with variable CD19 and CD56 positivity. Serum protein electrophoresis revealed M band, serum immunofixation electrophoresis corresponded to IgA -Kappa. The final diagnosis of chronic lymphocytic leukemia with concomittant presence of plasma cell myeloma was concluded. This case imparts an important message to look for presence of coexisting entities in a single specimen and highlights the benefits of testing both plasma cell and B-cell compartments when the clinical features are not entirely consistent Flow cytometry together with protein electrophoresis can help to clinch difficult and rare dual diagnosis. These cases are rare and pose therapeutic challenge.  To analyze the expression of various antigens on the leukemic blasts and to determine the hematological parameters, in Acute Lymphoblastic Leukemia (ALL) patients at presentation. Observational study. King Edward Medical University, Lahore and Hameed Latif Hospital, Lahore, from February 2013 to March 2014. A total of 50 newly diagnosed and untreated patients of ALL were selected from Mayo Hospital and Hameed Latif Hospital. These patients included both genders and all age groups. Hemoglobin, total leukocyte count and platelet count were determined on hematology analyser-Sysmex-Kx-2I. Blast cell percentage was estimated on Giemsa stained blood smears. Immunophenotyping was done on bone marrow samples by 5 colour flowcytometery on Beckman Coulter Navious Flowcytometer. An acute leukemia panel of 23 antibodies was used. The data was entered and analyzed in SPSS version 22. Of the 50 ALL patients, 36 (72%) were B-ALL and 14 (28%) T-ALL. There were 18 (36%) children and 32 (64%) adults. T-ALL included 22% of the childhood and 31% of the adult cases. Immunophenotypic analysis showed that CD19, CD79a and CD20 were B-lineage specific markers whereas cCD3, CD3 and CD5 were T-lineage specific. CD10 was the most sensitive marker for B-ALL and CD7 was the most sensitive marker of T-ALL. TdT was expressed in 92% B-ALL and 71% T-ALL cases, CD34 in 58% and 43% cases and CD45 in 83% and 100% respectively. High leukocyte count (&gt; 50 x 109/L) was present in 58% cases. Hemoglobin was &lt; 10 g/dl in 74% patients and platelet count was below 20 x 109/Lin 12% patients. Leukocyte count, hemoglobin, platelet count and blast cell % did not show a significant difference in the two ALL immunotypes. The frequency of T-ALL is higher in childhood as well as adult ALL in our population compared to the Western literature. Antigenic expression of the blast cells also shows some interesting differences. A large number of our patients present with high leukocyte count which is a known factor associated with poor prognosis.\nHere is the question:\nHEMATOLOGY: A 67-year-old patient who in the last 6 months, in two routine analyses, presents progressive lymphocytosis. In the last one, hemoglobin 15.4 g/dL; leukocytes 18.5 x103/μL with 82 % of mature lymphocytes that by flow cytometry express CD5/CD19/CD23 antigens and platelets 240 x103/μL. What do you think is the correct approach?\nHere are the potential choices:\n1. Study of TP53 mutations to establish prognosis.\n2. Bone aspirate/biopsy to confirm diagnosis.\n3. PET/CT to establish the therapeutic attitude.\n4. New clinical and analytical control in 6 months.\nThe correct answer is: 4. New clinical and analytical control in 6 months."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n History A 50-year-old woman presented to the emergency department of our hospital with a 2-day history of lower limb pain associated with unusual asthenia and diffuse arthralgia over the past 3 weeks. She was a native of Guinea and had lived in France for most of her life, working as a personal care assistant. Her only medical history of note was an occurrence of fetal death at 12 weeks gestation when she was 35 years old. She had bilateral lower limb swelling, without changes in skin temperature or color. All proximal and distal arterial pulses were felt. General physical examination findings were otherwise unremarkable. Her laboratory tests showed a decreased hemoglobin concentration of 8.9 g/dL (normal range, 12-16 g/dL), a decreased platelet count of 45 × 10<sup9</sup/L (normal range, [150-400] × 10<sup9</sup/L), a C-reactive protein level of 158 mg/L (normal range, &lt;5 mg/L), and a d-dimer level of 2000 mg/L (normal range, &lt;500 mg/L]). Compression US of the lower limbs revealed bilateral calf vein thrombosis involving the fibular and posterior tibial veins. Curative anticoagulation using low-molecular-weight heparin (enoxaparin, subcutaneous injection of 100 units per kilogram of body weight twice a day) was started. The day after the start of anticoagulation therapy, the patient reported dyspnea and acute chest and abdominal pain. Her vital signs were assessed, and she had elevated blood pressure and increased heart rate and respiratory rate, but she remained afebrile. Her cardiac auscultation was unremarkable, besides tachycardia. Skin examination revealed small areas of necrosis on the fingertips of her right hand. Laboratory studies were repeated and showed an increase in serum creatinine level from a baseline value of 0.49 mg/dL to a new value of 1.01 mg/dL (normal range, 0.6-1.1 mg/dL), an apparition of low-grade proteinuria of 0.43 g per day (normal range, &lt;0.3 g/ day), and a high serum troponin level of 1066 ng/L (normal range, &lt;14 ng/L), whereas electrocardiography showed no ST segment modification and echocardiography revealed a moderately altered left ventricular ejection fraction (45%). There was no coronary occlusion seen at emergency coronarography. Contrast-enhanced CT of the chest, abdomen, and pelvis was performed (Figs 1, 2) together with cardiac MRI (Figs 3, 4). Since the start of the global pandemic caused by coronavirus disease 2019 (COVID-19), there have been numerous reports of autoimmune and rheumatological disorders developing after infection with SARS-CoV-2. To date, there has been only one reported case of systemic sclerosis (SSc) developing after SARS-CoV-2 infection. Here, we present another case of SSc developing after infection with SARS-CoV-2. A 48-year-old female with past medical history of anxiety and depression presented to the rheumatology clinic after being referred for further evaluation of abnormal labs, Raynaud's phenomenon, and other concerning symptoms. Shortly after hospitalization for COVID-19 pneumonia, she began experiencing symptoms that included fatigue, xerostomia, dysphagia, bilateral lower extremity weakness, dyspnea with exertion, unintentional weight loss, and diffuse skin hyperpigmentation. Labs ordered shortly before presentation were significant for antinuclear antibody (ANA) titer &gt; 1:1280. Physical exam was remarkable for puffy fingers, sclerodactyly of the fingers, diffuse skin hyperpigmentation, and abnormal nailfold capillaries. Anti-RNA polymerase III, anti-Scl-70, anti-centromere, anti-SSA, anti-SSB, anti-Smith, and anti-Smith/RNP antibodies were all negative. BNP, aldolase, and serum myoglobin levels were within normal limits while creatine phosphokinase level was slightly decreased. Pulmonary function testing showed reduced diffusion capacity with normal lung mechanics and volumes. High-resolution CT scan of the chest showed interstitial lung disease, with findings suggestive of nonspecific interstitial pneumonia. Transthoracic echocardiogram showed mild elevation of right ventricular systolic pressure, but pulmonary hypertension was not found on right heart catheterization. Esophagogastroduodenoscopy (EGD) with biopsy performed for evaluation of esophageal dysphagia showed sliding hiatal hernia, irregular Z-line, and gastric hyperemia. Biopsy of the distal esophagus was consistent with Barrett's esophagus. The patient was diagnosed with SSc according to the 2013 American College of Rheumatology/European League Against Rheumatism (ACR-EULAR) classification criteria for SSc. She is currently being treated with mycophenolate mofetil, amlodipine, methotrexate, and prednisone. History A 50-year-old woman presented to the emergency department of our hospital with a 2-day history of lower limb pain associated with unusual asthenia and diffuse arthralgia over the past 3 weeks. She was a native of Guinea and had lived in France for most of her life, working as a personal care assistant. Her only medical history of note was an occurrence of fetal death at 12 weeks gestation when she was 35 years old. She had bilateral lower limb swelling, without changes in skin temperature or color. All proximal and distal arterial pulses were felt. General physical examination findings were otherwise unremarkable. Her laboratory tests showed a decreased hemoglobin concentration of 8.9 g/dL (normal range, 12-16 g/dL), a decreased platelet count of 45 × 10<sup9</sup/L (normal range, 150-400 × 10<sup9</sup/L), a C-reactive protein level of 158 mg/L (normal range, &lt;5 mg/L) and a d-dimer level of 2000 mg/L (normal range, &lt;500 mg/L). Compression US of the lower limbs revealed bilateral calf vein thrombosis involving the fibular and posterior tibial veins. Curative anticoagulation using low-molecular-weight heparin (enoxaparin, subcutaneous injection of 100 units per kilogram of body weight twice a day) was started. The day after the start of anticoagulation therapy, the patient reported dyspnea and acute chest and abdominal pain. Her vital signs were assessed, and she had elevated blood pressure and increased heart rate and respiratory rate, but she remained afebrile. Her cardiac auscultation was unremarkable, besides tachycardia. Skin examination revealed small areas of necrosis on the fingertips of her right hand. Laboratory studies were repeated and showed an increase in serum creatinine level from a baseline value of 0.49 mg/dL to a new value of 1.01 mg/dL (normal range, 0.6-1.1 mg/dL), an apparition of low-grade proteinuria of 0.43 g per day (normal range, &lt;0.3 g/day), and a high serum troponin level of 1066 ng/L (normal range, &lt;14 ng/L), whereas electrocardiography showed no ST segment modification and echocardiography revealed a moderately altered left ventricular ejection fraction (45%). There was no coronary occlusion seen at emergency coronarography. Contrast-enhanced CT of the chest, abdomen, and pelvis was performed (Figs 1, 2) together with cardiac MRI (Figs 3, 4). This case was a 51-year-old woman, who had been diagnosed as having rheumatoid arthritis at some clinic and had been treated with both non-steroidal anti-inflammatory drugs and steroid 3 years before visiting our clinic. When she noticed a decrease in visual acuity and general fatigue in June 1985, she was referred to an ophthalmologist of our hospital, and found to have blood pressure of 240/150 mmHg and KW grade IV retinal findings. She was admitted in our department to examine and treat malignant hypertension. On admission, remarkable hypergammaglobulinemia (29.3%), arthralgia, arthral deformity and pericardial effusion were present thus, she was suspected to be suffering from malignant rheumatoid arthritis. Anti-nuclear antibody (64X), anti-nuclear ribonucleoprotein antibody (64X) and anti-RNase sensitive antibody of anti-extractable nuclear antigens (ENA) antibody (81920X) were positive, while anti-RNase resistant antibody of anti-ENA antibody was negative. Immunologically, her condition was consistent with mixed connective tissue disease (MCTD). Since urinary protein was positive and creatinine clearance was 46.0 ml/min, renal function was thought to be diminished. Her chest roentgenogram revealed cardiomegaly (CTR 67.5%) and an increase in pulmonary vascular shadow. An echocardiogram demonstrated the presence of pericardial effusion. Plasma renin activity was 3.3 ng/ml/h and it was suspected that an intrarenal ischemic change resulted in increased renin release from the juxta-glomerular apparatus, leading to the marked hypertension. Treatment was started with prednisolone 60 mg/day during 4 weeks.(ABSTRACT TRUNCATED AT 250 WORDS) BACKGROUND The diagnosis of systemic sclerosis sine scleroderma (ssSSc) with renal crisis is difficult because of its unusual presentation and rarity. CASE REPORT A 45-year-old man presented to the Emergency Department with worsening nausea, vomiting, and exertional dyspnea for 3 weeks. Initial examination showed blood pressure 182/108 mmHg without skin thickening or other skin manifestations. Laboratory investigations showed serum creatinine level 21.73 mg/dL and diffuse airspace opacities on chest radiography. He was admitted to the intensive care unit and started on emergent hemodialysis. He was anemic and became gradually hypoxic, requiring supplemental oxygen. Computed tomography of the chest showed bilateral infiltrates. Antinuclear antibodies (ANA) were positive for centromere pattern with titer of 320. Antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibodies were negative. He was started on therapeutic plasmapheresis (TP) and captopril, which resulted in significant improvement of respiratory symptoms. The kidney biopsy revealed thrombotic microangiopathy. Anticentromere, anti-Scl-70, and antiribonucleic acid polymerase III antibodies, drawn after 4 sessions of TP, were not detected. CONCLUSIONS Here we report a rare case of ssSSc with renal crisis in a patient who presented with acute renal failure requiring hemodialysis and suspected pulmonary hemorrhage. Clinical improvement was achieved by TP and angiotensin-converting enzyme inhibitor. The diagnosis of ssSSc was difficult and required an ANA pattern and kidney biopsy. A case of dermatomyositis which developed one month after normal delivery and subsided spontaneously was reported. A 29-year-old woman gave birth to a healthy child. One month later, she noticed muscular pain and weakness of the upper extremities. On admission, there were diffuse edema of upper eyelids with heliotrope rash. The reddish skin rashes were observed on the extensor surfaces of the PIP and MP joints of fingers. Erythrocyte sedimentation rate was 29 mm/hr. The lactic dehydrogenase (LDH), SGOT, CK levels were 470 (normal 150 to 320 IU/l), 43 (normal 6 to 25 IU/l) and 317 (normal 21 to 110 IU/l) respectively. Autoantibodies to nuclear and cytoplasmic antigens were negative. Rheumatoid factor and anti-DNA antibody were negative. Thyroid function was normal. An electromyogram (EMG) demonstrated small amplitude short-duration polyphasic motor unit potentials. The muscle biopsy specimen from left upper arm showed degenerating muscle fibers and infiltration of inflammatory cells surrounding blood vessels. The skin biopsy revealed the presence of edema and perivascular infiltration of lymphocytes. Based on these clinical features and results of various diagnostic tests, a diagnosis of dermatomyositis was established. After the admission, muscle strength has improved dramatically and the CK returned to normal level without specific drug therapy. She has since been seen as an out patient, and complete remission lasted for two years up to date. Review of the literature disclosed that 13 cases of PM/DM which developed during pregnancy or postpartum have been reported including the present case. Detailed analysis showed that these patients were characterized by mild muscular diseases, rare occurrence of internal organ involvements and good response to steroid therapy. As our case, a spontaneous remission was also observed. Although the mechanism involved in occurrence of inflammatory myositis associated with pregnancy or delivery are not clarified, these patient indicated a presence of subset of PM/DM which do not require intensive drug therapy. A 58-year-old female was referred to our department with intermittent suffocation for 1.5 years, aggravated for a month. 1.5 years before she developed oral ulcer, raynaud phenomenon, proteinuria, bilateral pleural effusion, ANA and anti-dsDNA positive. This patient was diagnosed with systemic lupus erythematosus (SLE). After given hormones, hydroxychloroquine sulfate (HCQ), her symptom relieved soon. The patient stopped her pills 1 year ago. One month ago, she had chest tightness, increased urine foam, and suffered from oliguria. Her admission medical examination: blood pressure (BP) 130/80 mmHg, conjunctiva pale, and lower lung breath sounds reduced. There was no tenderness, rebound pain and abdominal muscle tension in the abdomen. Liver and spleen rib inferior, mobile dullness negative, and lower extremity edema. Blood routine tests were performed with hemoglobin (HGB) 57 g/L. Urine routine: BLD (3+). 24-hour urinary protein 3.2 g. serum albumin 20.5 g/L, C-reactive protein (CRP) 12.85 mg/L, erythrocyte sedimentation rate (ESR) 140 mm/h. Antinuclear antibody (ANA) (H)1:10 000, anti-dsDNA antibody 1:3 200; anti-Smith antibody, anti-U1-snRNP/Sm antibody were positive, blood complement 3(C3) 0.43 g/L, complement 4(C4) 0.07 g /L. Anticardiolipin antibody (ACL), anti-β2-GP1, lupus anticoagulant (LA) were negative; HRCT suggested bilateral medial pleural cavity product liquid. Admission diagnosis: SLE lupus nephritis, anemia, pleural effusion, and hypoproteinemia. We treated her with methylprednisolone 1 000 mg×3 d, late to 48 mg/d and cyclophosphamide 1.0 g, HCQ 0.2 g bid, gamma globulin 10 g×5 d. Day 2 of treatment, this patient developed acute right upper quadrant pain, not accompanied by nausea, vomiting, blood stool and diarrhea. Antipyretic antispasmodic treatment was invalid, after the morning to ease their own abdominal pain. Day 4 of treatment, daytime blood HGB 77 g/L. Bilateral renal vascular ultrasound: bilateral renal artery blood flow velocity was reduced. The abdominal pain of the above symptoms recurred at night, BP was 120/80 mmHg, and no positive signs were found on abdominal examination. No abnormality was found in the vertical abdominal plain film. Blood routine examination: HGB 53 g/L, Plasma D dimer 2 515 μg/L, amylase in hematuria was normal, the stool occult blood was negative. Abdominal computed tomography (CT): normal structure of right adrenal gland disappeared, irregular mass shadow could be seen in adrenal region, CT value was about 50 HU. Morphological density of left adrenal gland was not abnormal. The retroperitoneum descended along the inferior vena cava to the right iliac blood vessel and showed a bolus shadow. The density of some segments increased. The lesion involved the right renal periphery and reached the left side of abdominal aorta. Most lesions surrounded the inferior vena cava, the right renal vein and part of the small intestine. The boundary between the upper lesion and the vena cava was unclear. Iodinecontaining contrast agent was taken orally. No sign of contrast agent overflowing was found in the abdominal cavity. Hematoma and exudative changes were considered in retroperitoneum. CONCLUSION of contrast-enhanced ultrasound of blood vessels: The retroperitoneal inferior vena cava (volume 3.5 cm×3.5 cm×1.5 cm) was hypoechoic and had no blood flow lesion. The adrenal gland had a high possibility of origin. Left renal vein thrombosis extended to inferior vena cava. According to the above data, it was analyzed that the cause of retroperitoneal hematoma of the patient was left adrenal vein thrombosis caused by hypercoagulable state, which led to vascular rupture and hemorrhage caused by increased vascular pressure in adrenal gland. Therefore, on the basis of continuing to actively treat the primary disease, and on the basis of dynamic observation of no active hemorrhage for 3 days, the anticoagulant therapy was continued with 10 mg/d of apixaban. Clinical symptoms were gradually eased, HGB did not decrease. Two weeks later, the ultrasonic examination showed that the irregular cluster hypoechoic range behind the inferior vena cava was significantly smaller than that before (1.8 cm×1.2 cm×0.7 cm). Abdominal CT examination after 1 month showed that there was no abnormal morphological density of bilateral adrenal glands and basic absorption of retroperitoneal exudation. Adrenal hemorrhage is uncommon. SLE with adrenal hemorrhage is rarer. In SLE patients, especially those complicated with APS, if abdominal pain accompanied by HGB decrease occurs, except after gastrointestinal hemorrhage, the possibility of adrenal hemorrhage should be warned. A 47-year-old woman was admitted to our hospital for evaluation of general fatigue and dyspnea. She had been diagnosed with progressive systemic sclerosis (PSS) when she was 39 years of age, on the basis of Raynaud's phenomenon, proximal sclerosis, and pigmentation of the skin. On admission, her blood pressure was 206/128 mmHg. Funduscopy revealed grade III (Keith &amp; Wagener) hypertensive retinopathy. Laboratory data showed positivity for anti-nuclear antibody and anticardiolipin beta 2 glycoprotein I antibody, and the plasma level of renin activity (PRA) was abnormally high. Chest X-ray and UCG revealed massive pericardial effusion. On the second hospital day, she was operated on for pericardiodiaphragmatic fenestration. The volume of pericardial effusion amounted to more than 2000 ml. Post operative malignant hypertension persisted. Laboratory data showed thrombocytopenia, hemolytic anemia, and acute renal failure. We diagnosed scleroderma renal crisis (SRC) associated with antiphospholipid syndrome. Following the initiation of angiotensin converting enzyme inhibitor (ACE-I) combined with calcium antagonist and alpha-one blocker, her blood pressure and PRA decreased. She also had been treated with aspirin 81 mg daily. These therapies were effective in recovering the platelet count and stopped the progression of anemia and renal failure. Although either the finding of large pericardial effusion or SRC is associated with poor prognosis in PSS, this case has had a good clinical course. In this case, the findings suggested that anti-phospholipid antibody may have contributed to the pericarditis and SRC. A 74-year-old woman had for 3 weeks suffered from watery diarrhoea and diffuse abdominal pain. She felt restless, had a subfebrile temperature (37.8 degrees C), tachycardia and a blood pressure of 190/90 mmHg. Shortly after admission petechiae were found over the lower legs and she complained of joint pains. Laboratory tests established hyperthyroidism. Skin biopsy showed leukocytoclastic vasculitis. Tests for antinuclear antibodies, antistreptolysin titre, rheumatoid factors, cryoglobulins and TSH-receptor antibodies were negative, immunoglobulin A (IgA) was raised. As a drug-induced vasculitis was suspected treatment was started with methylprednisolone, 100 mg daily. Proteinuria (5.6 g daily) indicated renal biopsy, which revealed focal glomerulonephritis with deposits of IgA, fibrin/fibrinogen and complement factor 3. Gastroscopic biopsy, performed after an episode of gastrointestinal bleeding, demonstrated necrotizing vasculitis, confirming the diagnosis of Schönlein-Henoch-purpura (SHP). As the patient's condition rapidly worsened, cyclophosphamide was started additionally (2 mg/kg). She died on the 17th hospital day from acute cardiac failure. The lethal course of the disease in this elderly patient illustrates a previously not reported close temporal and clinical relationship between SHP and hyperthyroidism. A patient is said to have polyarteritis nodosa if he or she has three of the 10 signs known as the 1990 American College of Rheumatology (ACR) criteria, when a radiographic or pathological diagnosis of vasculitis is made: Weight loss greater than/equal to 4.5 kg Livedo reticularis (a mottled purplish skin discoloration over the extremities or torso) Testicular pain or tenderness (occasionally, a site biopsied for diagnosis) Muscle pain, weakness, or leg tenderness Nerve disease (either single or multiple) Diastolic blood pressure greater than 90 mmHg (high blood pressure) Elevated kidney blood tests (BUN greater than 40 mg/dL or creatinine greater than 1.5 mg/dL) Hepatitis B (not C) virus tests positive (for surface antigen or antibody) Arteriogram (angiogram) showing the arteries that are dilated (aneurysms) or constricted by the blood vessel inflammation A careful medical history will seek to identify or exclude possible secondary causes. Digital artery pressures are measured in the arteries of the fingers before and after the hands have been cooled. A decrease of at least 15 mmHg is diagnostic (positive). Doppler ultrasound to assess blood flow Full blood count may reveal a normocytic anaemia suggesting the anaemia of chronic disease or kidney failure. Blood test for urea and electrolytes may reveal kidney impairment. Thyroid function tests may reveal hypothyroidism. Tests for rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, and autoantibody screening may reveal specific causative illnesses or an inflammatory process. Anti-centromere antibodies are common in limited systemic sclerosis (CREST syndrome). Nail fold vasculature (capillaroscopy) can be examined under a microscope. A 40-year-old woman had complained of cyanosis induced by cold exposure from the age of 26. When she was 32 years old, Raynaud's phenomenon occurred. She developed diffuse cutaneous sclerosis affecting the upper limbs, face and trunk, digital pitting scar, flexion contractures of hands, dilatation of lower esophagus and pulmonary fibrosis, and she was diagnosed as scleroderma. Laboratory findings revealed positive anti-topoisomerase I antibody and hypergammaglobulinemia (IgG 2,782, IgA 632, IgM 146 mg/dl). However, serum complement levels were normal and anti-DNA antibodies measured by radioimmunoassay (RIA) were negative. Initial dose of oral prednisolone was 30 mg/day and afterwards 5 mg/day of prednisolone was maintained. At the age of 36, scleroderma and contraction of hands were progressed, and telangiectasias appeared on her chest at the age of 36. Laboratory tests revealed hypocomplementemia (C3 27, C4 9 mg/dl, CH50 16 U/ml) and high titers, more than 100 U/ml, of anti-DNA antibodies measured by RIA. Clinical evidence suggestive of SLE could not be found. Reexamination of previous sera by enzyme immunoassay, in which anti-DNA antibody could not be detected by RIA, clarified the presence of IgG anti-dsDNA antibodies. It was considered that there existed low avidity/affinity of anti-dsDNA antibodies at first, and afterwards high avidity/affinity of anti-dsDNA antibodies appeared. Increasing of oral prednisolone up to 30 mg/day normalized serum complements and decreased titers of anti-DNA antibodies. She had not developed any clinical evidence that suspected SLE throughout the course. A 42-year-old female was admitted to our hospital on October 1, 1990 because of one week history of back pain, weakness of her right lower extremity and sensory disturbance of her left lower extremity. Physical examination revealed swollen hands, Raynaud's phenomenon, sclerodactyly and heliotrope rash. The body temperature was 37.0 degrees C. Neurological findings included weakness in the right lower extremity, left hypalgesia and thermohypesthesia below Th4, hyperreflexia on the right lower extremity and right extensive plantar response. Laboratory data showed leucopenia (3,700/mm3) and hypergammaglobulinemia. Serological examination revealed antinuclear antibodies with a titer of 1:5120 (speckled pattern) and anti-RNP antibody with a titer of 1:32. Neither anti-DNA antibody nor anti-Sm antibody were detected. Serum C3 and C4 were normal. The cerebrospinal fluid (CSF) contained mononuclear cells of 5/mm3, protein 29 mg/dl and glucose 56 mg/dl. Queckenstedt test was negative. Treatment with prednisolone 60 mg daily was started. On the 8th day of therapy, she complained of a burning sensation in the back, then paraplegia and urinary retention developed. MRI examination showed a high intensity area of the spinal cord at the right Th4 on T2-weighted images. Next day the treatment with 1000-mg intravenous daily pulse of methylprednisolone for 3 days was started, followed by prednisolone 40 mg daily. After this pulse therapy, the CSF contained mononuclear cells of 52/mm3, protein 34 mg/dl, glucose 67 mg/dl and IgG 7.6 mg/dl. Her neurological manifestation gradually improved and at six weeks after the pulse therapy neurological examination revealed no abnormality except for painful tonic spasm. Prednisolone was slowly tapered to 15 mg daily.(ABSTRACT TRUNCATED AT 250 WORDS)\nHere is the question:\nRHEUMATOLOGY: A 45-year-old female patient with a history of gastroesophageal reflux has been presenting for the past year with episodes of pallor in some fingers with exposure to cold. She had recently been prescribed prednisone at a dose of 20 mg/day for joint pain and skin induration in the hands and arms. For the last 48 hours, she presented with general malaise and intense headache, for which she went to the emergency department. Examination revealed only a rhythmic tachycardia at 100 bpm, with no neurological focality. Blood pressure was 200/110 mmHg. The blood test shows only a creatinine level of 2.5 mg/dL. Indicate which of the following autoantibodies is best related to the process described:\nHere are the potential choices:\n1. Anti-RNA polymerase III antibodies.\n2. Anti-centromere antibodies.\n3. Anti-proteinase 3 antibodies.\n4. Anti-PM-Scl antibodies.\nThe correct answer is: ",
        "gold_answer": "1 Anti-RNA polymerase III antibodies.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n History A 50-year-old woman presented to the emergency department of our hospital with a 2-day history of lower limb pain associated with unusual asthenia and diffuse arthralgia over the past 3 weeks. She was a native of Guinea and had lived in France for most of her life, working as a personal care assistant. Her only medical history of note was an occurrence of fetal death at 12 weeks gestation when she was 35 years old. She had bilateral lower limb swelling, without changes in skin temperature or color. All proximal and distal arterial pulses were felt. General physical examination findings were otherwise unremarkable. Her laboratory tests showed a decreased hemoglobin concentration of 8.9 g/dL (normal range, 12-16 g/dL), a decreased platelet count of 45 × 10<sup9</sup/L (normal range, [150-400] × 10<sup9</sup/L), a C-reactive protein level of 158 mg/L (normal range, &lt;5 mg/L), and a d-dimer level of 2000 mg/L (normal range, &lt;500 mg/L]). Compression US of the lower limbs revealed bilateral calf vein thrombosis involving the fibular and posterior tibial veins. Curative anticoagulation using low-molecular-weight heparin (enoxaparin, subcutaneous injection of 100 units per kilogram of body weight twice a day) was started. The day after the start of anticoagulation therapy, the patient reported dyspnea and acute chest and abdominal pain. Her vital signs were assessed, and she had elevated blood pressure and increased heart rate and respiratory rate, but she remained afebrile. Her cardiac auscultation was unremarkable, besides tachycardia. Skin examination revealed small areas of necrosis on the fingertips of her right hand. Laboratory studies were repeated and showed an increase in serum creatinine level from a baseline value of 0.49 mg/dL to a new value of 1.01 mg/dL (normal range, 0.6-1.1 mg/dL), an apparition of low-grade proteinuria of 0.43 g per day (normal range, &lt;0.3 g/ day), and a high serum troponin level of 1066 ng/L (normal range, &lt;14 ng/L), whereas electrocardiography showed no ST segment modification and echocardiography revealed a moderately altered left ventricular ejection fraction (45%). There was no coronary occlusion seen at emergency coronarography. Contrast-enhanced CT of the chest, abdomen, and pelvis was performed (Figs 1, 2) together with cardiac MRI (Figs 3, 4). Since the start of the global pandemic caused by coronavirus disease 2019 (COVID-19), there have been numerous reports of autoimmune and rheumatological disorders developing after infection with SARS-CoV-2. To date, there has been only one reported case of systemic sclerosis (SSc) developing after SARS-CoV-2 infection. Here, we present another case of SSc developing after infection with SARS-CoV-2. A 48-year-old female with past medical history of anxiety and depression presented to the rheumatology clinic after being referred for further evaluation of abnormal labs, Raynaud's phenomenon, and other concerning symptoms. Shortly after hospitalization for COVID-19 pneumonia, she began experiencing symptoms that included fatigue, xerostomia, dysphagia, bilateral lower extremity weakness, dyspnea with exertion, unintentional weight loss, and diffuse skin hyperpigmentation. Labs ordered shortly before presentation were significant for antinuclear antibody (ANA) titer &gt; 1:1280. Physical exam was remarkable for puffy fingers, sclerodactyly of the fingers, diffuse skin hyperpigmentation, and abnormal nailfold capillaries. Anti-RNA polymerase III, anti-Scl-70, anti-centromere, anti-SSA, anti-SSB, anti-Smith, and anti-Smith/RNP antibodies were all negative. BNP, aldolase, and serum myoglobin levels were within normal limits while creatine phosphokinase level was slightly decreased. Pulmonary function testing showed reduced diffusion capacity with normal lung mechanics and volumes. High-resolution CT scan of the chest showed interstitial lung disease, with findings suggestive of nonspecific interstitial pneumonia. Transthoracic echocardiogram showed mild elevation of right ventricular systolic pressure, but pulmonary hypertension was not found on right heart catheterization. Esophagogastroduodenoscopy (EGD) with biopsy performed for evaluation of esophageal dysphagia showed sliding hiatal hernia, irregular Z-line, and gastric hyperemia. Biopsy of the distal esophagus was consistent with Barrett's esophagus. The patient was diagnosed with SSc according to the 2013 American College of Rheumatology/European League Against Rheumatism (ACR-EULAR) classification criteria for SSc. She is currently being treated with mycophenolate mofetil, amlodipine, methotrexate, and prednisone. History A 50-year-old woman presented to the emergency department of our hospital with a 2-day history of lower limb pain associated with unusual asthenia and diffuse arthralgia over the past 3 weeks. She was a native of Guinea and had lived in France for most of her life, working as a personal care assistant. Her only medical history of note was an occurrence of fetal death at 12 weeks gestation when she was 35 years old. She had bilateral lower limb swelling, without changes in skin temperature or color. All proximal and distal arterial pulses were felt. General physical examination findings were otherwise unremarkable. Her laboratory tests showed a decreased hemoglobin concentration of 8.9 g/dL (normal range, 12-16 g/dL), a decreased platelet count of 45 × 10<sup9</sup/L (normal range, 150-400 × 10<sup9</sup/L), a C-reactive protein level of 158 mg/L (normal range, &lt;5 mg/L) and a d-dimer level of 2000 mg/L (normal range, &lt;500 mg/L). Compression US of the lower limbs revealed bilateral calf vein thrombosis involving the fibular and posterior tibial veins. Curative anticoagulation using low-molecular-weight heparin (enoxaparin, subcutaneous injection of 100 units per kilogram of body weight twice a day) was started. The day after the start of anticoagulation therapy, the patient reported dyspnea and acute chest and abdominal pain. Her vital signs were assessed, and she had elevated blood pressure and increased heart rate and respiratory rate, but she remained afebrile. Her cardiac auscultation was unremarkable, besides tachycardia. Skin examination revealed small areas of necrosis on the fingertips of her right hand. Laboratory studies were repeated and showed an increase in serum creatinine level from a baseline value of 0.49 mg/dL to a new value of 1.01 mg/dL (normal range, 0.6-1.1 mg/dL), an apparition of low-grade proteinuria of 0.43 g per day (normal range, &lt;0.3 g/day), and a high serum troponin level of 1066 ng/L (normal range, &lt;14 ng/L), whereas electrocardiography showed no ST segment modification and echocardiography revealed a moderately altered left ventricular ejection fraction (45%). There was no coronary occlusion seen at emergency coronarography. Contrast-enhanced CT of the chest, abdomen, and pelvis was performed (Figs 1, 2) together with cardiac MRI (Figs 3, 4). This case was a 51-year-old woman, who had been diagnosed as having rheumatoid arthritis at some clinic and had been treated with both non-steroidal anti-inflammatory drugs and steroid 3 years before visiting our clinic. When she noticed a decrease in visual acuity and general fatigue in June 1985, she was referred to an ophthalmologist of our hospital, and found to have blood pressure of 240/150 mmHg and KW grade IV retinal findings. She was admitted in our department to examine and treat malignant hypertension. On admission, remarkable hypergammaglobulinemia (29.3%), arthralgia, arthral deformity and pericardial effusion were present thus, she was suspected to be suffering from malignant rheumatoid arthritis. Anti-nuclear antibody (64X), anti-nuclear ribonucleoprotein antibody (64X) and anti-RNase sensitive antibody of anti-extractable nuclear antigens (ENA) antibody (81920X) were positive, while anti-RNase resistant antibody of anti-ENA antibody was negative. Immunologically, her condition was consistent with mixed connective tissue disease (MCTD). Since urinary protein was positive and creatinine clearance was 46.0 ml/min, renal function was thought to be diminished. Her chest roentgenogram revealed cardiomegaly (CTR 67.5%) and an increase in pulmonary vascular shadow. An echocardiogram demonstrated the presence of pericardial effusion. Plasma renin activity was 3.3 ng/ml/h and it was suspected that an intrarenal ischemic change resulted in increased renin release from the juxta-glomerular apparatus, leading to the marked hypertension. Treatment was started with prednisolone 60 mg/day during 4 weeks.(ABSTRACT TRUNCATED AT 250 WORDS) BACKGROUND The diagnosis of systemic sclerosis sine scleroderma (ssSSc) with renal crisis is difficult because of its unusual presentation and rarity. CASE REPORT A 45-year-old man presented to the Emergency Department with worsening nausea, vomiting, and exertional dyspnea for 3 weeks. Initial examination showed blood pressure 182/108 mmHg without skin thickening or other skin manifestations. Laboratory investigations showed serum creatinine level 21.73 mg/dL and diffuse airspace opacities on chest radiography. He was admitted to the intensive care unit and started on emergent hemodialysis. He was anemic and became gradually hypoxic, requiring supplemental oxygen. Computed tomography of the chest showed bilateral infiltrates. Antinuclear antibodies (ANA) were positive for centromere pattern with titer of 320. Antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibodies were negative. He was started on therapeutic plasmapheresis (TP) and captopril, which resulted in significant improvement of respiratory symptoms. The kidney biopsy revealed thrombotic microangiopathy. Anticentromere, anti-Scl-70, and antiribonucleic acid polymerase III antibodies, drawn after 4 sessions of TP, were not detected. CONCLUSIONS Here we report a rare case of ssSSc with renal crisis in a patient who presented with acute renal failure requiring hemodialysis and suspected pulmonary hemorrhage. Clinical improvement was achieved by TP and angiotensin-converting enzyme inhibitor. The diagnosis of ssSSc was difficult and required an ANA pattern and kidney biopsy. A case of dermatomyositis which developed one month after normal delivery and subsided spontaneously was reported. A 29-year-old woman gave birth to a healthy child. One month later, she noticed muscular pain and weakness of the upper extremities. On admission, there were diffuse edema of upper eyelids with heliotrope rash. The reddish skin rashes were observed on the extensor surfaces of the PIP and MP joints of fingers. Erythrocyte sedimentation rate was 29 mm/hr. The lactic dehydrogenase (LDH), SGOT, CK levels were 470 (normal 150 to 320 IU/l), 43 (normal 6 to 25 IU/l) and 317 (normal 21 to 110 IU/l) respectively. Autoantibodies to nuclear and cytoplasmic antigens were negative. Rheumatoid factor and anti-DNA antibody were negative. Thyroid function was normal. An electromyogram (EMG) demonstrated small amplitude short-duration polyphasic motor unit potentials. The muscle biopsy specimen from left upper arm showed degenerating muscle fibers and infiltration of inflammatory cells surrounding blood vessels. The skin biopsy revealed the presence of edema and perivascular infiltration of lymphocytes. Based on these clinical features and results of various diagnostic tests, a diagnosis of dermatomyositis was established. After the admission, muscle strength has improved dramatically and the CK returned to normal level without specific drug therapy. She has since been seen as an out patient, and complete remission lasted for two years up to date. Review of the literature disclosed that 13 cases of PM/DM which developed during pregnancy or postpartum have been reported including the present case. Detailed analysis showed that these patients were characterized by mild muscular diseases, rare occurrence of internal organ involvements and good response to steroid therapy. As our case, a spontaneous remission was also observed. Although the mechanism involved in occurrence of inflammatory myositis associated with pregnancy or delivery are not clarified, these patient indicated a presence of subset of PM/DM which do not require intensive drug therapy. A 58-year-old female was referred to our department with intermittent suffocation for 1.5 years, aggravated for a month. 1.5 years before she developed oral ulcer, raynaud phenomenon, proteinuria, bilateral pleural effusion, ANA and anti-dsDNA positive. This patient was diagnosed with systemic lupus erythematosus (SLE). After given hormones, hydroxychloroquine sulfate (HCQ), her symptom relieved soon. The patient stopped her pills 1 year ago. One month ago, she had chest tightness, increased urine foam, and suffered from oliguria. Her admission medical examination: blood pressure (BP) 130/80 mmHg, conjunctiva pale, and lower lung breath sounds reduced. There was no tenderness, rebound pain and abdominal muscle tension in the abdomen. Liver and spleen rib inferior, mobile dullness negative, and lower extremity edema. Blood routine tests were performed with hemoglobin (HGB) 57 g/L. Urine routine: BLD (3+). 24-hour urinary protein 3.2 g. serum albumin 20.5 g/L, C-reactive protein (CRP) 12.85 mg/L, erythrocyte sedimentation rate (ESR) 140 mm/h. Antinuclear antibody (ANA) (H)1:10 000, anti-dsDNA antibody 1:3 200; anti-Smith antibody, anti-U1-snRNP/Sm antibody were positive, blood complement 3(C3) 0.43 g/L, complement 4(C4) 0.07 g /L. Anticardiolipin antibody (ACL), anti-β2-GP1, lupus anticoagulant (LA) were negative; HRCT suggested bilateral medial pleural cavity product liquid. Admission diagnosis: SLE lupus nephritis, anemia, pleural effusion, and hypoproteinemia. We treated her with methylprednisolone 1 000 mg×3 d, late to 48 mg/d and cyclophosphamide 1.0 g, HCQ 0.2 g bid, gamma globulin 10 g×5 d. Day 2 of treatment, this patient developed acute right upper quadrant pain, not accompanied by nausea, vomiting, blood stool and diarrhea. Antipyretic antispasmodic treatment was invalid, after the morning to ease their own abdominal pain. Day 4 of treatment, daytime blood HGB 77 g/L. Bilateral renal vascular ultrasound: bilateral renal artery blood flow velocity was reduced. The abdominal pain of the above symptoms recurred at night, BP was 120/80 mmHg, and no positive signs were found on abdominal examination. No abnormality was found in the vertical abdominal plain film. Blood routine examination: HGB 53 g/L, Plasma D dimer 2 515 μg/L, amylase in hematuria was normal, the stool occult blood was negative. Abdominal computed tomography (CT): normal structure of right adrenal gland disappeared, irregular mass shadow could be seen in adrenal region, CT value was about 50 HU. Morphological density of left adrenal gland was not abnormal. The retroperitoneum descended along the inferior vena cava to the right iliac blood vessel and showed a bolus shadow. The density of some segments increased. The lesion involved the right renal periphery and reached the left side of abdominal aorta. Most lesions surrounded the inferior vena cava, the right renal vein and part of the small intestine. The boundary between the upper lesion and the vena cava was unclear. Iodinecontaining contrast agent was taken orally. No sign of contrast agent overflowing was found in the abdominal cavity. Hematoma and exudative changes were considered in retroperitoneum. CONCLUSION of contrast-enhanced ultrasound of blood vessels: The retroperitoneal inferior vena cava (volume 3.5 cm×3.5 cm×1.5 cm) was hypoechoic and had no blood flow lesion. The adrenal gland had a high possibility of origin. Left renal vein thrombosis extended to inferior vena cava. According to the above data, it was analyzed that the cause of retroperitoneal hematoma of the patient was left adrenal vein thrombosis caused by hypercoagulable state, which led to vascular rupture and hemorrhage caused by increased vascular pressure in adrenal gland. Therefore, on the basis of continuing to actively treat the primary disease, and on the basis of dynamic observation of no active hemorrhage for 3 days, the anticoagulant therapy was continued with 10 mg/d of apixaban. Clinical symptoms were gradually eased, HGB did not decrease. Two weeks later, the ultrasonic examination showed that the irregular cluster hypoechoic range behind the inferior vena cava was significantly smaller than that before (1.8 cm×1.2 cm×0.7 cm). Abdominal CT examination after 1 month showed that there was no abnormal morphological density of bilateral adrenal glands and basic absorption of retroperitoneal exudation. Adrenal hemorrhage is uncommon. SLE with adrenal hemorrhage is rarer. In SLE patients, especially those complicated with APS, if abdominal pain accompanied by HGB decrease occurs, except after gastrointestinal hemorrhage, the possibility of adrenal hemorrhage should be warned. A 47-year-old woman was admitted to our hospital for evaluation of general fatigue and dyspnea. She had been diagnosed with progressive systemic sclerosis (PSS) when she was 39 years of age, on the basis of Raynaud's phenomenon, proximal sclerosis, and pigmentation of the skin. On admission, her blood pressure was 206/128 mmHg. Funduscopy revealed grade III (Keith &amp; Wagener) hypertensive retinopathy. Laboratory data showed positivity for anti-nuclear antibody and anticardiolipin beta 2 glycoprotein I antibody, and the plasma level of renin activity (PRA) was abnormally high. Chest X-ray and UCG revealed massive pericardial effusion. On the second hospital day, she was operated on for pericardiodiaphragmatic fenestration. The volume of pericardial effusion amounted to more than 2000 ml. Post operative malignant hypertension persisted. Laboratory data showed thrombocytopenia, hemolytic anemia, and acute renal failure. We diagnosed scleroderma renal crisis (SRC) associated with antiphospholipid syndrome. Following the initiation of angiotensin converting enzyme inhibitor (ACE-I) combined with calcium antagonist and alpha-one blocker, her blood pressure and PRA decreased. She also had been treated with aspirin 81 mg daily. These therapies were effective in recovering the platelet count and stopped the progression of anemia and renal failure. Although either the finding of large pericardial effusion or SRC is associated with poor prognosis in PSS, this case has had a good clinical course. In this case, the findings suggested that anti-phospholipid antibody may have contributed to the pericarditis and SRC. A 74-year-old woman had for 3 weeks suffered from watery diarrhoea and diffuse abdominal pain. She felt restless, had a subfebrile temperature (37.8 degrees C), tachycardia and a blood pressure of 190/90 mmHg. Shortly after admission petechiae were found over the lower legs and she complained of joint pains. Laboratory tests established hyperthyroidism. Skin biopsy showed leukocytoclastic vasculitis. Tests for antinuclear antibodies, antistreptolysin titre, rheumatoid factors, cryoglobulins and TSH-receptor antibodies were negative, immunoglobulin A (IgA) was raised. As a drug-induced vasculitis was suspected treatment was started with methylprednisolone, 100 mg daily. Proteinuria (5.6 g daily) indicated renal biopsy, which revealed focal glomerulonephritis with deposits of IgA, fibrin/fibrinogen and complement factor 3. Gastroscopic biopsy, performed after an episode of gastrointestinal bleeding, demonstrated necrotizing vasculitis, confirming the diagnosis of Schönlein-Henoch-purpura (SHP). As the patient's condition rapidly worsened, cyclophosphamide was started additionally (2 mg/kg). She died on the 17th hospital day from acute cardiac failure. The lethal course of the disease in this elderly patient illustrates a previously not reported close temporal and clinical relationship between SHP and hyperthyroidism. A patient is said to have polyarteritis nodosa if he or she has three of the 10 signs known as the 1990 American College of Rheumatology (ACR) criteria, when a radiographic or pathological diagnosis of vasculitis is made: Weight loss greater than/equal to 4.5 kg Livedo reticularis (a mottled purplish skin discoloration over the extremities or torso) Testicular pain or tenderness (occasionally, a site biopsied for diagnosis) Muscle pain, weakness, or leg tenderness Nerve disease (either single or multiple) Diastolic blood pressure greater than 90 mmHg (high blood pressure) Elevated kidney blood tests (BUN greater than 40 mg/dL or creatinine greater than 1.5 mg/dL) Hepatitis B (not C) virus tests positive (for surface antigen or antibody) Arteriogram (angiogram) showing the arteries that are dilated (aneurysms) or constricted by the blood vessel inflammation A careful medical history will seek to identify or exclude possible secondary causes. Digital artery pressures are measured in the arteries of the fingers before and after the hands have been cooled. A decrease of at least 15 mmHg is diagnostic (positive). Doppler ultrasound to assess blood flow Full blood count may reveal a normocytic anaemia suggesting the anaemia of chronic disease or kidney failure. Blood test for urea and electrolytes may reveal kidney impairment. Thyroid function tests may reveal hypothyroidism. Tests for rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, and autoantibody screening may reveal specific causative illnesses or an inflammatory process. Anti-centromere antibodies are common in limited systemic sclerosis (CREST syndrome). Nail fold vasculature (capillaroscopy) can be examined under a microscope. A 40-year-old woman had complained of cyanosis induced by cold exposure from the age of 26. When she was 32 years old, Raynaud's phenomenon occurred. She developed diffuse cutaneous sclerosis affecting the upper limbs, face and trunk, digital pitting scar, flexion contractures of hands, dilatation of lower esophagus and pulmonary fibrosis, and she was diagnosed as scleroderma. Laboratory findings revealed positive anti-topoisomerase I antibody and hypergammaglobulinemia (IgG 2,782, IgA 632, IgM 146 mg/dl). However, serum complement levels were normal and anti-DNA antibodies measured by radioimmunoassay (RIA) were negative. Initial dose of oral prednisolone was 30 mg/day and afterwards 5 mg/day of prednisolone was maintained. At the age of 36, scleroderma and contraction of hands were progressed, and telangiectasias appeared on her chest at the age of 36. Laboratory tests revealed hypocomplementemia (C3 27, C4 9 mg/dl, CH50 16 U/ml) and high titers, more than 100 U/ml, of anti-DNA antibodies measured by RIA. Clinical evidence suggestive of SLE could not be found. Reexamination of previous sera by enzyme immunoassay, in which anti-DNA antibody could not be detected by RIA, clarified the presence of IgG anti-dsDNA antibodies. It was considered that there existed low avidity/affinity of anti-dsDNA antibodies at first, and afterwards high avidity/affinity of anti-dsDNA antibodies appeared. Increasing of oral prednisolone up to 30 mg/day normalized serum complements and decreased titers of anti-DNA antibodies. She had not developed any clinical evidence that suspected SLE throughout the course. A 42-year-old female was admitted to our hospital on October 1, 1990 because of one week history of back pain, weakness of her right lower extremity and sensory disturbance of her left lower extremity. Physical examination revealed swollen hands, Raynaud's phenomenon, sclerodactyly and heliotrope rash. The body temperature was 37.0 degrees C. Neurological findings included weakness in the right lower extremity, left hypalgesia and thermohypesthesia below Th4, hyperreflexia on the right lower extremity and right extensive plantar response. Laboratory data showed leucopenia (3,700/mm3) and hypergammaglobulinemia. Serological examination revealed antinuclear antibodies with a titer of 1:5120 (speckled pattern) and anti-RNP antibody with a titer of 1:32. Neither anti-DNA antibody nor anti-Sm antibody were detected. Serum C3 and C4 were normal. The cerebrospinal fluid (CSF) contained mononuclear cells of 5/mm3, protein 29 mg/dl and glucose 56 mg/dl. Queckenstedt test was negative. Treatment with prednisolone 60 mg daily was started. On the 8th day of therapy, she complained of a burning sensation in the back, then paraplegia and urinary retention developed. MRI examination showed a high intensity area of the spinal cord at the right Th4 on T2-weighted images. Next day the treatment with 1000-mg intravenous daily pulse of methylprednisolone for 3 days was started, followed by prednisolone 40 mg daily. After this pulse therapy, the CSF contained mononuclear cells of 52/mm3, protein 34 mg/dl, glucose 67 mg/dl and IgG 7.6 mg/dl. Her neurological manifestation gradually improved and at six weeks after the pulse therapy neurological examination revealed no abnormality except for painful tonic spasm. Prednisolone was slowly tapered to 15 mg daily.(ABSTRACT TRUNCATED AT 250 WORDS)\nHere is the question:\nRHEUMATOLOGY: A 45-year-old female patient with a history of gastroesophageal reflux has been presenting for the past year with episodes of pallor in some fingers with exposure to cold. She had recently been prescribed prednisone at a dose of 20 mg/day for joint pain and skin induration in the hands and arms. For the last 48 hours, she presented with general malaise and intense headache, for which she went to the emergency department. Examination revealed only a rhythmic tachycardia at 100 bpm, with no neurological focality. Blood pressure was 200/110 mmHg. The blood test shows only a creatinine level of 2.5 mg/dL. Indicate which of the following autoantibodies is best related to the process described:\nHere are the potential choices:\n1. Anti-RNA polymerase III antibodies.\n2. Anti-centromere antibodies.\n3. Anti-proteinase 3 antibodies.\n4. Anti-PM-Scl antibodies.\nThe correct answer is: 1. Anti-RNA polymerase III antibodies."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Esophageal strictures and rings can be safely dilated in EoE. It is recommended to use a graduated balloon catheter for gradual dilation. The patient should be informed that after dilation they might experience chest pain and in addition risk of esophageal perforation and bleeding. Prognosis The long-term prognosis for patients with EoE is unknown. Some patients may follow a “waxing and waning” course characterized by symptomatic episodes followed by periods of remission. There have also been reports of apparent spontaneous disease remission in some patients; however, the risk of recurrence in these patients is unknown. It is possible that long-standing, untreated disease may result in esophageal remodeling, leading to strictures, Schatzki ring and, eventually, achalasia. History The first case of eosinophilic esophagitis was reported in 1978. In the early 1990s, it became recognized as a distinct disease. See also Eosinophilic gastroenteritis References External links A 40-year-old white male with atopy presented to our department in March 2004 with a history of chronic heartburn and solid-food dysphagia since 1994. The patient was taking on-demand salbutamol for asthma and ranitidine for mild heartburn, occurring less than once per week. Eight years previously, he had undergone esophageal dilatation for a Schatzki's ring. Physical examination, laboratory investigations, video esophagram, upper endoscopy with mid-esophageal biopsies, and skin testing for a number of food and environmental allergens. Diagnosis Eosinophilic esophagitis. Topical steroids with a fluticasone 220 microg multiple-dose inhaler, four puffs swallowed twice a day for 6 weeks. Eosinophilic esophagitis is a rare condition mainly affecting children, although the number of cases reported in adults is on the increase. It is characterized by intense infiltration of eosinophilic leukocytes in the esophageal mucosa, without involvement of other sections of the alimentary canal. Over the past year, following the performance of endoscopies and biopsies, our service identified nine patients who were diagnosed with suffering from this disorder. Each patient sought medical help for episodes of long-term, self-limited dysphagia or food impaction in the alimentary canal. Endoscopy revealed esophageal stenosis in the form of simultaneous contraction rings or regular stenosis. In six cases, the manometric study showed a nonspecific motor disorder of severe intensity affecting the esophageal body, and another patient had a disorder characterized by the presence of simultaneous waves and secondary peristaltic waves in the three thirds of the organ. These disorders are presumably due to eosinophilic infiltration of the muscular layer or ganglionar cells of the esophagus, and account for symptoms in these patients. Although the etiopathogenesis of this illness is uncertain, it is clearly an immunoallergic manifestation. As the number of diagnosed cases is on the increase, eosinophilic esophagitis is in adults a specific entity within the differential diagnosis of dysphagia in young males with a history of allergies. Eosiniphilic esophagitis responds in a different number of ways to therapies used. We successfully used fluticasone propionate, a synthetic corticoid applied topically, which proved to be efficient in the treatment of this illness by acting on the pathophysiological basis of the process. It does not have any adverse effects, thus offering advantages over other therapies such as systematic corticoids or endoscopic dilations. Eosinophilic esophagitis is an inflammatory condition in which there is dense eosinophilic infiltration of the surface lining of the esophagus. Reports of eosinophilic esophagitis pertain almost exclusively to pediatric populations. However, eosinophilic esophagitis is emerging as a clinical affliction of adults. This report describes the clinical and endoscopic findings of eosinophilic esophagitis in the largest cohort of adult patients reported to date. Twenty-nine patients (21 men, 8 women; mean age 35 years) with documented eosinophilic esophagitis (&gt;/=15 eosinophils per high-power field in biopsy specimens) and a significant history of chronic dysphagia for solid food (24 patients) were evaluated clinically and endoscopically during a 3-year period (1999-2002). Fourteen patients (48%) had a history of asthma, environmental allergy, or atopy. In a subset of 15 patients, the diagnostic accuracy of endoscopy was compared with that of barium contrast esophagography. Twenty-seven patients (93%) had abnormal endoscopic findings; 25 (86%) had unique esophageal structural changes, associated with a preserved mucosal surface, that were highly atypical for acid reflux injury. Structural alterations seen in adult patients with eosinophilic esophagitis may occur in combination or as a primary characteristic, e.g., uniform small-caliber esophagus, single or multiple corrugations (rings), proximal esophageal stenosis, or 1 to 2 mm whitish vesicles scattered over the mucosal surface. Barium contrast radiography combined with swallow of a barium-coated marshmallow identified 10 (67%) of the primary features observed endoscopically in 15 patients. However, radiography failed to detect other features noted at endoscopy (e.g., only 3/6 patients with proximal stenosis, 5/9 patients with concentric rings and none of 4 patients with small caliber esophagus). Eight of the 29 patients (20%) had a history of chronic heartburn. Twelve patients had been treated with a proton pump inhibitor and only 3 reported some improvement in the severity of dysphagia. Relatively young age, a history of chronic dysphagia for solid food, and endoscopic detection of unique structural alterations atypical for GERD in an adult patient should prompt a suspicion of EE and subsequent biopsy confirmation. Acid reflux appears to have a secondary role in eosinophilic esophagitis. In an uncontrolled comparison, endoscopy was superior to barium contrast radiography for the diagnosis of eosinophilic esophagitis. The incidence of eosinophilic esophagitis in adults appears to be increasing. Lymphocytic esophagitis is a newly recognized entity of unknown origin. Dysphagia is defined as difficulty swallowing and represents a common symptom in the general population with a prevalence of approximately 20%. Chronic inflammation of the esophageal wall may manifest itself clinically and endoscopically, mimicking inflammation of another origin. However, little is known about the pathogenesis of the disease, as patients are seldom suspected and rarely diagnosed with lymphocytic esophagitis. Here, we present a rare case of lymphocytic esophagitis in a patient with multiple allergies and suspected eosinophilic esophagitis. A 28-year-old woman with polyvalent sensitization to food and inhalant allergens presented with intermittent dysphagia, a sensation of a foreign body in the throat, itchiness of the oral cavity after ingesting certain foods, heartburn, and prolonged chewing time. A skin prick test showed positive results for birch-tree, alder, hazel, and rye pollen, as well as house dust mites. Apart from obesity (BMI 30 kg/m<sup2</sup), multiple pustules and excoriations on the skin, her physical examination was insignificant. Esophagogastroduodenoscopy (EGD) was performed revealing full-length but discrete trachealization of the esophagus. A barium swallow test showed slowing of esophageal peristalsis in the recumbent position. No esophageal pathology was observed. A histopathological analysis of mucosal samples revealed slight hyperplasia of the basal layer of the esophagus, and the stomach showed changes typical of chronic gastritis. In summary, this clinical case illustrates that lymphocytic esophagitis, as a newly recognized entity, should be considered in the differential diagnosis of chronic dysphagia. Additionally, when treating allergic patients, clinicians should be aware that lymphocytic esophagitis, distinct from eosinophilic esophagitis, should be considered in the diagnosis of patients with atopy and upper gastrointestinal symptoms. Risk factors Food bolus obstruction is most commonly caused by Schatzki rings, which are mucosal rings of unknown cause in the lower esophagus. Foodstuff jams into the esophagus due to the narrowing caused by the ring. An increasingly commonly recognized cause for esophageal food bolus obstruction is eosinophilic esophagitis, which is an inflammatory disorder of the mucosa of the esophagus, of unknown cause. Many alterations caused by eosinophilic esophagitis can predispose to food boluses; these include the presence of multiple rings and narrowing of the lumen. When considering esophageal dilation to treat a patient with food bolus obstruction, care must be made to look for features of eosinophilic esophagitis, as these patients are at a higher risk of dilation-associated complications. Eosinophilic esophagitis (EoE) is an emerging esophageal disease associated with dysphagia and food impaction. Practice guidelines have only recently been developed. It affects 1/1000 individuals, predominantly young men. As this demographic represents a substantial portion of the military aviation population, aerospace medicine clinicians should be familiar with this diagnosis when evaluating dysphagia or impactions. A 23-yr-old Caucasian man, a U.S. Air Force air traffic controller, presented to Flight Medicine following an episode of food impaction requiring evaluation in the local emergency department. The patient reported a 5-yr history of recurrent episodes of food lodging in his throat, requiring fluid and body repositioning for resolution. Medical history was significant for eczema. Upper endoscopy revealed an abnormal esophagus with macroscopic features of EoE and biopsies were also consistent with EoE. After further work-up, the patient was diagnosed with EoE and treated. Significant symptom improvement was noted after 2 mo of therapy. This case outlines the evaluation of food impaction as well as the diagnostic criteria for EoE, which is a disease that affects patients with demographics common to the military aviation community. As the diagnostic and treatment guidelines for EoE are relatively new, it may easily be overlooked by the primary care physician, causing a delay in subspecialist consultation, thus delaying treatment. EoE is a condition with symptoms that pose high risk to the performance of aircrew duties; therefore, flight surgeons must be familiar with the aeromedical standards that accompany this diagnosis. Eosinophilic esophagitis (EoE) is an emergent condition in which a mucosal infiltrate of &gt; 20 eosinophils per high power microscopic field is accompanied by motor disturbances that may cause food impaction in the absence of esophageal stricture. We report a series of such cases to point out the potential involvement of pediatric surgeons in diagnosis and treatment. Furthermore, data on the motor function of the esophagus investigated manometrically is included. Thirteen patients with EoE were referred to our emergency room for acute food bolus impaction. Their median age at diagnosis was 12 years (range 7.6-14.4). History of allergy, endoscopy with biopsy and esophageal function (24-h combined ambulatory manometry with simultaneous pH-metry) were investigated. In 7 patients emergency endoscopic extraction of the impacted bolus was necessary. Allergic tests were positive in eight patients. The pH probe showed gastroesophageal reflux in two cases. Upon endoscopy, typical features of EoE (esophageal trachealization and whitish papular exudates) were found. Ambulatory 24-h manometry revealed abnormal motility of the distal esophagus with strikingly high amplitudes (&gt; 150 mmHg) and long duration (&gt; 7 sec) of the waves, particularly during the night. Six patients responded rapidly to steroids and/or antiallergic treatment. The remaining patients had a good outcome with dietary treatment alone. EoE is an emergent condition that may involve the pediatric surgeon in both the diagnosis and treatment. Typical endoscopic findings and biopsy are required for proper diagnosis. Ambulatory manometry reveals a marked propulsive dysfunction that explains impaction. This dysfunction is reversible, since the symptoms usually disappear with steroids or antiallergic treatment. Eosinophilic esophagitis (EoE) is an immune-mediated disorder that may be related to exposure to additive chemicals in crops, air pollutants, or supplements found within livestock. Co-occurring allergic or atopic diseases including atopic dermatitis, food allergies, and asthma are also commonly seen in 70% of cases and help guide diagnosis. Diagnosis of EoE requires eosinophilic infiltration greater than 15 eosinophils per high power field (HPF) with endoscopic evidence of abnormal esophageal changes. Here, we discuss a rare presentation of food bolus impaction secondary to EoE after ingestion of a nasal decongestant and antihistamine pill that has previously never been described in the literature. A 22-year-old male with no significant past medical history presented to the emergency department (ED) with a chief complaint of a sudden onset respiratory distress, regurgitation of clear oral secretions, and globus sensation post ingestion of a fexofenadine-pseudoephedrine tablet. Prior to intake of the capsule, the patient was consuming liquids and solids appropriately. The patient was afebrile, hypertensive at 172/114, and found to have a normal heart rate of 88 bpm and a respiration rate of 18 breaths per minute. An esophagogastroduodenoscopy (EGD) was performed, which revealed a fexofenadine-pseudoephedrine capsule at 23 cm from the incisors along with a superficial ulceration at the corresponding level in the esophagus. The foreign body was successfully removed using raptor forceps. Further visualization demonstrated trachealization of the esophagus and furrowing and severe narrowing (&lt; 10mm), which raised suspicion for EoE. Proximal biopsy indicated 16 intraepithelial eosinophils per HPF within the squamous epithelium, likely compatible with EoE. The patient tolerated the procedure well and was discharged on an eight-week course of proton-pump inhibitors. EoE is defined as an immune-mediated esophageal disease characterized histologically by eosinophil-predominant inflammation. Our patient was reported to have up to 30 eosinophils per HPF from the proximal esophageal biopsy, which satisfies the requirements for an EoE diagnosis. Based on the current literature review, there have been no other reported cases of symptomatic food bolus impaction secondary to EoE after ingestion of antihistamines. Eosinophilic esophagitis (EE) is a motility disorder of the esophagus that typically presents with dysphagia. The objective of the present study was to explore patient characteristics, clinical and endoscopic features, and response to treatment of patients with EE. Patients were selected retrospectively based on a review of biopsy results from previous endoscopies performed between 2004 and 2008. A total of 54 patients (41 men and 13 women) with biopsy-proven EE were included in the study. Further information regarding the patients' clinical and endoscopic features, and response to treatment were obtained through chart reviews and patient telephone interviews. The mean age of the patients at symptom onset was 30 years. All patients complained of dysphagia, 81% had a history of bolus obstruction, 43% had a history of asthma and 70% had a history of environmental allergies. Thirty-three per cent had a family history of asthma, while 52% had a family history of food or seasonal allergies. The most common endoscopic findings were rings and⁄or corrugations, which were found in 63% of patients. Swallowed fluticasone therapy resulted in symptom resolution in 74% of patients; however, 79% of these patients relapsed after discontinuing fluticasone therapy and required repeat treatments. Esophageal dilation was complication free and resulted in improvement in 80% of patients. However, 83% of those reporting improvement relapsed within one year. The clinical and endoscopic findings were similar to those found in the literature, with most patients requiring ongoing, repeated therapies. Further studies are needed to assess the safety and efficacy of treatment modalities ideally suited to patients with EE. Esophagus GERD (most common cause of heartburn) occurs when acid refluxes from the stomach and inflames the esophagus. Esophageal spasms typically occur after eating or drinking and may be combined with difficulty swallowing. Esophageal strictures Esophageal cancers Esophagitis GERD Eosinophilic esophagitis - a disease commonly associated with other atopic diseases such as asthma, food allergies, seasonal allergies, and atopic skin disease Mallory-Weis tears - tears of the superficial mucosa of the esophagus that are subsequently exposed to gastric acid commonly due to vomiting and/or retching Chemical esophagitis - related to the intake of caustic substances, excessive amounts of hot liquids, alcohol, or tobacco smoke Infections may explain heartburn symptoms. These especially include CMV and certain fungal infections, most common in immunocompromised persons Stomach An esophageal food bolus obstruction is a medical emergency caused by the obstruction of the esophagus by an ingested foreign body. It is usually associated with diseases that may narrow the lumen of the esophagus, such as eosinophilic esophagitis, Schatzki rings, peptic strictures, webs, or cancers of the esophagus; rarely it can be seen in disorders of the movement of the esophagus, such as nutcracker esophagus. While some esophageal food boli can pass by themselves or with the assistance of medications, some require the use of endoscopy to push the obstructing food into the stomach, or remove it from the esophagus. The use of glucagon, while common, has not been found to be useful. Eponymous names include 'the steakhouse syndrome' and 'backyard barbeque syndrome'. Predominant symptoms in school-aged children and adolescents include difficulty swallowing, food impaction, and choking/gagging with meals- particularly when eating foods with coarse textures. Other symptoms in this age group can include abdominal/chest pain, vomiting, and regurgitation. The predominant symptom in adults is difficulty swallowing; however, intractable heartburn and food avoidance may also be present. Due to the long-standing inflammation and possible resultant scarring that may have gone unrecognized, adults presenting with EoE tend to have more episodes of esophageal food impaction as well as other esophageal abnormalities such as Schatzki ring, esophageal webs, and in some cases, achalasia. To investigate endoscopic findings in patients with Schatzki rings (SRs) with a focus on evidence for eosinophilic esophagitis (EoE). We consecutively approached all adult patients scheduled for elective outpatient upper endoscopy for a variety of indications at the German Diagnostic Clinic, Wiesbaden, Germany between July 2007 and July 2010. All patients with endoscopically diagnosed SRs, defined as thin, symmetrical, mucosal structures located at the esophagogastric junction, were prospectively registered. Additional endoscopic findings, clinical information and histopathological findings with a focus on esophageal eosinophilia (≥ 20 eosinophils/high power field) were recorded. The criteria for active EoE were defined as: (1) eosinophilic tissue infiltration ≥ 20 eosinophils/hpf; (2) symptoms of esophageal dysfunction; and (3) exclusion of other causes of esophageal eosinophilia. Gastroesophageal reflux disease was excluded by proton pump inhibitor treatment prior to endoscopy. The presence of ≥ 20 eosinophils/hpf in esophageal biopsies in patients that did not fulfil the criteria of EoE was defined as esophageal hypereosinophilia. A SR was diagnosed in 171 (3.3%; 128 males, 43 females, mean age 66 ± 12.9 years) of the 5163 patients that underwent upper gastrointestinal-endoscopy. Twenty of the 116 patients (17%) from whom esophageal biopsies were obtained showed histological hypereosinophilia (≥ 20 eosinophils/hpf). Nine of these patients (8 males, 1 female, mean age 49 ± 10 years) did not fulfill all diagnostic criteria of EoE, whereas in 11 (9%) patients with ≥ 20 eosinophils/hpf, a definite diagnosis of EoE was made. Three of the 11 patients (27%) with definite EoE had no suspicious endoscopic features of EoE. In contrast, in the 25 patients in whom EoE was suspected by endoscopic features, EoE was only confirmed in 7 (28%) patients. Patients with EoE were younger (mean age 41.5 ± 6.5 vs 50.5 ± 11.5 years, P = 0.012), were more likely to have a history of allergies (73% vs 29%, P = 0.007) and complained more often of dysphagia (91% vs 34%, P = 0.004) and food impaction (36% vs 6%, P = 0.007) than patients without EoE. Endoscopically, additional webs were found significantly more often in patients with EoE than in patients without EoE (36% vs 11%, P = 0.04). Furthermore, the SR had a tendency to be narrower in patients with EoE than in those without EoE (36% vs 18%, P = 0.22). The percentage of males (73% vs 72%, P = 1.0) and frequency of heartburn (27% vs 27%, P = 1.0) were not significantly different in both groups. The 9 patients with esophageal hypereosinophilia that did not fulfil the diagnostic criteria of EoE were younger (mean age 49 ± 10 years vs 58 ± 6 years, P = 0.0008) and were more likely to have a history of allergies (78% vs 24%, P = 0.003) than patients with &lt; 20 eosinophils/hpf. Predictors of EoE were younger age, presence of dysphagia or food impaction and a history of allergies. A significant proportion of patients with SRs also have EoE, which may not always be suspected according to other endoscopic features. Distal esophageal or Schatzki's rings are a common cause of intermittent solid food dysphagia requiring endoscopic dilation for relief. Similarly, eosinophilic esophagitis (EE) is a rapidly emerging disease in both children and young adults, and manifests as dysphagia to solids and/or episodic food bolus impaction. Endoscopic findings vary considerably among patients with EE, posing significant recognition and management challenges. Esophageal dilation in EE can be painful and risky. This case report describes a patient with acute food bolus impaction due to underlying Schatzki's ring and associated but clinically indolent EE, and highlights some safety aspects of esophageal dilation. EoE is diagnosed based on the combination of typical esophageal symptoms and esophageal mucosal biopsies demonstrating squamous epithelial eosinophil-predominant inflammation. Alternative etiologies of esophageal eosinophilia include GERD, drug hypersensitivity, connective tissue disorders, hypereosinophilic syndrome, and infection. Current evidence indicates that EoE is an immunologic disorder induced by antigen sensitization in susceptible individuals. Dietary factors play an important role in both the pathogenesis and treatment of EoE. Aeroallergens may also contribute, but the evidence is weaker. The natural history of EoE is unclear, but an increased risk of esophageal stricture development paralleling the duration of untreated disease has been noted. Diseases of the Esophagus FIGURE 347-11 Endoscopic features of (A) eosinophilic esophagitis (EoE), (B) Candida esophagitis, (C) giant ulcer associated with HIV, (D) and a Schatzki ring. Eosinophilic esophagitis (EE) is an inflammatory condition characterized by intense eosinophilic infiltration of the esophagus. EE is frequently misdiagnosed as gastroesophageal reflux disease. Here, we present a child with EE and a characteristic endoscopic finding, \"ringed esophagus\". An 11-year-old Saudi boy presented with dysphagia for 1 year. He had experienced an intermittent sensation of solid food sticking in his chest, which was relieved by drinking liquids. A barium swallow excluded anatomical causes of dysphagia, but revealed multiple-ringed esophagus. Endoscopy showed a furrowing and trachealizing appearance of the entire esophagus. Hisologically, extensive eosinophilic infiltration was a feature in biopsies obtained from the esophagus. The child responded well to a 2-month course of inhaled fluticasone. Symptoms recurred 3 months after discontinuation of therapy, which necessitated resumption of inhaled fluticasone. The endoscopic appearance of multiple esophageal rings should raise suspicion of EE and be confirmed by esophageal biopsies. For subtypes To treat eosinophilic esophagitis, avoiding any allergens that may be stimulating the eosinophils is recommended. As for medications, proton pump inhibitors and steroids can be prescribed. Steroids that are used to treat asthma can be swallowed to treat eosinophil esophagitis due to nonfood allergens. The removal of food allergens from the diet is included to help treat eosinophilic esophagitis. For infectious esophagitis, medicine is prescribed based on what type of infection is causing the esophagitis. These medicines are prescribed to treat bacterial, fungal, viral, and/or parasitic infections. Procedures An endoscopy can be used to remove ill fragments. Surgery can be done to remove the damaged part of the esophagus. For reflux esophagitis, a fundooplication can be done to help strengthen the lower esophageal sphincter from allowing backflow of the stomach into the esophagus. For esophageal stricture, a gastroenterologist can perform a dilation of the esophagus. A 17-year-old patient was transferred to the emergency room with an impacted food bolus by colleagues from the Department of Otorhinolaryngology. The examination of ear, nose and throat revealed significant amounts of saliva in both recessus piriformis, a radiologic examination of the esophagus showed a foreign body with a diameter of 1.6 cm in the region of the transitional zone of esophagus and stomach with a support level of the contrast medium. Clinical examination and laboratory tests showed no abnormalities. An emergency gastroscopy was performed. The foreign body, already evident in the barium swallow, was found in the distal esophagus. The foreign body was identified as a food bolus and gently advanced into the stomach with the aid of the gastroscope. In the stomach further food residues were detected and the examination was aborted because of increased risk of aspiration. On the next day, an elective gastroscopy was performed. Several biopsies were obtained from the esophagus because eosinophilic esophagitis (EE) was suspected due to clinical symptoms. Histological work-up showed a significant amount of eosinophilic granulocytes (&gt; 15 eosinophils/HPF, 400 x) and reactive changes in the distal esophagus. Therefore, EE was diagnosed. Fluticasone therapy led to amelioration of symptoms and there was no evidence of recurring bolus impaction during follow-up. Eosinophilic esophagitis (EoE) is an allergic inflammatory condition of the esophagus that involves eosinophils, a type of white blood cell. In healthy individuals, the esophagus is typically devoid of eosinophils. In EoE, eosinophils migrate to the esophagus in large numbers. When a trigger food is eaten, the eosinophils contribute to tissue damage and inflammation. Symptoms include swallowing difficulty, food impaction, vomiting, and heartburn. Eosinophilic esophagitis was first described in children but also occurs in adults. The condition is not well understood, but food allergy may play a significant role. The treatment may consist of removal of known or suspected triggers and medication to suppress the immune response. In severe cases, it may be necessary to enlarge the esophagus with an endoscopy procedure. While knowledge about EoE has been increasing rapidly, diagnosis of EoE can be challenging because the symptoms and histo-pathologic findings are not specific. Lymphocytic esophagitis Lymphocytic esophagitis is a rare and poorly understood entity associated with an increased amount of lymphocytes in the lining of the esophagus. It was first described in 2006. Disease associations may include Crohn's disease, gastroesophageal reflux disease and coeliac disease. It causes similar changes on endoscopy as eosinophilic esophagitis including esophageal rings, narrow-lumen esophagus, and linear furrows. Caustic esophagitis Caustic esophagitis is the damage of tissue via chemical origin. This occasionally occurs through occupational exposure (via breathing of fumes that mix into the saliva which is then swallowed) or through pica. It occurred in some teenagers during the fad of intentionally eating Tide pods. By severity The severity of reflux esophagitis is commonly classified into four grades according to the Los Angeles Classification: Eosinophilic esophagitis is an unrecognized and emerging entity. Its incidence increases with allergic disorders. A 29-year-old man presented with a 4-year history of intermittent and paroxysmal dysphagia. The triad including allergy, young age, and impaction of foreign bodies, combined with a chronic dysphagia is almost pathognomonic of eosinophilic esophagitis. Endoscopic esophageal features can be diverse, so systematic esophageal biopsies are required. Diagnosis is established with the demonstration of an eosinophilic infiltrate with a cell count exceeding 15 eosinophils per high power field (×400). First line therapy includes swallowed topical corticosteroids and removal of an allergic cause, when it could be identified.\nHere is the question:\nDIGESTIVE SYSTEM: 18-year-old young man with a history of asthma, allergy to pollens, mites and cat hair, comes to the emergency room referring sensation of food detention at retrosternal level with practical inability to swallow his own saliva. He refers similar episodes on other occasions that have subsided spontaneously within a few minutes. Which of the following is the most likely diagnosis?\nHere are the potential choices:\n1. Barrett's esophagus.\n2. Distal esophageal ring (Schatzki).\n3. Infectious esophagitis.\n4. Eosinophilic esophagitis.\nThe correct answer is: ",
        "gold_answer": "4 Eosinophilic esophagitis.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Esophageal strictures and rings can be safely dilated in EoE. It is recommended to use a graduated balloon catheter for gradual dilation. The patient should be informed that after dilation they might experience chest pain and in addition risk of esophageal perforation and bleeding. Prognosis The long-term prognosis for patients with EoE is unknown. Some patients may follow a “waxing and waning” course characterized by symptomatic episodes followed by periods of remission. There have also been reports of apparent spontaneous disease remission in some patients; however, the risk of recurrence in these patients is unknown. It is possible that long-standing, untreated disease may result in esophageal remodeling, leading to strictures, Schatzki ring and, eventually, achalasia. History The first case of eosinophilic esophagitis was reported in 1978. In the early 1990s, it became recognized as a distinct disease. See also Eosinophilic gastroenteritis References External links A 40-year-old white male with atopy presented to our department in March 2004 with a history of chronic heartburn and solid-food dysphagia since 1994. The patient was taking on-demand salbutamol for asthma and ranitidine for mild heartburn, occurring less than once per week. Eight years previously, he had undergone esophageal dilatation for a Schatzki's ring. Physical examination, laboratory investigations, video esophagram, upper endoscopy with mid-esophageal biopsies, and skin testing for a number of food and environmental allergens. Diagnosis Eosinophilic esophagitis. Topical steroids with a fluticasone 220 microg multiple-dose inhaler, four puffs swallowed twice a day for 6 weeks. Eosinophilic esophagitis is a rare condition mainly affecting children, although the number of cases reported in adults is on the increase. It is characterized by intense infiltration of eosinophilic leukocytes in the esophageal mucosa, without involvement of other sections of the alimentary canal. Over the past year, following the performance of endoscopies and biopsies, our service identified nine patients who were diagnosed with suffering from this disorder. Each patient sought medical help for episodes of long-term, self-limited dysphagia or food impaction in the alimentary canal. Endoscopy revealed esophageal stenosis in the form of simultaneous contraction rings or regular stenosis. In six cases, the manometric study showed a nonspecific motor disorder of severe intensity affecting the esophageal body, and another patient had a disorder characterized by the presence of simultaneous waves and secondary peristaltic waves in the three thirds of the organ. These disorders are presumably due to eosinophilic infiltration of the muscular layer or ganglionar cells of the esophagus, and account for symptoms in these patients. Although the etiopathogenesis of this illness is uncertain, it is clearly an immunoallergic manifestation. As the number of diagnosed cases is on the increase, eosinophilic esophagitis is in adults a specific entity within the differential diagnosis of dysphagia in young males with a history of allergies. Eosiniphilic esophagitis responds in a different number of ways to therapies used. We successfully used fluticasone propionate, a synthetic corticoid applied topically, which proved to be efficient in the treatment of this illness by acting on the pathophysiological basis of the process. It does not have any adverse effects, thus offering advantages over other therapies such as systematic corticoids or endoscopic dilations. Eosinophilic esophagitis is an inflammatory condition in which there is dense eosinophilic infiltration of the surface lining of the esophagus. Reports of eosinophilic esophagitis pertain almost exclusively to pediatric populations. However, eosinophilic esophagitis is emerging as a clinical affliction of adults. This report describes the clinical and endoscopic findings of eosinophilic esophagitis in the largest cohort of adult patients reported to date. Twenty-nine patients (21 men, 8 women; mean age 35 years) with documented eosinophilic esophagitis (&gt;/=15 eosinophils per high-power field in biopsy specimens) and a significant history of chronic dysphagia for solid food (24 patients) were evaluated clinically and endoscopically during a 3-year period (1999-2002). Fourteen patients (48%) had a history of asthma, environmental allergy, or atopy. In a subset of 15 patients, the diagnostic accuracy of endoscopy was compared with that of barium contrast esophagography. Twenty-seven patients (93%) had abnormal endoscopic findings; 25 (86%) had unique esophageal structural changes, associated with a preserved mucosal surface, that were highly atypical for acid reflux injury. Structural alterations seen in adult patients with eosinophilic esophagitis may occur in combination or as a primary characteristic, e.g., uniform small-caliber esophagus, single or multiple corrugations (rings), proximal esophageal stenosis, or 1 to 2 mm whitish vesicles scattered over the mucosal surface. Barium contrast radiography combined with swallow of a barium-coated marshmallow identified 10 (67%) of the primary features observed endoscopically in 15 patients. However, radiography failed to detect other features noted at endoscopy (e.g., only 3/6 patients with proximal stenosis, 5/9 patients with concentric rings and none of 4 patients with small caliber esophagus). Eight of the 29 patients (20%) had a history of chronic heartburn. Twelve patients had been treated with a proton pump inhibitor and only 3 reported some improvement in the severity of dysphagia. Relatively young age, a history of chronic dysphagia for solid food, and endoscopic detection of unique structural alterations atypical for GERD in an adult patient should prompt a suspicion of EE and subsequent biopsy confirmation. Acid reflux appears to have a secondary role in eosinophilic esophagitis. In an uncontrolled comparison, endoscopy was superior to barium contrast radiography for the diagnosis of eosinophilic esophagitis. The incidence of eosinophilic esophagitis in adults appears to be increasing. Lymphocytic esophagitis is a newly recognized entity of unknown origin. Dysphagia is defined as difficulty swallowing and represents a common symptom in the general population with a prevalence of approximately 20%. Chronic inflammation of the esophageal wall may manifest itself clinically and endoscopically, mimicking inflammation of another origin. However, little is known about the pathogenesis of the disease, as patients are seldom suspected and rarely diagnosed with lymphocytic esophagitis. Here, we present a rare case of lymphocytic esophagitis in a patient with multiple allergies and suspected eosinophilic esophagitis. A 28-year-old woman with polyvalent sensitization to food and inhalant allergens presented with intermittent dysphagia, a sensation of a foreign body in the throat, itchiness of the oral cavity after ingesting certain foods, heartburn, and prolonged chewing time. A skin prick test showed positive results for birch-tree, alder, hazel, and rye pollen, as well as house dust mites. Apart from obesity (BMI 30 kg/m<sup2</sup), multiple pustules and excoriations on the skin, her physical examination was insignificant. Esophagogastroduodenoscopy (EGD) was performed revealing full-length but discrete trachealization of the esophagus. A barium swallow test showed slowing of esophageal peristalsis in the recumbent position. No esophageal pathology was observed. A histopathological analysis of mucosal samples revealed slight hyperplasia of the basal layer of the esophagus, and the stomach showed changes typical of chronic gastritis. In summary, this clinical case illustrates that lymphocytic esophagitis, as a newly recognized entity, should be considered in the differential diagnosis of chronic dysphagia. Additionally, when treating allergic patients, clinicians should be aware that lymphocytic esophagitis, distinct from eosinophilic esophagitis, should be considered in the diagnosis of patients with atopy and upper gastrointestinal symptoms. Risk factors Food bolus obstruction is most commonly caused by Schatzki rings, which are mucosal rings of unknown cause in the lower esophagus. Foodstuff jams into the esophagus due to the narrowing caused by the ring. An increasingly commonly recognized cause for esophageal food bolus obstruction is eosinophilic esophagitis, which is an inflammatory disorder of the mucosa of the esophagus, of unknown cause. Many alterations caused by eosinophilic esophagitis can predispose to food boluses; these include the presence of multiple rings and narrowing of the lumen. When considering esophageal dilation to treat a patient with food bolus obstruction, care must be made to look for features of eosinophilic esophagitis, as these patients are at a higher risk of dilation-associated complications. Eosinophilic esophagitis (EoE) is an emerging esophageal disease associated with dysphagia and food impaction. Practice guidelines have only recently been developed. It affects 1/1000 individuals, predominantly young men. As this demographic represents a substantial portion of the military aviation population, aerospace medicine clinicians should be familiar with this diagnosis when evaluating dysphagia or impactions. A 23-yr-old Caucasian man, a U.S. Air Force air traffic controller, presented to Flight Medicine following an episode of food impaction requiring evaluation in the local emergency department. The patient reported a 5-yr history of recurrent episodes of food lodging in his throat, requiring fluid and body repositioning for resolution. Medical history was significant for eczema. Upper endoscopy revealed an abnormal esophagus with macroscopic features of EoE and biopsies were also consistent with EoE. After further work-up, the patient was diagnosed with EoE and treated. Significant symptom improvement was noted after 2 mo of therapy. This case outlines the evaluation of food impaction as well as the diagnostic criteria for EoE, which is a disease that affects patients with demographics common to the military aviation community. As the diagnostic and treatment guidelines for EoE are relatively new, it may easily be overlooked by the primary care physician, causing a delay in subspecialist consultation, thus delaying treatment. EoE is a condition with symptoms that pose high risk to the performance of aircrew duties; therefore, flight surgeons must be familiar with the aeromedical standards that accompany this diagnosis. Eosinophilic esophagitis (EoE) is an emergent condition in which a mucosal infiltrate of &gt; 20 eosinophils per high power microscopic field is accompanied by motor disturbances that may cause food impaction in the absence of esophageal stricture. We report a series of such cases to point out the potential involvement of pediatric surgeons in diagnosis and treatment. Furthermore, data on the motor function of the esophagus investigated manometrically is included. Thirteen patients with EoE were referred to our emergency room for acute food bolus impaction. Their median age at diagnosis was 12 years (range 7.6-14.4). History of allergy, endoscopy with biopsy and esophageal function (24-h combined ambulatory manometry with simultaneous pH-metry) were investigated. In 7 patients emergency endoscopic extraction of the impacted bolus was necessary. Allergic tests were positive in eight patients. The pH probe showed gastroesophageal reflux in two cases. Upon endoscopy, typical features of EoE (esophageal trachealization and whitish papular exudates) were found. Ambulatory 24-h manometry revealed abnormal motility of the distal esophagus with strikingly high amplitudes (&gt; 150 mmHg) and long duration (&gt; 7 sec) of the waves, particularly during the night. Six patients responded rapidly to steroids and/or antiallergic treatment. The remaining patients had a good outcome with dietary treatment alone. EoE is an emergent condition that may involve the pediatric surgeon in both the diagnosis and treatment. Typical endoscopic findings and biopsy are required for proper diagnosis. Ambulatory manometry reveals a marked propulsive dysfunction that explains impaction. This dysfunction is reversible, since the symptoms usually disappear with steroids or antiallergic treatment. Eosinophilic esophagitis (EoE) is an immune-mediated disorder that may be related to exposure to additive chemicals in crops, air pollutants, or supplements found within livestock. Co-occurring allergic or atopic diseases including atopic dermatitis, food allergies, and asthma are also commonly seen in 70% of cases and help guide diagnosis. Diagnosis of EoE requires eosinophilic infiltration greater than 15 eosinophils per high power field (HPF) with endoscopic evidence of abnormal esophageal changes. Here, we discuss a rare presentation of food bolus impaction secondary to EoE after ingestion of a nasal decongestant and antihistamine pill that has previously never been described in the literature. A 22-year-old male with no significant past medical history presented to the emergency department (ED) with a chief complaint of a sudden onset respiratory distress, regurgitation of clear oral secretions, and globus sensation post ingestion of a fexofenadine-pseudoephedrine tablet. Prior to intake of the capsule, the patient was consuming liquids and solids appropriately. The patient was afebrile, hypertensive at 172/114, and found to have a normal heart rate of 88 bpm and a respiration rate of 18 breaths per minute. An esophagogastroduodenoscopy (EGD) was performed, which revealed a fexofenadine-pseudoephedrine capsule at 23 cm from the incisors along with a superficial ulceration at the corresponding level in the esophagus. The foreign body was successfully removed using raptor forceps. Further visualization demonstrated trachealization of the esophagus and furrowing and severe narrowing (&lt; 10mm), which raised suspicion for EoE. Proximal biopsy indicated 16 intraepithelial eosinophils per HPF within the squamous epithelium, likely compatible with EoE. The patient tolerated the procedure well and was discharged on an eight-week course of proton-pump inhibitors. EoE is defined as an immune-mediated esophageal disease characterized histologically by eosinophil-predominant inflammation. Our patient was reported to have up to 30 eosinophils per HPF from the proximal esophageal biopsy, which satisfies the requirements for an EoE diagnosis. Based on the current literature review, there have been no other reported cases of symptomatic food bolus impaction secondary to EoE after ingestion of antihistamines. Eosinophilic esophagitis (EE) is a motility disorder of the esophagus that typically presents with dysphagia. The objective of the present study was to explore patient characteristics, clinical and endoscopic features, and response to treatment of patients with EE. Patients were selected retrospectively based on a review of biopsy results from previous endoscopies performed between 2004 and 2008. A total of 54 patients (41 men and 13 women) with biopsy-proven EE were included in the study. Further information regarding the patients' clinical and endoscopic features, and response to treatment were obtained through chart reviews and patient telephone interviews. The mean age of the patients at symptom onset was 30 years. All patients complained of dysphagia, 81% had a history of bolus obstruction, 43% had a history of asthma and 70% had a history of environmental allergies. Thirty-three per cent had a family history of asthma, while 52% had a family history of food or seasonal allergies. The most common endoscopic findings were rings and⁄or corrugations, which were found in 63% of patients. Swallowed fluticasone therapy resulted in symptom resolution in 74% of patients; however, 79% of these patients relapsed after discontinuing fluticasone therapy and required repeat treatments. Esophageal dilation was complication free and resulted in improvement in 80% of patients. However, 83% of those reporting improvement relapsed within one year. The clinical and endoscopic findings were similar to those found in the literature, with most patients requiring ongoing, repeated therapies. Further studies are needed to assess the safety and efficacy of treatment modalities ideally suited to patients with EE. Esophagus GERD (most common cause of heartburn) occurs when acid refluxes from the stomach and inflames the esophagus. Esophageal spasms typically occur after eating or drinking and may be combined with difficulty swallowing. Esophageal strictures Esophageal cancers Esophagitis GERD Eosinophilic esophagitis - a disease commonly associated with other atopic diseases such as asthma, food allergies, seasonal allergies, and atopic skin disease Mallory-Weis tears - tears of the superficial mucosa of the esophagus that are subsequently exposed to gastric acid commonly due to vomiting and/or retching Chemical esophagitis - related to the intake of caustic substances, excessive amounts of hot liquids, alcohol, or tobacco smoke Infections may explain heartburn symptoms. These especially include CMV and certain fungal infections, most common in immunocompromised persons Stomach An esophageal food bolus obstruction is a medical emergency caused by the obstruction of the esophagus by an ingested foreign body. It is usually associated with diseases that may narrow the lumen of the esophagus, such as eosinophilic esophagitis, Schatzki rings, peptic strictures, webs, or cancers of the esophagus; rarely it can be seen in disorders of the movement of the esophagus, such as nutcracker esophagus. While some esophageal food boli can pass by themselves or with the assistance of medications, some require the use of endoscopy to push the obstructing food into the stomach, or remove it from the esophagus. The use of glucagon, while common, has not been found to be useful. Eponymous names include 'the steakhouse syndrome' and 'backyard barbeque syndrome'. Predominant symptoms in school-aged children and adolescents include difficulty swallowing, food impaction, and choking/gagging with meals- particularly when eating foods with coarse textures. Other symptoms in this age group can include abdominal/chest pain, vomiting, and regurgitation. The predominant symptom in adults is difficulty swallowing; however, intractable heartburn and food avoidance may also be present. Due to the long-standing inflammation and possible resultant scarring that may have gone unrecognized, adults presenting with EoE tend to have more episodes of esophageal food impaction as well as other esophageal abnormalities such as Schatzki ring, esophageal webs, and in some cases, achalasia. To investigate endoscopic findings in patients with Schatzki rings (SRs) with a focus on evidence for eosinophilic esophagitis (EoE). We consecutively approached all adult patients scheduled for elective outpatient upper endoscopy for a variety of indications at the German Diagnostic Clinic, Wiesbaden, Germany between July 2007 and July 2010. All patients with endoscopically diagnosed SRs, defined as thin, symmetrical, mucosal structures located at the esophagogastric junction, were prospectively registered. Additional endoscopic findings, clinical information and histopathological findings with a focus on esophageal eosinophilia (≥ 20 eosinophils/high power field) were recorded. The criteria for active EoE were defined as: (1) eosinophilic tissue infiltration ≥ 20 eosinophils/hpf; (2) symptoms of esophageal dysfunction; and (3) exclusion of other causes of esophageal eosinophilia. Gastroesophageal reflux disease was excluded by proton pump inhibitor treatment prior to endoscopy. The presence of ≥ 20 eosinophils/hpf in esophageal biopsies in patients that did not fulfil the criteria of EoE was defined as esophageal hypereosinophilia. A SR was diagnosed in 171 (3.3%; 128 males, 43 females, mean age 66 ± 12.9 years) of the 5163 patients that underwent upper gastrointestinal-endoscopy. Twenty of the 116 patients (17%) from whom esophageal biopsies were obtained showed histological hypereosinophilia (≥ 20 eosinophils/hpf). Nine of these patients (8 males, 1 female, mean age 49 ± 10 years) did not fulfill all diagnostic criteria of EoE, whereas in 11 (9%) patients with ≥ 20 eosinophils/hpf, a definite diagnosis of EoE was made. Three of the 11 patients (27%) with definite EoE had no suspicious endoscopic features of EoE. In contrast, in the 25 patients in whom EoE was suspected by endoscopic features, EoE was only confirmed in 7 (28%) patients. Patients with EoE were younger (mean age 41.5 ± 6.5 vs 50.5 ± 11.5 years, P = 0.012), were more likely to have a history of allergies (73% vs 29%, P = 0.007) and complained more often of dysphagia (91% vs 34%, P = 0.004) and food impaction (36% vs 6%, P = 0.007) than patients without EoE. Endoscopically, additional webs were found significantly more often in patients with EoE than in patients without EoE (36% vs 11%, P = 0.04). Furthermore, the SR had a tendency to be narrower in patients with EoE than in those without EoE (36% vs 18%, P = 0.22). The percentage of males (73% vs 72%, P = 1.0) and frequency of heartburn (27% vs 27%, P = 1.0) were not significantly different in both groups. The 9 patients with esophageal hypereosinophilia that did not fulfil the diagnostic criteria of EoE were younger (mean age 49 ± 10 years vs 58 ± 6 years, P = 0.0008) and were more likely to have a history of allergies (78% vs 24%, P = 0.003) than patients with &lt; 20 eosinophils/hpf. Predictors of EoE were younger age, presence of dysphagia or food impaction and a history of allergies. A significant proportion of patients with SRs also have EoE, which may not always be suspected according to other endoscopic features. Distal esophageal or Schatzki's rings are a common cause of intermittent solid food dysphagia requiring endoscopic dilation for relief. Similarly, eosinophilic esophagitis (EE) is a rapidly emerging disease in both children and young adults, and manifests as dysphagia to solids and/or episodic food bolus impaction. Endoscopic findings vary considerably among patients with EE, posing significant recognition and management challenges. Esophageal dilation in EE can be painful and risky. This case report describes a patient with acute food bolus impaction due to underlying Schatzki's ring and associated but clinically indolent EE, and highlights some safety aspects of esophageal dilation. EoE is diagnosed based on the combination of typical esophageal symptoms and esophageal mucosal biopsies demonstrating squamous epithelial eosinophil-predominant inflammation. Alternative etiologies of esophageal eosinophilia include GERD, drug hypersensitivity, connective tissue disorders, hypereosinophilic syndrome, and infection. Current evidence indicates that EoE is an immunologic disorder induced by antigen sensitization in susceptible individuals. Dietary factors play an important role in both the pathogenesis and treatment of EoE. Aeroallergens may also contribute, but the evidence is weaker. The natural history of EoE is unclear, but an increased risk of esophageal stricture development paralleling the duration of untreated disease has been noted. Diseases of the Esophagus FIGURE 347-11 Endoscopic features of (A) eosinophilic esophagitis (EoE), (B) Candida esophagitis, (C) giant ulcer associated with HIV, (D) and a Schatzki ring. Eosinophilic esophagitis (EE) is an inflammatory condition characterized by intense eosinophilic infiltration of the esophagus. EE is frequently misdiagnosed as gastroesophageal reflux disease. Here, we present a child with EE and a characteristic endoscopic finding, \"ringed esophagus\". An 11-year-old Saudi boy presented with dysphagia for 1 year. He had experienced an intermittent sensation of solid food sticking in his chest, which was relieved by drinking liquids. A barium swallow excluded anatomical causes of dysphagia, but revealed multiple-ringed esophagus. Endoscopy showed a furrowing and trachealizing appearance of the entire esophagus. Hisologically, extensive eosinophilic infiltration was a feature in biopsies obtained from the esophagus. The child responded well to a 2-month course of inhaled fluticasone. Symptoms recurred 3 months after discontinuation of therapy, which necessitated resumption of inhaled fluticasone. The endoscopic appearance of multiple esophageal rings should raise suspicion of EE and be confirmed by esophageal biopsies. For subtypes To treat eosinophilic esophagitis, avoiding any allergens that may be stimulating the eosinophils is recommended. As for medications, proton pump inhibitors and steroids can be prescribed. Steroids that are used to treat asthma can be swallowed to treat eosinophil esophagitis due to nonfood allergens. The removal of food allergens from the diet is included to help treat eosinophilic esophagitis. For infectious esophagitis, medicine is prescribed based on what type of infection is causing the esophagitis. These medicines are prescribed to treat bacterial, fungal, viral, and/or parasitic infections. Procedures An endoscopy can be used to remove ill fragments. Surgery can be done to remove the damaged part of the esophagus. For reflux esophagitis, a fundooplication can be done to help strengthen the lower esophageal sphincter from allowing backflow of the stomach into the esophagus. For esophageal stricture, a gastroenterologist can perform a dilation of the esophagus. A 17-year-old patient was transferred to the emergency room with an impacted food bolus by colleagues from the Department of Otorhinolaryngology. The examination of ear, nose and throat revealed significant amounts of saliva in both recessus piriformis, a radiologic examination of the esophagus showed a foreign body with a diameter of 1.6 cm in the region of the transitional zone of esophagus and stomach with a support level of the contrast medium. Clinical examination and laboratory tests showed no abnormalities. An emergency gastroscopy was performed. The foreign body, already evident in the barium swallow, was found in the distal esophagus. The foreign body was identified as a food bolus and gently advanced into the stomach with the aid of the gastroscope. In the stomach further food residues were detected and the examination was aborted because of increased risk of aspiration. On the next day, an elective gastroscopy was performed. Several biopsies were obtained from the esophagus because eosinophilic esophagitis (EE) was suspected due to clinical symptoms. Histological work-up showed a significant amount of eosinophilic granulocytes (&gt; 15 eosinophils/HPF, 400 x) and reactive changes in the distal esophagus. Therefore, EE was diagnosed. Fluticasone therapy led to amelioration of symptoms and there was no evidence of recurring bolus impaction during follow-up. Eosinophilic esophagitis (EoE) is an allergic inflammatory condition of the esophagus that involves eosinophils, a type of white blood cell. In healthy individuals, the esophagus is typically devoid of eosinophils. In EoE, eosinophils migrate to the esophagus in large numbers. When a trigger food is eaten, the eosinophils contribute to tissue damage and inflammation. Symptoms include swallowing difficulty, food impaction, vomiting, and heartburn. Eosinophilic esophagitis was first described in children but also occurs in adults. The condition is not well understood, but food allergy may play a significant role. The treatment may consist of removal of known or suspected triggers and medication to suppress the immune response. In severe cases, it may be necessary to enlarge the esophagus with an endoscopy procedure. While knowledge about EoE has been increasing rapidly, diagnosis of EoE can be challenging because the symptoms and histo-pathologic findings are not specific. Lymphocytic esophagitis Lymphocytic esophagitis is a rare and poorly understood entity associated with an increased amount of lymphocytes in the lining of the esophagus. It was first described in 2006. Disease associations may include Crohn's disease, gastroesophageal reflux disease and coeliac disease. It causes similar changes on endoscopy as eosinophilic esophagitis including esophageal rings, narrow-lumen esophagus, and linear furrows. Caustic esophagitis Caustic esophagitis is the damage of tissue via chemical origin. This occasionally occurs through occupational exposure (via breathing of fumes that mix into the saliva which is then swallowed) or through pica. It occurred in some teenagers during the fad of intentionally eating Tide pods. By severity The severity of reflux esophagitis is commonly classified into four grades according to the Los Angeles Classification: Eosinophilic esophagitis is an unrecognized and emerging entity. Its incidence increases with allergic disorders. A 29-year-old man presented with a 4-year history of intermittent and paroxysmal dysphagia. The triad including allergy, young age, and impaction of foreign bodies, combined with a chronic dysphagia is almost pathognomonic of eosinophilic esophagitis. Endoscopic esophageal features can be diverse, so systematic esophageal biopsies are required. Diagnosis is established with the demonstration of an eosinophilic infiltrate with a cell count exceeding 15 eosinophils per high power field (×400). First line therapy includes swallowed topical corticosteroids and removal of an allergic cause, when it could be identified.\nHere is the question:\nDIGESTIVE SYSTEM: 18-year-old young man with a history of asthma, allergy to pollens, mites and cat hair, comes to the emergency room referring sensation of food detention at retrosternal level with practical inability to swallow his own saliva. He refers similar episodes on other occasions that have subsided spontaneously within a few minutes. Which of the following is the most likely diagnosis?\nHere are the potential choices:\n1. Barrett's esophagus.\n2. Distal esophageal ring (Schatzki).\n3. Infectious esophagitis.\n4. Eosinophilic esophagitis.\nThe correct answer is: 4. Eosinophilic esophagitis."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n This case sieries gives three different cases with three different presentation and different approaches to a patient with short stature. Material: CASE 1: A 13 Year old female brought by her parents with complaints of decreased height appropriate for age. O/E height- 127cm(&amp;lt;-3SD), weight 42kg, MPH- 150cm, arm span to height ratio- 1:1, secondary sexual characters- tanners stage 2. X-ray hand with wrist- bone age 0f 12 years. TFT- within normal limits. MRI pituitary- normal study. Patient suspected to have isolated growth harmone deficiency. Growth harmone stimulation test done after sex steroid priming which showed results of growth harmone deficiency. Patient started on 1.5mg growth harmone s/c per day. CASE 2: A 18 year old boy brought by his parents with complaints of decreased height appropriate for age and absence of facial, axillary and pubic hair. O/E height- 145cm, weight 55kg, MPH- 165cm, arm span to height ratio 1.1:1, external genitalia- male, testes in scrotum, testicular volume- 2.5ml, secondary sexual characters- tanners stage 1. Xray hand with wrist- bone age of 17years. TFT within normal limits. FSH, LH, testosterone levels were low. Growth harmone stimulation test after sex steroid priming showed low growth harmone levels. MRI pituitary showed empty sella. Patient diagnosed to have panhypopititarism and started on inj. Growth harmone 0.24mg/kg/week subcutaneous and inj.testosterone 100mg/month IM. CASE 3: A 17 year old female brought by her parents with complaints of decreased height appropriate for age and absent menstruation till date. O/E height- 143cm(&amp;lt;- 3SD), weight- 45 kg, MPH- 170cm, arm span to height ratio 1.1:1, external genitalia - female, secondary sexual characters - tanners stage 1. Xray hand with wrist - bone age of 16years. Further evaluation showed TSH-21.8. MRI pelvis showed streak gonads. Serum growth harmone and IGF levels within normal limits. Estradiol was low and FSH, LH were high. Karyotyping showed 45XO. Patient diagnosed to have turner's syndrome. Since x-ray showed non-closure of epiphysis, patient started on growth harmone 0.33 mg/kg/week and advised not to take estrogen till epiphyseal closure. Observation: case 1: functonal pituitary pathology Case 2: structural pituitary pathology Case 3: gonadal pathology Conclusion: Short stature can be a manifestation of isolated GH defeciency, Hypogonadotropic Hypogonadism or Hypergonadotropic hypergonadism. Turner Syndrome (TS) is caused by monosomy or structural abnormalities of the X chromosome, with a prevalence of about 1/2000 females live birth. Most important clinical features of TS are short stature and gonadal failure. Approximately one third of girls with TS may undergo spontaneous puberty. Here we report on the case of a girl with a rare 45X0/47XXX mosaic TS exhibiting a precocious puberty. The patient was diagnosed with TS at the age of 4 years, upon a diagnostic work-up for dysmorphic features. Chromosome analysis revealed a mosaic karyotype (45X0/47XXX). She presented with normal height and normal growth velocity so that Growth Hormone (GH) therapy was not started. She was referred to our Department at the age of 7 years and 10 months, because of vaginal bleeding. A physical examination revealed a Tanner stage III for breast and Tanner stage III for pubic hair development. Height and weight were within the normal range for age. Psychological evaluation showed moderate global developmental delay, together with emotional and social immaturity and reading difficulties. The growth rate was accelerated. Her bone age was 10 years. Pelvic ultrasound demonstrated increased size for age of both the uterus and the ovaries, with bilateral ovarian follicles. GnRH stimulation test revealed pubertal response of gonadotropins (peak LH 22.5 mIU/ml). MRI of the brain was normal. These clinical, radiologic and laboratory findings were consistent with a diagnosis of idiopathic central precocious puberty; therefore, GnRH analog therapy was started, in order to slow pubertal progression and to preserve adult stature. Furthermore, GH treatment was added to further improve adult height. Our case highlights the possibility of precocious puberty as an atypical clinical feature of TS. Thus, precocious puberty may occur in TS girls when a dosage compensation by the cell line with more than two X chromosomes allows normal ovarian function. GnRH analog therapy in addition to GH treatment should be recommended in TS girls with precocious puberty in order to slow pubertal progression and to preserve adult stature. Figure 29.13 Right A: A 16-year-old girl with delayed puberty. Breast budding began at 11 years of age, but there was no further development. During the year before presentation, her scholastic performance in school deteriorated, she gained 25 lb, she became increasingly lethargic, and nocturia and polydypsia were noted. Initial evaluation documented low follicle-stimulating hormone, elevated prolactin, and a bone age of 10.5 years. Computed tomography scanning documented a large hypothalamic neoplasm that proved to be an ectopic germinoma. The patient was also documented to be hypothyroid and hypoadrenal and to have diabetes insipidus. Despite the elevated prolactin, she had no galactorrhea because of the minimal breast development. (From Rebar RW. Normal and abnormal sexual differentiation and pubertal development. In: Moore TR, Reiter RC, Rebar RW, et al., eds. Gynecology and obstetrics: a longitudinal approach. New York: Churchill Livingstone, 1993:97–133, with permission.) Floating-Harbor syndrome (FHS) is a rare genetic disorder characterized by short stature, delayed bone age, mild to moderate mental retardation, speech problems, and peculiar craniofacial features. In these patients pubertal development has been reported to be normal. In this paper, we describe a girl with FHS who developed precocious puberty. FHS diagnosis was made at 2 years 5 months on the basis of peculiar clinical features. At 7 years 7 months, the girl began pubertal development; her height was 112.5 cm (-2.42 SDS) and pubertal staging was B2 PH2 AH1. LHRH test underlined LH and FSH peak values of 11.7 mIU/ml and 6.2 mIU/ml, respectively. Plasma levels of 17beta-estradiol were normal (8.5 pg/ml). Ophthalmological and neurological examinations, including nuclear magnetic resonance imaging of the brain, were normal. Treatment with gonadotrophin-releasing hormone analogue was begun. At 10 years 1 month, because of reduced height velocity, her growth hormone secretion was evaluated with diagnosis of neurosecretory dysfunction; hGH therapy was begun. The patient showed a good response to hGH treatment, reaching a normal adult height (156.1 cm; -1.20 SDS). This report suggests that, in patients with FHS, precocious puberty should be taken into consideration; in these patients, a careful endocrinological followup for the possible presence of growth and pubertal disorders is needed. Initial workup for delayed puberty not due to a chronic condition involves measuring serum FSH, LH, testosterone/estradiol, as well as bone age radiography. If it becomes clear that there is a permanent defect of the reproductive system, treatment usually involves replacement of the appropriate hormones (testosterone/dihydrotestosterone for boys, estradiol and progesterone for girls). Timing and definitions Puberty is considered delayed when the child has not begun puberty when two standard deviations or about 95% of children from similar backgrounds have. In North American girls, puberty is considered delayed when breast development has not begun by age 13, when they have not started menstruating by age 15, and when there is no increased growth rate. Furthermore, slowed progression through the Tanner scale or lack of menarche within 3 years of breast development may also be considered delayed puberty. Adiposogenital dystrophy is a condition that may be caused by tertiary hypogonadism originating from decreased levels in GnRH. Low levels of GnRH has been associated with defects of the feeding centers of the hypothalamus, leading to an increased consumption of food and thus caloric intake. Presentation It is characterized by: Obesity Growth delays and delayed sexual development, atrophy or hypoplasia of the gonads, and altered secondary sex characteristics, Headaches Problems with vision polyuria, polydipsia. It is usually associated with tumors of the hypothalamus, causing increased appetite and depressed secretion of gonadotropin. It seems to affect males mostly.Many overweight children may appear to have the disorder because of the concurrence of obesity and retarded sexual development; these children have no endocrine disturbances, however, and they mature normally after delayed puberty. Anorexia nervosa can have serious implications if its duration and severity are significant and if onset occurs before the completion of growth, pubertal maturation or prior to attaining peak bone mass. Both height gain and pubertal development are dependent on the release of growth hormone and gonadotrophins (LH and FSH) from the pituitary gland. Suppression of gonadotropins in patients with anorexia nervosa has been frequently documented. In some cases, especially where onset is pre-pubertal, physical consequences such as stunted growth and pubertal delay are usually fully reversible. Height potential is normally preserved if the duration and severity of anorexia nervosa are not significant and/or if the illness is accompanied with delayed bone age (especially prior to a bone age of approximately 15 years), as hypogonadism may negate the deleterious effects of undernutrition on stature by allowing for a longer duration of growth compared to controls. In such cases, appropriate early Children and adolescents Hyperthyroidism has unique effects in children on growth and pubertal development, e.g. causing epiphyseal maturation. In growing children, accelerated bone growth from hyperthyroidism can increase osteogenesis in the short term, but generally results in short-stature adults compared with the predicted heights. Pubertal development tends to be delayed, or slowed. Girls who have undergone menarche may develop secondary amenorrhea. Hyperthyroidism is associated with high sex hormone-binding globulin (SHBG), which may result in high serum estradiol levels in girls and testosterone levels in boys. However, unbound or free levels of these hormones are decreased. Hyperthyroidism before the age of four may cause neurodevelopmental delay. A study by Segni et al. suggests that permanent brain damage can occur as a result of the illness. Trichotillomania (TTM) is defined by the Diagnostics and Statistic Manual of Mental Disorders, 4th edition (DMS-IV) as hair loss from a patient`s repetitive self-pulling of hair. The disorder is included under anxiety disorders because it shares some obsessive-compulsive features. Patients have the tendency towards feelings of unattractiveness, body dissatisfaction, and low self-esteem (1,2). It is a major psychiatric problem, but many patients with this disorder first present to a dermatologist. An 11-year-old girl came to our department with a 2-month history of diffuse hair loss on the frontoparietal and parietotemporal area (Figure 1). She had originally been examined by a pediatrician with the diagnosis of alopecia areata. The patient`s personal history included hay fever and shortsightedness, and she suffered from varicella and mononucleosis. Nobody in the family history suffered from alopecia areata, but her father has male androgenetic alopecia (Norwood/Hamilton MAGA C3F3). The mother noticed that the child had had changeable mood for about 2 months and did not want to communicate with other persons in the family. The family did not have any pet at home. At school, her favorite subjects were Math and Computer Studies. She did not like Physical Education and did not participate in any sport activities during her free time. This was very strange because she was obese (body-mass index (BMI) 24.69). She was sometimes angry with her 13-year-old sister who had better results at school. The girl had suddenly started to wear a blue scarf. The parents did not notice that she pulled out her hair at home. Dermatological examination of the capillitium found a zone of incomplete alopecia in the frontoparietal and parietotemporal area, without inflammation, desquamation, and scaring. Hairs were of variable length (Figure 1). There was a patch of incomplete alopecia above the forehead between two stripes of hair of variable length (Figure 2). The hair pull test was negative along the edges of the alopecia. Mycological examination from the skin capillitium was negative. The trichoscopy and skin biopsy of the parietotemporal region of the capillitium (Figure 3) confirmed trichotillomania. Laboratory tests (blood count, iron, ferritin, transferrin, selenium, zinc, vitamin B12, folic acid, serology and hormones of thyroid gland) were negative. We referred the girl for ophthalmologic and psychological examination. Ophthalmologic examination proved that there was no need to add any more diopters. The psychological examination provided us with a picture in which she drew her family (Figure 4). The strongest authority in the family was the mother because she looked after the girls for most of the day. She was in the first place in the picture. The father had longer working hours and spent more time outside the home. He worked as a long vehicle driver. He was in the second place in the picture. There was sibling rivalry between the girls, but the parents did not notice this problem and preferred the older daughter. She was successful at school and was prettier (slim, higher, curly brown hair, without spectacles). Our 11-years-old patient noticed all these differences between them, but at her level of mental development was not able to cope with this problem. She wanted to be her sister's equal. The sister is drawn in the picture in the third place next to father, while the patient's own figure was drawn larger and slim even though she was obese. Notably, all three female figures had very nice long brown hair. It seemed that the mother and our patient had better quality of hair and more intense color than the sister in the drawing. The only hairless person in the picture was the father. The girl did not want to talk about her problems and feelings at home. Then it was confirmed that our patient was very sensitive, anxious, willful, and withdrawn. She was interested in her body and very perceptive of her physical appearance. From the psychological point of view, the parents started to pay more interest to their younger daughter and tried to understand and help her. After consultation with the psychiatrist, we did not start psychopharmacologic therapy for trichotillomania; instead, we started treatment with cognitive behavioral therapy, mild shampoo, mild topical steroids (e.g. hydrocortisone butyrate 0.1%) in solution and methionine in capsules. With parents' cooperation, the treatment was successful. The name trichotillomania was first employed by the French dermatologist Francois Henri Hallopeau in 1889, who described a young man pulling his hair out in tufts (3-5). The word is derived from the Greek thrix (hair), tillein (to pull), and mania (madness) (5). The prevalence of TTM in the general adult population ranges from 0.6% to 4%, and 2-4% of the general psychiatric outpatient population meet the criteria for TTM (2-5). The prevalence among children and adolescents has been estimated at less than 1% (5). The disease can occur at any age and in any sex. The age of onset of hair pulling is significantly later for men than for women (3). There are three subsets of age: preschool children, preadolescents to young adults, and adults. The mean age of onset is pre-pubertal. It ranges from 8 to 13 years (on average 11.3 years) (2-5). The occurrence of hair-pulling in the first year of life is a rare event, probably comprising &lt;1% of cases (5). The etiology of TTM is complex and may be triggered by a psychosocial stressor within the family, such as separation from an attachment figure, hospitalization of the child or parent, birth of a younger sibling, sibling rivalry, moving to a new house, or problems with school performance. It has been hypothesized that the habit may begin with \"playing\" with the hair, with later chronic pulling resulting in obvious hair loss (2). Environment is a factor because children usually pull their hair when alone and in relaxed surroundings. The bedroom, bathroom, or family room are \"high-risk\" situations for hair-pulling (5). Men and women also differed in terms of the hair pulling site (men pull hair from the stomach/back and the moustache/beard areas, while women pull from the scalp) (3). Pulling hair from siblings, pets, dolls, and stuffed animals has also been documented, often occurring in the same pattern as in the patient (5). Genetic factors contributing to the development of TTM are mutations of the SLITRK1 gene, which plays a role in cortex development and neuronal growth. The protein SAPAP3 has been present in 4.2% of TTM cases and patients with obsessive-compulsive disorder (OCD). It may be involved in the development of the spectrum of OCD. A significantly different concordance rate for TTM was found in monozygotic (38.1%) compared with dizygotic (0%) twins in 34 pairs (3). The core diagnostic feature is the repetitive pulling of hairs from one`s own body, resulting in hair loss. The targeted hair is mostly on the scalp (75%), but may also be from the eyebrows (42%), eyelashes (53%), beard (10%), and pubic area (17%) (3,5). There are three subtypes of hair pulling - early onset, automatic, and focused. Diagnostic criteria for TTM according to DSM-IV criteria are (2,3,5): 1) recurrent pulling of one`s hair resulting in noticeable hair loss; 2) an increasing sense of tension immediately prior to pulling out the hair or when attempting to resist the behavior; 3) pleasure, gratification, or relief when pulling out the hair; 4) the disturbance is not better accounted for by another mental disorder and is not due to a general medical condition (e.g., a dermatologic condition); 5) the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. The differential diagnosis includes alopecia areata (Table 1) (6), tinea capitis, telogen effluvium, secondary syphilis, traction alopecia, loose anagen syndrome, lichen planopilaris, alopecia mucinosa, and scleroderma (2-5). Biopsy of an involved area (ideally from a recent site of hair loss) can help to confirm the diagnosis (5). On histologic examination, there are typically increased numbers of catagen and telogen hairs without evidence of inflammation. Chronic hair pulling induces a catagen phase, and more hairs will be telogen hairs. Pigment casts and empty anagen follicles are often seen. Perifollicular hemorrhage near the hair bulb is an indicator of TTM (2). Complications of TTM are rare, but they comprise secondary bacterial infections with regional lymphadenopathy as a result of picking and scratching at the scalp. Many patients play with and ingest the pulled hairs (e.g. touching the hair to lips, biting, and chewing). Trichophagia (ingestion of the hair) can lead to a rare complication named trichobezoar (a \"hair ball\" in stomach). This habit is present in approximately 5% to 30% of adult patients, but it is less frequent in children. Patient with trichophagia present with pallor, nausea, vomiting, anorexia, and weight loss. Radiologic examination and gastroscopy should not be delayed (2,4,5). The management of the disease is difficult and requires strong cooperation between the physician, patient, and parents. The dermatologist cannot take part in the therapy, strictly speaking, but without the psychological, psychopharmacologic, and topic dermatologic treatment a vicious circle will be perpetuated.  The clinical and biological presentation of idiopathic growth hormone (GH) deficiency (GHD) varies greatly, demonstrating the variety of its pathogenic features and explaining why it is difficult to diagnose. We examined 48 patients (26 males) with certain idiopathic GHD diagnosed at 4.8 +/- 0.7 yr. The symptoms that led to the diagnosis of GHD were low growth rate (33 cases), hypoglycemia (12 cases), microphallus (1 case) and in 2 cases the GHD was diagnosed from magnetic resonance imaging (MRI) performed for delayed mental development (1 case), or congenital blindness (1 case). The 2 other cases were diagnosed from routine GH evaluation performed at birth because of idiopathic GHD in siblings. Thirteen had congenital malformation. Twenty three cases (48%) had features suggesting that the GHD was of antenatal origin. Six of them were born by breech delivery. Twenty one cases (44%) had features suggesting a hypothalamic origin. The decrease in growth rate occurred before 0.5 year in 21 (55%), before 1 year in 27 (71%) and before 2 years in 30 (79%): 8 patients (21%) maintained a normal growth rate after this age. Among these 8 patients, 5 had signs suggesting an antenatal origin and 4 had severe episodes of hypoglycemia from birth. The mean GH peak after the pharmacological stimulation test was 3.6 +/- 0.5 micrograms/l. The mean plasma insulin-like growth factor 1 (IGFI) was 0.1 +/- 0.02 U/ml. The GH deficiency was associated with deficiencies of thyrotropin in 26 (54%) and of adrenocorticotrophic hormone in 17 (35%) patients. Among the 15 patients of pubertal age, 9 (60%) had gonadotrophin deficiency. No patient had diabetes insipidus. The MRI showed pituitary stalk interruption syndrome in 39 patients and normal pituitary anatomy in 6 patients. GH treatment reduced the difference between target and actual heights from 3.5 SD (before) to I SD (after 3 years) in the 39 more recently seen patients given 0.5-0.6 U/kg/w GH in 6 or 7 weekly injections. Height gain during the first year and cumulative height gain over 3 years (SD) was correlated negatively with height (SD) at the start of treatment (p &lt; 0.01). We conclude that most of the patients with GHD have features suggesting an antenatal origin. Despite this early origin, the decreased growth rate may occur after 2 years. Twenty four children with hypopituitarism were treated with growth hormone from 6-15 years of age until cessation of growth. The height deficit decreased from -4.2SD to -2.2SD. Final height was above the 3rd percentile in half of the patients. There was no difference in final height between patients with and without additional gonadotropin deficiency. Spontaneous puberty started late but at a normal bone age and its course was normal. In girls with gonadotropin deficiency low dose oestrogen given at unchanged growth hormone doses did not accelerate growth. Final height was closely correlated with the degree of growth retardation at the beginning of treatment (r = 0.73, p less than 0.001). In 17 of the 79 patients treated with growth hormone compliance was bad. The main cause of bad compliance was the low educational level of the parents. It is concluded that final height in growth hormone deficiency can be increased with earlier diagnosis and improved compliance. The pathogenesis remains unknown in the majority of patients with precocious puberty, and yet infrequently such causative cerebral lesions as hypothalamic hamartomas are associated with sexual precocity. We reported a rare case of suprasellar arachnoid cyst in an infant presenting with precocious puberty, which eventually disappeared after a cyst-peritoneal shunt. It was believed that the mass effect of the arachnoid cyst upon the hypothalamus was, at least in part, responsible for development of precocious puberty. The role of surgical decompression of the cyst was also discussed. A one-year-old girl was admitted to the hospital for evaluation of genital bleeding which had persisted on and off for two months. The height, 80cm, and the weight, 12.4kg, exceeded by far the two standard deviations from the mean level of the normal population. In addition she had the development of breast tissue as classified Tanner's Stage II, and both pubic and axillary hair. The bone age by skeletal survey of the hand was rated as 3 years. Endocrinological examination showed that serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol had increased for her age, to levels equivalent to those for females at puberty. An LH-RH test revealed an excessive LH reaction. There were no definite neurological deficits. CT and MRI demonstrated the presence of a large arachnoid cyst involving the suprasellar region as well as the right middle and posterior fossa. After the patient underwent a cyst-peritoneal shunt, the cyst decreased in size and such symptoms as genital bleeding and breast growth disappeared. Serum levels of her LH and FSH also significantly decreased.(ABSTRACT TRUNCATED AT 250 WORDS) Autoimmune thyroiditis, the most frequent cause of acquired hypothyroidism in childhood and adolescents, is characterized by raised levels of the specific antibodies to thyroperoxidase (TPOAb) and thyroglobulin (TgAb). We report a girl aged 10 years and 9 months who presented with arrested growth and breast development (thelarche). She also exhibited myxedema of the face and legs, prominent striae on the thighs, dry, cold skin, and hypertrichosis on her back. There was no goiter, no history of thyroid pain and no family history of thyroid disease. She complained occasionally of a transient headache. The patient's height was below the 3rd percentile, while her body weight was at the 50th percentile and bone age was normal. Laboratory tests proved severe hypothyroidism (fT4 0 ng/dl, fT3 0.99 pg/ml, TSH &gt;100 microIU/ml plus an increased titer of TPOAb). Thyroid ultrasound supported the diagnosis of thyroiditis. Pituitary PRL and FSH levels and peripheral estradiol were all elevated. L-Thyroxine therapy, instituted following diagnosis, improved the growth velocity to 11 cm/year and the FSH and E2 levels were normalized to prepubertal values. Complete regression of the breast development was observed within 4 months. However, 4 months later a true (central), isosexual LHRH-dependent puberty started. The pubertal features at the time of the original diagnosis might be explained by: 1. the direct action of elevated TRH on gonadotropes to stimulate gonadotropin secretion and on lactotrophes to stimulate PRL secretion, and 2. TSH action on LH and mostly FSH receptors (homologous to TSH receptors) in the ovary, stimulating the secretion of estradiol. Twenty-seven out of thirty craniopharyngioma patients treated with human growth hormone (hGH) for 2 years or more (average 4.5 years) reached final adult heights above the population third centile, though none was above the fiftieth centile. However, only twelve of twenty-eight patients had final heights above the lower limits to be expected from their parents' heights. All patient eventually had long legs relative to sitting height (final mean subischial leg length SDS = + 0.2, final mean sitting height SDS = -3.0). Twenty-nine patients were TSH-deficient, twenty-two were ACTH-deficient, thirteen were deficient in ADH and all had total (85%) or partial (15%) gonadotrophin deficiency. Following the administration of testosterone or hCG the boys had, on average, only half the normal adolescent growth spurt. This may have been due to the lateness of starting androgens in these patients and we recommend, when considering height, that testosterone or hCG should be started when a bone age of 13.0 \"years' is reached or when a lower bone age has remained unchanged for a year. The girls showed adolescent height spurt; the average increase after oestrogen treatment commended was 1.7 cm.\nHere is the question:\nENDOCRINOLOGY: 14-year-old girl who consults for decreased growth for 2-3 years previously normal (provides data) and that other girls her age have greater physical and sexual development. Lately she has had headaches and visual problems that she notices in class and when studying. She has not had menarche or polydipsia or polyuria. Parents with normal height. Examination: short stature at -2.1 standard deviations, normal body proportions, little pubic hair and breast development. Campimetry shows left temporal partial hemianopsia. Bone age: delay of 2 years. General laboratory tests were normal. Gonadotrophins (FSH and LH) and estradiol are low. What do you think is the most appropriate response?\nHere are the potential choices:\n1. Decreased growth and sexual development, delayed bone age, headache and visual alteration suggest hormonal deficit and involvement of the optic chiasm.\n2. As she is a girl of pubertal age, it is most likely that her decreased growth and sexual retardation are due to Turner syndrome.\n3. She must not have a hypothalamic tumor because of the absence of polyuria and polydipsia. She probably has constitutional delay and her visual problem is refractive.\n4. A growth hormone deficiency may explain the developmental delay and low estradiol. To evaluate if she needs glasses, due to her headaches and visual disturbances.\n5. She could have a craniopharyngioma, but it would be rare if she had not shown symptoms before. Also, it would not justify low gonadotrophins and estradiol.\nThe correct answer is: ",
        "gold_answer": "1 Decreased growth and sexual development, delayed bone age, headache and visual alteration suggest hormonal deficit and involvement of the optic chiasm.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n This case sieries gives three different cases with three different presentation and different approaches to a patient with short stature. Material: CASE 1: A 13 Year old female brought by her parents with complaints of decreased height appropriate for age. O/E height- 127cm(&amp;lt;-3SD), weight 42kg, MPH- 150cm, arm span to height ratio- 1:1, secondary sexual characters- tanners stage 2. X-ray hand with wrist- bone age 0f 12 years. TFT- within normal limits. MRI pituitary- normal study. Patient suspected to have isolated growth harmone deficiency. Growth harmone stimulation test done after sex steroid priming which showed results of growth harmone deficiency. Patient started on 1.5mg growth harmone s/c per day. CASE 2: A 18 year old boy brought by his parents with complaints of decreased height appropriate for age and absence of facial, axillary and pubic hair. O/E height- 145cm, weight 55kg, MPH- 165cm, arm span to height ratio 1.1:1, external genitalia- male, testes in scrotum, testicular volume- 2.5ml, secondary sexual characters- tanners stage 1. Xray hand with wrist- bone age of 17years. TFT within normal limits. FSH, LH, testosterone levels were low. Growth harmone stimulation test after sex steroid priming showed low growth harmone levels. MRI pituitary showed empty sella. Patient diagnosed to have panhypopititarism and started on inj. Growth harmone 0.24mg/kg/week subcutaneous and inj.testosterone 100mg/month IM. CASE 3: A 17 year old female brought by her parents with complaints of decreased height appropriate for age and absent menstruation till date. O/E height- 143cm(&amp;lt;- 3SD), weight- 45 kg, MPH- 170cm, arm span to height ratio 1.1:1, external genitalia - female, secondary sexual characters - tanners stage 1. Xray hand with wrist - bone age of 16years. Further evaluation showed TSH-21.8. MRI pelvis showed streak gonads. Serum growth harmone and IGF levels within normal limits. Estradiol was low and FSH, LH were high. Karyotyping showed 45XO. Patient diagnosed to have turner's syndrome. Since x-ray showed non-closure of epiphysis, patient started on growth harmone 0.33 mg/kg/week and advised not to take estrogen till epiphyseal closure. Observation: case 1: functonal pituitary pathology Case 2: structural pituitary pathology Case 3: gonadal pathology Conclusion: Short stature can be a manifestation of isolated GH defeciency, Hypogonadotropic Hypogonadism or Hypergonadotropic hypergonadism. Turner Syndrome (TS) is caused by monosomy or structural abnormalities of the X chromosome, with a prevalence of about 1/2000 females live birth. Most important clinical features of TS are short stature and gonadal failure. Approximately one third of girls with TS may undergo spontaneous puberty. Here we report on the case of a girl with a rare 45X0/47XXX mosaic TS exhibiting a precocious puberty. The patient was diagnosed with TS at the age of 4 years, upon a diagnostic work-up for dysmorphic features. Chromosome analysis revealed a mosaic karyotype (45X0/47XXX). She presented with normal height and normal growth velocity so that Growth Hormone (GH) therapy was not started. She was referred to our Department at the age of 7 years and 10 months, because of vaginal bleeding. A physical examination revealed a Tanner stage III for breast and Tanner stage III for pubic hair development. Height and weight were within the normal range for age. Psychological evaluation showed moderate global developmental delay, together with emotional and social immaturity and reading difficulties. The growth rate was accelerated. Her bone age was 10 years. Pelvic ultrasound demonstrated increased size for age of both the uterus and the ovaries, with bilateral ovarian follicles. GnRH stimulation test revealed pubertal response of gonadotropins (peak LH 22.5 mIU/ml). MRI of the brain was normal. These clinical, radiologic and laboratory findings were consistent with a diagnosis of idiopathic central precocious puberty; therefore, GnRH analog therapy was started, in order to slow pubertal progression and to preserve adult stature. Furthermore, GH treatment was added to further improve adult height. Our case highlights the possibility of precocious puberty as an atypical clinical feature of TS. Thus, precocious puberty may occur in TS girls when a dosage compensation by the cell line with more than two X chromosomes allows normal ovarian function. GnRH analog therapy in addition to GH treatment should be recommended in TS girls with precocious puberty in order to slow pubertal progression and to preserve adult stature. Figure 29.13 Right A: A 16-year-old girl with delayed puberty. Breast budding began at 11 years of age, but there was no further development. During the year before presentation, her scholastic performance in school deteriorated, she gained 25 lb, she became increasingly lethargic, and nocturia and polydypsia were noted. Initial evaluation documented low follicle-stimulating hormone, elevated prolactin, and a bone age of 10.5 years. Computed tomography scanning documented a large hypothalamic neoplasm that proved to be an ectopic germinoma. The patient was also documented to be hypothyroid and hypoadrenal and to have diabetes insipidus. Despite the elevated prolactin, she had no galactorrhea because of the minimal breast development. (From Rebar RW. Normal and abnormal sexual differentiation and pubertal development. In: Moore TR, Reiter RC, Rebar RW, et al., eds. Gynecology and obstetrics: a longitudinal approach. New York: Churchill Livingstone, 1993:97–133, with permission.) Floating-Harbor syndrome (FHS) is a rare genetic disorder characterized by short stature, delayed bone age, mild to moderate mental retardation, speech problems, and peculiar craniofacial features. In these patients pubertal development has been reported to be normal. In this paper, we describe a girl with FHS who developed precocious puberty. FHS diagnosis was made at 2 years 5 months on the basis of peculiar clinical features. At 7 years 7 months, the girl began pubertal development; her height was 112.5 cm (-2.42 SDS) and pubertal staging was B2 PH2 AH1. LHRH test underlined LH and FSH peak values of 11.7 mIU/ml and 6.2 mIU/ml, respectively. Plasma levels of 17beta-estradiol were normal (8.5 pg/ml). Ophthalmological and neurological examinations, including nuclear magnetic resonance imaging of the brain, were normal. Treatment with gonadotrophin-releasing hormone analogue was begun. At 10 years 1 month, because of reduced height velocity, her growth hormone secretion was evaluated with diagnosis of neurosecretory dysfunction; hGH therapy was begun. The patient showed a good response to hGH treatment, reaching a normal adult height (156.1 cm; -1.20 SDS). This report suggests that, in patients with FHS, precocious puberty should be taken into consideration; in these patients, a careful endocrinological followup for the possible presence of growth and pubertal disorders is needed. Initial workup for delayed puberty not due to a chronic condition involves measuring serum FSH, LH, testosterone/estradiol, as well as bone age radiography. If it becomes clear that there is a permanent defect of the reproductive system, treatment usually involves replacement of the appropriate hormones (testosterone/dihydrotestosterone for boys, estradiol and progesterone for girls). Timing and definitions Puberty is considered delayed when the child has not begun puberty when two standard deviations or about 95% of children from similar backgrounds have. In North American girls, puberty is considered delayed when breast development has not begun by age 13, when they have not started menstruating by age 15, and when there is no increased growth rate. Furthermore, slowed progression through the Tanner scale or lack of menarche within 3 years of breast development may also be considered delayed puberty. Adiposogenital dystrophy is a condition that may be caused by tertiary hypogonadism originating from decreased levels in GnRH. Low levels of GnRH has been associated with defects of the feeding centers of the hypothalamus, leading to an increased consumption of food and thus caloric intake. Presentation It is characterized by: Obesity Growth delays and delayed sexual development, atrophy or hypoplasia of the gonads, and altered secondary sex characteristics, Headaches Problems with vision polyuria, polydipsia. It is usually associated with tumors of the hypothalamus, causing increased appetite and depressed secretion of gonadotropin. It seems to affect males mostly.Many overweight children may appear to have the disorder because of the concurrence of obesity and retarded sexual development; these children have no endocrine disturbances, however, and they mature normally after delayed puberty. Anorexia nervosa can have serious implications if its duration and severity are significant and if onset occurs before the completion of growth, pubertal maturation or prior to attaining peak bone mass. Both height gain and pubertal development are dependent on the release of growth hormone and gonadotrophins (LH and FSH) from the pituitary gland. Suppression of gonadotropins in patients with anorexia nervosa has been frequently documented. In some cases, especially where onset is pre-pubertal, physical consequences such as stunted growth and pubertal delay are usually fully reversible. Height potential is normally preserved if the duration and severity of anorexia nervosa are not significant and/or if the illness is accompanied with delayed bone age (especially prior to a bone age of approximately 15 years), as hypogonadism may negate the deleterious effects of undernutrition on stature by allowing for a longer duration of growth compared to controls. In such cases, appropriate early Children and adolescents Hyperthyroidism has unique effects in children on growth and pubertal development, e.g. causing epiphyseal maturation. In growing children, accelerated bone growth from hyperthyroidism can increase osteogenesis in the short term, but generally results in short-stature adults compared with the predicted heights. Pubertal development tends to be delayed, or slowed. Girls who have undergone menarche may develop secondary amenorrhea. Hyperthyroidism is associated with high sex hormone-binding globulin (SHBG), which may result in high serum estradiol levels in girls and testosterone levels in boys. However, unbound or free levels of these hormones are decreased. Hyperthyroidism before the age of four may cause neurodevelopmental delay. A study by Segni et al. suggests that permanent brain damage can occur as a result of the illness. Trichotillomania (TTM) is defined by the Diagnostics and Statistic Manual of Mental Disorders, 4th edition (DMS-IV) as hair loss from a patient`s repetitive self-pulling of hair. The disorder is included under anxiety disorders because it shares some obsessive-compulsive features. Patients have the tendency towards feelings of unattractiveness, body dissatisfaction, and low self-esteem (1,2). It is a major psychiatric problem, but many patients with this disorder first present to a dermatologist. An 11-year-old girl came to our department with a 2-month history of diffuse hair loss on the frontoparietal and parietotemporal area (Figure 1). She had originally been examined by a pediatrician with the diagnosis of alopecia areata. The patient`s personal history included hay fever and shortsightedness, and she suffered from varicella and mononucleosis. Nobody in the family history suffered from alopecia areata, but her father has male androgenetic alopecia (Norwood/Hamilton MAGA C3F3). The mother noticed that the child had had changeable mood for about 2 months and did not want to communicate with other persons in the family. The family did not have any pet at home. At school, her favorite subjects were Math and Computer Studies. She did not like Physical Education and did not participate in any sport activities during her free time. This was very strange because she was obese (body-mass index (BMI) 24.69). She was sometimes angry with her 13-year-old sister who had better results at school. The girl had suddenly started to wear a blue scarf. The parents did not notice that she pulled out her hair at home. Dermatological examination of the capillitium found a zone of incomplete alopecia in the frontoparietal and parietotemporal area, without inflammation, desquamation, and scaring. Hairs were of variable length (Figure 1). There was a patch of incomplete alopecia above the forehead between two stripes of hair of variable length (Figure 2). The hair pull test was negative along the edges of the alopecia. Mycological examination from the skin capillitium was negative. The trichoscopy and skin biopsy of the parietotemporal region of the capillitium (Figure 3) confirmed trichotillomania. Laboratory tests (blood count, iron, ferritin, transferrin, selenium, zinc, vitamin B12, folic acid, serology and hormones of thyroid gland) were negative. We referred the girl for ophthalmologic and psychological examination. Ophthalmologic examination proved that there was no need to add any more diopters. The psychological examination provided us with a picture in which she drew her family (Figure 4). The strongest authority in the family was the mother because she looked after the girls for most of the day. She was in the first place in the picture. The father had longer working hours and spent more time outside the home. He worked as a long vehicle driver. He was in the second place in the picture. There was sibling rivalry between the girls, but the parents did not notice this problem and preferred the older daughter. She was successful at school and was prettier (slim, higher, curly brown hair, without spectacles). Our 11-years-old patient noticed all these differences between them, but at her level of mental development was not able to cope with this problem. She wanted to be her sister's equal. The sister is drawn in the picture in the third place next to father, while the patient's own figure was drawn larger and slim even though she was obese. Notably, all three female figures had very nice long brown hair. It seemed that the mother and our patient had better quality of hair and more intense color than the sister in the drawing. The only hairless person in the picture was the father. The girl did not want to talk about her problems and feelings at home. Then it was confirmed that our patient was very sensitive, anxious, willful, and withdrawn. She was interested in her body and very perceptive of her physical appearance. From the psychological point of view, the parents started to pay more interest to their younger daughter and tried to understand and help her. After consultation with the psychiatrist, we did not start psychopharmacologic therapy for trichotillomania; instead, we started treatment with cognitive behavioral therapy, mild shampoo, mild topical steroids (e.g. hydrocortisone butyrate 0.1%) in solution and methionine in capsules. With parents' cooperation, the treatment was successful. The name trichotillomania was first employed by the French dermatologist Francois Henri Hallopeau in 1889, who described a young man pulling his hair out in tufts (3-5). The word is derived from the Greek thrix (hair), tillein (to pull), and mania (madness) (5). The prevalence of TTM in the general adult population ranges from 0.6% to 4%, and 2-4% of the general psychiatric outpatient population meet the criteria for TTM (2-5). The prevalence among children and adolescents has been estimated at less than 1% (5). The disease can occur at any age and in any sex. The age of onset of hair pulling is significantly later for men than for women (3). There are three subsets of age: preschool children, preadolescents to young adults, and adults. The mean age of onset is pre-pubertal. It ranges from 8 to 13 years (on average 11.3 years) (2-5). The occurrence of hair-pulling in the first year of life is a rare event, probably comprising &lt;1% of cases (5). The etiology of TTM is complex and may be triggered by a psychosocial stressor within the family, such as separation from an attachment figure, hospitalization of the child or parent, birth of a younger sibling, sibling rivalry, moving to a new house, or problems with school performance. It has been hypothesized that the habit may begin with \"playing\" with the hair, with later chronic pulling resulting in obvious hair loss (2). Environment is a factor because children usually pull their hair when alone and in relaxed surroundings. The bedroom, bathroom, or family room are \"high-risk\" situations for hair-pulling (5). Men and women also differed in terms of the hair pulling site (men pull hair from the stomach/back and the moustache/beard areas, while women pull from the scalp) (3). Pulling hair from siblings, pets, dolls, and stuffed animals has also been documented, often occurring in the same pattern as in the patient (5). Genetic factors contributing to the development of TTM are mutations of the SLITRK1 gene, which plays a role in cortex development and neuronal growth. The protein SAPAP3 has been present in 4.2% of TTM cases and patients with obsessive-compulsive disorder (OCD). It may be involved in the development of the spectrum of OCD. A significantly different concordance rate for TTM was found in monozygotic (38.1%) compared with dizygotic (0%) twins in 34 pairs (3). The core diagnostic feature is the repetitive pulling of hairs from one`s own body, resulting in hair loss. The targeted hair is mostly on the scalp (75%), but may also be from the eyebrows (42%), eyelashes (53%), beard (10%), and pubic area (17%) (3,5). There are three subtypes of hair pulling - early onset, automatic, and focused. Diagnostic criteria for TTM according to DSM-IV criteria are (2,3,5): 1) recurrent pulling of one`s hair resulting in noticeable hair loss; 2) an increasing sense of tension immediately prior to pulling out the hair or when attempting to resist the behavior; 3) pleasure, gratification, or relief when pulling out the hair; 4) the disturbance is not better accounted for by another mental disorder and is not due to a general medical condition (e.g., a dermatologic condition); 5) the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. The differential diagnosis includes alopecia areata (Table 1) (6), tinea capitis, telogen effluvium, secondary syphilis, traction alopecia, loose anagen syndrome, lichen planopilaris, alopecia mucinosa, and scleroderma (2-5). Biopsy of an involved area (ideally from a recent site of hair loss) can help to confirm the diagnosis (5). On histologic examination, there are typically increased numbers of catagen and telogen hairs without evidence of inflammation. Chronic hair pulling induces a catagen phase, and more hairs will be telogen hairs. Pigment casts and empty anagen follicles are often seen. Perifollicular hemorrhage near the hair bulb is an indicator of TTM (2). Complications of TTM are rare, but they comprise secondary bacterial infections with regional lymphadenopathy as a result of picking and scratching at the scalp. Many patients play with and ingest the pulled hairs (e.g. touching the hair to lips, biting, and chewing). Trichophagia (ingestion of the hair) can lead to a rare complication named trichobezoar (a \"hair ball\" in stomach). This habit is present in approximately 5% to 30% of adult patients, but it is less frequent in children. Patient with trichophagia present with pallor, nausea, vomiting, anorexia, and weight loss. Radiologic examination and gastroscopy should not be delayed (2,4,5). The management of the disease is difficult and requires strong cooperation between the physician, patient, and parents. The dermatologist cannot take part in the therapy, strictly speaking, but without the psychological, psychopharmacologic, and topic dermatologic treatment a vicious circle will be perpetuated.  The clinical and biological presentation of idiopathic growth hormone (GH) deficiency (GHD) varies greatly, demonstrating the variety of its pathogenic features and explaining why it is difficult to diagnose. We examined 48 patients (26 males) with certain idiopathic GHD diagnosed at 4.8 +/- 0.7 yr. The symptoms that led to the diagnosis of GHD were low growth rate (33 cases), hypoglycemia (12 cases), microphallus (1 case) and in 2 cases the GHD was diagnosed from magnetic resonance imaging (MRI) performed for delayed mental development (1 case), or congenital blindness (1 case). The 2 other cases were diagnosed from routine GH evaluation performed at birth because of idiopathic GHD in siblings. Thirteen had congenital malformation. Twenty three cases (48%) had features suggesting that the GHD was of antenatal origin. Six of them were born by breech delivery. Twenty one cases (44%) had features suggesting a hypothalamic origin. The decrease in growth rate occurred before 0.5 year in 21 (55%), before 1 year in 27 (71%) and before 2 years in 30 (79%): 8 patients (21%) maintained a normal growth rate after this age. Among these 8 patients, 5 had signs suggesting an antenatal origin and 4 had severe episodes of hypoglycemia from birth. The mean GH peak after the pharmacological stimulation test was 3.6 +/- 0.5 micrograms/l. The mean plasma insulin-like growth factor 1 (IGFI) was 0.1 +/- 0.02 U/ml. The GH deficiency was associated with deficiencies of thyrotropin in 26 (54%) and of adrenocorticotrophic hormone in 17 (35%) patients. Among the 15 patients of pubertal age, 9 (60%) had gonadotrophin deficiency. No patient had diabetes insipidus. The MRI showed pituitary stalk interruption syndrome in 39 patients and normal pituitary anatomy in 6 patients. GH treatment reduced the difference between target and actual heights from 3.5 SD (before) to I SD (after 3 years) in the 39 more recently seen patients given 0.5-0.6 U/kg/w GH in 6 or 7 weekly injections. Height gain during the first year and cumulative height gain over 3 years (SD) was correlated negatively with height (SD) at the start of treatment (p &lt; 0.01). We conclude that most of the patients with GHD have features suggesting an antenatal origin. Despite this early origin, the decreased growth rate may occur after 2 years. Twenty four children with hypopituitarism were treated with growth hormone from 6-15 years of age until cessation of growth. The height deficit decreased from -4.2SD to -2.2SD. Final height was above the 3rd percentile in half of the patients. There was no difference in final height between patients with and without additional gonadotropin deficiency. Spontaneous puberty started late but at a normal bone age and its course was normal. In girls with gonadotropin deficiency low dose oestrogen given at unchanged growth hormone doses did not accelerate growth. Final height was closely correlated with the degree of growth retardation at the beginning of treatment (r = 0.73, p less than 0.001). In 17 of the 79 patients treated with growth hormone compliance was bad. The main cause of bad compliance was the low educational level of the parents. It is concluded that final height in growth hormone deficiency can be increased with earlier diagnosis and improved compliance. The pathogenesis remains unknown in the majority of patients with precocious puberty, and yet infrequently such causative cerebral lesions as hypothalamic hamartomas are associated with sexual precocity. We reported a rare case of suprasellar arachnoid cyst in an infant presenting with precocious puberty, which eventually disappeared after a cyst-peritoneal shunt. It was believed that the mass effect of the arachnoid cyst upon the hypothalamus was, at least in part, responsible for development of precocious puberty. The role of surgical decompression of the cyst was also discussed. A one-year-old girl was admitted to the hospital for evaluation of genital bleeding which had persisted on and off for two months. The height, 80cm, and the weight, 12.4kg, exceeded by far the two standard deviations from the mean level of the normal population. In addition she had the development of breast tissue as classified Tanner's Stage II, and both pubic and axillary hair. The bone age by skeletal survey of the hand was rated as 3 years. Endocrinological examination showed that serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol had increased for her age, to levels equivalent to those for females at puberty. An LH-RH test revealed an excessive LH reaction. There were no definite neurological deficits. CT and MRI demonstrated the presence of a large arachnoid cyst involving the suprasellar region as well as the right middle and posterior fossa. After the patient underwent a cyst-peritoneal shunt, the cyst decreased in size and such symptoms as genital bleeding and breast growth disappeared. Serum levels of her LH and FSH also significantly decreased.(ABSTRACT TRUNCATED AT 250 WORDS) Autoimmune thyroiditis, the most frequent cause of acquired hypothyroidism in childhood and adolescents, is characterized by raised levels of the specific antibodies to thyroperoxidase (TPOAb) and thyroglobulin (TgAb). We report a girl aged 10 years and 9 months who presented with arrested growth and breast development (thelarche). She also exhibited myxedema of the face and legs, prominent striae on the thighs, dry, cold skin, and hypertrichosis on her back. There was no goiter, no history of thyroid pain and no family history of thyroid disease. She complained occasionally of a transient headache. The patient's height was below the 3rd percentile, while her body weight was at the 50th percentile and bone age was normal. Laboratory tests proved severe hypothyroidism (fT4 0 ng/dl, fT3 0.99 pg/ml, TSH &gt;100 microIU/ml plus an increased titer of TPOAb). Thyroid ultrasound supported the diagnosis of thyroiditis. Pituitary PRL and FSH levels and peripheral estradiol were all elevated. L-Thyroxine therapy, instituted following diagnosis, improved the growth velocity to 11 cm/year and the FSH and E2 levels were normalized to prepubertal values. Complete regression of the breast development was observed within 4 months. However, 4 months later a true (central), isosexual LHRH-dependent puberty started. The pubertal features at the time of the original diagnosis might be explained by: 1. the direct action of elevated TRH on gonadotropes to stimulate gonadotropin secretion and on lactotrophes to stimulate PRL secretion, and 2. TSH action on LH and mostly FSH receptors (homologous to TSH receptors) in the ovary, stimulating the secretion of estradiol. Twenty-seven out of thirty craniopharyngioma patients treated with human growth hormone (hGH) for 2 years or more (average 4.5 years) reached final adult heights above the population third centile, though none was above the fiftieth centile. However, only twelve of twenty-eight patients had final heights above the lower limits to be expected from their parents' heights. All patient eventually had long legs relative to sitting height (final mean subischial leg length SDS = + 0.2, final mean sitting height SDS = -3.0). Twenty-nine patients were TSH-deficient, twenty-two were ACTH-deficient, thirteen were deficient in ADH and all had total (85%) or partial (15%) gonadotrophin deficiency. Following the administration of testosterone or hCG the boys had, on average, only half the normal adolescent growth spurt. This may have been due to the lateness of starting androgens in these patients and we recommend, when considering height, that testosterone or hCG should be started when a bone age of 13.0 \"years' is reached or when a lower bone age has remained unchanged for a year. The girls showed adolescent height spurt; the average increase after oestrogen treatment commended was 1.7 cm.\nHere is the question:\nENDOCRINOLOGY: 14-year-old girl who consults for decreased growth for 2-3 years previously normal (provides data) and that other girls her age have greater physical and sexual development. Lately she has had headaches and visual problems that she notices in class and when studying. She has not had menarche or polydipsia or polyuria. Parents with normal height. Examination: short stature at -2.1 standard deviations, normal body proportions, little pubic hair and breast development. Campimetry shows left temporal partial hemianopsia. Bone age: delay of 2 years. General laboratory tests were normal. Gonadotrophins (FSH and LH) and estradiol are low. What do you think is the most appropriate response?\nHere are the potential choices:\n1. Decreased growth and sexual development, delayed bone age, headache and visual alteration suggest hormonal deficit and involvement of the optic chiasm.\n2. As she is a girl of pubertal age, it is most likely that her decreased growth and sexual retardation are due to Turner syndrome.\n3. She must not have a hypothalamic tumor because of the absence of polyuria and polydipsia. She probably has constitutional delay and her visual problem is refractive.\n4. A growth hormone deficiency may explain the developmental delay and low estradiol. To evaluate if she needs glasses, due to her headaches and visual disturbances.\n5. She could have a craniopharyngioma, but it would be rare if she had not shown symptoms before. Also, it would not justify low gonadotrophins and estradiol.\nThe correct answer is: 1. Decreased growth and sexual development, delayed bone age, headache and visual alteration suggest hormonal deficit and involvement of the optic chiasm."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n With a PCA the patient is protected from overdose by the caregiver programming the PCA to deliver a dose at set intervals. If the patient presses the button sooner than the prescribed intake pressing the button does not operate the PCA. (The PCA can be set to emit a beep telling the patient a dose was NOT delivered). Dosage is also controlled when the patient is too sedated to press the button; preventing the patient from receiving needless doses and keeping the patient safe from overdosing. Epidural Patient-controlled epidural analgesia (PCEA) is a related term describing the patient-controlled administration of analgesic medicine in the epidural space, by way of intermittent boluses or infusion pumps. This can be used by women in labour, terminally ill cancer patients or to manage post-operative pain. Analgesics should not be taken \"on demand\" but \"by the clock\" (every 3–6 hours), with each dose delivered before the preceding dose has worn off, in doses sufficiently high to ensure continuous pain relief. People taking slow-release morphine should also be provided with immediate-release (\"rescue\") morphine to use as necessary, for pain spikes (breakthrough pain) that are not suppressed by the regular medication. Oral analgesia is the cheapest and simplest mode of delivery. Other delivery routes such as sublingual, topical, transdermal, parenteral, rectal or spinal should be considered if the need is urgent, or in case of vomiting, impaired swallow, obstruction of the gastrointestinal tract, poor absorption or coma. Current evidence for the effectiveness of fentanyl transdermal patches in controlling chronic cancer pain is weak but they may reduce complaints of constipation compared with oral morphine. activation (desensitization of antinociceptive mechanisms) and opioid receptor down-regulation (internalization of membrane receptors). In opioid-induced hyperalgesia, sensitization of pronociceptive mechanisms occurs, resulting in a decrease in the pain threshold, or allodynia. In addition, what appears to be opioid tolerance can be caused by opioid-induced hyperalgesia lowering the baseline pain level, thus masking the drug's analgesic effects. Identifying the development of hyperalgesia is of great clinical importance since patients receiving opioids to relieve pain may paradoxically experience more pain as a result of treatment. Whereas increasing the dose of opioid can be an effective way to overcome tolerance, doing so to compensate for opioid-induced hyperalgesia may worsen the patient's condition by increasing sensitivity to pain while escalating physical dependence. Pain is one of the symptoms that many tumor patients are especially afraid of in the final phase of their illness. Symptoms can change rapidly, making quick adaptation of the therapy necessary. This poses particular challenges to organizational structures in outpatient treatment if the patients' desire to spend their last days of life in their accustomed surroundings is to be realized. Pain intensity and the associated symptoms in a WHO step III opiate therapy during the last 3 days of life were investigated retrospectively among 601 tumor patients who had received medical care from Home Care Berlin. Differences in gender, age, living conditions/care situation and place of death were evaluated with due consideration for the different pain medications administered and for the different forms and routes of administration. More than 80% of the patients reported freedom from pain or only moderate pain during the opiate therapy. Care provided by the hospice-at-home medical service Home Care Berlin allowed excellent control of tumor patients' symptoms with only moderate side-effects in their final days of life. Among patients receiving opioids by the transdermal route there were significantly more frequent complaints of pain (p=0.004) and nausea (p=0.001). During the last days of life continuous subcutaneous infusions containing opiates facilitated good analgesia within an acceptable spectrum of side-effects. Most problems with controlling symptoms in outpatients were encountered in younger patients. Morphine emerged as the drug of first choice in this investigation, because it can be given parenterally and also because of its price. The use of subcutaneous and intravenous administration systems such as PCA pumps requires trained nursing services and regular house visits by physicians experienced in palliative medicine. Treatment administration and side effects Racotumomab is administered in patients who have previously received the oncospecific treatment established in the oncological therapeutic standards (surgery, chemotherapy and radiation therapy). A Racotumomab-alum solution is administered by intradermal injection every 14 days for the first 2 months (5 doses), followed by monthly booster doses. Racotumomab is well tolerated by patients. The overall toxicity of the vaccine has been classified as grade 1 and 2, according to the NCI Common Toxicity Criteria (version 3.0). Treatment is mostly associated with mild to moderate injection-site reactions (local erythema, induration and pain), which disappear within 24–48 hours. Systemic reactions, such as flu-like symptoms and chills are less frequent, reversible, and self-limited. Approvals and indications Some 129 cancer patients were taken care of at home by the visiting nurse team of our hospital since 1994 to 1997; 116 patients have already died, 50 of them at home (group A), and 66 at the hospital (group B). We analyze the differences the between two groups in nutritional assistance, pain control and manpower in looking after a patient. Twice as many patients in group A took nutritional medication (drip infusion or intravenous hyperalimentation, for example) than group B. More patients in group A used oral and suppository morphine than group B. In group A 70% of patients (56% in group B) had more than two persons looking after at home. The important factors for a good recuperation at home are: 1. Available nutritional assist available. 2. Good control. 3. Less burden and anxiety of the person looked after. To spend pain desirable last moments together, it is important for the visiting nurse team to take proper care and to confirm the wishes of the patient and family, considering the rapidly changing conditions of the individual patient. The effectiveness of ubrogepant for the acute treatment of migraine was demonstrated in two randomized, double-blind, placebo-controlled trials. In these studies, 1,439 adult patients with a history of migraine, with and without aura, received the approved doses of ubrogepant to treat an ongoing migraine. In both studies, the percentages of patients achieving pain freedom two hours after treatment (defined as a reduction in headache severity from moderate or severe pain to no pain) and whose most bothersome migraine symptom (nausea, light sensitivity or sound sensitivity) stopped two hours after treatment were significantly greater among patients receiving ubrogepant (19–21% depending on the dose) compared to those receiving placebo (12%). Patients were allowed to take their usual acute treatment of migraine at least two hours after taking ubrogepant. 23% of patients were taking a preventive medication for migraine. Management of cancer pain is one of the most important goals of palliative care. Relieving pain is often problematic. High doses of morphine at home may be required to relieve patients' pain, and is therefore feared. The goals of the current study were to assess the feasibility of high-dose morphine use at home, to characterize the patients, and to examine whether the use of high-dose morphine might affect their survival. The authors retrospectively studied the medical charts of 661 outpatients, which were completed by a home-care hospice team. The authors collected data regarding demographic parameters, medical diagnosis, pain type, morphine dosage, use of rescue doses in addition to regular doses, use of coanalgesics and adjuvant treatments, and survival time as associated with morphine dosage. The authors also compared the data of patients receiving high-dose morphine with those of a group of patients receiving regular doses. The authors identified 435 patients (65.8%) who received morphine for pain relief. Of these, 396 patients (91%) received a dose of 5-299 mg of morphine per day), 32 patients (7.4%) received 300-599 mg of morphine per day), and 7 patients (1.6%) received very high doses (&gt; or = 600 mg of morphine per day). Overall, 39 patients (9%) received &gt; 299 mg per day. Morphine dosage was found to be inversely correlated (r) with age (r = -0.254; P &lt; 0.001). Male patients required slightly higher dosages than female patients (62.5% of high-dose and 71% of very high-morphine groups, respectively). Primary gastrointestinal (P = 0.015) and lung (P = 0.027) carcinomas, as well as metastatic bone disease (P = 0.001), ovarian carcinoma (P = 0.037), and brain tumors (P = 0.0053) were associated with higher and very higher morphine dosages. Adverse effects were similar in the groups receiving regular, high, and very high doses of morphine. The median survival of patients treated with high doses of morphine was 27 days and was 37 days for those treated with very high doses. Patients treated with low doses of morphine survived for 18 days. Patients not treated with morphine survived for 22 days (P = 0.001 by Mantel-Cox analysis; P = 0.029 by Breslow analysis). The use of high and very high morphine doses at home proved safe and did not appear to affect the patients' life expectancy adversely. The use of high or very high-dose morphine should not be a barrier to providing palliative terminal care for home-care hospice patients. The use of an NSAID, especially some COX-2 inhibitors, or acetaminophen either as monotherapy or combination therapy is also suggested as a possible treatment option. Research needs It can be difficult to apply research into OIH to average patients, because some research focused on people taking very high doses or in methadone rehabilitation programs. Opioid-induced hyperalgesia has also been criticized as overdiagnosed among chronic pain patients, due to poor differential practice in distinguishing it from the much more common phenomenon of opioid tolerance. The misdiagnosis of common opioid tolerance (OT) as opioid-induced hyperalgesia (OIH) can be problematic as the clinical actions suggested by each condition can be contrary to each other. Patients misdiagnosed with OIH may have their opioid dose mistakenly decreased (in the attempt to counter OIH) at times when it is actually appropriate for their dose to be increased or rotated (as a counter to opioid tolerance). The aim of this study was to present how opioids are used in an acute pain relief and palliative care unit (APRPCU), where many patients with difficult pain conditions are admitted from GPs, home palliative care programs, oncology departments, other hospitals or emergency units, and other regional places. From a consecutive sample of cancer patients admitted to an APRPCU for a period of 6 months, patients who had been administered opioids were included in this survey. Basic information was collected as well as opioid therapy prescribed at admission and, subsequently, during admission and at time of discharge. Patients were discharged once stabilization of pain and symptoms were obtained and the treatment was considered to be optimized. One week after being discharged, patients or relatives were contacted by phone to gather information about the availability of opioids at dosages prescribed at time of discharge. One hundred eighty six of 231 patients were specifically admitted for uncontrolled pain, with a mean pain intensity of 6.8 (SD 2.5). The mean dose of oral morphine equivalents in patients receiving opioids before admission was 45 mg/day (range 10-500 mg). One hundred seventy five patients (75.7 %) were prescribed around the clock opioids at admission. About one third of patients changed treatment (opioid or route). Forty two of 175 (24 %), 27/58 (46.5 %), 10/22 (45.4 %), and 2/4 (50 %) patients were receiving more than 200 mg of oral morphine equivalents, as maximum dose of the first, second, third, and fourth opioid prescriptions, respectively. The pattern of opioids changed, with the highest doses administered with subsequent line options. The mean final dose of opioids, expressed as oral morphine equivalents, for all patients was 318 mg/day (SD 798), that is more than six times the doses of pre-admission opioid doses. One hundred eighty six patients (80.5 %) were prescribed a breakthrough cancer pain (BTcP) medication at admission. Sixty five patients changed their BTcP prescription, and further 27 patients changed again. Finally, eight patients were prescribed a fourth BTcP medication. Of 46 patients available for interview, the majority of them (n = 39, 84 %) did not have problems with their GPs, who facilitated prescription and availability of opioids at the dosages prescribed at discharge. For patients with severe distress, APRPCUs may guarantee a high-level support to optimize pain and symptom intensities providing intensive approach and resolving highly distressing situations in a short time by optimizing the use of opioids. Karen After her patient, Thomas Grey, reveals that he is dying of lung cancer and that he has been in love with her for a year, Karen begins having an affair with him. To help him end his life when the pain becomes too much, Karen prescribes Thomas fatal doses of morphine, which his wife, Elizabeth, helps to administrate. The insurance company begins to investigate Thomas' death, going so far as to approach Karen for the notes from her sessions with Thomas. However, Karen had destroyed anything relating to Thomas being her patient. While grieving his father's death, Thomas' son Sam turns to Karen for advice as he has discovered that his father was having an affair. Even though Savi advises Karen to cut all ties with the Grey Family, Karen begins helping Sam. Things take a dangerous turn after Sam falls in love with Karen and begins stalking her. CroFab antivenin has been used successfully to treat Osage copperhead bites, although a lack of complete cross-tolerance requires careful administration and close supervision during the full course of treatment to ensure that the lowest effective dose is administered (a lower dose would not fully treat the envenomation, and a higher dose may be particularly dangerous to children, the elderly, and infirm adults). Not uncommonly, opiate/opioid narcotic analgesics (ex. morphine, fentanyl), muscle relaxerss (ex. diazepam, tizanidine, orphenadrine), and broad-spectrum antibiotics are administered. A few days' supply of weaker analgesics and muscle relaxers may be prescribed for the patient to control pain after he or she returns home as the pain resolves completely within one to three days. Patients also receive a prescription for an intensive antibiotic therapy, which much be taken until the supplies are depleted, giving the drug enough time to fully treat any opportunistic infections Pain relief is a quite important subject for maintaining the home medical care of patients with terminal cancer. Therefore, the opioid rotation should be made in conjunction with an individual medical condition, which is of growing importance in a proper pain management. We considered what opioid rotation is desirable in the home medical care service by analyzing the cases at our clinic. The most important thing in the opioid rotation at home is to perform a rotation before exacerbation of pain becomes apparent. For this purpose, morphine hydrochloride injection is thought to be the best dosage form because it has advantages of: (1) quickness in varying the amount, (2) immediate rescue efficacy, and (3) usefulness in case of ingestion. Oxycodone has a half-life of 4.5 hours. It is available as a generic medication. The manufacturer of OxyContin, a controlled-release preparation of oxycodone, Purdue Pharma, claimed in their 1992 patent application that the duration of action of OxyContin is 12 hours in \"90% of patients.\" It has never performed any clinical studies in which OxyContin was given at more frequent intervals. In a separate filing, Purdue claims that controlled-release oxycodone \"provides pain relief in said patient for at least 12 hours after administration.\" However, in 2016 an investigation by the Los Angeles Times found that \"the drug weans off hours early in many people,\" inducing symptoms of opiate withdrawal and intense cravings for OxyContin. One doctor, Lawrence Robbins, told journalists that over 70% of his patients would report that OxyContin would only provide 4–7 hours of relief. Doctors in the 1990s often would switch their patients to a dosing schedule of once every eight hours when they In this case report, we describe continuous subcutaneous infusion of opiates as PCAO (patient controlled analgesia in outpatients) in one patient with metastatic carcinoma of the rectum (liver and bone metastases, partial bowel obstruction) with severe cancer pain and vomiting in the terminal phase. The parenteral administration of opioids extended over 58 days. The infusion was powered by an external portable clockwork-driven syringe pump (Perfusor M, Braun Medical/Germany). The open-accessible pump has a syringe volume of 10 ml, and its maximal infusion time is 24 h. The 27-G infusion needle (Sub-Q-Set, Baxter/USA) was inserted in the side of the abdomen and was left in the same position for 10 to 20 days. It took the patient and his family only 1.5 h to familiarize themselves with the use of the pump. They were trained in its use in our outpatient pain department. For pain control both the variable continuous infusion and the extra injection doses could be administered by the way of the syringe driver. The patient was given a stock of 120 ampoules of morphine for further treatment at home. For optimal pain control he decided to raise the daily dose of opioid infusion from the initial 60 mg to 240 mg morphine within 48 h. In this way, PCAO-besides rapid titration of the opioid dose to achieve analgesia-allows the use of opioids controlled by the patient himself. In the present case this procedure was also important when an outpatient radiation therapy became urgently necessary to prevent a fracture of the spine because of metastasis. The pain control by the patient himself was the main factor to get free of pain during the transport to the hospital. Even positioning for radiation was possible without pain. When he received outpatient radiation therapy the patient needed extra injection doses of up to 360 mg morphine a day. The PCAO procedure by continuous subcutaneous infusion with opiates is a safe and efficient method of pain management for outpatient patients suffering from severe cancer pain and intractable nausea in the terminal phase. Its validity has also been proven especially for radiation treatment of bone metastases. was well tolerated by the 30 patients who were enrolled in this study. All were treated with 2 fields, and the average whole brain dose was 3.2–6.1 Gy (weighted), and the minimum dose to the tumor ranged from 15.4 to 54.3 Gy (w). There has been some disagreement among the Swedish investigators regarding the evaluation of the results. Based on incomplete survival data, the MeST was reported as 14.2 months and the time to tumor progression was 5.8 months. However, more careful examination of the complete survival data revealed that the MeST was 17.7 months compared to 15.5 months that has been reported for patients who received standard therapy of surgery, followed by radiotherapy (RT) and the drug temozolomide (TMZ). Furthermore, the frequency of adverse events was lower after BNCT (14%) than after radiation therapy (RT) alone (21%) and both of these were lower than those seen following RT in combination with TMZ. If this improved survival data, obtained using the higher dose of BPA In a multicenter study, 28 patients with cancer pain and insufficient pain relief with analgesic treatment according to step II of the guidelines of the World Health Organization (WHO) were switched to oral slow-release morphine. Patients received intravenous morphine through a patient-controlled pump (PCA) for the first 24 hours (bolus = 1 mg, lockout interval = 5 minutes, maximum dose = 12 mg/hour). From day 2 patients were treated with oral slow-release morphine. Daily doses were calculated from the requirements of the day before. Breakthrough pain was treated with PCA until stable doses were reached (&lt;2 boluses/day) and then with oral immediate-release morphine solution. Pain intensity was reported in a diary four times a day, in addition to mood, activity, and quality of sleep once daily. Mean duration until adequate pain relief reported (&lt;30 on a 101-step numerical scale; NRS) was 5 hours (range = 80-620 minutes). Mean pain intensity was reduced from 67 NRS to 22 NRS. Mean doses of oral morphine were 133 mg/day initially and then 154 mg/day on day 14. Serious adverse events such as respiratory depression were not observed. Two patients terminated the study due to progressive symptoms of gastrointestinal obstruction. Seventy-five percent of the patients evaluated the effectiveness of the analgesic regime as good. Dose finding with intravenous PCA may be appropriate for a small minority of patients with severe pain. Higher treatment costs and the risk of complications are drawbacks of this method compared with conventional oral titration. After embolization, patients are observed in the post-anesthesia care unit for several hours. Patients are discharged from the hospital when taking adequate nutrition by mouth, when pain is adequately controlled with oral narcotics and when the temperature is lower than 38.5 for 24 hours. Post-procedure evaluation Follow-up triple phase CT is performed 2 to 4 weeks after treatment is complete and reviewed for any evidence of persistent untreated disease. If there is no evidence of enhancement of the treated tumor, these patients are monitored with triple phase CT every 3 months for the first year and every 6 months thereafter. When there is evidence of untreated disease, recurrent disease, or new disease elsewhere within the liver the patient is scheduled for additional embolization. References Hepatology Diseases of liver Pain control in hospice patients in the home may be compromised by concerns about overuse of analgesics, particularly narcotics. A retrospective chart audit of analgesic type and amount was performed on the medical records of 100 cancer patients receiving hospice care in the home. Different types and amounts of analgesics were converted to a common standard, an oral morphine equivalent (OME) relative to 1 mg of oral morphine sulfate. Descriptive statistics were used to characterize patient analgesic use during the entire course of hospice care and the last 5 days of life. Associations between analgesic use and select patient characteristics (age, sex, cancer site, metastases, and pain intensity at admission) were explored. Ninety-one percent of the sample had used analgesics at some time during hospice care. The proportion of patients using analgesics increased as death approached. The mean and median daily analgesic use over the entire period were 114 and 82 OMEs and during the last 5 days 140 and 84 OMEs, respectively. The range of mean daily analgesic use was between 10 and 735 OMEs. Individual variability in analgesic use was demonstrated. Not all patients required analgesics, and among those who did there was remarkable variation in the amount used. Large and even enormous doses of analgesics may sometimes be required to control cancer pain. Case Study  Sarah is a 58-year-old breast cancer survivor, social worker, and health-care administrator at a long-term care facility. She lives with her husband and enjoys gardening and reading. She has two grown children and three grandchildren who live approximately 180 miles away. SECOND CANCER DIAGNOSIS  One morning while showering, Sarah detected a painless quarter-sized lump on her inner thigh. While she thought it was unusual, she felt it would probably go away. One month later, she felt the lump again; she thought that it had grown, so she scheduled a visit with her primary care physician. A CT scan revealed a 6.2-cm soft-tissue mass in the left groin. She was referred to an oncologic surgeon and underwent an excision of the groin mass. Pathology revealed a grade 3 malignant melanoma. She was later tested and found to have BRAF-negative status. Following her recovery from surgery, Sarah was further evaluated with an MRI scan of the brain, which was negative, and a PET scan, which revealed two nodules in the left lung. As Sarah had attended a cancer support group during her breast cancer treatment in the past, she decided to go back to the group when she learned of her melanoma diagnosis. While the treatment options for her lung lesions included interleukin-2, ipilimumab (Yervoy), temozolomide, dacarbazine, a clinical trial, or radiosurgery, Sarah's oncologist felt that ipilimumab or radiosurgery would be the best course of action. She shared with her support group that she was ambivalent about this decision, as she had experienced profound fatigue and nausea with chemotherapy during her past treatment for breast cancer. She eventually opted to undergo stereotactic radiosurgery. DISEASE RECURRENCE  After the radiosurgery, Sarah was followed every 2 months. She complained of shortness of breath about 2 weeks prior to each follow-up visit. Each time her chest x-ray was normal, and she eventually believed that her breathlessness was anxiety-related. Unfortunately, Sarah's 1-year follow-up exam revealed a 2 cm × 3 cm mass in her left lung, for which she had a surgical wedge resection. Her complaints of shortness of breath increased following the surgery and occurred most often with anxiety, heat, and gardening activities, especially when she needed to bend over. Sarah also complained of a burning \"pins and needles\" sensation at the surgical chest wall site that was bothersome and would wake her up at night. Sarah met with the nurse practitioner in the symptom management clinic to discuss her concerns. Upon physical examination, observable signs of breathlessness were lacking, and oxygen saturation remained stable at 94%, but Sarah rated her breathlessness as 7 on the 0 to 10 Borg scale. The nurse practitioner prescribed duloxetine to help manage the surgical site neuropathic pain and to assist with anxiety, which in turn could possibly improve Sarah's breathlessness. Several nonpharmacologic modalities for breathlessness were also recommended: using a fan directed toward her face, working in the garden in the early morning when the weather is cooler, gardening in containers that are at eye level to avoid the need to bend down, and performing relaxation exercises with pursed lip breathing to relieve anxiety-provoked breathlessness. One month later, Sarah reported relief of her anxiety; she stated that the fan directed toward her face helped most when she started to feel \"air hungry.\" She rated her breathlessness at 4/10 on the Borg scale. SECOND RECURRENCE: MULTIPLE PULMONARY NODULES  Sarah's chest x-rays remained clear for 6 months, but she developed a chronic cough shortly before the 9-month exam. An x-ray revealed several bilateral lung lesions and growth in the area of the previously resected lung nodule. Systemic therapy was recommended, and she underwent two cycles of ipilimumab. Sarah's cough and breathlessness worsened, she developed colitis, and she decided to stop therapy after the third cycle. In addition, her coughing spells triggered bronchospasms that resulted in severe anxiety, panic attacks, and air hunger. She rated her breathlessness at 10/10 on the Borg scale during these episodes. She found communication difficult due to the cough and began to isolate herself. She continued to attend the support group weekly but had difficulty participating in conversation due to her cough. Sarah was seen in the symptom management clinic every 2 weeks or more often as needed. No acute distress was present at the beginning of each visit, but when Sarah began to talk about her symptoms and fear of dying, her shortness of breath and anxiety increased. The symptom management nurse practitioner treated the suspected underlying cause of the breathlessness and prescribed oral lorazepam (0.5 to 1 mg every 6 hours) for anxiety and codeine cough syrup for the cough. Opioids were initiated for chest wall pain and to control the breathlessness. Controlled-release oxycodone was started at 10 mg every 12 hours with a breakthrough pain (BTP) dose of 5 mg every 2 hours as needed for breathlessness or pain. Sarah noted improvement in her symptoms and reported a Borg scale rating of 5/10. Oxygen therapy was attempted, but subjective improvement in Sarah's breathlessness was lacking. END OF LIFE  Sarah's disease progressed to the liver, and she began experiencing more notable signs of breathlessness: nasal flaring, tachycardia, and restlessness. Opioid doses were titrated over the course of 3 months to oxycodone (40 mg every 12 hours) with a BTP dose of 10 to 15 mg every 2 hours as needed, but her breathlessness caused significant distress, which she rated 8/10. The oxycodone was rotated to IV morphine continuous infusion with patient-controlled analgesia (PCA) that was delivered through her implantable port. This combination allowed Sarah to depress the PCA as needed and achieve immediate control of her dyspneic episodes. Oral lorazepam was also continued as needed. Sarah's daughter moved home to take care of her mother, and hospice became involved for end-of-life care. As Sarah became less responsive, nurses maintained doses of morphine for control of pain and breathlessness and used a respiratory distress observation scale to assess for breathlessness since Sarah could no longer self-report. A bolus PCA dose of morphine was administered by Sarah's daughter if her mother appeared to be in distress. Sarah died peacefully in her home without signs of distress.  Even when the guidelines for cancer pain management are followed, acute severe pain requiring immediate treatment will occur in some patients. Titration with intravenous morphine may provide fast and efficient pain relief and give an indication of the amount of opioid necessary for continuous treatment. In cooperation with a general practitioner we performed an intravenous morphine titration in a patient with severe cancer pain at home. Adequate analgesia was reached with 20 mg intravenous morphine. Blood pressure, cardiac frequency and oxygen saturation did not change. No side effects were reported during the titration, and the previous regimen with tramadol 150 mg per day was switched to slow release morphine 300 mg per day. This medication was prescribed by the general practitioner and provided good pain relief until the patient died two weeks later. We conclude that intravenous morphine titration may be performed even in cancer patients at home, adequate monitoring, however, should be available. The initial 24 hours after opioid administration appear to be the most critical with regard to life-threatening OIRD, but may be preventable with a more cautious approach to opioid use. Patients with cardiac, respiratory disease and/or obstructive sleep apnoea are at increased risk for OIRD. Increased pain sensitivity Opioid-induced hyperalgesia – where individuals using opioids to relieve pain paradoxically experience more pain as a result of that medication – has been observed in some people. This phenomenon, although uncommon, is seen in some people receiving palliative care, most often when dose is increased rapidly. If encountered, rotation between several different opioid pain medications may decrease the development of increased pain. Opioid induced hyperalgesia more commonly occurs with chronic use or brief high doses but some research suggests that it may also occur with very low doses.\nHere is the question:\nPRIMARY CARE: The patient comes to the home of an oncology patient whose pain has not been well controlled lately. On physical examination there appears to be no evidence of tumor progression, and no previously known data of interest is revealed. In the anamnesis, the main caregiver states that the patient has pain 8 hours after receiving the prescribed basal dose of morphine every 12 hours. This clinical situation is referred to as:\nHere are the potential choices:\n1. Tolerance\n2. Hyperalgesia\n3. Dependency\n4. Ineffectiveness\nThe correct answer is: ",
        "gold_answer": "1 Tolerance",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n With a PCA the patient is protected from overdose by the caregiver programming the PCA to deliver a dose at set intervals. If the patient presses the button sooner than the prescribed intake pressing the button does not operate the PCA. (The PCA can be set to emit a beep telling the patient a dose was NOT delivered). Dosage is also controlled when the patient is too sedated to press the button; preventing the patient from receiving needless doses and keeping the patient safe from overdosing. Epidural Patient-controlled epidural analgesia (PCEA) is a related term describing the patient-controlled administration of analgesic medicine in the epidural space, by way of intermittent boluses or infusion pumps. This can be used by women in labour, terminally ill cancer patients or to manage post-operative pain. Analgesics should not be taken \"on demand\" but \"by the clock\" (every 3–6 hours), with each dose delivered before the preceding dose has worn off, in doses sufficiently high to ensure continuous pain relief. People taking slow-release morphine should also be provided with immediate-release (\"rescue\") morphine to use as necessary, for pain spikes (breakthrough pain) that are not suppressed by the regular medication. Oral analgesia is the cheapest and simplest mode of delivery. Other delivery routes such as sublingual, topical, transdermal, parenteral, rectal or spinal should be considered if the need is urgent, or in case of vomiting, impaired swallow, obstruction of the gastrointestinal tract, poor absorption or coma. Current evidence for the effectiveness of fentanyl transdermal patches in controlling chronic cancer pain is weak but they may reduce complaints of constipation compared with oral morphine. activation (desensitization of antinociceptive mechanisms) and opioid receptor down-regulation (internalization of membrane receptors). In opioid-induced hyperalgesia, sensitization of pronociceptive mechanisms occurs, resulting in a decrease in the pain threshold, or allodynia. In addition, what appears to be opioid tolerance can be caused by opioid-induced hyperalgesia lowering the baseline pain level, thus masking the drug's analgesic effects. Identifying the development of hyperalgesia is of great clinical importance since patients receiving opioids to relieve pain may paradoxically experience more pain as a result of treatment. Whereas increasing the dose of opioid can be an effective way to overcome tolerance, doing so to compensate for opioid-induced hyperalgesia may worsen the patient's condition by increasing sensitivity to pain while escalating physical dependence. Pain is one of the symptoms that many tumor patients are especially afraid of in the final phase of their illness. Symptoms can change rapidly, making quick adaptation of the therapy necessary. This poses particular challenges to organizational structures in outpatient treatment if the patients' desire to spend their last days of life in their accustomed surroundings is to be realized. Pain intensity and the associated symptoms in a WHO step III opiate therapy during the last 3 days of life were investigated retrospectively among 601 tumor patients who had received medical care from Home Care Berlin. Differences in gender, age, living conditions/care situation and place of death were evaluated with due consideration for the different pain medications administered and for the different forms and routes of administration. More than 80% of the patients reported freedom from pain or only moderate pain during the opiate therapy. Care provided by the hospice-at-home medical service Home Care Berlin allowed excellent control of tumor patients' symptoms with only moderate side-effects in their final days of life. Among patients receiving opioids by the transdermal route there were significantly more frequent complaints of pain (p=0.004) and nausea (p=0.001). During the last days of life continuous subcutaneous infusions containing opiates facilitated good analgesia within an acceptable spectrum of side-effects. Most problems with controlling symptoms in outpatients were encountered in younger patients. Morphine emerged as the drug of first choice in this investigation, because it can be given parenterally and also because of its price. The use of subcutaneous and intravenous administration systems such as PCA pumps requires trained nursing services and regular house visits by physicians experienced in palliative medicine. Treatment administration and side effects Racotumomab is administered in patients who have previously received the oncospecific treatment established in the oncological therapeutic standards (surgery, chemotherapy and radiation therapy). A Racotumomab-alum solution is administered by intradermal injection every 14 days for the first 2 months (5 doses), followed by monthly booster doses. Racotumomab is well tolerated by patients. The overall toxicity of the vaccine has been classified as grade 1 and 2, according to the NCI Common Toxicity Criteria (version 3.0). Treatment is mostly associated with mild to moderate injection-site reactions (local erythema, induration and pain), which disappear within 24–48 hours. Systemic reactions, such as flu-like symptoms and chills are less frequent, reversible, and self-limited. Approvals and indications Some 129 cancer patients were taken care of at home by the visiting nurse team of our hospital since 1994 to 1997; 116 patients have already died, 50 of them at home (group A), and 66 at the hospital (group B). We analyze the differences the between two groups in nutritional assistance, pain control and manpower in looking after a patient. Twice as many patients in group A took nutritional medication (drip infusion or intravenous hyperalimentation, for example) than group B. More patients in group A used oral and suppository morphine than group B. In group A 70% of patients (56% in group B) had more than two persons looking after at home. The important factors for a good recuperation at home are: 1. Available nutritional assist available. 2. Good control. 3. Less burden and anxiety of the person looked after. To spend pain desirable last moments together, it is important for the visiting nurse team to take proper care and to confirm the wishes of the patient and family, considering the rapidly changing conditions of the individual patient. The effectiveness of ubrogepant for the acute treatment of migraine was demonstrated in two randomized, double-blind, placebo-controlled trials. In these studies, 1,439 adult patients with a history of migraine, with and without aura, received the approved doses of ubrogepant to treat an ongoing migraine. In both studies, the percentages of patients achieving pain freedom two hours after treatment (defined as a reduction in headache severity from moderate or severe pain to no pain) and whose most bothersome migraine symptom (nausea, light sensitivity or sound sensitivity) stopped two hours after treatment were significantly greater among patients receiving ubrogepant (19–21% depending on the dose) compared to those receiving placebo (12%). Patients were allowed to take their usual acute treatment of migraine at least two hours after taking ubrogepant. 23% of patients were taking a preventive medication for migraine. Management of cancer pain is one of the most important goals of palliative care. Relieving pain is often problematic. High doses of morphine at home may be required to relieve patients' pain, and is therefore feared. The goals of the current study were to assess the feasibility of high-dose morphine use at home, to characterize the patients, and to examine whether the use of high-dose morphine might affect their survival. The authors retrospectively studied the medical charts of 661 outpatients, which were completed by a home-care hospice team. The authors collected data regarding demographic parameters, medical diagnosis, pain type, morphine dosage, use of rescue doses in addition to regular doses, use of coanalgesics and adjuvant treatments, and survival time as associated with morphine dosage. The authors also compared the data of patients receiving high-dose morphine with those of a group of patients receiving regular doses. The authors identified 435 patients (65.8%) who received morphine for pain relief. Of these, 396 patients (91%) received a dose of 5-299 mg of morphine per day), 32 patients (7.4%) received 300-599 mg of morphine per day), and 7 patients (1.6%) received very high doses (&gt; or = 600 mg of morphine per day). Overall, 39 patients (9%) received &gt; 299 mg per day. Morphine dosage was found to be inversely correlated (r) with age (r = -0.254; P &lt; 0.001). Male patients required slightly higher dosages than female patients (62.5% of high-dose and 71% of very high-morphine groups, respectively). Primary gastrointestinal (P = 0.015) and lung (P = 0.027) carcinomas, as well as metastatic bone disease (P = 0.001), ovarian carcinoma (P = 0.037), and brain tumors (P = 0.0053) were associated with higher and very higher morphine dosages. Adverse effects were similar in the groups receiving regular, high, and very high doses of morphine. The median survival of patients treated with high doses of morphine was 27 days and was 37 days for those treated with very high doses. Patients treated with low doses of morphine survived for 18 days. Patients not treated with morphine survived for 22 days (P = 0.001 by Mantel-Cox analysis; P = 0.029 by Breslow analysis). The use of high and very high morphine doses at home proved safe and did not appear to affect the patients' life expectancy adversely. The use of high or very high-dose morphine should not be a barrier to providing palliative terminal care for home-care hospice patients. The use of an NSAID, especially some COX-2 inhibitors, or acetaminophen either as monotherapy or combination therapy is also suggested as a possible treatment option. Research needs It can be difficult to apply research into OIH to average patients, because some research focused on people taking very high doses or in methadone rehabilitation programs. Opioid-induced hyperalgesia has also been criticized as overdiagnosed among chronic pain patients, due to poor differential practice in distinguishing it from the much more common phenomenon of opioid tolerance. The misdiagnosis of common opioid tolerance (OT) as opioid-induced hyperalgesia (OIH) can be problematic as the clinical actions suggested by each condition can be contrary to each other. Patients misdiagnosed with OIH may have their opioid dose mistakenly decreased (in the attempt to counter OIH) at times when it is actually appropriate for their dose to be increased or rotated (as a counter to opioid tolerance). The aim of this study was to present how opioids are used in an acute pain relief and palliative care unit (APRPCU), where many patients with difficult pain conditions are admitted from GPs, home palliative care programs, oncology departments, other hospitals or emergency units, and other regional places. From a consecutive sample of cancer patients admitted to an APRPCU for a period of 6 months, patients who had been administered opioids were included in this survey. Basic information was collected as well as opioid therapy prescribed at admission and, subsequently, during admission and at time of discharge. Patients were discharged once stabilization of pain and symptoms were obtained and the treatment was considered to be optimized. One week after being discharged, patients or relatives were contacted by phone to gather information about the availability of opioids at dosages prescribed at time of discharge. One hundred eighty six of 231 patients were specifically admitted for uncontrolled pain, with a mean pain intensity of 6.8 (SD 2.5). The mean dose of oral morphine equivalents in patients receiving opioids before admission was 45 mg/day (range 10-500 mg). One hundred seventy five patients (75.7 %) were prescribed around the clock opioids at admission. About one third of patients changed treatment (opioid or route). Forty two of 175 (24 %), 27/58 (46.5 %), 10/22 (45.4 %), and 2/4 (50 %) patients were receiving more than 200 mg of oral morphine equivalents, as maximum dose of the first, second, third, and fourth opioid prescriptions, respectively. The pattern of opioids changed, with the highest doses administered with subsequent line options. The mean final dose of opioids, expressed as oral morphine equivalents, for all patients was 318 mg/day (SD 798), that is more than six times the doses of pre-admission opioid doses. One hundred eighty six patients (80.5 %) were prescribed a breakthrough cancer pain (BTcP) medication at admission. Sixty five patients changed their BTcP prescription, and further 27 patients changed again. Finally, eight patients were prescribed a fourth BTcP medication. Of 46 patients available for interview, the majority of them (n = 39, 84 %) did not have problems with their GPs, who facilitated prescription and availability of opioids at the dosages prescribed at discharge. For patients with severe distress, APRPCUs may guarantee a high-level support to optimize pain and symptom intensities providing intensive approach and resolving highly distressing situations in a short time by optimizing the use of opioids. Karen After her patient, Thomas Grey, reveals that he is dying of lung cancer and that he has been in love with her for a year, Karen begins having an affair with him. To help him end his life when the pain becomes too much, Karen prescribes Thomas fatal doses of morphine, which his wife, Elizabeth, helps to administrate. The insurance company begins to investigate Thomas' death, going so far as to approach Karen for the notes from her sessions with Thomas. However, Karen had destroyed anything relating to Thomas being her patient. While grieving his father's death, Thomas' son Sam turns to Karen for advice as he has discovered that his father was having an affair. Even though Savi advises Karen to cut all ties with the Grey Family, Karen begins helping Sam. Things take a dangerous turn after Sam falls in love with Karen and begins stalking her. CroFab antivenin has been used successfully to treat Osage copperhead bites, although a lack of complete cross-tolerance requires careful administration and close supervision during the full course of treatment to ensure that the lowest effective dose is administered (a lower dose would not fully treat the envenomation, and a higher dose may be particularly dangerous to children, the elderly, and infirm adults). Not uncommonly, opiate/opioid narcotic analgesics (ex. morphine, fentanyl), muscle relaxerss (ex. diazepam, tizanidine, orphenadrine), and broad-spectrum antibiotics are administered. A few days' supply of weaker analgesics and muscle relaxers may be prescribed for the patient to control pain after he or she returns home as the pain resolves completely within one to three days. Patients also receive a prescription for an intensive antibiotic therapy, which much be taken until the supplies are depleted, giving the drug enough time to fully treat any opportunistic infections Pain relief is a quite important subject for maintaining the home medical care of patients with terminal cancer. Therefore, the opioid rotation should be made in conjunction with an individual medical condition, which is of growing importance in a proper pain management. We considered what opioid rotation is desirable in the home medical care service by analyzing the cases at our clinic. The most important thing in the opioid rotation at home is to perform a rotation before exacerbation of pain becomes apparent. For this purpose, morphine hydrochloride injection is thought to be the best dosage form because it has advantages of: (1) quickness in varying the amount, (2) immediate rescue efficacy, and (3) usefulness in case of ingestion. Oxycodone has a half-life of 4.5 hours. It is available as a generic medication. The manufacturer of OxyContin, a controlled-release preparation of oxycodone, Purdue Pharma, claimed in their 1992 patent application that the duration of action of OxyContin is 12 hours in \"90% of patients.\" It has never performed any clinical studies in which OxyContin was given at more frequent intervals. In a separate filing, Purdue claims that controlled-release oxycodone \"provides pain relief in said patient for at least 12 hours after administration.\" However, in 2016 an investigation by the Los Angeles Times found that \"the drug weans off hours early in many people,\" inducing symptoms of opiate withdrawal and intense cravings for OxyContin. One doctor, Lawrence Robbins, told journalists that over 70% of his patients would report that OxyContin would only provide 4–7 hours of relief. Doctors in the 1990s often would switch their patients to a dosing schedule of once every eight hours when they In this case report, we describe continuous subcutaneous infusion of opiates as PCAO (patient controlled analgesia in outpatients) in one patient with metastatic carcinoma of the rectum (liver and bone metastases, partial bowel obstruction) with severe cancer pain and vomiting in the terminal phase. The parenteral administration of opioids extended over 58 days. The infusion was powered by an external portable clockwork-driven syringe pump (Perfusor M, Braun Medical/Germany). The open-accessible pump has a syringe volume of 10 ml, and its maximal infusion time is 24 h. The 27-G infusion needle (Sub-Q-Set, Baxter/USA) was inserted in the side of the abdomen and was left in the same position for 10 to 20 days. It took the patient and his family only 1.5 h to familiarize themselves with the use of the pump. They were trained in its use in our outpatient pain department. For pain control both the variable continuous infusion and the extra injection doses could be administered by the way of the syringe driver. The patient was given a stock of 120 ampoules of morphine for further treatment at home. For optimal pain control he decided to raise the daily dose of opioid infusion from the initial 60 mg to 240 mg morphine within 48 h. In this way, PCAO-besides rapid titration of the opioid dose to achieve analgesia-allows the use of opioids controlled by the patient himself. In the present case this procedure was also important when an outpatient radiation therapy became urgently necessary to prevent a fracture of the spine because of metastasis. The pain control by the patient himself was the main factor to get free of pain during the transport to the hospital. Even positioning for radiation was possible without pain. When he received outpatient radiation therapy the patient needed extra injection doses of up to 360 mg morphine a day. The PCAO procedure by continuous subcutaneous infusion with opiates is a safe and efficient method of pain management for outpatient patients suffering from severe cancer pain and intractable nausea in the terminal phase. Its validity has also been proven especially for radiation treatment of bone metastases. was well tolerated by the 30 patients who were enrolled in this study. All were treated with 2 fields, and the average whole brain dose was 3.2–6.1 Gy (weighted), and the minimum dose to the tumor ranged from 15.4 to 54.3 Gy (w). There has been some disagreement among the Swedish investigators regarding the evaluation of the results. Based on incomplete survival data, the MeST was reported as 14.2 months and the time to tumor progression was 5.8 months. However, more careful examination of the complete survival data revealed that the MeST was 17.7 months compared to 15.5 months that has been reported for patients who received standard therapy of surgery, followed by radiotherapy (RT) and the drug temozolomide (TMZ). Furthermore, the frequency of adverse events was lower after BNCT (14%) than after radiation therapy (RT) alone (21%) and both of these were lower than those seen following RT in combination with TMZ. If this improved survival data, obtained using the higher dose of BPA In a multicenter study, 28 patients with cancer pain and insufficient pain relief with analgesic treatment according to step II of the guidelines of the World Health Organization (WHO) were switched to oral slow-release morphine. Patients received intravenous morphine through a patient-controlled pump (PCA) for the first 24 hours (bolus = 1 mg, lockout interval = 5 minutes, maximum dose = 12 mg/hour). From day 2 patients were treated with oral slow-release morphine. Daily doses were calculated from the requirements of the day before. Breakthrough pain was treated with PCA until stable doses were reached (&lt;2 boluses/day) and then with oral immediate-release morphine solution. Pain intensity was reported in a diary four times a day, in addition to mood, activity, and quality of sleep once daily. Mean duration until adequate pain relief reported (&lt;30 on a 101-step numerical scale; NRS) was 5 hours (range = 80-620 minutes). Mean pain intensity was reduced from 67 NRS to 22 NRS. Mean doses of oral morphine were 133 mg/day initially and then 154 mg/day on day 14. Serious adverse events such as respiratory depression were not observed. Two patients terminated the study due to progressive symptoms of gastrointestinal obstruction. Seventy-five percent of the patients evaluated the effectiveness of the analgesic regime as good. Dose finding with intravenous PCA may be appropriate for a small minority of patients with severe pain. Higher treatment costs and the risk of complications are drawbacks of this method compared with conventional oral titration. After embolization, patients are observed in the post-anesthesia care unit for several hours. Patients are discharged from the hospital when taking adequate nutrition by mouth, when pain is adequately controlled with oral narcotics and when the temperature is lower than 38.5 for 24 hours. Post-procedure evaluation Follow-up triple phase CT is performed 2 to 4 weeks after treatment is complete and reviewed for any evidence of persistent untreated disease. If there is no evidence of enhancement of the treated tumor, these patients are monitored with triple phase CT every 3 months for the first year and every 6 months thereafter. When there is evidence of untreated disease, recurrent disease, or new disease elsewhere within the liver the patient is scheduled for additional embolization. References Hepatology Diseases of liver Pain control in hospice patients in the home may be compromised by concerns about overuse of analgesics, particularly narcotics. A retrospective chart audit of analgesic type and amount was performed on the medical records of 100 cancer patients receiving hospice care in the home. Different types and amounts of analgesics were converted to a common standard, an oral morphine equivalent (OME) relative to 1 mg of oral morphine sulfate. Descriptive statistics were used to characterize patient analgesic use during the entire course of hospice care and the last 5 days of life. Associations between analgesic use and select patient characteristics (age, sex, cancer site, metastases, and pain intensity at admission) were explored. Ninety-one percent of the sample had used analgesics at some time during hospice care. The proportion of patients using analgesics increased as death approached. The mean and median daily analgesic use over the entire period were 114 and 82 OMEs and during the last 5 days 140 and 84 OMEs, respectively. The range of mean daily analgesic use was between 10 and 735 OMEs. Individual variability in analgesic use was demonstrated. Not all patients required analgesics, and among those who did there was remarkable variation in the amount used. Large and even enormous doses of analgesics may sometimes be required to control cancer pain. Case Study  Sarah is a 58-year-old breast cancer survivor, social worker, and health-care administrator at a long-term care facility. She lives with her husband and enjoys gardening and reading. She has two grown children and three grandchildren who live approximately 180 miles away. SECOND CANCER DIAGNOSIS  One morning while showering, Sarah detected a painless quarter-sized lump on her inner thigh. While she thought it was unusual, she felt it would probably go away. One month later, she felt the lump again; she thought that it had grown, so she scheduled a visit with her primary care physician. A CT scan revealed a 6.2-cm soft-tissue mass in the left groin. She was referred to an oncologic surgeon and underwent an excision of the groin mass. Pathology revealed a grade 3 malignant melanoma. She was later tested and found to have BRAF-negative status. Following her recovery from surgery, Sarah was further evaluated with an MRI scan of the brain, which was negative, and a PET scan, which revealed two nodules in the left lung. As Sarah had attended a cancer support group during her breast cancer treatment in the past, she decided to go back to the group when she learned of her melanoma diagnosis. While the treatment options for her lung lesions included interleukin-2, ipilimumab (Yervoy), temozolomide, dacarbazine, a clinical trial, or radiosurgery, Sarah's oncologist felt that ipilimumab or radiosurgery would be the best course of action. She shared with her support group that she was ambivalent about this decision, as she had experienced profound fatigue and nausea with chemotherapy during her past treatment for breast cancer. She eventually opted to undergo stereotactic radiosurgery. DISEASE RECURRENCE  After the radiosurgery, Sarah was followed every 2 months. She complained of shortness of breath about 2 weeks prior to each follow-up visit. Each time her chest x-ray was normal, and she eventually believed that her breathlessness was anxiety-related. Unfortunately, Sarah's 1-year follow-up exam revealed a 2 cm × 3 cm mass in her left lung, for which she had a surgical wedge resection. Her complaints of shortness of breath increased following the surgery and occurred most often with anxiety, heat, and gardening activities, especially when she needed to bend over. Sarah also complained of a burning \"pins and needles\" sensation at the surgical chest wall site that was bothersome and would wake her up at night. Sarah met with the nurse practitioner in the symptom management clinic to discuss her concerns. Upon physical examination, observable signs of breathlessness were lacking, and oxygen saturation remained stable at 94%, but Sarah rated her breathlessness as 7 on the 0 to 10 Borg scale. The nurse practitioner prescribed duloxetine to help manage the surgical site neuropathic pain and to assist with anxiety, which in turn could possibly improve Sarah's breathlessness. Several nonpharmacologic modalities for breathlessness were also recommended: using a fan directed toward her face, working in the garden in the early morning when the weather is cooler, gardening in containers that are at eye level to avoid the need to bend down, and performing relaxation exercises with pursed lip breathing to relieve anxiety-provoked breathlessness. One month later, Sarah reported relief of her anxiety; she stated that the fan directed toward her face helped most when she started to feel \"air hungry.\" She rated her breathlessness at 4/10 on the Borg scale. SECOND RECURRENCE: MULTIPLE PULMONARY NODULES  Sarah's chest x-rays remained clear for 6 months, but she developed a chronic cough shortly before the 9-month exam. An x-ray revealed several bilateral lung lesions and growth in the area of the previously resected lung nodule. Systemic therapy was recommended, and she underwent two cycles of ipilimumab. Sarah's cough and breathlessness worsened, she developed colitis, and she decided to stop therapy after the third cycle. In addition, her coughing spells triggered bronchospasms that resulted in severe anxiety, panic attacks, and air hunger. She rated her breathlessness at 10/10 on the Borg scale during these episodes. She found communication difficult due to the cough and began to isolate herself. She continued to attend the support group weekly but had difficulty participating in conversation due to her cough. Sarah was seen in the symptom management clinic every 2 weeks or more often as needed. No acute distress was present at the beginning of each visit, but when Sarah began to talk about her symptoms and fear of dying, her shortness of breath and anxiety increased. The symptom management nurse practitioner treated the suspected underlying cause of the breathlessness and prescribed oral lorazepam (0.5 to 1 mg every 6 hours) for anxiety and codeine cough syrup for the cough. Opioids were initiated for chest wall pain and to control the breathlessness. Controlled-release oxycodone was started at 10 mg every 12 hours with a breakthrough pain (BTP) dose of 5 mg every 2 hours as needed for breathlessness or pain. Sarah noted improvement in her symptoms and reported a Borg scale rating of 5/10. Oxygen therapy was attempted, but subjective improvement in Sarah's breathlessness was lacking. END OF LIFE  Sarah's disease progressed to the liver, and she began experiencing more notable signs of breathlessness: nasal flaring, tachycardia, and restlessness. Opioid doses were titrated over the course of 3 months to oxycodone (40 mg every 12 hours) with a BTP dose of 10 to 15 mg every 2 hours as needed, but her breathlessness caused significant distress, which she rated 8/10. The oxycodone was rotated to IV morphine continuous infusion with patient-controlled analgesia (PCA) that was delivered through her implantable port. This combination allowed Sarah to depress the PCA as needed and achieve immediate control of her dyspneic episodes. Oral lorazepam was also continued as needed. Sarah's daughter moved home to take care of her mother, and hospice became involved for end-of-life care. As Sarah became less responsive, nurses maintained doses of morphine for control of pain and breathlessness and used a respiratory distress observation scale to assess for breathlessness since Sarah could no longer self-report. A bolus PCA dose of morphine was administered by Sarah's daughter if her mother appeared to be in distress. Sarah died peacefully in her home without signs of distress.  Even when the guidelines for cancer pain management are followed, acute severe pain requiring immediate treatment will occur in some patients. Titration with intravenous morphine may provide fast and efficient pain relief and give an indication of the amount of opioid necessary for continuous treatment. In cooperation with a general practitioner we performed an intravenous morphine titration in a patient with severe cancer pain at home. Adequate analgesia was reached with 20 mg intravenous morphine. Blood pressure, cardiac frequency and oxygen saturation did not change. No side effects were reported during the titration, and the previous regimen with tramadol 150 mg per day was switched to slow release morphine 300 mg per day. This medication was prescribed by the general practitioner and provided good pain relief until the patient died two weeks later. We conclude that intravenous morphine titration may be performed even in cancer patients at home, adequate monitoring, however, should be available. The initial 24 hours after opioid administration appear to be the most critical with regard to life-threatening OIRD, but may be preventable with a more cautious approach to opioid use. Patients with cardiac, respiratory disease and/or obstructive sleep apnoea are at increased risk for OIRD. Increased pain sensitivity Opioid-induced hyperalgesia – where individuals using opioids to relieve pain paradoxically experience more pain as a result of that medication – has been observed in some people. This phenomenon, although uncommon, is seen in some people receiving palliative care, most often when dose is increased rapidly. If encountered, rotation between several different opioid pain medications may decrease the development of increased pain. Opioid induced hyperalgesia more commonly occurs with chronic use or brief high doses but some research suggests that it may also occur with very low doses.\nHere is the question:\nPRIMARY CARE: The patient comes to the home of an oncology patient whose pain has not been well controlled lately. On physical examination there appears to be no evidence of tumor progression, and no previously known data of interest is revealed. In the anamnesis, the main caregiver states that the patient has pain 8 hours after receiving the prescribed basal dose of morphine every 12 hours. This clinical situation is referred to as:\nHere are the potential choices:\n1. Tolerance\n2. Hyperalgesia\n3. Dependency\n4. Ineffectiveness\nThe correct answer is: 2. Hyperalgesia"
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Despite the destruction of platelets by splenic macrophages, the spleen is normally not enlarged. In fact, an enlarged spleen should lead to a search for other possible causes for the thrombocytopenia. Bleeding time is usually prolonged in ITP patients. However, the use of bleeding time in diagnosis is discouraged by the American Society of Hematology practice guidelines and a normal bleeding time does not exclude a platelet disorder. Bone marrow examination may be performed on patients over the age of 60 and those who do not respond to treatment, or when the diagnosis is in doubt. On examination of the marrow, an increase in the production of megakaryocytes may be observed and may help in establishing a diagnosis of ITP. An analysis for anti-platelet antibodies is a matter of clinician's preference, as there is disagreement on whether the 80 percent specificity of this test is sufficient to be clinically useful. ITP is an autoimmune disease with antibodies detectable against several platelet surface structures. ITP is diagnosed by identifying a low platelet count on a complete blood count (a common blood test). However, since the diagnosis depends on the exclusion of other causes of a low platelet count, additional investigations (such as a bone marrow biopsy) may be necessary in some cases. In mild cases, only careful observation may be required but very low counts or significant bleeding may prompt treatment with corticosteroids, intravenous immunoglobulin, anti-D immunoglobulin, or immunosuppressive medications. Refractory ITP (not responsive to conventional treatment or constant relapsing after splenectomy) requires treatment to reduce the risk of clinically significant bleeding. Platelet transfusions may be used in severe cases with very low platelet counts in people who are bleeding. Sometimes the body may compensate by making abnormally large platelets. Idiopathic (immune) thrombocytopenic purpura (ITP) is the most frequent hemorrhagic disease in children. It represents the acquired megakaryocytic thrombocytopenia with the shortened life of platelets because of immunologic damage (antibodies absorbed by platelets). In the case of this acquired hemorrhagic disorder, in spite of compensatory increased function of the bone marrow, there is a reduced number of platelets because of their increased destruction by the reticuloendothelial system (destructive thrombocytopenia). There are three forms of ITP: acute, chronic and intermittent. The acute form occurs in 80-90% of cases with bleeding episodes lasting a few days or weeks, but no longer than 6 months. The chronic form occurs in 10-15% of children, while the rarest-intermittent form is characterized by periods of normalization in regard to the number of platelets but also with relapse in intervals of 1-3 months. The disease is caused by an immunological disorder in the sense of an imbalanced immune response. Immunologic damages of platelets cause shortening of the opsonized platelets life span. The most frequent platelet opsonins are the immumoglobulin G (IgG) antibodies directed at the platelet membrane in the form of autoantibodies, alloantibodies or possibly absorbed antigen caused by microorganism infection or drug intake. It is typical for the phenomenon of bleeding that it starts suddenly and without any other sign of illness. The most frequent acute form appears between the second and fourth year, and is characterized by seasonal occurrence usually after acute viral infections. Children older than 10 years of age, like adults, often have the chronic form associated with other immunologic disorders. The disease affects girls more often than boys (about three times more often) with moderate and constant increase of antiplatelet antibodies. Hemorrhagic manifestations include: petechiae, purpura, epistaxis, gastrointestinal and genitourinary bleeding. They depend on the grade of thrombocytopenia, although there is no strict correlation between the number of platelets and volume of bleeding. Low mortality of the acute ITP is almost exclusively due to intracranial hemorrhage. LABORATORY STUDIES: Thrombocytopenia represents a decrease in the number of blood platelets being a basic abnormality of the blood count. The half-life of platelets in ITP is shortened. Detection of antiplatelet antibodies is connected with technical difficulties, so they are established in about 30% of cases. Bleeding time is prolonged and so is the coagulum retraction which may be completely missed. The Rumpel-Leede test is positive. Clinical differentiation of drug-induced thrombocytopenia is not possible. However, other differential diagnostic possibilities are thrombotic-thrombocytopenic purpura and hemolytic-uremic syndrome. A child with aplastic anemia or acute leukemia, beside thrombocytopenia, has a characteristic finding of white and red blood cell count. Thrombocytopenia with absent radii syndrome is associated with skeletal system abnormalities. New knowledge about the role of the immune system in ITP determines the modern therapeutic modalities. In cases of acute ITP in children, there are two therapeutic options or therapies of choice: corticosteroids and high doses of intravenous immunoglobulin. Immunosupressive therapy means anti Rh(D) immunoglobulin, cyclosporine, cytostatics, danazol, loaded platelets. In cases of distinctive hemorrhagic syndrome there are also indications for platelet transfusion. Nowadays splenectomy is more restricted, because one third of cases is unsuccessful, whereas plasmapheresis is rarely used in children because of possible complications. ITP is the most frequent hemorrhagic disease in children. The disease is basically caused by an immunologic disorder with platelet destruction due to increased immunoglobulin on their membrane. (ABSTRACT TRUNCATED) To identify initial laboratory findings useful for the later diagnosis of idiopathic thrombocytopenic purpura (ITP) in adult patients with thrombocytopenia. We studied 62 consecutive adult patients who had thrombocytopenia and whose peripheral blood film was normal except for thrombocytopenia at presentation. Each patient underwent physical examination and routine laboratory tests and was prospectively followed for 22.5 +/- 9.8 months (range, 8 to 41 months). The frequency of antiglycoprotein (GP) IIb/IIIa antibody-producing B cells, the presence of platelet-associated and plasma anti-GPIIb/IIIa antibodies, the percentage of reticulated platelets, and the plasma thrombopoietin level were examined at the first visit. The final diagnosis was based on the clinical history, physical examination, complete blood test, bone marrow findings, and the clinical course at last observation. Forty-six patients were diagnosed as having ITP and 16 as having another disorder, including myelodysplastic syndrome, aplastic anemia, amegakaryocytic thrombocytopenia, and reduced platelet production, with or without other cytopenias, and without dysplasia or evidence for destruction. Six initial laboratory findings discriminated ITP from other diagnoses: the absence of anemia, absence of leukocytopenia, increased frequency of anti-GPIIb/IIIa antibody-producing B cells, increased platelet-associated anti-GPIIb/IIIa antibodies, elevated percentage of reticulated platelets, and a normal or slightly increased plasma thrombopoietin level. Three or more of these ITP-associated findings were found at presentation in 44 patients (96%) with thrombocytopenia later diagnosed as ITP, compared with only 1 patient (6%) whose disorder was non-ITP. Initial laboratory findings can well predict future diagnosis of ITP. Further studies prospectively evaluating these same diagnostic criteria on another, independent set of patients are necessary. The need for a bone marrow examination was assessed in patients with clinical and laboratory features consistent with ITP; the literature was reviewed. The records of all patients undergoing a bone marrow examination between January 1988 to January 1998 were retrospectively reviewed to determine which were motivated by the suspicion of ITP. Data were collected from hospital and outpatient medical and pathology records. Eighty-six patients with isolated thrombocytopenia (i.e., normal white blood cell count, hemoglobin, peripheral smear and clotting studies) were studied. The bone marrow was consistent with ITP in 82 patients, (i.e., normal or increased megakaryocytes and other hemopoietic lineages normal.) Four patients had decreased megakaryocytes, but all patients responded to corticosteroids. All 86 patients were followed up for a median of 22 months after bone marrow aspiration (range, 2-76 months.) During that time, none of the patients developed features to suggest an alternative diagnosis to ITP. The initial clinical and laboratory findings of 99 patients with acute leukemia were also reviewed; all had features atypical of ITP. These data suggest that routine performance of a bone marrow examination for the diagnosis of ITP is not necessary, provided that a thorough history and physical examination are performed and that the complete blood cell count, peripheral blood smear, and routine clotting studies show no abnormalities apart from thrombocytopenia. The findings of seven prior retrospective studies, two in adults and five in children are consistent with the previous findings. However, the value of marrow investigation in ITP remains unresolved and data from a large prospective study would be helpful. Immune thrombocytopenic purpura Many cases of immune thrombocytopenic purpura (ITP) also known as idiopathic thrombocytopenic purpura, can be left untreated, and spontaneous remission (especially in children) is not uncommon. However, counts under 50,000 are usually monitored with regular blood tests, and those with counts under 10,000 are usually treated, as the risk of serious spontaneous bleeding is high with such low platelet counts. Any patient experiencing severe bleeding symptoms is also usually treated. The threshold for treating ITP has decreased since the 1990s; hematologists recognize that patients rarely spontaneously bleed with platelet counts greater than 10,000, although exceptions to this observation have been documented. Immune thrombocytopenia (ITP) is characterized by a platelet count less than 100 × 10^9/L without anemia or leukopenia. Patients with ITP may be asymptomatic, or they may have mild bleeding like petechiae, purpura, or epistaxis. In rare cases, they may present to the emergency department (ED) with life-threatening bleeding as a result of their thrombocytopenia. The emergency physician should thus be prepared to diagnose ITP and treat the bleeding that can result from it. The diagnosis of ITP requires excluding secondary causes of thrombocytopenia, and in the ED, the bare minimum workup for ITP includes a complete blood count and a peripheral blood smear. The peripheral blood smear should show a small number of large platelets with normal morphology, and there should not be an increased number of schistocytes. Many patients with ITP require no emergent treatment. However, if a patient with suspected ITP presents to the ED with critical hemorrhage, the emergency physician should initiate treatment with a platelet transfusion, corticosteroids, and intravenous immune globulin (IVIG) as soon as possible. For less severe bleeding, platelet transfusions are not recommended, and the treatment consists of corticosteroids by themselves or in conjunction with IVIG. Idiopathic thrombocytopenic purpura(ITP) is a hematologic disorder which causes thrombocytopenia. The diagnosis of ITP is based on the history, physical examination and, complete blood count, and examination of the peripheral smear. The diagnostic criteria of ITP established by the Ministry of Health, Welfare, and Labor in Japan requires the bone marrow examination and the measurement of platelet associated IgG, but those tests are not always necessary according to the guidelines developed by the American Society of Hematology. The appropriate strategies for the diagnosis of ITP need to be established. In this paper, some new examinations which may help the diagnosis of ITP are also demonstrated. Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is a type of thrombocytopenic purpura defined as an isolated low platelet count with a normal bone marrow in the absence of other causes of low platelets. It causes a characteristic red or purple bruise-like rash and an increased tendency to bleed. Two distinct clinical syndromes manifest as an acute condition in children and a chronic condition in adults. The acute form often follows an infection and spontaneously resolves within two months. Chronic immune thrombocytopenia persists longer than six months with a specific cause being unknown. ITP is an autoimmune disease with antibodies detectable against several platelet surface structures. Immune thrombocytopenic purpura (ITP) is a bleeding disorder characterized by isolated thrombocytopenia (platelet count &lt;150,000 u/L), which is not associated with a systemic illness. ITP is reported in approximately 2 per 100,000 adults. The mean age of diagnosis is 50 years. ITP is more common in females of childbearing age and in pregnancy. In adults, the course is more chronic although spontaneous remission can also occur within months of initial diagnosis. A thorough and timely workup of thrombocytopenia is imperative to rule out other differentials of ITP as it is considered a diagnosis of exclusion. Primary care physicians encounter patients who exhibit signs of thrombocytopenia such as petechiae or purpura on a regular basis. A high index of clinical suspicion is required to accurately diagnose ITP and commence the appropriate treatment including glucocorticoids to increase the chances of a favorable prognosis as described by the authors. This report illustrates the importance of a detailed history and physical exam and careful analysis of hematologic parameters when diagnosing ITP. This case demonstrates that even with subtle deviations from typical ITP findings one must promptly reevaluate the diagnosis. This case also highlights the importance of peripheral smear review by an expert in pediatric hematopathology. A previously healthy 10 year-old Asian boy presented with 2 months of easy bruising. Review of systems was negative for any constitutional symptoms. On examination, he appeared well but had numerous large ecchymoses. He had no appreciable lymphadenopathy or splenomegaly. The liver was palpable 1.5 cm below the costal margin. A complete blood count (CBC) showed: platelets = 17 × 109/L, hemoglobin = 128 g/L, white blood cell count = 5.43 × 109/L, and neutrophils = 1.63 × 109/L. A blood smear was reported as normal. Urate was 370 umol/L and lactate dehydrogenase (LDH) was 803 U/L. The child was admitted with a presumptive diagnosis of immune thrombocytopenic purpura (ITP) and treated with intravenous immunoglobulin. The following day, the blood smear was reviewed by a hematopathologist who identified blasts. A bone marrow aspiration (BMA) confirmed the diagnosis of precursor B-cell acute lymphoblastic leukemia. In children presenting with suspected ITP, leukemia should always be considered. A BMA was historically performed on all patients with presumed ITP to rule out leukemia. In 2011, the American Society of Hematology (ASH) stopped recommending routine BMA in patients suspected of having ITP. ASH advises in cases with unusual findings on history, physical examination or CBC, it is reasonable to perform a BMA. Our patient had mild hepatomegaly, which may have qualified him for a BMA. He also had an elevated LDH and urate, which are not listed as criteria for BMA by ASH but were considered atypical for ITP by the clinical team. A literature search did not reveal any primary data assessing these markers. While corticosteroids are a first line treatment in ITP, they must be reserved for when clinicians are confident that the patient does not have leukemia. Steroid administration prior to diagnosing leukemia results in delayed diagnosis and may increase the risk of complications and decrease survival. A review is made of the data in the literature and of the authors' experience regarding the etiology and pathogenesis, diagnosis and therapy of the chronic form of idiopathic thrombocytopenic purpura (ITP). The mechanisms of production (after McMillan et al.) are presented schematically and the five criteria of ITP diagnosis suggested by Karpatkin are discussed: 1) decreased blood platelet count with direct or indirect signs of thrombocytolysis; 2) increased number of megakaryocytes in the bone marrow and/or signs of intramedullary thrombocytolysis; 3) direct or indirect signs of antiplatelet autoantibody presence in the plasma; 4) exclusion of a primary disorder and 5) absence of splenomegaly. The results of corticotherapy, splenectomy, platelet transfusion and immunosuppression (including \"target\" immunosuppressive therapy) in 188 patients with ITP, admitted to the clinic of Hematology--Bucharest between 1966 and 1978, are presented and analysed. It is recommended that pregnant women with thrombocytopenia or a previous diagnosis of ITP should be tested for serum antiplatelet antibodies. A woman with symptomatic thrombocytopenia and an identifiable antiplatelet antibody should be started on therapy for their ITP which may include steroids or IVIG. Fetal blood analysis to determine the platelet count is not generally performed as ITP-induced thrombocytopenia in the fetus is generally less severe than NAIT. Platelet transfusions may be performed in newborns, depending on the degree of thrombocytopenia. It is recommended that neonates be followed with serial platelet counts for the first few days after birth. ITP is associated with a range of conditions, including lymphoma, leukemia, SLE, HIV, and HCV. The clinical presentation is as follows: Acute: Abrupt onset of hemorrhagic complications following a viral illness. Commonly affects children 2–6 years of age, with males and females affected equally. Chronic: Insidious onset that is unrelated to infection. Most often affects adults 20–40 years of age; women are three times more likely to be affected than men. A diagnosis of exclusion, as the test for platelet-associated antibodies is a poor one. Once other causes of thrombocytopenia have been ruled out, a diagnosis can be made on the basis of the history and physical, a CBC, and a peripheral blood smear showing normal RBC morphology. Most patients do not require bone marrow biopsy, which would show ↑ megakaryocytes as the only abnormality. Most patients with acute childhood ITP spontaneously remit, but this is rarely the case in chronic ITP. Diagnosis The diagnosis of ITP is a process of exclusion. First, it has to be determined that there are no blood abnormalities other than a low platelet count, and no physical signs other than bleeding. Then, secondary causes (5–10 percent of suspected ITP cases) should be excluded. Such secondary causes include leukemia, medications (e.g., quinine, heparin), lupus erythematosus, cirrhosis, HIV, hepatitis C, congenital causes, antiphospholipid syndrome, von Willebrand factor deficiency, onyalai and others. All patients with presumed ITP should be tested for HIV and hepatitis C virus, as platelet counts may be corrected by treating the underlying disease. In approximately 2.7 to 5 percent of cases, autoimmune hemolytic anemia and ITP coexist, a condition referred to as Evans syndrome. Immune thrombocytopenic purpura (ITP) is an immune-mediated acquired disease found in both adults and children. It is characterized by transient or persistent decreases in the platelet count. We report a case of ITP detected based on oral hemorrhagic symptoms. The patient was a 79-year-old female with no significant past medical history. She presented with sudden onset of gingival bleeding and hemorrhagic bullae on the buccal mucosa. Gingival bleeding was difficult to control. Laboratory tests revealed severe thrombocytopenia with a platelet count as low as 2000/μL. Under a provisional diagnosis of a hematological disorder, she was referred to a hematologist. A peripheral smear showed normal-sized platelets. A bone marrow examination revealed increased numbers of megakaryocytes without morphologic abnormalities. The patient was diagnosed with ITP and treated with a combination of pulsed steroid therapy and high-dose immunoglobulin therapy. However, her severe thrombocytopenia was refractory to these treatments. Then, a thrombopoietin receptor agonist was begun as a second-line treatment. Her platelets rapidly increased, and no bleeding complications were reported. Because oral symptoms can be one of the initial manifestations of ITP, dentists should be familiar with the clinical appearance of ITP, and attention must be paid to detect and diagnose unidentified cases. Immune thrombocytopenia (ITP) is a diagnosis of exclusion that can resemble other thrombocytopenic disorders. To develop a clinical prediction model (CPM) for the diagnosis of ITP to aid hematogists in investigating patients presenting with undifferentiated thrombocytopenia. We designed a CPM for ITP diagnosis at the time of the initial hematology consultation using penalized logistic regression based on data from patients with thrombocytopenia enrolled in the McMaster ITP registry (n = 523) called the Predict-ITP Tool. The case definition for ITP was a platelet count less than 100 × 10<sup9</sup /L and a platelet count response after high-dose corticosteroids or intravenous immune globulin, defined as the achievement of a platelet count above 50 × 10<sup9</sup /L and at least a doubling of baseline. Internal validation was done using bootstrap resampling. Model discrimination was assessed by the c-statistic, and calibration was assessed by the calibration slope, calibration-in-the-large, and calibration plot. The final model included the following variables: (1) platelet count variability (based on three or more platelet count values), (2) lowest platelet count value, (3) maximum mean platelet volume, and (4) history of major bleeding (defined by the ITP bleeding scale). The optimism-corrected c-statistic was 0.83, the calibration slope was 0.88, and calibration-in-the-large for all performance measures was &lt;0.001 with standard error &lt;0.001, indicating good discrimination and excellent calibration. The Predict-ITP Tool can estimate the likelihood of ITP for a given patient with thrombocytopenia at the time of the initial hematology consultation. The tool had high predictive accuracy for the diagnosis of ITP. laboratory testing in itp Laboratory testing for antibodies (serologic testing) is usually not helpful due to the low sensitivity and specificity of the current tests. Bone marrow examination can be reserved for those who have other signs or laboratory abnormalities not explained by ITP or in patients who do not respond to initial therapy. The peripheral blood smear may show large platelets, with otherwise normal morphology. Depending on the bleeding history, iron-deficiency anemia may be present. Laboratory testing is performed to evaluate for secondary causes of ITP and should include testing for HIV infection and hepatitis C (and other infections if indicated). Serologic testing for SLE, serum protein electrophoresis, immunoglobulin levels to potentially detect hypogammaglobulinemia, selective testing for IgA deficiency or monoclonal gammopathies, and testing for H. pylori infection should be considered, depending on the clinical circumstance. If anemia is present, direct antiglobulin testing (Coombs’ test) should be performed to rule out combined autoimmune hemolytic anemia with ITP (Evans’ syndrome). The treatment of ITP uses drugs that decrease reticuloendothelial uptake of the antibody-bound platelet, decrease antibody production, and/or increase platelet production. The diagnosis of ITP does not necessarily mean that treatment must be instituted. Patients with platelet counts >30,000/μL appear not to have increased mortality related to the thrombocytopenia. Pregnancy Anti-platelet autoantibodies in a pregnant woman with ITP will attack the patient's own platelets and will also cross the placenta and react against fetal platelets. Therefore, ITP is a significant cause of fetal and neonatal immune thrombocytopenia. Approximately 10% of newborns affected by ITP will have platelet counts <50,000/uL and 1% to 2% will have a risk of intracerebral hemorrhage comparable to infants with neonatal alloimmune thrombocytopenia (NAIT). No lab test can reliably predict if neonatal thrombocytopenia will occur. The risk of neonatal thrombocytopenia is increased with: Mothers with a history of splenectomy for ITP Mothers who had a previous infant affected with ITP Gestational (maternal) platelet count less than 100,000/uL Disorders Adapted from: The three broad categories of platelet disorders are \"not enough\"; \"dysfunctional\"; and \"too many\". Thrombocytopenia Immune thrombocytopenias (ITP) – formerly known as immune thrombocytopenic purpura and idiopathic thrombocytopenic purpura Splenomegaly Gaucher's disease Familial thrombocytopenia Chemotherapy Babesiosis Dengue fever Onyalai Thrombotic thrombocytopenic purpura HELLP syndrome Hemolytic–uremic syndrome Drug-induced thrombocytopenic purpura (five known drugs – most problematic is heparin-induced thrombocytopenia (HIT) Pregnancy-associated Neonatal alloimmune associated Aplastic anemia Transfusion-associated Pseudothrombocytopenia idiopathic thrombocytopenic purpura Vaccine induced immune thrombocytopenia Gilbert's syndrome Causes Although Evans syndrome seems to be a disorder of immune regulation, the exact pathophysiology is unknown, but a gradual loss of self-tolerance is postulated. Autoantibodies targeted at different antigenic determinants on red cells and platelets are assumed to cause isolated episodes of hemolytic anemia and thrombocytopenia, respectively. Diagnosis The diagnosis of primary Evans syndrome is made upon blood tests to confirm not only hemolytic anemia and immune thrombocytopenic purpura, but also a positive direct antiglobulin test (DAT) and an absence of any known underlying cause. In 27% to 50% of cases there is an associated malignancy or a predisposing autoimmune disease (e.g. systemic lupus erythematosus), it is then common to denote it as secondary Evans syndrome. Other antibodies may occur directed against neutrophils and lymphocytes, and \"immunopancytopenia\" has been suggested as a term for this syndrome. In patients with isolated thrombocytopenia, but without significant dysplasia, diagnosis of idiopathic thrombocytopenic purpura (ITP) rather than myelodysplastic syndrome (MDS) may be taken into account. It is important to make an accurate diagnosis because different treatments are used for ITP and MDS. The purpose of this study was to investigate the clinical and hematologic features of patients who were initially diagnosed as ITP but had cytogenetic abnormalities. We retrospectively reviewed cytogenetic studies of 100 patients who were diagnosed as ITP from 2004 to 2009 at Mokdong Hospital of Ewha Womans University based on clinical features and hematologic studies. Bone marrow pathology was re-evaluated based on 2008 WHO classification. Cytogenetic analysis was performed by 24-48 hr culture of bone marrow aspirates without using mitogens and 20 metaphases were analyzed. Of the 100 patients diagnosed as ITP initially, three patients (3%) had cytogenetic abnormalities. They had no thrombocytopenia-related symptoms and thrombocytopenia was found accidentally. The numbers of megakaryocytes in bone marrow were increased and dysplasia was not found in megakaryocyte, erythroid, and myeloid cell lineages. The proportion of blasts was within normal limits. Clonal chromosomal abnormalities found were der(1;7)(q10;p10), add(9)(q12), or t(7;11)(p22;q12). Presumptive diagnosis of MDS or diagnosis of idiopathic cytopenia of undetermined significance (ICUS) was made according to 2008 WHO classification. During the follow up, disease progression was not found. In patients with suspected ITP, cytogenetic analysis should be done. If specific clonal chromosomal abnormality is found, presumptive diagnosis of MDS has to be considered and close follow up is needed. The Harrington–Hollingsworth experiment was an experiment that established the autoimmune nature of the blood disorder immune thrombocytopenic purpura. It was performed in 1950 by the academic staff of Barnes-Jewish Hospital in St. Louis, Missouri. Experiment The experiment was undertaken in 1950 by William J. Harrington and James W. Hollingsworth, who postulated that in patients with idiopathic thrombocytopenic purpura (ITP), it was a blood factor that caused the destruction of platelets. To test this hypothesis, Harrington received 500 ml of blood from a patient with ITP. Within three hours, his platelets dropped to dangerously low levels and he experienced a seizure. His platelet count remained extremely low for four days, finally returning to normal levels by the fifth day. Bone marrow biopsy from Harrington's sternum demonstrated normal megakaryocytes, the cells necessary for platelet production. Diagnosis. The diagnosis of ITP usually is based on clinical presentation and the platelet count and does not often require a bone marrow examination. If atypical findings are noted, however, marrow examination is indicated to rule out an infiltrative disorder (leukemia) or an aplastic process (aplastic anemia). In ITP, an examination of the bone marrow reveals increased megakaryocytes and normal erythroid and myeloid elements.\nHere is the question:\nHEMATOLOGY: A 33-year-old woman consults for repeated epistaxis, petechiae and ecchymosis. Laboratory tests show thrombocytopenia with a platelet count of 4000 platelets/microliter. The initial presumptive diagnosis is chronic immune thrombocytopenic purpura (ITP). Which of the following statements is FALSE regarding the diagnosis of ITP?\nHere are the potential choices:\n1. The presence of lymphadenopathy or splenomegaly in the physical examination suggests a different diagnosis of ITP.\n2. Bone marrow analysis shows a decreased number of megakaryocytes without other alterations.\n3. Complete blood count shows isolated thrombocytopenia with often large platelets, without anemia unless there is significant bleeding or associated autoimmune hemolysis (Evans syndrome).\n4. The diagnosis of ITP is established by exclusion of other processes causing thrombocytopenia.\n5. The determination of antiplatelet antibodies is not accurate to establish the diagnosis.\nThe correct answer is: ",
        "gold_answer": "2 Bone marrow analysis shows a decreased number of megakaryocytes without other alterations.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Despite the destruction of platelets by splenic macrophages, the spleen is normally not enlarged. In fact, an enlarged spleen should lead to a search for other possible causes for the thrombocytopenia. Bleeding time is usually prolonged in ITP patients. However, the use of bleeding time in diagnosis is discouraged by the American Society of Hematology practice guidelines and a normal bleeding time does not exclude a platelet disorder. Bone marrow examination may be performed on patients over the age of 60 and those who do not respond to treatment, or when the diagnosis is in doubt. On examination of the marrow, an increase in the production of megakaryocytes may be observed and may help in establishing a diagnosis of ITP. An analysis for anti-platelet antibodies is a matter of clinician's preference, as there is disagreement on whether the 80 percent specificity of this test is sufficient to be clinically useful. ITP is an autoimmune disease with antibodies detectable against several platelet surface structures. ITP is diagnosed by identifying a low platelet count on a complete blood count (a common blood test). However, since the diagnosis depends on the exclusion of other causes of a low platelet count, additional investigations (such as a bone marrow biopsy) may be necessary in some cases. In mild cases, only careful observation may be required but very low counts or significant bleeding may prompt treatment with corticosteroids, intravenous immunoglobulin, anti-D immunoglobulin, or immunosuppressive medications. Refractory ITP (not responsive to conventional treatment or constant relapsing after splenectomy) requires treatment to reduce the risk of clinically significant bleeding. Platelet transfusions may be used in severe cases with very low platelet counts in people who are bleeding. Sometimes the body may compensate by making abnormally large platelets. Idiopathic (immune) thrombocytopenic purpura (ITP) is the most frequent hemorrhagic disease in children. It represents the acquired megakaryocytic thrombocytopenia with the shortened life of platelets because of immunologic damage (antibodies absorbed by platelets). In the case of this acquired hemorrhagic disorder, in spite of compensatory increased function of the bone marrow, there is a reduced number of platelets because of their increased destruction by the reticuloendothelial system (destructive thrombocytopenia). There are three forms of ITP: acute, chronic and intermittent. The acute form occurs in 80-90% of cases with bleeding episodes lasting a few days or weeks, but no longer than 6 months. The chronic form occurs in 10-15% of children, while the rarest-intermittent form is characterized by periods of normalization in regard to the number of platelets but also with relapse in intervals of 1-3 months. The disease is caused by an immunological disorder in the sense of an imbalanced immune response. Immunologic damages of platelets cause shortening of the opsonized platelets life span. The most frequent platelet opsonins are the immumoglobulin G (IgG) antibodies directed at the platelet membrane in the form of autoantibodies, alloantibodies or possibly absorbed antigen caused by microorganism infection or drug intake. It is typical for the phenomenon of bleeding that it starts suddenly and without any other sign of illness. The most frequent acute form appears between the second and fourth year, and is characterized by seasonal occurrence usually after acute viral infections. Children older than 10 years of age, like adults, often have the chronic form associated with other immunologic disorders. The disease affects girls more often than boys (about three times more often) with moderate and constant increase of antiplatelet antibodies. Hemorrhagic manifestations include: petechiae, purpura, epistaxis, gastrointestinal and genitourinary bleeding. They depend on the grade of thrombocytopenia, although there is no strict correlation between the number of platelets and volume of bleeding. Low mortality of the acute ITP is almost exclusively due to intracranial hemorrhage. LABORATORY STUDIES: Thrombocytopenia represents a decrease in the number of blood platelets being a basic abnormality of the blood count. The half-life of platelets in ITP is shortened. Detection of antiplatelet antibodies is connected with technical difficulties, so they are established in about 30% of cases. Bleeding time is prolonged and so is the coagulum retraction which may be completely missed. The Rumpel-Leede test is positive. Clinical differentiation of drug-induced thrombocytopenia is not possible. However, other differential diagnostic possibilities are thrombotic-thrombocytopenic purpura and hemolytic-uremic syndrome. A child with aplastic anemia or acute leukemia, beside thrombocytopenia, has a characteristic finding of white and red blood cell count. Thrombocytopenia with absent radii syndrome is associated with skeletal system abnormalities. New knowledge about the role of the immune system in ITP determines the modern therapeutic modalities. In cases of acute ITP in children, there are two therapeutic options or therapies of choice: corticosteroids and high doses of intravenous immunoglobulin. Immunosupressive therapy means anti Rh(D) immunoglobulin, cyclosporine, cytostatics, danazol, loaded platelets. In cases of distinctive hemorrhagic syndrome there are also indications for platelet transfusion. Nowadays splenectomy is more restricted, because one third of cases is unsuccessful, whereas plasmapheresis is rarely used in children because of possible complications. ITP is the most frequent hemorrhagic disease in children. The disease is basically caused by an immunologic disorder with platelet destruction due to increased immunoglobulin on their membrane. (ABSTRACT TRUNCATED) To identify initial laboratory findings useful for the later diagnosis of idiopathic thrombocytopenic purpura (ITP) in adult patients with thrombocytopenia. We studied 62 consecutive adult patients who had thrombocytopenia and whose peripheral blood film was normal except for thrombocytopenia at presentation. Each patient underwent physical examination and routine laboratory tests and was prospectively followed for 22.5 +/- 9.8 months (range, 8 to 41 months). The frequency of antiglycoprotein (GP) IIb/IIIa antibody-producing B cells, the presence of platelet-associated and plasma anti-GPIIb/IIIa antibodies, the percentage of reticulated platelets, and the plasma thrombopoietin level were examined at the first visit. The final diagnosis was based on the clinical history, physical examination, complete blood test, bone marrow findings, and the clinical course at last observation. Forty-six patients were diagnosed as having ITP and 16 as having another disorder, including myelodysplastic syndrome, aplastic anemia, amegakaryocytic thrombocytopenia, and reduced platelet production, with or without other cytopenias, and without dysplasia or evidence for destruction. Six initial laboratory findings discriminated ITP from other diagnoses: the absence of anemia, absence of leukocytopenia, increased frequency of anti-GPIIb/IIIa antibody-producing B cells, increased platelet-associated anti-GPIIb/IIIa antibodies, elevated percentage of reticulated platelets, and a normal or slightly increased plasma thrombopoietin level. Three or more of these ITP-associated findings were found at presentation in 44 patients (96%) with thrombocytopenia later diagnosed as ITP, compared with only 1 patient (6%) whose disorder was non-ITP. Initial laboratory findings can well predict future diagnosis of ITP. Further studies prospectively evaluating these same diagnostic criteria on another, independent set of patients are necessary. The need for a bone marrow examination was assessed in patients with clinical and laboratory features consistent with ITP; the literature was reviewed. The records of all patients undergoing a bone marrow examination between January 1988 to January 1998 were retrospectively reviewed to determine which were motivated by the suspicion of ITP. Data were collected from hospital and outpatient medical and pathology records. Eighty-six patients with isolated thrombocytopenia (i.e., normal white blood cell count, hemoglobin, peripheral smear and clotting studies) were studied. The bone marrow was consistent with ITP in 82 patients, (i.e., normal or increased megakaryocytes and other hemopoietic lineages normal.) Four patients had decreased megakaryocytes, but all patients responded to corticosteroids. All 86 patients were followed up for a median of 22 months after bone marrow aspiration (range, 2-76 months.) During that time, none of the patients developed features to suggest an alternative diagnosis to ITP. The initial clinical and laboratory findings of 99 patients with acute leukemia were also reviewed; all had features atypical of ITP. These data suggest that routine performance of a bone marrow examination for the diagnosis of ITP is not necessary, provided that a thorough history and physical examination are performed and that the complete blood cell count, peripheral blood smear, and routine clotting studies show no abnormalities apart from thrombocytopenia. The findings of seven prior retrospective studies, two in adults and five in children are consistent with the previous findings. However, the value of marrow investigation in ITP remains unresolved and data from a large prospective study would be helpful. Immune thrombocytopenic purpura Many cases of immune thrombocytopenic purpura (ITP) also known as idiopathic thrombocytopenic purpura, can be left untreated, and spontaneous remission (especially in children) is not uncommon. However, counts under 50,000 are usually monitored with regular blood tests, and those with counts under 10,000 are usually treated, as the risk of serious spontaneous bleeding is high with such low platelet counts. Any patient experiencing severe bleeding symptoms is also usually treated. The threshold for treating ITP has decreased since the 1990s; hematologists recognize that patients rarely spontaneously bleed with platelet counts greater than 10,000, although exceptions to this observation have been documented. Immune thrombocytopenia (ITP) is characterized by a platelet count less than 100 × 10^9/L without anemia or leukopenia. Patients with ITP may be asymptomatic, or they may have mild bleeding like petechiae, purpura, or epistaxis. In rare cases, they may present to the emergency department (ED) with life-threatening bleeding as a result of their thrombocytopenia. The emergency physician should thus be prepared to diagnose ITP and treat the bleeding that can result from it. The diagnosis of ITP requires excluding secondary causes of thrombocytopenia, and in the ED, the bare minimum workup for ITP includes a complete blood count and a peripheral blood smear. The peripheral blood smear should show a small number of large platelets with normal morphology, and there should not be an increased number of schistocytes. Many patients with ITP require no emergent treatment. However, if a patient with suspected ITP presents to the ED with critical hemorrhage, the emergency physician should initiate treatment with a platelet transfusion, corticosteroids, and intravenous immune globulin (IVIG) as soon as possible. For less severe bleeding, platelet transfusions are not recommended, and the treatment consists of corticosteroids by themselves or in conjunction with IVIG. Idiopathic thrombocytopenic purpura(ITP) is a hematologic disorder which causes thrombocytopenia. The diagnosis of ITP is based on the history, physical examination and, complete blood count, and examination of the peripheral smear. The diagnostic criteria of ITP established by the Ministry of Health, Welfare, and Labor in Japan requires the bone marrow examination and the measurement of platelet associated IgG, but those tests are not always necessary according to the guidelines developed by the American Society of Hematology. The appropriate strategies for the diagnosis of ITP need to be established. In this paper, some new examinations which may help the diagnosis of ITP are also demonstrated. Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is a type of thrombocytopenic purpura defined as an isolated low platelet count with a normal bone marrow in the absence of other causes of low platelets. It causes a characteristic red or purple bruise-like rash and an increased tendency to bleed. Two distinct clinical syndromes manifest as an acute condition in children and a chronic condition in adults. The acute form often follows an infection and spontaneously resolves within two months. Chronic immune thrombocytopenia persists longer than six months with a specific cause being unknown. ITP is an autoimmune disease with antibodies detectable against several platelet surface structures. Immune thrombocytopenic purpura (ITP) is a bleeding disorder characterized by isolated thrombocytopenia (platelet count &lt;150,000 u/L), which is not associated with a systemic illness. ITP is reported in approximately 2 per 100,000 adults. The mean age of diagnosis is 50 years. ITP is more common in females of childbearing age and in pregnancy. In adults, the course is more chronic although spontaneous remission can also occur within months of initial diagnosis. A thorough and timely workup of thrombocytopenia is imperative to rule out other differentials of ITP as it is considered a diagnosis of exclusion. Primary care physicians encounter patients who exhibit signs of thrombocytopenia such as petechiae or purpura on a regular basis. A high index of clinical suspicion is required to accurately diagnose ITP and commence the appropriate treatment including glucocorticoids to increase the chances of a favorable prognosis as described by the authors. This report illustrates the importance of a detailed history and physical exam and careful analysis of hematologic parameters when diagnosing ITP. This case demonstrates that even with subtle deviations from typical ITP findings one must promptly reevaluate the diagnosis. This case also highlights the importance of peripheral smear review by an expert in pediatric hematopathology. A previously healthy 10 year-old Asian boy presented with 2 months of easy bruising. Review of systems was negative for any constitutional symptoms. On examination, he appeared well but had numerous large ecchymoses. He had no appreciable lymphadenopathy or splenomegaly. The liver was palpable 1.5 cm below the costal margin. A complete blood count (CBC) showed: platelets = 17 × 109/L, hemoglobin = 128 g/L, white blood cell count = 5.43 × 109/L, and neutrophils = 1.63 × 109/L. A blood smear was reported as normal. Urate was 370 umol/L and lactate dehydrogenase (LDH) was 803 U/L. The child was admitted with a presumptive diagnosis of immune thrombocytopenic purpura (ITP) and treated with intravenous immunoglobulin. The following day, the blood smear was reviewed by a hematopathologist who identified blasts. A bone marrow aspiration (BMA) confirmed the diagnosis of precursor B-cell acute lymphoblastic leukemia. In children presenting with suspected ITP, leukemia should always be considered. A BMA was historically performed on all patients with presumed ITP to rule out leukemia. In 2011, the American Society of Hematology (ASH) stopped recommending routine BMA in patients suspected of having ITP. ASH advises in cases with unusual findings on history, physical examination or CBC, it is reasonable to perform a BMA. Our patient had mild hepatomegaly, which may have qualified him for a BMA. He also had an elevated LDH and urate, which are not listed as criteria for BMA by ASH but were considered atypical for ITP by the clinical team. A literature search did not reveal any primary data assessing these markers. While corticosteroids are a first line treatment in ITP, they must be reserved for when clinicians are confident that the patient does not have leukemia. Steroid administration prior to diagnosing leukemia results in delayed diagnosis and may increase the risk of complications and decrease survival. A review is made of the data in the literature and of the authors' experience regarding the etiology and pathogenesis, diagnosis and therapy of the chronic form of idiopathic thrombocytopenic purpura (ITP). The mechanisms of production (after McMillan et al.) are presented schematically and the five criteria of ITP diagnosis suggested by Karpatkin are discussed: 1) decreased blood platelet count with direct or indirect signs of thrombocytolysis; 2) increased number of megakaryocytes in the bone marrow and/or signs of intramedullary thrombocytolysis; 3) direct or indirect signs of antiplatelet autoantibody presence in the plasma; 4) exclusion of a primary disorder and 5) absence of splenomegaly. The results of corticotherapy, splenectomy, platelet transfusion and immunosuppression (including \"target\" immunosuppressive therapy) in 188 patients with ITP, admitted to the clinic of Hematology--Bucharest between 1966 and 1978, are presented and analysed. It is recommended that pregnant women with thrombocytopenia or a previous diagnosis of ITP should be tested for serum antiplatelet antibodies. A woman with symptomatic thrombocytopenia and an identifiable antiplatelet antibody should be started on therapy for their ITP which may include steroids or IVIG. Fetal blood analysis to determine the platelet count is not generally performed as ITP-induced thrombocytopenia in the fetus is generally less severe than NAIT. Platelet transfusions may be performed in newborns, depending on the degree of thrombocytopenia. It is recommended that neonates be followed with serial platelet counts for the first few days after birth. ITP is associated with a range of conditions, including lymphoma, leukemia, SLE, HIV, and HCV. The clinical presentation is as follows: Acute: Abrupt onset of hemorrhagic complications following a viral illness. Commonly affects children 2–6 years of age, with males and females affected equally. Chronic: Insidious onset that is unrelated to infection. Most often affects adults 20–40 years of age; women are three times more likely to be affected than men. A diagnosis of exclusion, as the test for platelet-associated antibodies is a poor one. Once other causes of thrombocytopenia have been ruled out, a diagnosis can be made on the basis of the history and physical, a CBC, and a peripheral blood smear showing normal RBC morphology. Most patients do not require bone marrow biopsy, which would show ↑ megakaryocytes as the only abnormality. Most patients with acute childhood ITP spontaneously remit, but this is rarely the case in chronic ITP. Diagnosis The diagnosis of ITP is a process of exclusion. First, it has to be determined that there are no blood abnormalities other than a low platelet count, and no physical signs other than bleeding. Then, secondary causes (5–10 percent of suspected ITP cases) should be excluded. Such secondary causes include leukemia, medications (e.g., quinine, heparin), lupus erythematosus, cirrhosis, HIV, hepatitis C, congenital causes, antiphospholipid syndrome, von Willebrand factor deficiency, onyalai and others. All patients with presumed ITP should be tested for HIV and hepatitis C virus, as platelet counts may be corrected by treating the underlying disease. In approximately 2.7 to 5 percent of cases, autoimmune hemolytic anemia and ITP coexist, a condition referred to as Evans syndrome. Immune thrombocytopenic purpura (ITP) is an immune-mediated acquired disease found in both adults and children. It is characterized by transient or persistent decreases in the platelet count. We report a case of ITP detected based on oral hemorrhagic symptoms. The patient was a 79-year-old female with no significant past medical history. She presented with sudden onset of gingival bleeding and hemorrhagic bullae on the buccal mucosa. Gingival bleeding was difficult to control. Laboratory tests revealed severe thrombocytopenia with a platelet count as low as 2000/μL. Under a provisional diagnosis of a hematological disorder, she was referred to a hematologist. A peripheral smear showed normal-sized platelets. A bone marrow examination revealed increased numbers of megakaryocytes without morphologic abnormalities. The patient was diagnosed with ITP and treated with a combination of pulsed steroid therapy and high-dose immunoglobulin therapy. However, her severe thrombocytopenia was refractory to these treatments. Then, a thrombopoietin receptor agonist was begun as a second-line treatment. Her platelets rapidly increased, and no bleeding complications were reported. Because oral symptoms can be one of the initial manifestations of ITP, dentists should be familiar with the clinical appearance of ITP, and attention must be paid to detect and diagnose unidentified cases. Immune thrombocytopenia (ITP) is a diagnosis of exclusion that can resemble other thrombocytopenic disorders. To develop a clinical prediction model (CPM) for the diagnosis of ITP to aid hematogists in investigating patients presenting with undifferentiated thrombocytopenia. We designed a CPM for ITP diagnosis at the time of the initial hematology consultation using penalized logistic regression based on data from patients with thrombocytopenia enrolled in the McMaster ITP registry (n = 523) called the Predict-ITP Tool. The case definition for ITP was a platelet count less than 100 × 10<sup9</sup /L and a platelet count response after high-dose corticosteroids or intravenous immune globulin, defined as the achievement of a platelet count above 50 × 10<sup9</sup /L and at least a doubling of baseline. Internal validation was done using bootstrap resampling. Model discrimination was assessed by the c-statistic, and calibration was assessed by the calibration slope, calibration-in-the-large, and calibration plot. The final model included the following variables: (1) platelet count variability (based on three or more platelet count values), (2) lowest platelet count value, (3) maximum mean platelet volume, and (4) history of major bleeding (defined by the ITP bleeding scale). The optimism-corrected c-statistic was 0.83, the calibration slope was 0.88, and calibration-in-the-large for all performance measures was &lt;0.001 with standard error &lt;0.001, indicating good discrimination and excellent calibration. The Predict-ITP Tool can estimate the likelihood of ITP for a given patient with thrombocytopenia at the time of the initial hematology consultation. The tool had high predictive accuracy for the diagnosis of ITP. laboratory testing in itp Laboratory testing for antibodies (serologic testing) is usually not helpful due to the low sensitivity and specificity of the current tests. Bone marrow examination can be reserved for those who have other signs or laboratory abnormalities not explained by ITP or in patients who do not respond to initial therapy. The peripheral blood smear may show large platelets, with otherwise normal morphology. Depending on the bleeding history, iron-deficiency anemia may be present. Laboratory testing is performed to evaluate for secondary causes of ITP and should include testing for HIV infection and hepatitis C (and other infections if indicated). Serologic testing for SLE, serum protein electrophoresis, immunoglobulin levels to potentially detect hypogammaglobulinemia, selective testing for IgA deficiency or monoclonal gammopathies, and testing for H. pylori infection should be considered, depending on the clinical circumstance. If anemia is present, direct antiglobulin testing (Coombs’ test) should be performed to rule out combined autoimmune hemolytic anemia with ITP (Evans’ syndrome). The treatment of ITP uses drugs that decrease reticuloendothelial uptake of the antibody-bound platelet, decrease antibody production, and/or increase platelet production. The diagnosis of ITP does not necessarily mean that treatment must be instituted. Patients with platelet counts >30,000/μL appear not to have increased mortality related to the thrombocytopenia. Pregnancy Anti-platelet autoantibodies in a pregnant woman with ITP will attack the patient's own platelets and will also cross the placenta and react against fetal platelets. Therefore, ITP is a significant cause of fetal and neonatal immune thrombocytopenia. Approximately 10% of newborns affected by ITP will have platelet counts <50,000/uL and 1% to 2% will have a risk of intracerebral hemorrhage comparable to infants with neonatal alloimmune thrombocytopenia (NAIT). No lab test can reliably predict if neonatal thrombocytopenia will occur. The risk of neonatal thrombocytopenia is increased with: Mothers with a history of splenectomy for ITP Mothers who had a previous infant affected with ITP Gestational (maternal) platelet count less than 100,000/uL Disorders Adapted from: The three broad categories of platelet disorders are \"not enough\"; \"dysfunctional\"; and \"too many\". Thrombocytopenia Immune thrombocytopenias (ITP) – formerly known as immune thrombocytopenic purpura and idiopathic thrombocytopenic purpura Splenomegaly Gaucher's disease Familial thrombocytopenia Chemotherapy Babesiosis Dengue fever Onyalai Thrombotic thrombocytopenic purpura HELLP syndrome Hemolytic–uremic syndrome Drug-induced thrombocytopenic purpura (five known drugs – most problematic is heparin-induced thrombocytopenia (HIT) Pregnancy-associated Neonatal alloimmune associated Aplastic anemia Transfusion-associated Pseudothrombocytopenia idiopathic thrombocytopenic purpura Vaccine induced immune thrombocytopenia Gilbert's syndrome Causes Although Evans syndrome seems to be a disorder of immune regulation, the exact pathophysiology is unknown, but a gradual loss of self-tolerance is postulated. Autoantibodies targeted at different antigenic determinants on red cells and platelets are assumed to cause isolated episodes of hemolytic anemia and thrombocytopenia, respectively. Diagnosis The diagnosis of primary Evans syndrome is made upon blood tests to confirm not only hemolytic anemia and immune thrombocytopenic purpura, but also a positive direct antiglobulin test (DAT) and an absence of any known underlying cause. In 27% to 50% of cases there is an associated malignancy or a predisposing autoimmune disease (e.g. systemic lupus erythematosus), it is then common to denote it as secondary Evans syndrome. Other antibodies may occur directed against neutrophils and lymphocytes, and \"immunopancytopenia\" has been suggested as a term for this syndrome. In patients with isolated thrombocytopenia, but without significant dysplasia, diagnosis of idiopathic thrombocytopenic purpura (ITP) rather than myelodysplastic syndrome (MDS) may be taken into account. It is important to make an accurate diagnosis because different treatments are used for ITP and MDS. The purpose of this study was to investigate the clinical and hematologic features of patients who were initially diagnosed as ITP but had cytogenetic abnormalities. We retrospectively reviewed cytogenetic studies of 100 patients who were diagnosed as ITP from 2004 to 2009 at Mokdong Hospital of Ewha Womans University based on clinical features and hematologic studies. Bone marrow pathology was re-evaluated based on 2008 WHO classification. Cytogenetic analysis was performed by 24-48 hr culture of bone marrow aspirates without using mitogens and 20 metaphases were analyzed. Of the 100 patients diagnosed as ITP initially, three patients (3%) had cytogenetic abnormalities. They had no thrombocytopenia-related symptoms and thrombocytopenia was found accidentally. The numbers of megakaryocytes in bone marrow were increased and dysplasia was not found in megakaryocyte, erythroid, and myeloid cell lineages. The proportion of blasts was within normal limits. Clonal chromosomal abnormalities found were der(1;7)(q10;p10), add(9)(q12), or t(7;11)(p22;q12). Presumptive diagnosis of MDS or diagnosis of idiopathic cytopenia of undetermined significance (ICUS) was made according to 2008 WHO classification. During the follow up, disease progression was not found. In patients with suspected ITP, cytogenetic analysis should be done. If specific clonal chromosomal abnormality is found, presumptive diagnosis of MDS has to be considered and close follow up is needed. The Harrington–Hollingsworth experiment was an experiment that established the autoimmune nature of the blood disorder immune thrombocytopenic purpura. It was performed in 1950 by the academic staff of Barnes-Jewish Hospital in St. Louis, Missouri. Experiment The experiment was undertaken in 1950 by William J. Harrington and James W. Hollingsworth, who postulated that in patients with idiopathic thrombocytopenic purpura (ITP), it was a blood factor that caused the destruction of platelets. To test this hypothesis, Harrington received 500 ml of blood from a patient with ITP. Within three hours, his platelets dropped to dangerously low levels and he experienced a seizure. His platelet count remained extremely low for four days, finally returning to normal levels by the fifth day. Bone marrow biopsy from Harrington's sternum demonstrated normal megakaryocytes, the cells necessary for platelet production. Diagnosis. The diagnosis of ITP usually is based on clinical presentation and the platelet count and does not often require a bone marrow examination. If atypical findings are noted, however, marrow examination is indicated to rule out an infiltrative disorder (leukemia) or an aplastic process (aplastic anemia). In ITP, an examination of the bone marrow reveals increased megakaryocytes and normal erythroid and myeloid elements.\nHere is the question:\nHEMATOLOGY: A 33-year-old woman consults for repeated epistaxis, petechiae and ecchymosis. Laboratory tests show thrombocytopenia with a platelet count of 4000 platelets/microliter. The initial presumptive diagnosis is chronic immune thrombocytopenic purpura (ITP). Which of the following statements is FALSE regarding the diagnosis of ITP?\nHere are the potential choices:\n1. The presence of lymphadenopathy or splenomegaly in the physical examination suggests a different diagnosis of ITP.\n2. Bone marrow analysis shows a decreased number of megakaryocytes without other alterations.\n3. Complete blood count shows isolated thrombocytopenia with often large platelets, without anemia unless there is significant bleeding or associated autoimmune hemolysis (Evans syndrome).\n4. The diagnosis of ITP is established by exclusion of other processes causing thrombocytopenia.\n5. The determination of antiplatelet antibodies is not accurate to establish the diagnosis.\nThe correct answer is: 2. Bone marrow analysis shows a decreased number of megakaryocytes without other alterations."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n To show how the evaluation for endometriosis can be included in the routine pelvic ultrasound examination. Stepwise narrated video demonstration of the sonographic evaluation for endometriosis in routine pelvic ultrasound following the recommended sonographic approach published in the 2016 consensus paper by the International Deep Endometriosis Analysis (IDEA) group [1]. Endometriosis is a common and often debilitating gynecological disorder that affects 5-10% of women [2]. The prevalence is even higher among women with symptoms of endometriosis [2], which include chronic pelvic pain, acquired dysmenorrhea, dyspareunia, dyschezia, menorrhagia, abnormal bleeding, and infertility. Approximately 80% of women who have endometriosis have superficial lesions, whereas 20% have deep infiltrating endometriosis (DIE; [3]). Laparoscopy is the gold standard for diagnosing endometriosis, because it allows the diagnosis of all forms of endometriosis and often immediate removal of superficial endometriosis. The removal of DIE is considerably more complicated and usually cannot be completed unless it was diagnosed preoperatively. The technique to diagnose DIE with transvaginal ultrasound (TVUS) was first described in detail in 2009 [4]. Since then, the accuracy of TVUS for the prediction of DIE has been well established in the literature [5-7]. TVUS is widely used as a first-line investigation for women with gynecological symptoms. The inclusion of an assessment for endometriosis in the routine pelvic ultrasound allows earlier diagnosis and better surgical outcomes for all women with DIE. The evaluation for endometriosis in routine pelvic ultrasound based on the IDEA consensus promotes a 4-step dynamic ultrasound approach [1]: (1) routine evaluation of uterus and adnexa with particular attention for sonographic signs of adenomyosis and the presence or absence of endometriomas; (2) evaluation of transvaginal sonographic 'soft markers' such as site-specific tenderness and ovarian mobility; (3) assessment of status of pouch of Douglas using the real-time ultrasound-based \"sliding sign;\" and (4) assessment of DIE nodules in the anterior and posterior compartments, which involves assessment of the bladder, vaginal vault, uterosacral ligaments, and bowel, including rectum, rectosigmoid junction, and sigmoid colon. Because 5-10% of women with DIE also have ureteric endometriosis, it is useful to assess the kidneys. Silent hydronephrosis is easily identified in 50-60% of patients with ureteric involvement. Although it is possible to identify DIE involving the ureters more directly, this requires more advanced skills, and further studies are still needed to better define the accuracy of ureteric DIE detection by TVUS [8-10]. Traditionally, only pathologies of the uterus and ovaries are assessed during a routine pelvic ultrasound. Here we demonstrate that the routine ultrasound examination can easily be extended beyond the uterus and ovaries into the posterior and anterior pelvic compartments to evaluate structural mobility and to look for deep infiltrating endometriotic nodules, wherewith women suffering from DIE can benefit from a preoperative diagnosis and subsequently, a single, well-planned procedure in the hands of a well-prepared team. Adolescent Patients A pelvic examination may be less revealing in an adolescent than in an older woman, particularly if it is the patient’s first examination or if it takes place on an emergency basis. An adolescent who presents with excessive bleeding should have a pelvic examination if she had intercourse, if the results of a pregnancy test are positive, if she has abdominal pain, if she is markedly anemic, or if she is bleeding heavily enough to compromise hemodynamic stability. The pelvic examination occasionally may be deferred in young teenagers who have a classic history of irregular cycles soon after menarche, who have normal hematocrit levels, who deny sexual activity, and who will reliably return for follow-up. A pelvic examination may be deferred in adolescents who present to the office requesting oral contraceptives before the initiation of intercourse or at the patient’s request, even if she has had intercourse. Newer testing methods using DNA amplification techniques To describe the management and the fertility-enhancing potential of surgery in an infertile patient with deep-infiltrating endometriosis and adenomyosis externa. Video case report. Minimally invasive and robotic gynecologic surgery unit of a university hospital. A 31-year-old nulliparous patient with dysmenorrhea, dysuria, dyspareunia, and primary infertility. Bimanual examination, transvaginal ultrasound, and magnetic resonance imaging (MRI) were performed as a comprehensive preoperative workup. The findings were consistent with bladder endometriosis and a 4-cm right pararectal cystic mass suggestive of adenomyosis externa. Laparoscopic excision of all visible endometriosis was performed. A pararectal lesion was found, completely developing in the retroperitoneal spaces, from the right medial pararectal space to the rectovaginal space, reaching the pelvic floor fascia without infiltration of the levator ani muscle. According to Koninckx classification, this kind of lesion corresponds to type III endometriosis or adenomyosis externa. Nerve-sparing eradication of the nodule was performed. The decision to use these techniques was taken with the intention to treat the patient, and not with the aim of testing the procedures performed. Therefore, as a common clinical practice in our institution and for the above reasons, there was no need for consultation of the institutional review board for approval. Improvement of symptoms and spontaneous conception after surgical removal of all endometriotic implants. There were no intraoperative or postoperative complications, and the patient was discharged after 3 days. She discontinued postoperative hormone therapy with gonadotropin-releasing hormone analogue after 3 months because she desired fertility. She conceived spontaneously after 2 months of attempting. She delivered vaginally and had no complications during pregnancy and labor. Neither recurrence of pain symptoms nor voiding or rectal dysfunctions were reported by the patient. In the management of a case of deep endometriosis, the preoperative assessment should be carefully carried out to give the surgeon the most accurate information about the extent of the disease and the patient's main objectives. Imaging techniques such as ultrasound and MRI play a fundamental role along with the clinical evaluation in also detecting lesions that are not visible at first laparoscopic inspection. In this case of a young woman without any detectable fertility issues except for endometriosis, the laparoscopic excision of endometriosis was feasible, safe, and effective in improving the patient's fertility and pain symptoms. The fertility-enhancing potential of complete eradication of pelvic endometriosis, including removal of deep posterior localizations such those presented in this case, has been hypothesized by various investigators. It has been suggested that skilled surgical management for symptomatic deep endometriosis may be followed by a high pregnancy rate, with most pregnancies resulting from postoperative natural conception even in patients with primary infertility. The uterus is typically diffusely enlarged, although usually less than 14 cm in size, and is often soft and tender, particularly at the time of menses. Mobility of the uterus is not restricted, and there is no associated adnexal pathology (48). Adenomyosis is a clinical diagnosis. Imaging studies including pelvic ultrasound or MRI, although helpful, are not definitive. Because of the cost of MRI and negligible improvement in diagnostic accuracy, this study is not recommended routinely. In women with diffuse uterine enlargement and negative pregnancy test results, secondary dysmenorrhea may be attributed to adenomyosis; however, the pathologic confirmation of suspected adenomyosis can be made only at the time of hysterectomy. To demonstrate the technique of laparoscopic approach in a rare case of rectovaginal splenosis with severe dyspareunia and dyschesia. A step-by-step explanation of the patient's condition, diagnosis, surgical technique, and postoperative results (Canadian Task Force classification II-3). Splenosis consists of ectopic functioning splenic tissue that can be located anywhere within the abdomen or pelvis. Fragments are often multiple and range in diameter from a few millimeters to a few centimeters. They are reddish-blue and are sessile or pedunculated. Their appearance can mimic that of neoplasms or endometriosis, which are the main differential diagnoses. Trauma and subsequent splenectomy is the cause in most cases. Splenosis is a benign condition usually found incidentally and is usually asymptomatic. The need for therapy is controversial, and treatment is suggested only in symptomatic cases, primarily those related to pelvic or abdominal lesions, as in our patient. The diagnosis of splenosis in a woman complaining of pelvic pain may present diagnostic difficulties. The splenic tissue has the macroscopic appearance of endometriosis, and its position in the pelvis also may suggest this diagnosis. Where excision of splenosis is considered necessary, the approach should be laparoscopic, unless this is considered too risky owing to the proximity of vital structures. A 40-year-old woman was referred to our department for severe dyspareunia and dyschezia. The gynecologic examination revealed a painfull nodularity on the posterior vaginal cul de sac. Further evaluation with 2- and 3-dimensional ultrasound and magnetic resonance imaging revealed several soft tissue nodules in the pouch of Douglas (POD), which were enhanced on contrast administration. She had undergone a splenectomy 15 years earlier after a car accident. A laparoscopic approach to a rectovaginal nodularity was performed. Under general anesthesia, the patient was placed in the dorsal decubitus position with her arms alongside her body and her legs in abduction. Pneumoperitoneum was achieved using a Veres needle placed at the umbilicus. Four trocars were placed: a 10-mm trocar at the umbilicus for the 0-degree laparoscope; a 5-mm trocar at the right anterosuperior iliac spine; a 5-mm trocar in the midline between the umbilicus and the pubic symphysis, approximately 8 to 10 cm inferior to the umbilical trocar; and a 5-mm trocar at the left anterosuperior iliac spine. The entire pelvis was inspected for endometriotic lesions. In the pelvis, hypervascular and bluish nodules were visible with extension from the POD into the deep rectovaginal space. The macroscopic appearance was atypical for endometriotic implants. The nodularities were carefully dissected and excised, and histological assessment revealed splenic tissue. At the time of this report, the patient had been asymptomatic for 6 months after surgery. Rectovaginal splenosis may mimic endometriosis. The laparoscopic approach to rectovaginal splenosis avoids an abdominal incision, with its associated pain and possible adhesion formation. It also provides a better view for dissection. In this patient, the splenosis was removed by laparoscopy, with no postoperative dyspareunia or dyschesia. The efficacy of medical and surgical treatment of endometriosis and pelvic pain is a source of questions and controversies. Complete resolution of endometriosis is not yet possible but therapy has essentially three main objectives: 1) to reduce pain; 2) to increase the possibility of pregnancy; 3) to delay recurrence for as long as possible. In case of moderate and severe endometriosis, operative laparoscopy must be considered as first line treatment. The mean pregnancy rate of 50% reported in the literature following surgery provides scientific proof that operative treatment should first be undertaken to give our patients the best chance of conceiving naturally. In case of rectovaginal adenomyotic nodules, surgery must also be considered as first line therapy, medical therapy being relatively inefficacious. Careful preoperative examination is mandatory (transrectal sonography, magnetic resonance imaging, bowel barium enema or intravenous pyelography) to evaluate potentially severe complications of the disease. Endometriosis is defined as the presence of endometrial tissue outside the uterine cavity. It generally involves the peritoneum, ovaries and rectovaginal septum. Its characteristic symptoms include dysmenorrhea, pelvic pain, deep dyspareunia and infertility. It may also involve the gastrointestinal tract, urinary tract or extra abdominal sites, giving rise to a wide variety of clinical symptoms such as bloody stools, renal haemorrhage, hemoptysis and pleural effusion during menstruation. Recurrent hemorrhagic ascites secondary to endometriosis is an unusual occurrence, 41 cases have been reported since 1954. Here we report an additional case, in order to draw attention to this condition. A 28 years-old black nulligravida woman was seen for the first time in april 2000 with a chief complaint of infertility. Her past medical history was unremarkable. She had regular menses but associated with severe dysmenorrhea. She also recalled abdominal and pelvic pain for several years. She underwent an ovulation induction with gonadotrophin, which resulted in a progressive increase of pelvic pain. A first laparoscopy was performed, revealing voluminous ascites (10 I). Two years later the ascites recurred spontaneously. Ultrasound examination revealed suspect \"para uterine masses\". A second exploratory laparoscopy showed a voluminous bloody ascites (71), and extensive adhesions. On histologic examination all specimens (peritoneal biopsies) were compatible with endometriosis and ruled out malignancy. Treatment with Gn RH analog was performed and full remission was obtained after 6 months. One year later the ascites recurred again spontaneously, leading to a third laparoscopy in an other medical institution. Histologic examination showed endometrial stromal tissue and fibrous proliferation. Later she became pregnant after in vitro fertilization. In the first trimester of pregnancy, the pelvic ultrasound showed only a small effusion in the pouch of Douglas. Still, the ascites did not progress during pregnancy. The patient was hospitalized from 27 to 33 weeks of gestational age for threatened labor, but she finally had a normal vaginal delivery at 36 weeks of gestational age. Four months later, she had no complaint, but the pelvic ultrasound showed the recurrence of the ascites. She will have a drainage. The future treatement will consists of GnRH analog for about six months, which will be relayed by a long term progestative therapy. A diagnosis of endometriosis should always be considered in middle-age women who presents with bloody ascites. Long follow-up is advisable for patients who undergo conservative treatment because of thehigh risk of recurrence. Although gastrointestinal endometriosis is an uncommon and often unexpected finding, the best treatment requires removal of all endometriotic lesions. The purpose of our study was to report our experience with the diagnosis and treatment of bowel endometriosis. From January 1997 to January 2004, 13 patients (mean 35.7y ; range 21-55y) were operated for bowel endometriosis. We noted: age, history of endometriosis, previous pregnancies, preoperative investigations and symptoms, operative procedure and intraoperative findings. Follow-up varied between one month postoperative examination and seven years. Presenting symptoms of the cases were: acute appendicitis (3), dysmenorrhoea (7), constipation (6), pelvic pain (2), rectal bleeding (3) and dyspareunia (2). Operative management was performed in accordance with the anatomical distribution. Seven patients had a history of previous operations and multifocal involvement was present in 61.5% of cases. At a median follow-up of 12.2 months, 83.3% had complete relief of their initial complaints, with only one reoperation needed. The pregnancy rate after surgery was 66.6%. Preoperative tests were: ultrasound for ovarian endometriomas, coloscopy, barium enema, vaginal palpation for detecting rectovaginal involvement, MRI and CT scan. These tests predicted the extension of endometriotic process correctly in 50% of the cases. Endometriosis of the sigmoid and rectum is rare but can give rise to severe gastrointestinal and pelvic symptoms. Preoperative investigations are not infallible in predicting the extent of the disease, sometimes placing the surgeon before a dilemma, because it involves mostly young women in the reproductive phase of life. The colorectal surgeon, therefore, should seek the advice of an experienced gynaecologist and vice versa. Removal of all endometriotic lesions is mandatory for obtaining an optimal relief of symptoms. To describe a multidisciplinary approach for the resection of deeply infiltrative endometriosis using the robotic platform. A technical video showing a step-by-step approach for the resection of deeply infiltrative endometriosis (Canadian Task Force classification level III). Institutional review board approval was not required for this study. There is considerable involvement of the bowel and bladder with deeply infiltrative endometriosis [1-3]. The need for operative procedures involving multiple organs while performing a complete resection is common. The benefits of minimally invasive surgery for a gynecologic pathology have been documented in numerous studies. Patients had fewer medical and surgical complications postoperatively, better cosmesis, and better quality of life [4-6]. We believe that deeply infiltrative endometriosis does not preclude patients from having a minimally invasive resection procedure. In this video, we describe how the robotic platform was used for a seamless transition between surgical specialties including gynecology, colorectal, and urology to ensure complete resection of endometriosis lesions involving multiple organs. A 47-year-old woman with a 4-year history of severe pelvic pain, dysuria, dyspareunia, dyschezia, and dysmenorrhea failing multiple medical therapies presented to our clinic to discuss surgical options. After thorough counseling, the decision was made to proceed with definitive surgical management. Postoperatively, the patient was admitted for 2 days of postoperative inpatient care. After meeting all immediate postoperative milestones, she was discharged with an indwelling Foley catheter and instructed to follow up in the clinic with all 3 surgical specialties. At the 1-week interval, she was seen by the urology team; her indwelling catheter was removed after a cystoscopy was performed documenting adequate healing. Two weeks postoperatively, the patient was seen by the gynecology and colorectal teams and was noted to be healing adequately from the procedure. Her six-week visit was also unremarkable. She continued to follow up with the gynecology team for her yearly well-woman examinations and has been symptom free for 2 years after the surgery. She takes norethindrone daily to minimize recurrence. Preoperative pelvic magnetic resonance imaging (MRI) showed bladder endometriosis and extensive rectovaginal endometriosis. We describe the multidisciplinary approach used for surgery and the procedures performed by each specialty. The urology team performed a cystoscopy preoperatively to assess for full-thickness erosions and the location of those lesions in that event. The urology team also reviewed the magnetic resonance images with the radiology team, and the endometriosis lesions were suspected to be close to the bladder trigone, keeping in mind that this finding could be overestimated given that the bladder was deflated at the time the imaging was obtained. Accordingly, at the time of surgery, the decision was made to proceed with cystoscopy and the placement of ureteral stents as a prophylactic measure. An intentional cystotomy and resection of the bladder section involved with endometriosis were performed followed by watertight closure. The trigone area of the bladder was not involved, and ureteral reimplantation was not needed in this case. The gynecology team operated second and performed an extensive dissection of the retroperitoneal space with the development of the pararectal and paravesical spaces. They also ligated the uterine artery at its origin followed by dissection of the uterovesical space, effectively reflecting the bladder off of the lower uterine segment. At this point, they proceeded with a total hysterectomy, and the specimen was removed from the pelvis through the vaginal cuff. Preoperatively, the colorectal surgeon ordered a colonoscopy to determine if full-thickness erosions were present and reviewed the magnetic resonance images with the radiology team. Based on the MRI and colonoscopy, all patients are counseled and consented for the possibility of a low anterior resection and loop ileostomy to protect the anastomosis. Based on the understanding that colorectal and gynecologic surgeries have a different approach when dissecting the pararectal space at our institution, a discussion between the 2 teams is initiated at the multidisciplinary session for surgery planning. In the case we present, the colorectal surgeon opted for the removal of the uterus before his dissection was initiated given that he dissects this space presacrally and not retroperitoneally like the gynecology counterpart. He would also benefit from the extra space for dissection with the uterus out of the pelvis. The colorectal part of the case was initiated by mobilization of the rectum and dissecting the obliterated rectovaginal space. The presacral space was then opened followed by mobilization of the rectosigmoid from its attachment. The case was concluded with full transection and reanastomosis of the rectum section involved with endometriosis. The specimen was also removed from the pelvis through the vaginal cuff. Complete resection of deeply infiltrative endometriosis spanning beyond the scope of 1 surgical specialty. No immediate intraoperative, perioperative, or long-term complications from surgery. Complete resolution of endometriosis symptoms. We encourage collaborative care for planning and performing comprehensive and safe resection of deeply infiltrative endometriosis. 2. Loose stools are rarely present without the use of laxatives, and there are insufficient criteria for IBS. 3. a Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis. From Drossman DA, Corazziari E, Talley NJ, et al., eds. Rome III: the functional gastrointestinal disorders. 3nd ed. McLean, VA: Degnon Associates, 2006:885–897, Appendix A, with permission. Table 28.6 Functional Defecation Disorders 1. The patient must satisfy diagnostic criteria for functional constipation (Table 28.5) 2. During repeated attempts to defecate must have at least two of the following: a. Evidence of impaired evacuation, based on balloon expulsion test or imaging b. Inappropriate contraction of the pelvic floor muscles (i.e., anal sphincter or puborectalis) or less than 20% relaxation of basal resting sphincter pressure by manometry, imaging, or EMG c. 27 year old Melinda presents to you with increasingly severe dysmenorrhoea. She has been using condoms for contraception and is no longer able to control the pain with the anti inflammatory tablets you suggested at the last consultation 6 months ago. She also complains of the recent development of deep dyspareunia. She has been in her current relationship for the last 5 years. Examination illicits similar pain and tenderness to that which she feels during intercourse. A Pap smear and STD screen are normal. You refer her to a gynaecologist who undertakes a laparoscopy on Melinda. What is seen? Ovarian adhesions secondary to endometriosis (Figure 1). Classic endometriosis (Figure 2). The aim of the authors is to show the data for the reception diagnosis, age, histological results and the conduct after the performed diagnostic hysteroscopies in Gynecological clinic of UMBAL-Pleven. For the fulfillment of this aim was made a prospective study for 7 years' period: from 01/01/1997 to 31/01/2003. The objects of observation were 74 women of age from 16 to 65 years, with performed hysteroscopies for gynecologic complaints. There were performed 74 diagnostic hysteroscopies for the studied period. The hysteroscopic findings were 20 cases with endometrial polyposis, 14--submucosal myoamatic nodes, deforming the uterine cavity, 4--cervical polyp, 19--increased endometrium, 9--Asherman syndrome, 1--bicomous uterus, 1--a suspected section for endometrial carcinoma and 6 cases without pathologic findings. There were performed 59 trial abrasions and the removed materials were sent for histological examination The performed comparative analysis between the hysteroscopic presentation and histological findings showed a coincidence of the diagnosis. It was made the conclusion, that the hysteroscopy is an easy, accessible and inexpensive diagnostic method, which must take its place as one of the basic contemporary diagnostic methods in gynecology. To describe how a hydronephrosis can lead to a difficult differential diagnosis between endometriosis and retroperitoneal fibrosis. Case report. Department of Obstetrics and Gynecology, Sacro Cuore Don Calabria General Hospital, Negrar, Verona, Italy. The history of a 34-year-old woman revealed the appearance of hydroureteronephrosis on the right side at the 35th week of pregnancy. She had an magnetic resonance imaging scan and was diagnosed with a spread retroperitoneal fibrosis. After 2 months, the patient reported the occurrence of pelvic pain, dyspareunia and dysmenorrhea. She was treated with corticosteroids and tamoxifen with no results. Laparoscopic surgery. A complete retroperitoneal extirpation was done of an endometriotic nodule of the right broad ligament, near the right ureter (without stenosis). Reduction of pelvic pain. She noticed an important decrease of pain. The cause of hydronephrosis could be a physiologic hydroureteronephrosis, which is the most common cause of dilatation of the urinary tract in pregnancy. The pain symptoms of the patients seemed to be linked to endometriosis and not to retroperitoneal fibrosis. Magnetic resonance imaging sometimes does not enable a correct diagnosis between these two pathologies. Fertile women with suspected fibrosis should undergo a diagnostic laparoscopy by an expert surgeon in retroperitoneal surgery. Pelvic congestion affects women of reproductive age. Typical symptoms include bilateral lower abdominal and back pain that is increased with standing for long periods, secondary dysmenorrhea, dyspareunia, abnormal uterine bleeding, chronic fatigue, and irritable bowel symptoms (97). Pain usually begins with ovulation and lasts until the end of menses. The uterus is often bulky, and the ovaries are enlarged with multiple functional cysts. The uterus, parametria, and uterosacral ligaments are tender. Transuterine venography is the primary method for diagnosis, although other modalities, such as pelvic ultrasound, magnetic resonance imaging, and laparoscopy, may disclose varicosities (93). Because of the cost and possible side effects of treatment, further management should be based on related symptoms and not simply on the presence of varicosities. Heidi is an almost 6-year-old girl presenting to your primary care office to establish care because of a change in insurance status. You review her previous medical records before seeing her.She was diagnosed with autism spectrum disorder (ASD) when she was 25 months old. Her parents were initially concerned about language delay. Through a comprehensive evaluation by a developmental-behavioral pediatrician and a child psychologist, including administration of the Bayley Scales of Infant and Toddler Development and the Autism Diagnostic Observation Schedule, she was diagnosed with ASD. Her cognitive skills were reported to be within the average range. Soon after the diagnosis, she began receiving 20 hours of applied behavioral analysis (ABA) per week, as well as music therapy, occupational therapy, and a toddler playgroup through early intervention. Four months after the initial diagnosis, her parents reported that she had started making small improvements in her behavior, used more eye contact, and seemed more socially engaged. Approximately 1 year after the diagnosis, she was receiving 6 hours of ABA per week in addition to starting preschool with an Individualized Education Program. She reportedly continued to show progress with social communication and pretend play skills.At the age of 3 years, 8 months, neuropsychological testing was completed at her parent's request, and her cognitive skills and adaptive skills were reported to be within the average range. She continued to meet the diagnostic criteria for ASD, given her challenges with social awareness, communication, delayed play skills, decreased flexibility, and tendency toward subtle self-direction. She continued to receive speech/language therapy and attended an integrated preschool program within the school district because of her social and communication challenges. She also received ABA 4 hours weekly at home.During your first visit with Heidi, her parents report that she has continued to make progress in all areas, including social skills. She can engage in imaginary play with her friends, ask strangers questions, and comprehend the perspective of others, and she is no longer \"rigid.\" She is not receiving services outside of school and is only receiving once weekly speech/language therapy in school. Her parents no longer believe that she meets the criteria for ASD, and they are interested in further evaluation. Her parents ask if it is possible to \"lose\" the diagnosis of ASD. They also want to know if there are other things to be concerned about for her future. How do you respond? Imaging Tests The role of imaging techniques in studying female urinary incontinence is not yet established. Researchers are evaluating the potential roles of ultrasonography, fluoroscopy, functional neuroimaging, and magnetic resonance imaging (MRI). These tests should not be done routinely but are useful in certain conditions. If the patient’s symptoms (easily remembered by the three Ds: dysuria, dribbling, and dyspareunia) or examination suggests a urethral diverticulum, MRI is the test of choice (44).\nHere is the question:\nGYNECOLOGY AND OBSTETRICS: A 27-year-old woman referred to the gynecology office for evaluation referring dyspareunia for about 8 months, along with dyschezia and occasional rectorrhagia coinciding with menstruation for 3-4 months. She also reports dysmenorrhea for years, which she controls well with ibuprofen. She has been trying to get pregnant for 16 months without success. In the gynecological examination she only has pain when pressing on the posterior vaginal fornix. Which test do you consider would allow you to reach a diagnosis of certainty of her pathology?\nHere are the potential choices:\n1. Transvaginal ultrasound.\n2. Diagnostic laparoscopy.\n3. Magnetic resonance imaging.\n4. Colonoscopy.\nThe correct answer is: ",
        "gold_answer": "2 Diagnostic laparoscopy.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n To show how the evaluation for endometriosis can be included in the routine pelvic ultrasound examination. Stepwise narrated video demonstration of the sonographic evaluation for endometriosis in routine pelvic ultrasound following the recommended sonographic approach published in the 2016 consensus paper by the International Deep Endometriosis Analysis (IDEA) group [1]. Endometriosis is a common and often debilitating gynecological disorder that affects 5-10% of women [2]. The prevalence is even higher among women with symptoms of endometriosis [2], which include chronic pelvic pain, acquired dysmenorrhea, dyspareunia, dyschezia, menorrhagia, abnormal bleeding, and infertility. Approximately 80% of women who have endometriosis have superficial lesions, whereas 20% have deep infiltrating endometriosis (DIE; [3]). Laparoscopy is the gold standard for diagnosing endometriosis, because it allows the diagnosis of all forms of endometriosis and often immediate removal of superficial endometriosis. The removal of DIE is considerably more complicated and usually cannot be completed unless it was diagnosed preoperatively. The technique to diagnose DIE with transvaginal ultrasound (TVUS) was first described in detail in 2009 [4]. Since then, the accuracy of TVUS for the prediction of DIE has been well established in the literature [5-7]. TVUS is widely used as a first-line investigation for women with gynecological symptoms. The inclusion of an assessment for endometriosis in the routine pelvic ultrasound allows earlier diagnosis and better surgical outcomes for all women with DIE. The evaluation for endometriosis in routine pelvic ultrasound based on the IDEA consensus promotes a 4-step dynamic ultrasound approach [1]: (1) routine evaluation of uterus and adnexa with particular attention for sonographic signs of adenomyosis and the presence or absence of endometriomas; (2) evaluation of transvaginal sonographic 'soft markers' such as site-specific tenderness and ovarian mobility; (3) assessment of status of pouch of Douglas using the real-time ultrasound-based \"sliding sign;\" and (4) assessment of DIE nodules in the anterior and posterior compartments, which involves assessment of the bladder, vaginal vault, uterosacral ligaments, and bowel, including rectum, rectosigmoid junction, and sigmoid colon. Because 5-10% of women with DIE also have ureteric endometriosis, it is useful to assess the kidneys. Silent hydronephrosis is easily identified in 50-60% of patients with ureteric involvement. Although it is possible to identify DIE involving the ureters more directly, this requires more advanced skills, and further studies are still needed to better define the accuracy of ureteric DIE detection by TVUS [8-10]. Traditionally, only pathologies of the uterus and ovaries are assessed during a routine pelvic ultrasound. Here we demonstrate that the routine ultrasound examination can easily be extended beyond the uterus and ovaries into the posterior and anterior pelvic compartments to evaluate structural mobility and to look for deep infiltrating endometriotic nodules, wherewith women suffering from DIE can benefit from a preoperative diagnosis and subsequently, a single, well-planned procedure in the hands of a well-prepared team. Adolescent Patients A pelvic examination may be less revealing in an adolescent than in an older woman, particularly if it is the patient’s first examination or if it takes place on an emergency basis. An adolescent who presents with excessive bleeding should have a pelvic examination if she had intercourse, if the results of a pregnancy test are positive, if she has abdominal pain, if she is markedly anemic, or if she is bleeding heavily enough to compromise hemodynamic stability. The pelvic examination occasionally may be deferred in young teenagers who have a classic history of irregular cycles soon after menarche, who have normal hematocrit levels, who deny sexual activity, and who will reliably return for follow-up. A pelvic examination may be deferred in adolescents who present to the office requesting oral contraceptives before the initiation of intercourse or at the patient’s request, even if she has had intercourse. Newer testing methods using DNA amplification techniques To describe the management and the fertility-enhancing potential of surgery in an infertile patient with deep-infiltrating endometriosis and adenomyosis externa. Video case report. Minimally invasive and robotic gynecologic surgery unit of a university hospital. A 31-year-old nulliparous patient with dysmenorrhea, dysuria, dyspareunia, and primary infertility. Bimanual examination, transvaginal ultrasound, and magnetic resonance imaging (MRI) were performed as a comprehensive preoperative workup. The findings were consistent with bladder endometriosis and a 4-cm right pararectal cystic mass suggestive of adenomyosis externa. Laparoscopic excision of all visible endometriosis was performed. A pararectal lesion was found, completely developing in the retroperitoneal spaces, from the right medial pararectal space to the rectovaginal space, reaching the pelvic floor fascia without infiltration of the levator ani muscle. According to Koninckx classification, this kind of lesion corresponds to type III endometriosis or adenomyosis externa. Nerve-sparing eradication of the nodule was performed. The decision to use these techniques was taken with the intention to treat the patient, and not with the aim of testing the procedures performed. Therefore, as a common clinical practice in our institution and for the above reasons, there was no need for consultation of the institutional review board for approval. Improvement of symptoms and spontaneous conception after surgical removal of all endometriotic implants. There were no intraoperative or postoperative complications, and the patient was discharged after 3 days. She discontinued postoperative hormone therapy with gonadotropin-releasing hormone analogue after 3 months because she desired fertility. She conceived spontaneously after 2 months of attempting. She delivered vaginally and had no complications during pregnancy and labor. Neither recurrence of pain symptoms nor voiding or rectal dysfunctions were reported by the patient. In the management of a case of deep endometriosis, the preoperative assessment should be carefully carried out to give the surgeon the most accurate information about the extent of the disease and the patient's main objectives. Imaging techniques such as ultrasound and MRI play a fundamental role along with the clinical evaluation in also detecting lesions that are not visible at first laparoscopic inspection. In this case of a young woman without any detectable fertility issues except for endometriosis, the laparoscopic excision of endometriosis was feasible, safe, and effective in improving the patient's fertility and pain symptoms. The fertility-enhancing potential of complete eradication of pelvic endometriosis, including removal of deep posterior localizations such those presented in this case, has been hypothesized by various investigators. It has been suggested that skilled surgical management for symptomatic deep endometriosis may be followed by a high pregnancy rate, with most pregnancies resulting from postoperative natural conception even in patients with primary infertility. The uterus is typically diffusely enlarged, although usually less than 14 cm in size, and is often soft and tender, particularly at the time of menses. Mobility of the uterus is not restricted, and there is no associated adnexal pathology (48). Adenomyosis is a clinical diagnosis. Imaging studies including pelvic ultrasound or MRI, although helpful, are not definitive. Because of the cost of MRI and negligible improvement in diagnostic accuracy, this study is not recommended routinely. In women with diffuse uterine enlargement and negative pregnancy test results, secondary dysmenorrhea may be attributed to adenomyosis; however, the pathologic confirmation of suspected adenomyosis can be made only at the time of hysterectomy. To demonstrate the technique of laparoscopic approach in a rare case of rectovaginal splenosis with severe dyspareunia and dyschesia. A step-by-step explanation of the patient's condition, diagnosis, surgical technique, and postoperative results (Canadian Task Force classification II-3). Splenosis consists of ectopic functioning splenic tissue that can be located anywhere within the abdomen or pelvis. Fragments are often multiple and range in diameter from a few millimeters to a few centimeters. They are reddish-blue and are sessile or pedunculated. Their appearance can mimic that of neoplasms or endometriosis, which are the main differential diagnoses. Trauma and subsequent splenectomy is the cause in most cases. Splenosis is a benign condition usually found incidentally and is usually asymptomatic. The need for therapy is controversial, and treatment is suggested only in symptomatic cases, primarily those related to pelvic or abdominal lesions, as in our patient. The diagnosis of splenosis in a woman complaining of pelvic pain may present diagnostic difficulties. The splenic tissue has the macroscopic appearance of endometriosis, and its position in the pelvis also may suggest this diagnosis. Where excision of splenosis is considered necessary, the approach should be laparoscopic, unless this is considered too risky owing to the proximity of vital structures. A 40-year-old woman was referred to our department for severe dyspareunia and dyschezia. The gynecologic examination revealed a painfull nodularity on the posterior vaginal cul de sac. Further evaluation with 2- and 3-dimensional ultrasound and magnetic resonance imaging revealed several soft tissue nodules in the pouch of Douglas (POD), which were enhanced on contrast administration. She had undergone a splenectomy 15 years earlier after a car accident. A laparoscopic approach to a rectovaginal nodularity was performed. Under general anesthesia, the patient was placed in the dorsal decubitus position with her arms alongside her body and her legs in abduction. Pneumoperitoneum was achieved using a Veres needle placed at the umbilicus. Four trocars were placed: a 10-mm trocar at the umbilicus for the 0-degree laparoscope; a 5-mm trocar at the right anterosuperior iliac spine; a 5-mm trocar in the midline between the umbilicus and the pubic symphysis, approximately 8 to 10 cm inferior to the umbilical trocar; and a 5-mm trocar at the left anterosuperior iliac spine. The entire pelvis was inspected for endometriotic lesions. In the pelvis, hypervascular and bluish nodules were visible with extension from the POD into the deep rectovaginal space. The macroscopic appearance was atypical for endometriotic implants. The nodularities were carefully dissected and excised, and histological assessment revealed splenic tissue. At the time of this report, the patient had been asymptomatic for 6 months after surgery. Rectovaginal splenosis may mimic endometriosis. The laparoscopic approach to rectovaginal splenosis avoids an abdominal incision, with its associated pain and possible adhesion formation. It also provides a better view for dissection. In this patient, the splenosis was removed by laparoscopy, with no postoperative dyspareunia or dyschesia. The efficacy of medical and surgical treatment of endometriosis and pelvic pain is a source of questions and controversies. Complete resolution of endometriosis is not yet possible but therapy has essentially three main objectives: 1) to reduce pain; 2) to increase the possibility of pregnancy; 3) to delay recurrence for as long as possible. In case of moderate and severe endometriosis, operative laparoscopy must be considered as first line treatment. The mean pregnancy rate of 50% reported in the literature following surgery provides scientific proof that operative treatment should first be undertaken to give our patients the best chance of conceiving naturally. In case of rectovaginal adenomyotic nodules, surgery must also be considered as first line therapy, medical therapy being relatively inefficacious. Careful preoperative examination is mandatory (transrectal sonography, magnetic resonance imaging, bowel barium enema or intravenous pyelography) to evaluate potentially severe complications of the disease. Endometriosis is defined as the presence of endometrial tissue outside the uterine cavity. It generally involves the peritoneum, ovaries and rectovaginal septum. Its characteristic symptoms include dysmenorrhea, pelvic pain, deep dyspareunia and infertility. It may also involve the gastrointestinal tract, urinary tract or extra abdominal sites, giving rise to a wide variety of clinical symptoms such as bloody stools, renal haemorrhage, hemoptysis and pleural effusion during menstruation. Recurrent hemorrhagic ascites secondary to endometriosis is an unusual occurrence, 41 cases have been reported since 1954. Here we report an additional case, in order to draw attention to this condition. A 28 years-old black nulligravida woman was seen for the first time in april 2000 with a chief complaint of infertility. Her past medical history was unremarkable. She had regular menses but associated with severe dysmenorrhea. She also recalled abdominal and pelvic pain for several years. She underwent an ovulation induction with gonadotrophin, which resulted in a progressive increase of pelvic pain. A first laparoscopy was performed, revealing voluminous ascites (10 I). Two years later the ascites recurred spontaneously. Ultrasound examination revealed suspect \"para uterine masses\". A second exploratory laparoscopy showed a voluminous bloody ascites (71), and extensive adhesions. On histologic examination all specimens (peritoneal biopsies) were compatible with endometriosis and ruled out malignancy. Treatment with Gn RH analog was performed and full remission was obtained after 6 months. One year later the ascites recurred again spontaneously, leading to a third laparoscopy in an other medical institution. Histologic examination showed endometrial stromal tissue and fibrous proliferation. Later she became pregnant after in vitro fertilization. In the first trimester of pregnancy, the pelvic ultrasound showed only a small effusion in the pouch of Douglas. Still, the ascites did not progress during pregnancy. The patient was hospitalized from 27 to 33 weeks of gestational age for threatened labor, but she finally had a normal vaginal delivery at 36 weeks of gestational age. Four months later, she had no complaint, but the pelvic ultrasound showed the recurrence of the ascites. She will have a drainage. The future treatement will consists of GnRH analog for about six months, which will be relayed by a long term progestative therapy. A diagnosis of endometriosis should always be considered in middle-age women who presents with bloody ascites. Long follow-up is advisable for patients who undergo conservative treatment because of thehigh risk of recurrence. Although gastrointestinal endometriosis is an uncommon and often unexpected finding, the best treatment requires removal of all endometriotic lesions. The purpose of our study was to report our experience with the diagnosis and treatment of bowel endometriosis. From January 1997 to January 2004, 13 patients (mean 35.7y ; range 21-55y) were operated for bowel endometriosis. We noted: age, history of endometriosis, previous pregnancies, preoperative investigations and symptoms, operative procedure and intraoperative findings. Follow-up varied between one month postoperative examination and seven years. Presenting symptoms of the cases were: acute appendicitis (3), dysmenorrhoea (7), constipation (6), pelvic pain (2), rectal bleeding (3) and dyspareunia (2). Operative management was performed in accordance with the anatomical distribution. Seven patients had a history of previous operations and multifocal involvement was present in 61.5% of cases. At a median follow-up of 12.2 months, 83.3% had complete relief of their initial complaints, with only one reoperation needed. The pregnancy rate after surgery was 66.6%. Preoperative tests were: ultrasound for ovarian endometriomas, coloscopy, barium enema, vaginal palpation for detecting rectovaginal involvement, MRI and CT scan. These tests predicted the extension of endometriotic process correctly in 50% of the cases. Endometriosis of the sigmoid and rectum is rare but can give rise to severe gastrointestinal and pelvic symptoms. Preoperative investigations are not infallible in predicting the extent of the disease, sometimes placing the surgeon before a dilemma, because it involves mostly young women in the reproductive phase of life. The colorectal surgeon, therefore, should seek the advice of an experienced gynaecologist and vice versa. Removal of all endometriotic lesions is mandatory for obtaining an optimal relief of symptoms. To describe a multidisciplinary approach for the resection of deeply infiltrative endometriosis using the robotic platform. A technical video showing a step-by-step approach for the resection of deeply infiltrative endometriosis (Canadian Task Force classification level III). Institutional review board approval was not required for this study. There is considerable involvement of the bowel and bladder with deeply infiltrative endometriosis [1-3]. The need for operative procedures involving multiple organs while performing a complete resection is common. The benefits of minimally invasive surgery for a gynecologic pathology have been documented in numerous studies. Patients had fewer medical and surgical complications postoperatively, better cosmesis, and better quality of life [4-6]. We believe that deeply infiltrative endometriosis does not preclude patients from having a minimally invasive resection procedure. In this video, we describe how the robotic platform was used for a seamless transition between surgical specialties including gynecology, colorectal, and urology to ensure complete resection of endometriosis lesions involving multiple organs. A 47-year-old woman with a 4-year history of severe pelvic pain, dysuria, dyspareunia, dyschezia, and dysmenorrhea failing multiple medical therapies presented to our clinic to discuss surgical options. After thorough counseling, the decision was made to proceed with definitive surgical management. Postoperatively, the patient was admitted for 2 days of postoperative inpatient care. After meeting all immediate postoperative milestones, she was discharged with an indwelling Foley catheter and instructed to follow up in the clinic with all 3 surgical specialties. At the 1-week interval, she was seen by the urology team; her indwelling catheter was removed after a cystoscopy was performed documenting adequate healing. Two weeks postoperatively, the patient was seen by the gynecology and colorectal teams and was noted to be healing adequately from the procedure. Her six-week visit was also unremarkable. She continued to follow up with the gynecology team for her yearly well-woman examinations and has been symptom free for 2 years after the surgery. She takes norethindrone daily to minimize recurrence. Preoperative pelvic magnetic resonance imaging (MRI) showed bladder endometriosis and extensive rectovaginal endometriosis. We describe the multidisciplinary approach used for surgery and the procedures performed by each specialty. The urology team performed a cystoscopy preoperatively to assess for full-thickness erosions and the location of those lesions in that event. The urology team also reviewed the magnetic resonance images with the radiology team, and the endometriosis lesions were suspected to be close to the bladder trigone, keeping in mind that this finding could be overestimated given that the bladder was deflated at the time the imaging was obtained. Accordingly, at the time of surgery, the decision was made to proceed with cystoscopy and the placement of ureteral stents as a prophylactic measure. An intentional cystotomy and resection of the bladder section involved with endometriosis were performed followed by watertight closure. The trigone area of the bladder was not involved, and ureteral reimplantation was not needed in this case. The gynecology team operated second and performed an extensive dissection of the retroperitoneal space with the development of the pararectal and paravesical spaces. They also ligated the uterine artery at its origin followed by dissection of the uterovesical space, effectively reflecting the bladder off of the lower uterine segment. At this point, they proceeded with a total hysterectomy, and the specimen was removed from the pelvis through the vaginal cuff. Preoperatively, the colorectal surgeon ordered a colonoscopy to determine if full-thickness erosions were present and reviewed the magnetic resonance images with the radiology team. Based on the MRI and colonoscopy, all patients are counseled and consented for the possibility of a low anterior resection and loop ileostomy to protect the anastomosis. Based on the understanding that colorectal and gynecologic surgeries have a different approach when dissecting the pararectal space at our institution, a discussion between the 2 teams is initiated at the multidisciplinary session for surgery planning. In the case we present, the colorectal surgeon opted for the removal of the uterus before his dissection was initiated given that he dissects this space presacrally and not retroperitoneally like the gynecology counterpart. He would also benefit from the extra space for dissection with the uterus out of the pelvis. The colorectal part of the case was initiated by mobilization of the rectum and dissecting the obliterated rectovaginal space. The presacral space was then opened followed by mobilization of the rectosigmoid from its attachment. The case was concluded with full transection and reanastomosis of the rectum section involved with endometriosis. The specimen was also removed from the pelvis through the vaginal cuff. Complete resection of deeply infiltrative endometriosis spanning beyond the scope of 1 surgical specialty. No immediate intraoperative, perioperative, or long-term complications from surgery. Complete resolution of endometriosis symptoms. We encourage collaborative care for planning and performing comprehensive and safe resection of deeply infiltrative endometriosis. 2. Loose stools are rarely present without the use of laxatives, and there are insufficient criteria for IBS. 3. a Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis. From Drossman DA, Corazziari E, Talley NJ, et al., eds. Rome III: the functional gastrointestinal disorders. 3nd ed. McLean, VA: Degnon Associates, 2006:885–897, Appendix A, with permission. Table 28.6 Functional Defecation Disorders 1. The patient must satisfy diagnostic criteria for functional constipation (Table 28.5) 2. During repeated attempts to defecate must have at least two of the following: a. Evidence of impaired evacuation, based on balloon expulsion test or imaging b. Inappropriate contraction of the pelvic floor muscles (i.e., anal sphincter or puborectalis) or less than 20% relaxation of basal resting sphincter pressure by manometry, imaging, or EMG c. 27 year old Melinda presents to you with increasingly severe dysmenorrhoea. She has been using condoms for contraception and is no longer able to control the pain with the anti inflammatory tablets you suggested at the last consultation 6 months ago. She also complains of the recent development of deep dyspareunia. She has been in her current relationship for the last 5 years. Examination illicits similar pain and tenderness to that which she feels during intercourse. A Pap smear and STD screen are normal. You refer her to a gynaecologist who undertakes a laparoscopy on Melinda. What is seen? Ovarian adhesions secondary to endometriosis (Figure 1). Classic endometriosis (Figure 2). The aim of the authors is to show the data for the reception diagnosis, age, histological results and the conduct after the performed diagnostic hysteroscopies in Gynecological clinic of UMBAL-Pleven. For the fulfillment of this aim was made a prospective study for 7 years' period: from 01/01/1997 to 31/01/2003. The objects of observation were 74 women of age from 16 to 65 years, with performed hysteroscopies for gynecologic complaints. There were performed 74 diagnostic hysteroscopies for the studied period. The hysteroscopic findings were 20 cases with endometrial polyposis, 14--submucosal myoamatic nodes, deforming the uterine cavity, 4--cervical polyp, 19--increased endometrium, 9--Asherman syndrome, 1--bicomous uterus, 1--a suspected section for endometrial carcinoma and 6 cases without pathologic findings. There were performed 59 trial abrasions and the removed materials were sent for histological examination The performed comparative analysis between the hysteroscopic presentation and histological findings showed a coincidence of the diagnosis. It was made the conclusion, that the hysteroscopy is an easy, accessible and inexpensive diagnostic method, which must take its place as one of the basic contemporary diagnostic methods in gynecology. To describe how a hydronephrosis can lead to a difficult differential diagnosis between endometriosis and retroperitoneal fibrosis. Case report. Department of Obstetrics and Gynecology, Sacro Cuore Don Calabria General Hospital, Negrar, Verona, Italy. The history of a 34-year-old woman revealed the appearance of hydroureteronephrosis on the right side at the 35th week of pregnancy. She had an magnetic resonance imaging scan and was diagnosed with a spread retroperitoneal fibrosis. After 2 months, the patient reported the occurrence of pelvic pain, dyspareunia and dysmenorrhea. She was treated with corticosteroids and tamoxifen with no results. Laparoscopic surgery. A complete retroperitoneal extirpation was done of an endometriotic nodule of the right broad ligament, near the right ureter (without stenosis). Reduction of pelvic pain. She noticed an important decrease of pain. The cause of hydronephrosis could be a physiologic hydroureteronephrosis, which is the most common cause of dilatation of the urinary tract in pregnancy. The pain symptoms of the patients seemed to be linked to endometriosis and not to retroperitoneal fibrosis. Magnetic resonance imaging sometimes does not enable a correct diagnosis between these two pathologies. Fertile women with suspected fibrosis should undergo a diagnostic laparoscopy by an expert surgeon in retroperitoneal surgery. Pelvic congestion affects women of reproductive age. Typical symptoms include bilateral lower abdominal and back pain that is increased with standing for long periods, secondary dysmenorrhea, dyspareunia, abnormal uterine bleeding, chronic fatigue, and irritable bowel symptoms (97). Pain usually begins with ovulation and lasts until the end of menses. The uterus is often bulky, and the ovaries are enlarged with multiple functional cysts. The uterus, parametria, and uterosacral ligaments are tender. Transuterine venography is the primary method for diagnosis, although other modalities, such as pelvic ultrasound, magnetic resonance imaging, and laparoscopy, may disclose varicosities (93). Because of the cost and possible side effects of treatment, further management should be based on related symptoms and not simply on the presence of varicosities. Heidi is an almost 6-year-old girl presenting to your primary care office to establish care because of a change in insurance status. You review her previous medical records before seeing her.She was diagnosed with autism spectrum disorder (ASD) when she was 25 months old. Her parents were initially concerned about language delay. Through a comprehensive evaluation by a developmental-behavioral pediatrician and a child psychologist, including administration of the Bayley Scales of Infant and Toddler Development and the Autism Diagnostic Observation Schedule, she was diagnosed with ASD. Her cognitive skills were reported to be within the average range. Soon after the diagnosis, she began receiving 20 hours of applied behavioral analysis (ABA) per week, as well as music therapy, occupational therapy, and a toddler playgroup through early intervention. Four months after the initial diagnosis, her parents reported that she had started making small improvements in her behavior, used more eye contact, and seemed more socially engaged. Approximately 1 year after the diagnosis, she was receiving 6 hours of ABA per week in addition to starting preschool with an Individualized Education Program. She reportedly continued to show progress with social communication and pretend play skills.At the age of 3 years, 8 months, neuropsychological testing was completed at her parent's request, and her cognitive skills and adaptive skills were reported to be within the average range. She continued to meet the diagnostic criteria for ASD, given her challenges with social awareness, communication, delayed play skills, decreased flexibility, and tendency toward subtle self-direction. She continued to receive speech/language therapy and attended an integrated preschool program within the school district because of her social and communication challenges. She also received ABA 4 hours weekly at home.During your first visit with Heidi, her parents report that she has continued to make progress in all areas, including social skills. She can engage in imaginary play with her friends, ask strangers questions, and comprehend the perspective of others, and she is no longer \"rigid.\" She is not receiving services outside of school and is only receiving once weekly speech/language therapy in school. Her parents no longer believe that she meets the criteria for ASD, and they are interested in further evaluation. Her parents ask if it is possible to \"lose\" the diagnosis of ASD. They also want to know if there are other things to be concerned about for her future. How do you respond? Imaging Tests The role of imaging techniques in studying female urinary incontinence is not yet established. Researchers are evaluating the potential roles of ultrasonography, fluoroscopy, functional neuroimaging, and magnetic resonance imaging (MRI). These tests should not be done routinely but are useful in certain conditions. If the patient’s symptoms (easily remembered by the three Ds: dysuria, dribbling, and dyspareunia) or examination suggests a urethral diverticulum, MRI is the test of choice (44).\nHere is the question:\nGYNECOLOGY AND OBSTETRICS: A 27-year-old woman referred to the gynecology office for evaluation referring dyspareunia for about 8 months, along with dyschezia and occasional rectorrhagia coinciding with menstruation for 3-4 months. She also reports dysmenorrhea for years, which she controls well with ibuprofen. She has been trying to get pregnant for 16 months without success. In the gynecological examination she only has pain when pressing on the posterior vaginal fornix. Which test do you consider would allow you to reach a diagnosis of certainty of her pathology?\nHere are the potential choices:\n1. Transvaginal ultrasound.\n2. Diagnostic laparoscopy.\n3. Magnetic resonance imaging.\n4. Colonoscopy.\nThe correct answer is: 2. Diagnostic laparoscopy."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Psittacosis, caused by the bacteria Chlamydia psittaci, is primarily a disease of birds that can be transmitted to humans. The clinical manifestations of the disease are wide, ranging from asymptomatic illness to fulminant psittacosis with multi-organ failure. The organism gets attached to the upper respiratory mucosa after inhalation and the majority remain asymptomatic. However, some people may develop symptoms of atypical pneumonia. Psittacosis usually presents with sudden onset fever with chills and rigor, headache, and myalgia. Here we present a case of a 35 years old female with a history of close contact with parrots who presented to the ER with complaints of high-grade fever and headache for 2 weeks which started 2 days after her parrots died. The disease usually manifests as flu-like symptoms or pneumonia and is included in the differential diagnosis of community-acquired pneumonia. Investigations reveal neutrophilia, raised erythrocyte sedimentation rate, C-reactive protein, and elevated liver enzymes which were consistent with the findings of our patient. Chest X-ray showed ill-defined consolidation in the right middle and lower lobes which were inconclusive. Hence, a CT chest was done which revealed patchy ground glass opacities with surrounding consolidation giving a reverse halo sign. Due to her contact with birds and CT findings which were suggestive of psittacosis, she was started on doxycycline and her condition improved thereafter. We highlight the importance of proper history taking and awareness on zoonotic diseases to the general public to prevent, diagnose and treat the disease effectively. Three familial cases of psittacosis are reported. The first case was a 46-year-old woman, the second case, her 18-year-old daughter. Both of them often visited the house of the third case, a 49-year-old women, who was the elder sister of case 1 and who took care of the chick of a budgerigar which she kept in the house. Case 1 came to our hospital with abrupt onset of fever, headache, nausea and general malaise. Because she was suspected to have meningitis, she was admitted to the Department of Neurology. On admission, her chest X-ray film showed bilateral ground glass shadows. She also had hypoxemia and liver dysfunction. On learning of her history of contact with the chick, psittacosis was suspected. Case 2 suffered from fever and headache. Her chest X-ray film revealed opaque infiltration in the right lower lung field. Case 3 complained of fever, headache and vomiting. Her chest X-ray film showed fan-shaped faint shadows in the left upper, middle and lower lung fields. We interpreted these findings as showing psittacosis based on anamnesis. The result of the complement fixation (CF) antibody titer against chlamydia was 1:32 in cases 2 and 3, enabling a serological diagnosis of psittacosis. The corresponding result was 1:16 in case 1. Although the CF antibody titer showed no increase, we diagnosed the case clinically as psittacosis. It is difficult to correctly diagnose psittacosis only from the physical findings and chest X-ray films. Detailed anamnesis, in particular taking a history of exposure to birds, is an important clue for diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS) Coxiella burnetii (C.b.) is a strictly intracellular, Gram-negative bacterium. It causes Q fever in humans and animals worldwide. The animal Q fever is sometimes designated \"coxiellosis\". This infection has many different reservoirs including arthropods, birds and mammals. Domestic animals and pets, are the most frequent source of human infections. Q fever may appear basically in two forms, acute and chronic (persistent). The latter form of Q fever in animals is characteristic by shedding C.b. into the environment during parturition or abortion. Human Q fever results usually from inhalation of contaminated aerosols originating mostly from tissue and body fluids of infected animals. Q fever may appear in humans either in an acute form accompanied mainly by fever (pneumonia, flu-like disease, hepatitis) or in a chronic form (mainly endocarditis). Diagnosis of Q fever is based on isolation of the agent in cell culture, its direct detection, namely by PCR, and serology. Detection of high phase II antibodies titers 1-3 weeks after the onset of symptoms and identification of IgM antibodies are indicative to acute infection. High phase I IgG antibody titers &gt;800 as revealed by microimmunofluorescence offer evidence of chronic C.b. infection. For acute Q fever, a two-weeks-treatment with doxycycline is recommended as the first-line therapy. In the case of Q fever endocarditis a long-term combined antibiotic therapy is necessary to prevent relapses. Application of Q fever vaccines containing or prepared from phase I C.b. corpuscles should be considered at least for professionally exposed groups of the population. Infections caused by C.b. are spread worldwide and may pose serious and often underestimated health problems in human but also in veterinary medicine. Though during the last decades substantial progress in investigation of C.b. has been achieved and many data concerning this pathogen has been accumulated, some questions, namely those related to the pathogenesis of the disease, remain open. Q fever which is caused by Coxiella burnetii, is a worldwide zoonosis. Many species of wild and domestic mammals, birds, and arthropods, are reservoirs of C.burnetii in nature, however farm animals are the most frequent sources of human infection. The most frequent way of transmission is by inhalation of contaminated aerosols. The clinical presentation of Q fever is polymorphic and nonspecific. Q fever may present as acute or chronic disease. In acute cases, the most common clinical syndromes are selflimited febrile illness, granulomatous hepatitis, and pneumonia, but it can also be asymptomatic. Fever with hepatitis associated with Q fever has rarely been described in the literature. Herein we report two cases of C.burnetii hepatitis presented with jaundice. In May 2011, two male cases, who inhabited in Malkara village of Tekirdag province (located at Trace region of Turkey), were admitted to the hospital with the complaints of persistent high grade fever, chills and sweats, icterus, disseminated myalgia and headache. Physical examination revealed fever, icterus and the patient appeared to be mildly ill but had no localizing signs of infection. Radiological findings of the patients were in normal limits. Laboratory findings revealed leukocytosis, increased hepatic and cholestatic enzyme levels, and moderate hyperbilirubinemia- mainly direct bilirubin, whereas serum C-reactive protein and erythrocyte sedimentation rate were found normal. Blood and urine cultures of the patients yielded no bacterial growth. Serological markers for acute viral hepatitis, citomegalovirus and Epstein-Barr virus infections, brucellosis, salmonellosis, toxoplasmosis and leptospirosis were found negative. Acute Q fever diagnosis of the cases were based on the positive results obtained by C.burnetii Phase II IgM and IgG ELISA (Vircell SL, Spain) test, and the serological diagnosis were confirmed by Phase I and II immunofluorescence (Vircell SL, Spain) method. Both cases were treated with doxycycline for 14 days and became afebrile within four days. These cases were presented to emphasize that C.burnetii infection should be considered in the differential diagnosis of patients with fever and elevated serum transaminase levels, irrespective of the presence of abdominal pain and exposure to potentially infected animals. A 58-year-old man was admitted because of respiratory failure, episodic fever with chilling, cough, malaise, fatigue, myalgia and weight loss lasting for at least one month. Chest x-rays and CT scan of the chest showed bilateral pulmonary consolidations in upper lobes, the left lower lobe, and mediastinal lymphadenopathy. Bronchoscopy with cytology was unremarkable. A needle CT-guided lung biopsy documented an inflammatory pseudotumor, lymphoplasmacytic type. Serology showed high titer antibodies to phase II Coxiella burnetii infection. Therapy with doxycycline and hydroxychloroquine for three months led to a complete resolution of symptoms and radiological findings, and a marked decrease in titers to Q fever.  Q fever is a bacterial infection affecting mainly the lungs, liver, and heart. It is found around the world and is caused by the bacteria Coxiella burnetii. The bacteria affects sheep, goats, cattle, dogs, cats, birds, rodents, and ticks. Infected animals shed this bacteria in birth products, feces, milk, and urine. Humans usually get Q fever by breathing in contaminated droplets released by infected animals and drinking raw milk. People at highest risk for this infection are farmers, laboratory workers, sheep and dairy workers, and veterinarians. Chronic Q fever develops in people who have been infected for more than 6 months. It usually takes about 20 days after exposure to the bacteria for symptoms to occur. Most cases are mild, yet some severe cases have been reported. Symptoms of acute Q fever may include: chest pain with breathing, cough, fever, headache, jaundice, muscle pains, and shortness of breath. Symptoms of chronic Q fever may include chills, fatigue, night sweats, prolonged fever, and shortness of breath. Q fever is diagnosed with a blood antibody test. The main treatment for the disease is with antibiotics. For acute Q fever, doxycycline is recommended. For chronic Q fever, a combination of doxycycline and hydroxychloroquine is often used long term. Complications are cirrhosis, hepatitis, encephalitis, endocarditis, pericarditis, myocarditis, interstitial pulmonary fibrosis, meningitis, and pneumonia. People at risk should always: carefully dispose of animal products that may be infected, disinfect any contaminated areas, and thoroughly wash their hands. Pasteurizing milk can also help prevent Q fever. The brucellosis and Q-fever coinfection is very rarely reported. To our knowledge, this is the first case report of concomitant brucellosis and Q-fever, most likely imported in Croatia. A 30-year-old male agricultural worker was hospitalized on 22 April 2017 after a ten days fever up to 40°C with chills, shivering, excessive sweating, general weakness, loss of appetite and headache. A month and a half prior to the hospitalization he lost 18 kg of body weight. Three weeks before hospitalization the patient returned from Kupres (Bosnia and Herzegovina) where he was working for the past year on a sheep farm and consumed unpasteurized dairy products of sheep origin. At admission, his condition was moderately severe due to pronounced dehydration. Routine laboratory tests showed slightly elevated erythrocyte sedimentation rate, anemia, thrombocytopenia and elevated liver transaminases. The chest X-ray showed an inhomogeneous infiltrate of the lower right lung. Three sets of blood culture were cultivated. After 48 hours incubation, bacterial growth was detected in aerobic bottles. Gram-stained smear revealed small, gram-negative coccobacilli. Specimens were subcultured on blood and chocolate agar plates. Using a Vitek GN identification card, the isolated organism was identified as Brucella melitensis. 16S rRNA gene sequencing of the isolate confirmed it as a Brucella sp. Rose-Bengal test was positive, while Wright agglutination test showed a significant increase in antibody titer from 80 to 640 in paired sera. Using indirect immunofluorescence assay (IFA), Coxiella burnetii phase II IgM/IgG titers were 50 and 1024, respectively indicating acute Q-fever. The patient was treated with doxycycline and rifampicin. So far, there has been no relapse or signs of chronic infection. Diagnosis The diagnosis of acute chest syndrome is made difficult by its similarity in presentation with pneumonia. Both may present with a new opacification of the lung on chest x-ray. The presence of fevers, low oxygen levels in the blood, increased respiratory rate, chest pain, and cough are also common in acute chest syndrome. Diagnostic workup includes chest x-ray, complete cell count, reticulocyte count, ECG, and blood and sputum cultures. Patients may also require additional blood tests or imaging (e.g. a CT scan) to exclude a heart attack or other pulmonary pathology. Prevention Hydroxyurea is a medication that can help to prevent acute chest syndrome. It may cause a low white blood cell count, which can predispose the person to some types of infection. Treatment Broad spectrum antibiotics to cover common infections such as Streptococcus pneumoniae and mycoplasma, pain control, and blood transfusion. Acute chest syndrome is an indication for exchange transfusion. Signs and symptoms Initially, HPS has an incubation phase of 2–4 weeks, in which patients remain asymptomatic. Subsequently, patients can experience 3–5 days of flu-like prodromal phase symptoms, including fever, cough, muscle pain, headache, lethargy, shortness of breath, nausea, vomiting and diarrhea. In the following 5–7 day cardiopulmonary phase, the patient's condition rapidly deteriorates into acute respiratory failure, characterized by the sudden onset of shortness of breath with rapidly evolving pulmonary edema, as well as cardiac failure, with hypotension, tachycardia and shock. In this phase, patients may develop acute respiratory distress syndrome. It is often fatal despite mechanical ventilation and intervention with diuretics. After the cardiopulmonary phase, patients can enter a diuretic phase of 2–3 days characterized by symptom improvement and diuresis. Subsequent convalescence can last months to years. As of 2017, patient mortality in the USA from HPS is 36%. Brucellosis is a zoonotic disease caused by a Gram-negative bacillus of the Brucella genus with multisystem involvement, primarily affecting the reticuloendothelial system, joints, heart and kidneys. Although the disease can be spread by inhalation, pulmonary involvement is rare. To report a case of brucellosis with pulmonary involvement. CASE PRESENTAION: A previously healthy 36-year-old woman was admitted with complaints of fever, weakness, night sweats, dry cough and bilateral chest pain. She hed been diagnosed with pneumonia 20 days previously and was started on a course of ampicillin for 14 days, with no response. Her chest auscultation revealed diminished breath sounds and scattered crackles and rhonchi over the inferior zone of the right hemithorax. Wright and Coombs testing resulted in titres of 1:1280 and 1:640, respectively. Chest radiography revealed an area of confluent lobar consolidation in the right lower lobe. Treatment was started with a six-week course of oral doxycycline 200 mg/day and rifampicin 600 mg/day. This treatment regimen rapidly improved the patient's condition. Follow-up after one year showed no residual effects from the infection. Pulmonary involvement is a rare event in the course of brucellosis, but the rate could be higher than currently estimated. In endemic regions, brucellosis should be considered as a causative agent in patients with pulmonary symptoms. Brucellosis is a zoonotic disease caused by a Gram-negative bacillus of the <iBrucella</i genus with multisystem involvement, primarily affecting the reticuloendothelial system, joints, heart and kidneys. Although the disease can be spread by inhalation, pulmonary involvement is rare. To report a case of brucellosis with pulmonary involvement. A previously healthy 36-year-old woman was admitted with complaints of fever, weakness, night sweats, dry cough and bilateral chest pain. She hed been diagnosed with pneumonia 20 days previously and was started on a course of ampicillin for 14 days, with no response. Her chest auscultation revealed diminished breath sounds and scattered crackles and rhonchi over the inferior zone of the right hemithorax. Wright and Coombs testing resulted in titres of 1:1280 and 1:640, respectively. Chest radiography revealed an area of confluent lobar consolidation in the right lower lobe. Treatment was started with a six-week course of oral doxycycline 200 mg/day and rifampicin 600 mg/day. This treatment regimen rapidly improved the patient’s condition. Follow-up after one year showed no residual effects from the infection. Pulmonary involvement is a rare event in the course of brucellosis, but the rate could be higher than currently estimated. In endemic regions, brucellosis should be considered as a causative agent in patients with pulmonary symptoms. A 46-year-old woman was referred to our department in July 1996 with complaints of fever and myalgia in her calves. She had a 20-year history of purulent sputum; diffuse panbronchiolitis had been diagnosed in 1983. Physical examination revealed low-pithed rhonchi over the lung fieldis and hypesthesia of the right leg. She had a white blood cell count of 16,100/mm3, including 4% eosinophils, and a platelet count of 80.0 x 10(4)/mm3. The serum IgE level was 2,200 U/ml, and the cold hemagglutinin titer was high. Pulmonary-function tests showed mixed ventilatory dysfunction, and arterial blood gas analysis revealed a PaO2 of 55.8 Torr on room air. Pseudomonas aeruginosa was cultured from her sputum. A chest X-ray film and CT scan showed diffuse nodular shadows and bronchiectatic changes with mild hyperinflation. An infiltrative lesion in right S6 area could also be seen. Administration of broad-spectrum antibiotics did not alleviate her symptoms. The level of myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA) in serum was 245 EU/ml, and 67Ga scintigraphy showed marked accumulation in the abdomen. Abdominal angiography demonstrated a bead-like appearance and irregularities in the peripheral branches of the hapatic artery, the splenic artery, the cystic artery, and the superior mesenteric artery. Because of the high MPO-ANCA level and the angiographic abnormalities, MPO-ANCA-related vasculitis was diagnosed. She was treated with 1 g of methylprednisolone daily for 3 days, followed by 60 mg of prednisolone and 50 mg of cyclophosphamide daily. Her condition improved dramatically, and the MPO-ANCA level became almost normal. During treatment, her blood pressure rose markedly with a normal serum creatinine level and normal urinalysis. Plasma renin activity was 13.3 ng/ml/hr. Renal angiography showed stenoses and irregularities in the peripheral branches of renal arteries bilaterally. These findings led to a diagnosis of renovascular hypertension due to vasculitis. Her blood pressure was controlled with an angiotensin-converting enzyme inhibitor and a calcium antagonist. Vasculitis associated with chronic supportive lung disease has occasionally been reported, which suggests a casual relation between chronic respiratory infection and ANCA-related vasculitis. Systemic vasculitis should be taken into account as a potential complication of chronic suppurative lung disease. Primary infections are frequently asymptomatic, or the patients tend to ignore mild flu-like symptoms. The major determinant of symptoms is the inoculum size. The typical incubation period is seven to 21 days. High fever, headache, nonproductive cough, and chest pain are the main symptoms. This chest pain is not pleuritic and is in the anterior chest and is believed to be due to enlargement of mediastinal or hilar lymph nodes. Most of the symptoms resolve in 10 days. Rheumatologic manifestations can occur such as arthralgias, erythema nodosum or erythema multiforme in a small number of patients (6%, mostly women). This syndrome appears to be less frequent in histoplasmosis when compared to coccidioidomycosis. Imaging shows patchy diffuse pneumonitis and hilar lymphadenopathy. There is no granulomatous inflammation as cellular immunity matures by two weeks in primary infection. During the acute pulmonary infections, a skin test may be positive in more than 90% of cases, antibody to H. capsulatum may be present in 25% to 85% of cases, the urinary antigen may be positive in 20% of cases, and sputum culture from lungs may be positive in less than 25% of cases. Patients with acute viral infections, such as Epstein-Barr virus, cytomegalovirus, influenza, hepatitis A, B, or C virus, have similar presenting complaints, such as febrile illness, hepatitis, and myalgia. Serological tests and PCR assays are used to identify these infections. Atypical pneumonia caused by Legionella and Mycoplasma needs to be considered. They can be ruled out by detecting urine antigen or serum antibody titers. Tick-borne illnesses such as Lyme disease, relapsing fever, and Rocky Mountain spotted fever manifest with fever and headache with or without a rash. Anaplasmosis and ehrlichiosis present with fever, headache, and hepatitis, with a lesser incidence of rash. Tick-borne diseases are detected via PCR and/or serology. Zoonotic diseases such as brucellosis and leptospirosis can manifest as an acute flu-like illness with a history of exposure to animals or animal products. Q fever is usually acquired by contact with aerosols generated during parturition of domestic ungulates (e.g., sheep, cows, goats). In the maritime provinces of Canada, parturient cats have also been implicated in its transmission. A 66-year-old woman from eastern Maine developed high fever, rigors, headache, myalgias, pulmonary infiltrates, and elevated hepatocellular enzymes, and the diagnosis of acute Q fever was confirmed serologically. She and 14 other family members had attended a family reunion in Maine 2 weeks earlier, when they were exposed to a parturient cat. All 11 adults and older children attending the reunion developed symptoms consistent with acute Q fever. Serum samples were obtained from 10 who attended the reunion and 8 who did not attend. Titers greater than or equal to 1:64 to Coxiella burnetii were present in all who attended the reunion but in none of those who did not. Cat-associated Q fever should be considered when sporadic cases of the disease occur in the United States. Signs and symptoms Acute Stage: After four to eight hours symptoms such as headache, irritating cough, and shortness of breath upon physical exertion, appear. Subacute Stage: Symptoms persist without further exposure, and increase in severity. Symptoms include: shortness of breath upon exertion, chronic coughing, physical weakness, occasional fever and sweating, decrease in appetite, aches and pains. Chronic Stage: Debilitating effects are now considered long-term. Symptoms include: severe shortness of breath, chronic coughing, physical weakness, occasional fever and sweating at night, decrease in appetite, and general aches and pains. These symptoms develop between four and eight hours after exposure to the antigens. In acute attacks, the symptoms mimic pneumonia or flu. In chronic attacks, there is a possibility of the victim going into shock and dying from the attack. A 52-year-old woman visited a local hospital with a high fever, non-productive cough and general fatigue. Her chest X-ray showed infiltrate in the right middle lung field. Computed tomography scans revealed ground-glass opacity and surrounding ring-shaped air-space consolidation, the \"reversed halo sign\". Cefpirom was administered, but her symptoms persisted and the infiltrate migrated to the left upper lobe. As cryptogenic organizing pneumonia was suspected, she was then treated with intravenously pulsed methylprednisolone followed by prednisolone. Despite these therapies, acute respiratory failure occurred and she was therefore transferred to our hospital. On admission, severe hypoxemia and diffuse bilateral infiltrates on chest images suggested acute respiratory distress syndrome. As we obtained information that a parakeet had recently died at her home, minocycline was administered, resulting in prompt improvement of the symptoms, respiratory insufficiency and pulmonary infiltrates. Finally, elevated antibody titers against Chlamydophila psittasi confirmed a diagnosis of Psittacosis. Sequential chest computed tomography scans in this case indicate that absorption of marginal air-space consolidation with extended central ground glass attenuation in concordance with a new infiltrate on another lung field appeared to create wandering infiltrate. Wandering infiltrate on chest X-ray in psittacosis may be a sign of disease progression. a flu-like illness with fever, chills, arthralgia (joint pain), myalgia (muscle pain), headache, and a nonproductive cough which resolves within days. an acute illness resembling bacterial pneumonia, with symptoms of high fever, chills, a productive cough, and pleuritic chest pain. a chronic illness that mimics tuberculosis or lung cancer, with symptoms of low-grade fever, a productive cough, night sweats, and weight loss. a fast, progressive, and severe disease that manifests as ARDS, with fever, shortness of breath, tachypnea, hypoxemia, and diffuse pulmonary infiltrates. skin lesions, usually asymptomatic, can be verrucous (wart-like) or ulcerated with small pustules at the margins. bone lytic lesions can cause bone or joint pain. prostatitis may be asymptomatic or may cause pain on urinating. laryngeal involvement causes hoarseness. 40% immunocompromised individuals have CNS involvement and present as brain abscess, epidural abscess or meningitis. \"Q fever\" is a generic term for infection caused, mostly in the form of pneumonia or bronchitis, by Coxiella burnetii (Q-fever Coxiella), a pathogen closely related to Rickettsia and Legionella. Q fever is an influenza-like, transient febrile infectious disease that is common to humans and animals; it develops after the transmission of the infectious agent from livestock or pet animals, but person-to-person transmission is rare. In Europe and the United States, it is ranked fourth or fifth as an underlying cause of community-acquired pneumonia. Many patients with Q fever have a good prognosis, and their mortality is about 1%-2% when left untreated. However, because some patients may take a long time to be cured or may have a chronic condition with poor prognosis, patients with definitely diagnosed Q fever or those strongly suspected of having Q fever are strongly recommended to receive treatment. The definite diagnosis of Q fever is made based on a significant increase in serum antibody titers, the determination of which often requires considerable time, and therefore patients must be monitored for a certain period. Q-fever Coxiella, an obligate intracellular parasite, is basically not susceptible to beta-lactam antibiotics, which barely permeate into the cells, but the parasite is susceptible to tetracyclines, macrolides, and quinolones, with these agents being sufficiently permeable into the cells. However, there are many cases of spontaneous cure, and it is likely that beta-lactam treatment may have been involved in these cases. Vaccination against Q fever is not common in Japan. BACKGROUND This case series describes 5 patients with SARS-CoV-2 infection and COVID-19 in Ecuador who had been treated with hydroxychloroquine for systemic lupus erythematosus (SLE) prior to their COVID-19 illness. CASE REPORT Case #1 reports a 29-year-old woman who had been treated with 200 mg of hydroxychloroquine per day for 1 year and presented with flu-like symptoms, chest pain, fever, odynophagia, asthenia, dry cough, and chills. Case #2 was a 34-year-old woman whose treatment for SLE included 200 mg of hydroxychloroquine per day since 2017. She arrived at the clinic with a dry cough, asthenia, and myalgias. Case #3 was a 24-year-old woman who had been using 200 mg of hydroxychloroquine per day since 2010. She presented with asthenia, myalgias, headaches, hypogeusia, and anosmia. Case #4 was a 39-year-old woman taking 200 mg of hydroxychloroquine every day for SLE who presented with dyspnea, chest pain, odynophagia, hypogeusia, anosmia, diarrhea, and fever. Case #5 was a 46-year-old woman who had been taking 200 mg of hydroxychloroquine since 2019. She came to our hospital complaining of chest pain, fever, and dyspnea. In all 5 patients, SARS-CoV-2 infection was confirmed with a nasopharyngeal SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) test using the Cepheid/GeneXpert system. CONCLUSIONS All 5 of our patients with SLE who were taking hydroxychloroquine presented with SARS-CoV-2 infection and symptoms of COVID-19. This case series provides support for a lack of prevention of COVID-19 by hydroxychloroquine.\nHere is the question:\nEPIDEMIOLOGY AND PREVENTIVE MEDICINE: A 38-year-old woman of veterinary profession, in charge of monitoring wild animals and assisting in the delivery of domestic livestock. She starts with a high fever with chills, headache, myalgia and non-productive cough that she interprets as a flu-like process. She presented with chest pain. Chest X-ray showed bilateral pulmonary infiltrates in lower fields. A serologic test was performed with elevated titers of antibodies against phase II antigens. Which of the following statements is TRUE?\nHere are the potential choices:\n1. This entity is transmitted by ticks.\n2. Both doxycycline and hydroxychloroquine are effective in treating acute forms of this disease.\n3. In the acute form, the patient also generally has elevated antibodies to phase I antigens.\n4. Mortality in acute forms is almost nonexistent.\nThe correct answer is: ",
        "gold_answer": "4 Mortality in acute forms is almost nonexistent.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Psittacosis, caused by the bacteria Chlamydia psittaci, is primarily a disease of birds that can be transmitted to humans. The clinical manifestations of the disease are wide, ranging from asymptomatic illness to fulminant psittacosis with multi-organ failure. The organism gets attached to the upper respiratory mucosa after inhalation and the majority remain asymptomatic. However, some people may develop symptoms of atypical pneumonia. Psittacosis usually presents with sudden onset fever with chills and rigor, headache, and myalgia. Here we present a case of a 35 years old female with a history of close contact with parrots who presented to the ER with complaints of high-grade fever and headache for 2 weeks which started 2 days after her parrots died. The disease usually manifests as flu-like symptoms or pneumonia and is included in the differential diagnosis of community-acquired pneumonia. Investigations reveal neutrophilia, raised erythrocyte sedimentation rate, C-reactive protein, and elevated liver enzymes which were consistent with the findings of our patient. Chest X-ray showed ill-defined consolidation in the right middle and lower lobes which were inconclusive. Hence, a CT chest was done which revealed patchy ground glass opacities with surrounding consolidation giving a reverse halo sign. Due to her contact with birds and CT findings which were suggestive of psittacosis, she was started on doxycycline and her condition improved thereafter. We highlight the importance of proper history taking and awareness on zoonotic diseases to the general public to prevent, diagnose and treat the disease effectively. Three familial cases of psittacosis are reported. The first case was a 46-year-old woman, the second case, her 18-year-old daughter. Both of them often visited the house of the third case, a 49-year-old women, who was the elder sister of case 1 and who took care of the chick of a budgerigar which she kept in the house. Case 1 came to our hospital with abrupt onset of fever, headache, nausea and general malaise. Because she was suspected to have meningitis, she was admitted to the Department of Neurology. On admission, her chest X-ray film showed bilateral ground glass shadows. She also had hypoxemia and liver dysfunction. On learning of her history of contact with the chick, psittacosis was suspected. Case 2 suffered from fever and headache. Her chest X-ray film revealed opaque infiltration in the right lower lung field. Case 3 complained of fever, headache and vomiting. Her chest X-ray film showed fan-shaped faint shadows in the left upper, middle and lower lung fields. We interpreted these findings as showing psittacosis based on anamnesis. The result of the complement fixation (CF) antibody titer against chlamydia was 1:32 in cases 2 and 3, enabling a serological diagnosis of psittacosis. The corresponding result was 1:16 in case 1. Although the CF antibody titer showed no increase, we diagnosed the case clinically as psittacosis. It is difficult to correctly diagnose psittacosis only from the physical findings and chest X-ray films. Detailed anamnesis, in particular taking a history of exposure to birds, is an important clue for diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS) Coxiella burnetii (C.b.) is a strictly intracellular, Gram-negative bacterium. It causes Q fever in humans and animals worldwide. The animal Q fever is sometimes designated \"coxiellosis\". This infection has many different reservoirs including arthropods, birds and mammals. Domestic animals and pets, are the most frequent source of human infections. Q fever may appear basically in two forms, acute and chronic (persistent). The latter form of Q fever in animals is characteristic by shedding C.b. into the environment during parturition or abortion. Human Q fever results usually from inhalation of contaminated aerosols originating mostly from tissue and body fluids of infected animals. Q fever may appear in humans either in an acute form accompanied mainly by fever (pneumonia, flu-like disease, hepatitis) or in a chronic form (mainly endocarditis). Diagnosis of Q fever is based on isolation of the agent in cell culture, its direct detection, namely by PCR, and serology. Detection of high phase II antibodies titers 1-3 weeks after the onset of symptoms and identification of IgM antibodies are indicative to acute infection. High phase I IgG antibody titers &gt;800 as revealed by microimmunofluorescence offer evidence of chronic C.b. infection. For acute Q fever, a two-weeks-treatment with doxycycline is recommended as the first-line therapy. In the case of Q fever endocarditis a long-term combined antibiotic therapy is necessary to prevent relapses. Application of Q fever vaccines containing or prepared from phase I C.b. corpuscles should be considered at least for professionally exposed groups of the population. Infections caused by C.b. are spread worldwide and may pose serious and often underestimated health problems in human but also in veterinary medicine. Though during the last decades substantial progress in investigation of C.b. has been achieved and many data concerning this pathogen has been accumulated, some questions, namely those related to the pathogenesis of the disease, remain open. Q fever which is caused by Coxiella burnetii, is a worldwide zoonosis. Many species of wild and domestic mammals, birds, and arthropods, are reservoirs of C.burnetii in nature, however farm animals are the most frequent sources of human infection. The most frequent way of transmission is by inhalation of contaminated aerosols. The clinical presentation of Q fever is polymorphic and nonspecific. Q fever may present as acute or chronic disease. In acute cases, the most common clinical syndromes are selflimited febrile illness, granulomatous hepatitis, and pneumonia, but it can also be asymptomatic. Fever with hepatitis associated with Q fever has rarely been described in the literature. Herein we report two cases of C.burnetii hepatitis presented with jaundice. In May 2011, two male cases, who inhabited in Malkara village of Tekirdag province (located at Trace region of Turkey), were admitted to the hospital with the complaints of persistent high grade fever, chills and sweats, icterus, disseminated myalgia and headache. Physical examination revealed fever, icterus and the patient appeared to be mildly ill but had no localizing signs of infection. Radiological findings of the patients were in normal limits. Laboratory findings revealed leukocytosis, increased hepatic and cholestatic enzyme levels, and moderate hyperbilirubinemia- mainly direct bilirubin, whereas serum C-reactive protein and erythrocyte sedimentation rate were found normal. Blood and urine cultures of the patients yielded no bacterial growth. Serological markers for acute viral hepatitis, citomegalovirus and Epstein-Barr virus infections, brucellosis, salmonellosis, toxoplasmosis and leptospirosis were found negative. Acute Q fever diagnosis of the cases were based on the positive results obtained by C.burnetii Phase II IgM and IgG ELISA (Vircell SL, Spain) test, and the serological diagnosis were confirmed by Phase I and II immunofluorescence (Vircell SL, Spain) method. Both cases were treated with doxycycline for 14 days and became afebrile within four days. These cases were presented to emphasize that C.burnetii infection should be considered in the differential diagnosis of patients with fever and elevated serum transaminase levels, irrespective of the presence of abdominal pain and exposure to potentially infected animals. A 58-year-old man was admitted because of respiratory failure, episodic fever with chilling, cough, malaise, fatigue, myalgia and weight loss lasting for at least one month. Chest x-rays and CT scan of the chest showed bilateral pulmonary consolidations in upper lobes, the left lower lobe, and mediastinal lymphadenopathy. Bronchoscopy with cytology was unremarkable. A needle CT-guided lung biopsy documented an inflammatory pseudotumor, lymphoplasmacytic type. Serology showed high titer antibodies to phase II Coxiella burnetii infection. Therapy with doxycycline and hydroxychloroquine for three months led to a complete resolution of symptoms and radiological findings, and a marked decrease in titers to Q fever.  Q fever is a bacterial infection affecting mainly the lungs, liver, and heart. It is found around the world and is caused by the bacteria Coxiella burnetii. The bacteria affects sheep, goats, cattle, dogs, cats, birds, rodents, and ticks. Infected animals shed this bacteria in birth products, feces, milk, and urine. Humans usually get Q fever by breathing in contaminated droplets released by infected animals and drinking raw milk. People at highest risk for this infection are farmers, laboratory workers, sheep and dairy workers, and veterinarians. Chronic Q fever develops in people who have been infected for more than 6 months. It usually takes about 20 days after exposure to the bacteria for symptoms to occur. Most cases are mild, yet some severe cases have been reported. Symptoms of acute Q fever may include: chest pain with breathing, cough, fever, headache, jaundice, muscle pains, and shortness of breath. Symptoms of chronic Q fever may include chills, fatigue, night sweats, prolonged fever, and shortness of breath. Q fever is diagnosed with a blood antibody test. The main treatment for the disease is with antibiotics. For acute Q fever, doxycycline is recommended. For chronic Q fever, a combination of doxycycline and hydroxychloroquine is often used long term. Complications are cirrhosis, hepatitis, encephalitis, endocarditis, pericarditis, myocarditis, interstitial pulmonary fibrosis, meningitis, and pneumonia. People at risk should always: carefully dispose of animal products that may be infected, disinfect any contaminated areas, and thoroughly wash their hands. Pasteurizing milk can also help prevent Q fever. The brucellosis and Q-fever coinfection is very rarely reported. To our knowledge, this is the first case report of concomitant brucellosis and Q-fever, most likely imported in Croatia. A 30-year-old male agricultural worker was hospitalized on 22 April 2017 after a ten days fever up to 40°C with chills, shivering, excessive sweating, general weakness, loss of appetite and headache. A month and a half prior to the hospitalization he lost 18 kg of body weight. Three weeks before hospitalization the patient returned from Kupres (Bosnia and Herzegovina) where he was working for the past year on a sheep farm and consumed unpasteurized dairy products of sheep origin. At admission, his condition was moderately severe due to pronounced dehydration. Routine laboratory tests showed slightly elevated erythrocyte sedimentation rate, anemia, thrombocytopenia and elevated liver transaminases. The chest X-ray showed an inhomogeneous infiltrate of the lower right lung. Three sets of blood culture were cultivated. After 48 hours incubation, bacterial growth was detected in aerobic bottles. Gram-stained smear revealed small, gram-negative coccobacilli. Specimens were subcultured on blood and chocolate agar plates. Using a Vitek GN identification card, the isolated organism was identified as Brucella melitensis. 16S rRNA gene sequencing of the isolate confirmed it as a Brucella sp. Rose-Bengal test was positive, while Wright agglutination test showed a significant increase in antibody titer from 80 to 640 in paired sera. Using indirect immunofluorescence assay (IFA), Coxiella burnetii phase II IgM/IgG titers were 50 and 1024, respectively indicating acute Q-fever. The patient was treated with doxycycline and rifampicin. So far, there has been no relapse or signs of chronic infection. Diagnosis The diagnosis of acute chest syndrome is made difficult by its similarity in presentation with pneumonia. Both may present with a new opacification of the lung on chest x-ray. The presence of fevers, low oxygen levels in the blood, increased respiratory rate, chest pain, and cough are also common in acute chest syndrome. Diagnostic workup includes chest x-ray, complete cell count, reticulocyte count, ECG, and blood and sputum cultures. Patients may also require additional blood tests or imaging (e.g. a CT scan) to exclude a heart attack or other pulmonary pathology. Prevention Hydroxyurea is a medication that can help to prevent acute chest syndrome. It may cause a low white blood cell count, which can predispose the person to some types of infection. Treatment Broad spectrum antibiotics to cover common infections such as Streptococcus pneumoniae and mycoplasma, pain control, and blood transfusion. Acute chest syndrome is an indication for exchange transfusion. Signs and symptoms Initially, HPS has an incubation phase of 2–4 weeks, in which patients remain asymptomatic. Subsequently, patients can experience 3–5 days of flu-like prodromal phase symptoms, including fever, cough, muscle pain, headache, lethargy, shortness of breath, nausea, vomiting and diarrhea. In the following 5–7 day cardiopulmonary phase, the patient's condition rapidly deteriorates into acute respiratory failure, characterized by the sudden onset of shortness of breath with rapidly evolving pulmonary edema, as well as cardiac failure, with hypotension, tachycardia and shock. In this phase, patients may develop acute respiratory distress syndrome. It is often fatal despite mechanical ventilation and intervention with diuretics. After the cardiopulmonary phase, patients can enter a diuretic phase of 2–3 days characterized by symptom improvement and diuresis. Subsequent convalescence can last months to years. As of 2017, patient mortality in the USA from HPS is 36%. Brucellosis is a zoonotic disease caused by a Gram-negative bacillus of the Brucella genus with multisystem involvement, primarily affecting the reticuloendothelial system, joints, heart and kidneys. Although the disease can be spread by inhalation, pulmonary involvement is rare. To report a case of brucellosis with pulmonary involvement. CASE PRESENTAION: A previously healthy 36-year-old woman was admitted with complaints of fever, weakness, night sweats, dry cough and bilateral chest pain. She hed been diagnosed with pneumonia 20 days previously and was started on a course of ampicillin for 14 days, with no response. Her chest auscultation revealed diminished breath sounds and scattered crackles and rhonchi over the inferior zone of the right hemithorax. Wright and Coombs testing resulted in titres of 1:1280 and 1:640, respectively. Chest radiography revealed an area of confluent lobar consolidation in the right lower lobe. Treatment was started with a six-week course of oral doxycycline 200 mg/day and rifampicin 600 mg/day. This treatment regimen rapidly improved the patient's condition. Follow-up after one year showed no residual effects from the infection. Pulmonary involvement is a rare event in the course of brucellosis, but the rate could be higher than currently estimated. In endemic regions, brucellosis should be considered as a causative agent in patients with pulmonary symptoms. Brucellosis is a zoonotic disease caused by a Gram-negative bacillus of the <iBrucella</i genus with multisystem involvement, primarily affecting the reticuloendothelial system, joints, heart and kidneys. Although the disease can be spread by inhalation, pulmonary involvement is rare. To report a case of brucellosis with pulmonary involvement. A previously healthy 36-year-old woman was admitted with complaints of fever, weakness, night sweats, dry cough and bilateral chest pain. She hed been diagnosed with pneumonia 20 days previously and was started on a course of ampicillin for 14 days, with no response. Her chest auscultation revealed diminished breath sounds and scattered crackles and rhonchi over the inferior zone of the right hemithorax. Wright and Coombs testing resulted in titres of 1:1280 and 1:640, respectively. Chest radiography revealed an area of confluent lobar consolidation in the right lower lobe. Treatment was started with a six-week course of oral doxycycline 200 mg/day and rifampicin 600 mg/day. This treatment regimen rapidly improved the patient’s condition. Follow-up after one year showed no residual effects from the infection. Pulmonary involvement is a rare event in the course of brucellosis, but the rate could be higher than currently estimated. In endemic regions, brucellosis should be considered as a causative agent in patients with pulmonary symptoms. A 46-year-old woman was referred to our department in July 1996 with complaints of fever and myalgia in her calves. She had a 20-year history of purulent sputum; diffuse panbronchiolitis had been diagnosed in 1983. Physical examination revealed low-pithed rhonchi over the lung fieldis and hypesthesia of the right leg. She had a white blood cell count of 16,100/mm3, including 4% eosinophils, and a platelet count of 80.0 x 10(4)/mm3. The serum IgE level was 2,200 U/ml, and the cold hemagglutinin titer was high. Pulmonary-function tests showed mixed ventilatory dysfunction, and arterial blood gas analysis revealed a PaO2 of 55.8 Torr on room air. Pseudomonas aeruginosa was cultured from her sputum. A chest X-ray film and CT scan showed diffuse nodular shadows and bronchiectatic changes with mild hyperinflation. An infiltrative lesion in right S6 area could also be seen. Administration of broad-spectrum antibiotics did not alleviate her symptoms. The level of myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA) in serum was 245 EU/ml, and 67Ga scintigraphy showed marked accumulation in the abdomen. Abdominal angiography demonstrated a bead-like appearance and irregularities in the peripheral branches of the hapatic artery, the splenic artery, the cystic artery, and the superior mesenteric artery. Because of the high MPO-ANCA level and the angiographic abnormalities, MPO-ANCA-related vasculitis was diagnosed. She was treated with 1 g of methylprednisolone daily for 3 days, followed by 60 mg of prednisolone and 50 mg of cyclophosphamide daily. Her condition improved dramatically, and the MPO-ANCA level became almost normal. During treatment, her blood pressure rose markedly with a normal serum creatinine level and normal urinalysis. Plasma renin activity was 13.3 ng/ml/hr. Renal angiography showed stenoses and irregularities in the peripheral branches of renal arteries bilaterally. These findings led to a diagnosis of renovascular hypertension due to vasculitis. Her blood pressure was controlled with an angiotensin-converting enzyme inhibitor and a calcium antagonist. Vasculitis associated with chronic supportive lung disease has occasionally been reported, which suggests a casual relation between chronic respiratory infection and ANCA-related vasculitis. Systemic vasculitis should be taken into account as a potential complication of chronic suppurative lung disease. Primary infections are frequently asymptomatic, or the patients tend to ignore mild flu-like symptoms. The major determinant of symptoms is the inoculum size. The typical incubation period is seven to 21 days. High fever, headache, nonproductive cough, and chest pain are the main symptoms. This chest pain is not pleuritic and is in the anterior chest and is believed to be due to enlargement of mediastinal or hilar lymph nodes. Most of the symptoms resolve in 10 days. Rheumatologic manifestations can occur such as arthralgias, erythema nodosum or erythema multiforme in a small number of patients (6%, mostly women). This syndrome appears to be less frequent in histoplasmosis when compared to coccidioidomycosis. Imaging shows patchy diffuse pneumonitis and hilar lymphadenopathy. There is no granulomatous inflammation as cellular immunity matures by two weeks in primary infection. During the acute pulmonary infections, a skin test may be positive in more than 90% of cases, antibody to H. capsulatum may be present in 25% to 85% of cases, the urinary antigen may be positive in 20% of cases, and sputum culture from lungs may be positive in less than 25% of cases. Patients with acute viral infections, such as Epstein-Barr virus, cytomegalovirus, influenza, hepatitis A, B, or C virus, have similar presenting complaints, such as febrile illness, hepatitis, and myalgia. Serological tests and PCR assays are used to identify these infections. Atypical pneumonia caused by Legionella and Mycoplasma needs to be considered. They can be ruled out by detecting urine antigen or serum antibody titers. Tick-borne illnesses such as Lyme disease, relapsing fever, and Rocky Mountain spotted fever manifest with fever and headache with or without a rash. Anaplasmosis and ehrlichiosis present with fever, headache, and hepatitis, with a lesser incidence of rash. Tick-borne diseases are detected via PCR and/or serology. Zoonotic diseases such as brucellosis and leptospirosis can manifest as an acute flu-like illness with a history of exposure to animals or animal products. Q fever is usually acquired by contact with aerosols generated during parturition of domestic ungulates (e.g., sheep, cows, goats). In the maritime provinces of Canada, parturient cats have also been implicated in its transmission. A 66-year-old woman from eastern Maine developed high fever, rigors, headache, myalgias, pulmonary infiltrates, and elevated hepatocellular enzymes, and the diagnosis of acute Q fever was confirmed serologically. She and 14 other family members had attended a family reunion in Maine 2 weeks earlier, when they were exposed to a parturient cat. All 11 adults and older children attending the reunion developed symptoms consistent with acute Q fever. Serum samples were obtained from 10 who attended the reunion and 8 who did not attend. Titers greater than or equal to 1:64 to Coxiella burnetii were present in all who attended the reunion but in none of those who did not. Cat-associated Q fever should be considered when sporadic cases of the disease occur in the United States. Signs and symptoms Acute Stage: After four to eight hours symptoms such as headache, irritating cough, and shortness of breath upon physical exertion, appear. Subacute Stage: Symptoms persist without further exposure, and increase in severity. Symptoms include: shortness of breath upon exertion, chronic coughing, physical weakness, occasional fever and sweating, decrease in appetite, aches and pains. Chronic Stage: Debilitating effects are now considered long-term. Symptoms include: severe shortness of breath, chronic coughing, physical weakness, occasional fever and sweating at night, decrease in appetite, and general aches and pains. These symptoms develop between four and eight hours after exposure to the antigens. In acute attacks, the symptoms mimic pneumonia or flu. In chronic attacks, there is a possibility of the victim going into shock and dying from the attack. A 52-year-old woman visited a local hospital with a high fever, non-productive cough and general fatigue. Her chest X-ray showed infiltrate in the right middle lung field. Computed tomography scans revealed ground-glass opacity and surrounding ring-shaped air-space consolidation, the \"reversed halo sign\". Cefpirom was administered, but her symptoms persisted and the infiltrate migrated to the left upper lobe. As cryptogenic organizing pneumonia was suspected, she was then treated with intravenously pulsed methylprednisolone followed by prednisolone. Despite these therapies, acute respiratory failure occurred and she was therefore transferred to our hospital. On admission, severe hypoxemia and diffuse bilateral infiltrates on chest images suggested acute respiratory distress syndrome. As we obtained information that a parakeet had recently died at her home, minocycline was administered, resulting in prompt improvement of the symptoms, respiratory insufficiency and pulmonary infiltrates. Finally, elevated antibody titers against Chlamydophila psittasi confirmed a diagnosis of Psittacosis. Sequential chest computed tomography scans in this case indicate that absorption of marginal air-space consolidation with extended central ground glass attenuation in concordance with a new infiltrate on another lung field appeared to create wandering infiltrate. Wandering infiltrate on chest X-ray in psittacosis may be a sign of disease progression. a flu-like illness with fever, chills, arthralgia (joint pain), myalgia (muscle pain), headache, and a nonproductive cough which resolves within days. an acute illness resembling bacterial pneumonia, with symptoms of high fever, chills, a productive cough, and pleuritic chest pain. a chronic illness that mimics tuberculosis or lung cancer, with symptoms of low-grade fever, a productive cough, night sweats, and weight loss. a fast, progressive, and severe disease that manifests as ARDS, with fever, shortness of breath, tachypnea, hypoxemia, and diffuse pulmonary infiltrates. skin lesions, usually asymptomatic, can be verrucous (wart-like) or ulcerated with small pustules at the margins. bone lytic lesions can cause bone or joint pain. prostatitis may be asymptomatic or may cause pain on urinating. laryngeal involvement causes hoarseness. 40% immunocompromised individuals have CNS involvement and present as brain abscess, epidural abscess or meningitis. \"Q fever\" is a generic term for infection caused, mostly in the form of pneumonia or bronchitis, by Coxiella burnetii (Q-fever Coxiella), a pathogen closely related to Rickettsia and Legionella. Q fever is an influenza-like, transient febrile infectious disease that is common to humans and animals; it develops after the transmission of the infectious agent from livestock or pet animals, but person-to-person transmission is rare. In Europe and the United States, it is ranked fourth or fifth as an underlying cause of community-acquired pneumonia. Many patients with Q fever have a good prognosis, and their mortality is about 1%-2% when left untreated. However, because some patients may take a long time to be cured or may have a chronic condition with poor prognosis, patients with definitely diagnosed Q fever or those strongly suspected of having Q fever are strongly recommended to receive treatment. The definite diagnosis of Q fever is made based on a significant increase in serum antibody titers, the determination of which often requires considerable time, and therefore patients must be monitored for a certain period. Q-fever Coxiella, an obligate intracellular parasite, is basically not susceptible to beta-lactam antibiotics, which barely permeate into the cells, but the parasite is susceptible to tetracyclines, macrolides, and quinolones, with these agents being sufficiently permeable into the cells. However, there are many cases of spontaneous cure, and it is likely that beta-lactam treatment may have been involved in these cases. Vaccination against Q fever is not common in Japan. BACKGROUND This case series describes 5 patients with SARS-CoV-2 infection and COVID-19 in Ecuador who had been treated with hydroxychloroquine for systemic lupus erythematosus (SLE) prior to their COVID-19 illness. CASE REPORT Case #1 reports a 29-year-old woman who had been treated with 200 mg of hydroxychloroquine per day for 1 year and presented with flu-like symptoms, chest pain, fever, odynophagia, asthenia, dry cough, and chills. Case #2 was a 34-year-old woman whose treatment for SLE included 200 mg of hydroxychloroquine per day since 2017. She arrived at the clinic with a dry cough, asthenia, and myalgias. Case #3 was a 24-year-old woman who had been using 200 mg of hydroxychloroquine per day since 2010. She presented with asthenia, myalgias, headaches, hypogeusia, and anosmia. Case #4 was a 39-year-old woman taking 200 mg of hydroxychloroquine every day for SLE who presented with dyspnea, chest pain, odynophagia, hypogeusia, anosmia, diarrhea, and fever. Case #5 was a 46-year-old woman who had been taking 200 mg of hydroxychloroquine since 2019. She came to our hospital complaining of chest pain, fever, and dyspnea. In all 5 patients, SARS-CoV-2 infection was confirmed with a nasopharyngeal SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) test using the Cepheid/GeneXpert system. CONCLUSIONS All 5 of our patients with SLE who were taking hydroxychloroquine presented with SARS-CoV-2 infection and symptoms of COVID-19. This case series provides support for a lack of prevention of COVID-19 by hydroxychloroquine.\nHere is the question:\nEPIDEMIOLOGY AND PREVENTIVE MEDICINE: A 38-year-old woman of veterinary profession, in charge of monitoring wild animals and assisting in the delivery of domestic livestock. She starts with a high fever with chills, headache, myalgia and non-productive cough that she interprets as a flu-like process. She presented with chest pain. Chest X-ray showed bilateral pulmonary infiltrates in lower fields. A serologic test was performed with elevated titers of antibodies against phase II antigens. Which of the following statements is TRUE?\nHere are the potential choices:\n1. This entity is transmitted by ticks.\n2. Both doxycycline and hydroxychloroquine are effective in treating acute forms of this disease.\n3. In the acute form, the patient also generally has elevated antibodies to phase I antigens.\n4. Mortality in acute forms is almost nonexistent.\nThe correct answer is: 4. Mortality in acute forms is almost nonexistent."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The effects of decompressive craniectomy in the treatment of severe head injury remain unclear. Only very few randomized studies relating to this topic exist in the literature, including a very small number of patients with no class I evidence. We rretrospectively reviewed a series of 221 patients operated on for a head injury during a 25-month period. Of these, 48 patients underwent a decompressive craniectomy. All data available on patients' Glasgow Coma Scale score, pupil size and reaction, and intracranial pressure were collected and analyzed. The patients' outcome was evaluated by the Glasgow Outcome Scale (GOS) and the results compared with the data available in the Traumatic Coma Data Bank. Furthermore, the results were analyzed in respect of the time of surgical intervention (early or late), age, and the preoperative Glasgow Coma Score. Decompressive craniectomy reduced the midline shift in all patients with monolateral diffuse brain edema and contusions having a median value of 7 mm; in the remaining, it ameliorated the basal cisterns effacement. At a mean follow-up of 14 months, 6 (12.5%) patients died, 7 (15%) were discharged home with a GOS of 5, 18 (40%) showed a favorable outcome after rehabilitation with a GOS of 4 and 5, 6 (12.5%) had a severe disability (GOS 3), 9 (20%) were in a vegetative state (GOS 2), and 2 were lost to follow-up. The younger age, earlier surgery, and higher preoperative Glasgow Coma Scale score were related to better outcome (P &lt; .001, P &lt; .05, and P &lt; .034, respectively). Our results seem to support the idea that decompressive craniectomy coupled with neurointensive care may be an effective way to reduce intractable raised intracranial pressure, and probably to improve patients outcome. However, it should be obvious that our results and those available in the literature can not be considered conclusive. Additionally, ventilation with use of positive pressure (PEEP) can improve oxygenation with the negative effect of decreasing cerebral venous drainage and increasing intracranial pressure (ICP), and thus, must be used with caution. Fluid management and cerebral perfusion Maintenance of cerebral perfusion pressure using appropriate fluid management is essential in patients with brain injury. Dehydration, or intravascular volume loss, and the use of hypotonic fluids, such as D5W or half normal saline, should be avoided. Blood serum ion concentration, or osmolality, should be maintained in the normo to hyperosmolar range. Judicial use of hypertonic saline can be used to increase serum osmolality and decrease cerebral edema, as discussed below. Intracranial pressure monitoring Intracranial pressure (ICP) and its management is a fundamental concept in traumatic brain injury (TBI). The Brain Trauma Foundation guidelines recommend ICP monitoring in individuals with TBI that have decreased Glasgow-Coma Scale (GCS) scores, abnormal CT scans, or additional risk factors such as older age and elevated blood pressure. However, no such guidelines exist for ICP monitoring in other brain injuries such as ischemic stroke, intracerebral hemorrhage, cerebral neoplasm. The treatment of cerebral edema depends on the cause and includes monitoring of the person's airway and intracranial pressure, proper positioning, controlled hyperventilation, medications, fluid management, steroids. Extensive cerebral edema can also be treated surgically with a decompressive craniectomy. Cerebral edema is a major cause of brain damage and contributes significantly to the mortality of ischemic strokes and traumatic brain injuries. As cerebral edema is present with many common cerebral pathologies, the epidemiology of the disease is not easily defined. The incidence of this disorder should be considered in terms of its potential causes and is present in most cases of traumatic brain injury, central nervous system tumors, brain ischemia, and intracerebral hemorrhage. For example, malignant brain edema was present in roughly 31% of people with ischemic strokes within 30 days after onset. The heart and lungs are vital organs for human life due to their ability to properly oxygenate human blood (lungs) and distribute this blood to all vital organs (heart). Hence failure of the heart to pump blood or the lungs to obtain oxygen can lead to a cardiopulmonary death where the heart stops pumping and there is no pulse. In the brain, this can be manifested by a hypoxic state which leads to cerebral edema and thus an increase in intracranial pressure. The rise in intracranial pressure can lead to further disruption in cerebral blood flow, leading to necrosis or tissue death. The aforementioned mechanism is the most common cause of brain death, however this increase in intracranial pressure does not always occur due to an arrest in cardiopulmonary function. Traumatic brain injuries and subarachnoid hemorrhages can also increase the intracranial pressure in the brain leading to a cessation of brain function and hence death. While cardiopulmonary death can be easily assessed by An increase in cerebral water content is called cerebral edema and it usually results from traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), subdural hematoma, ischemic stroke, brain tumors, infectious disorders and intracranial surgery. Cerebral edema may result in compromised regional cerebral blood flow (CBF) and intracranial pressure (ICP) gradients which could lead to death of the affected. Increased ICP leads to increased intracranial volume. Unmonitored ICP leads to brain damage by global hypoxic ischemic injury due to reduction in cerebral perfusion pressure (CPP) which is found by subtracting the ICP from mean arterial pressure (MAP), cerebral blood flow, and mechanical compression of brain tissue due to compartmentalized ICP gradients. Cerebral edema is mainly classified into cytotoxic edema, vasogenic edema and interstitial edema. It is important to note that prolonged hyperventilation in those with traumatic brain injuries has been shown to worsen outcomes. Barbiturates Induction of a coma via the use of barbiturates, most notably pentobarbital and thiopental, after brain injury is used for secondary treatment of refractory ICP. Yet their use is not without controversy and it is not clear whether barbiturates are favored over surgical decompression. In patients with traumatic brain injuries, barbiturates are effective in reducing ICP but have failed to show benefit to clinical outcomes. Evidence is limited for their use in cerebral disease that include tumor, intracranial hypertension, and ischemic stroke. There are several adverse effects of barbiturates that limit their use, such as lowering of systemic blood pressure and cerebral perfusion pressure, cardiodepression, immunosuppression, and systemic hypothermia. The aim of the study was to assess (i) a group of patients with established intracranial pressure (ICP) sensor in severe brain injuries scoring 3 points of Glasgow Coma Scale, (ii) mortality and survival of the patients within periods of 7, 30, 180 and 270 days; and (iii) predictive value of intracranial pressure and cerebral perfusion pressure for short and long-term survival of patients with traumatic brain injury. The group consisted of 61 patients with trauma brain injury scoring 3 points of Glasgow Coma Scale, continuously monitored for intracranial pressure cerebral perfusion pressure at the Intensive Care Unit setting in Nové Zámky. Follow-up period was between 7 and 270 days. Measured values and other recorded data were analysed using methods of descriptive and inferential statistics. ICP values below 20 mmHg were associated with a significantly lower risk of death of an individual patient at particular time. Accordingly, cerebral perfusion pressure values above 70 mmHg during 0-2 days were associated with a significantly higher long-term survival. Overall mortality rates within 30 days showed no peaks on survival curves. In the periods of 0-7 days, within 30 days, and between 30 and 180 days we recorded 24, 51 and 2 deaths, respectively. In the period between 180 and 270 days, mortality was zero. The survival of trauma brain injury patients depends on the speed and quality of pre-hospital care and adequate follow-up treatment at specialized intensive care units. High levels of intracranial pressure and low cerebral perfusion pressure values in the early period after brain injury are closely related to mortality of patients within 30 days. Intracranial pressure monitoring may help to avoid problems and allow intervention before they become life-threatening (Tab. 4, Fig. 4, Ref. 23). Text in PDF www.elis.sk. PRx and outcome prediction A high PRx indicating disturbed pressure autoregulation predicts poor outcome in traumatic brain injury. PRx as a treatment target PRx varies with the concurrent cerebral perfusion pressure (CPP) in a U-shaped way. It has been suggested that the CPP with the lowest PRx is optimal (CPPopt) and CPP-values close to optimal have been associated with better outcome. CPP values above CPPopt are believed to cause hyperemia, i.e. to high cerebral blood flow that may cause cerebral edema and intracranial hypertension, whereas CPP values below CPPopt are believed to cause hypoperfusion and ischemia resulting in tissue damage. See also Cerebral autoregulation Intracranial pressure Cushing's triad References Intensive care medicine Neurotrauma Neurophysiology Brain death occurs as a result of an acute catastrophic brain injury. Abrupt loss of cerebral perfusion occurs if a concomitant elevation of intracranial pressure is more than mean arterial pressure (cerebral perfusion pressure (CPP) = mean arterial pressure (MAP) - intracranial pressure (ICP). This process was studied by monitoring brain tissue oxygenation in patients with brain death and can occur via two different mechanisms: Clinical researches have recommended ICP and cerebral perfusion pressure (CPP) monitoring in any persons with cerebral injury who are at risk of elevated intracranial pressure based on clinical and neuroimaging features. Early monitoring can be used to guide medical and surgical decision making and to detect potentially life-threatening brain herniation. There was however, conflicting evidence on the threshold values of ICP that indicated the need for intervention. Researches also recommend that medical decisions should be tailored to the specific diagnosis (e.g. subarachnoid hemorrhage, TBI, encephalitis) and that ICP elevation should be used in conjunction with clinical and neuroimaging and not as an isolated prognostic marker. After severe head injury intracranial pressure (ICP) must be measured continuously for management to assess and maintain the cerebral perfusion. Therefore in our hospital epidural transducers are used. To prove the efficiency of this method in a 12-month period the clinical courses of 23 patients with intracranial pressure transducers were analysed retrospectively. Eighteen patients survived, 5 of them without residuals, 13 with residuals and 2 remained in coma. In 14 patients secondary rises of intracranial pressure were observed between days 3 and 6 post injury. The mean ICP value of the survivors revealed 25 mm Hg. whereas the expired showed 60 mm Hg. In 17 patients the measurements were considered as reliable, 6 measurements were not reliable, which included 1 of the 5 patients who died. One transduce was displaced, another one showed a hemorrhage at the drill hole. There was no infection. Secondary injury events include damage to the blood–brain barrier, release of factors that cause inflammation, free radical overload, excessive release of the neurotransmitter glutamate (excitotoxicity), influx of calcium and sodium ions into neurons, and dysfunction of mitochondria. Injured axons in the brain's white matter may separate from their cell bodies as a result of secondary injury, potentially killing those neurons. Other factors in secondary injury are changes in the blood flow to the brain; ischemia (insufficient blood flow); cerebral hypoxia (insufficient oxygen in the brain); cerebral edema (swelling of the brain); and raised intracranial pressure (the pressure within the skull). Intracranial pressure may rise due to swelling or a mass effect from a lesion, such as a hemorrhage. As a result, cerebral perfusion pressure (the pressure of blood flow in the brain) is reduced; ischemia results. When the pressure within the skull rises too high, it can cause brain death or To determine the influence of positive end-expiratory pressure (PEEP) on intracranial pressure and cerebral perfusion pressure. Neurosurgical intensive care patients requiring intracranial pressure monitoring and mechanical ventilation were studied in a randomized, controlled study. Tertiary care, neurosurgical intensive care unit. Eighteen patients were enrolled in the study. Patients had posttraumatic head injuries (n = 9), subarachnoid hemorrhage (n = 7), obstructive hydrocephalus (n = 1), and intracerebral hemorrhage of unknown cause (n = 1). Patients had PEEP levels of 5, 10, and 15 cm H2O applied to their lungs. Changes in intracranial pressure, mean arterial pressure, and cerebral perfusion pressure were measured. The results were analyzed separately for patients with normal and increased intracranial pressure (&gt; 15 mm Hg). PEEP at 5 cm H2O had no effect on intracranial pressure in the group with normal intracranial pressure. However, PEEP at 10 and 15 cm H2O produced a significant (p &lt; .05) increase in intracranial pressure (1.9 and 1.5 mm Hg, respectively). In the group with increased intracranial pressure, no significant change in intracranial pressure occurred at any of the PEEP levels used. In both groups, cerebral perfusion pressure was unchanged throughout. In patients with normal intracranial pressure, PEEP at 5 cm H2O did not significantly alter intracranial pressure. The clinical relevance of the intracranial pressure increase at PEEP levels of 10 and 15 cm H2O is questionable because cerebral perfusion pressure did not change and remained &gt; 60 mm Hg. In patients with increased intracranial pressure, higher levels of PEEP did not significantly change intracranial pressure or cerebral perfusion pressure. Most patients with more severe traumatic brain injury have of a combination of intracranial injuries, which can include diffuse axonal injury, cerebral contusions, and intracranial bleeding, including subarachnoid hemorrhage, subdural hematoma, epidural hematoma, and intraparenchymal hemorrhage. The recovery of brain function following a traumatic accident is highly variable and depends upon the specific intracranial injuries that occur, however there is significant correlation between the severity of the initial insult as well as the level of neurologic function during the initial assessment and the level of lasting neurologic deficits. Initial treatment may be targeted at reducing the intracranial pressure if there is concern for swelling or bleeding within this skull, which may require surgery such as a hemicraniectomy, in which part of the skull is removed. Blunt trauma to extremities There are several clinical conditions in which vasogenic edema is present: CNS tumors, like glioblastoma and meningioma Infections like meningitis, abscess, and encephalitis Inflammatory central nervous system disease such as multiple sclerosis Brain hemorrhage Traumatic brain injuries can lead to increased intracranial pressure, local damage, reduced cerebral blood flow, and focal ischemia secondary to vasogenic edema. Late stage of ischemic stroke after rapid recovery from cytotoxic edema Hypertensive encephalopathy Radiation injury Ionic (Osmotic) In ionic edema, the solute concentration (osmolality) of the brain exceeds that of the plasma and the abnormal pressure gradient leads to accumulation of water intake into the brain parenchyma through the process of osmosis. The blood-brain barrier is intact and maintains the osmotic gradient. The solute concentration of the blood plasma can be diluted by several mechanisms: Head injury is the main cause of death or disability among under-45-year-olds. This review covers the main pathophysiological aspects of head injury as well as initial treatment and management in the intensive care recovery ward. The chief therapeutic aim is to maintain adequate cerebral perfusion pressure rather than to maintain normal levels of intracranial pressure. An important challenge is to avoid development of secondary lesions, and in this context arterial hypotensive events that affect prognosis and the survival of such patients merit special attention. We reject treatment based on indiscriminate use of hyperventilation and mannitol and underline the importance of providing adequate sedation and analgesia while maintaining normal flow and pressure and adequate monitoring of such patients. Pathophysiology Cerebral perfusion pressure (CPP), the pressure of blood flowing to the brain, is normally fairly constant due to autoregulation, but for abnormal mean arterial pressure (MAP) or abnormal ICP the cerebral perfusion pressure is calculated by subtracting the intracranial pressure from the mean arterial pressure: CPP = MAP − ICP . One of the main dangers of increased ICP is that it can cause ischemia by decreasing CPP. Once the ICP approaches the level of the mean systemic pressure, cerebral perfusion falls. The body's response to a fall in CPP is to raise systemic blood pressure and dilate cerebral blood vessels. This results in increased cerebral blood volume, which increases ICP, lowering CPP further and causing a vicious cycle. This results in widespread reduction in cerebral flow and perfusion, eventually leading to ischemia and brain infarction. Increased blood pressure can also make intracranial hemorrhages bleed faster, also increasing ICP. Monitoring and management of intracranial pressure (ICP) are fundamental to modern neurotraumatology. Although never formally proven to independently improve outcome in prospective, randomized, placebo-controlled trials, there is such a predominance of indirect support for this modality that most neurotrauma protocols are impossible with-out its inclusion and ethical considerations virtually preclude placebo-controlled trials of its efficacy. In addition to the question of improving outcome, ICP monitoring is also useful in guiding the use of potentially harmful treatment modalities such as hyperventilation, mannitol, and barbiturates, and also provides important prognostic data. ICP monitoring provides information on the likelihood of cerebral herniation and allows calculation of the cerebral perfusion pressure (CPP). Although there is no constant threshold for herniation, the most commonly used treatment threshold is 20 to 25 mm Hg. In addition, ICP trends are indispensable in providing the earliest possible indication of critical intracranial mass effects when combined with other clinical indicators. CPP is the difference between mean arterial pressure and ICP. CPP is an important clinical indicator of cerebral blood flow (CBF). Cerebral autoregulation generally remains at least partially preserved after severe head injury, although the CPP value at which it is activated appears to be shifted upward. Therefore, maintaining adequate CBF appears to require using an elevated minimal CPP threshold when treating the injured brain. A generally accepted value of 70 mm Hg is suggested. Increased intracranial pressure (ICP) is a life-threatening surgical emergency marked by symptoms of headache, nausea, vomiting, decreased consciousness. Symptoms are frequently accompanied by visual disturbances such as gaze paresis, reduced vision, and dizziness. Increased pressures within the skull can cause a compensatory elevation of blood pressure to maintain cerebral blood flow, which, when associated with irregular breathing and a decreased heart rate, is called the Cushing reflex. The Cushing reflex often indicates compression of the brain on brain tissue and blood vessels, leading to decreased blood flow to the brain and eventually death. Causes Cerebral edema is frequently encountered in acute brain injuries from a variety of origins, including but not limited to: To explore the clinical application of intracranial pressure (ICP) monitoring and its prognostic correlation in patients with severe craniocerebral injury. A total of 216 severe craniocerebral injury patients with scores of Glasgow coma scale 3-8 underwent craniotomy at Affiliated Qilu Hospital, Shandong University.And 168 cases of ICP monitoring were divided into 3 treatment groups and another 48 cases without ICP monitoring selected as the control group.According to ICP, stepwise treatment was administered to control the level of ICP and maintain the cerebral perfusion pressure to analyze the relationship between ICP monitoring and prognosis. As compared with the control group, there were significant decreases of disability and mortality rate for patients with ICP monitoring (A, B, C group). Especially group C had a better prognosis than the other groups for statistical significance.In addition, the dose and duration of mannitol of group A, B or C were significantly lower than those of the control group (P &lt; 0.05). The application of ICP monitoring is capable of reducing mortality, improving prognosis and enhancing success rate of treating severe craniocerebral injury. Depending upon the location and severity of the occlusion, signs and symptoms may vary within the population affected with MCA syndrome. More distal blockages tend to produce milder deficits due to more extensive branching of the artery and less ischemic response. In contrast, the most proximal occlusions result in widespread effects that can lead to significant cerebral edema, increased intracranial pressure, loss of consciousness and could even be fatal. In such occasions, mannitol (osmotic diuretic) or hypertonic saline are given to draw fluid out of the edematous cerebrum to minimise secondary injury. Hypertonic saline is better than mannitol, as mannitol being a diuretic will decrease the mean arterial pressure and since cerebral perfusion is mean arterial pressure minus intracranial pressure, mannitol will also cause a decrease in cerebral perfusion. The treatment of head-injured patients has over the past 15 years become significantly more complex and involved. The rising interest in the treatment of these patients has been driven in large part by the growing body of evidence showing that there is a definite association between elevated ICP and increased mortality and long-term morbidity. The effective treatment of intracranial hypertension with hyperventilation, osmotic agents, and barbiturate therapy has been aided by the regular use of ICP monitoring in most neurosurgical centers. A continuing and ongoing record of ICP allows for the judicial and appropriate use of modern treatment modalities. On the basis of a series of 75 patients, the practical use of Icp continuous long-term recording in severe head injuries without mass lesions or remaining deeply comatose after surgical procedures is critically analyzed. ICP monitoring alone seems to be not essential for prognosis. Conversely it is of much greater use as a guide to management (respirator treatment, osmotics, CSF drainage). If the pros and cons of the procedure are carefully weighed, it would appear that, for the time being, ICP long-term monitoring is justified only in comatose patients on intensive care. Authors of recent studies have championed the importance of maintaining cerebral perfusion pressure (CPP) to prevent secondary brain injury following traumatic head injury. Data from these studies have provided little information regarding outcome following severe head injury in patients with an intracranial pressure (ICP) greater than 40 mm Hg, however, in July 1997 the authors instituted a protocol for the management of severe head injury in patients with a Glasgow Coma Scale score lower than 9. The protocol was focused on resuscitation from acidosis, maintenance of a CPP greater than 60 mm Hg through whatever means necessary as well as elevation of the head of the bed, mannitol infusion, and ventriculostomy with cerebrospinal fluid drainage for control of ICP. Since the institution of this protocol, nine patients had a sustained ICP greater than 40 mm Hg for 2 or more hours, and five of these had an ICP greater than 75 mm Hg on insertion of the ICP monitor and later experienced herniation and expired within 24 hours. Because of the severe nature of the injuries demonstrated on computerized tomography scans and their physical examinations, these patients were not aggressively treated under this protocol. The authors vigorously attempted to maintain a CPP greater than 60 mm Hg with intensive fluid resuscitation and the administration of pressor agents in the four remaining patients who had developed an ICP higher than 40 mm Hg after placement of the ICP monitor. Two patients had an episodic ICP greater than 40 mm Hg for more than 36 hours, the third patient had an episodic ICP greater than of 50 mm Hg for more than 36 hours, and the fourth patient had an episodic ICP greater than 50 mm Hg for more than 48 hours. On discharge, all four patients were able to perform normal activities of daily living with minimal assistance and experience ongoing improvement. Data from this preliminary study indicate that intense, aggressive management of CPP can lead to good neurological outcomes despite extremely high ICP. Aggressive CPP therapy should be performed and maintained even though apparently lethal ICP levels may be present. Further study is needed to support these encouraging results. Other effects In addition to reducing ICP, studies have found decompressive craniectomy to improve cerebral perfusion pressure and cerebral blood flow in head injured patients. Decompressive craniectomy is also used to manage major strokes, associated with \"malignant\" edema and intracranial hypertension. The pooled evidence from three randomised controlled trials in Europe supports the retrospective observations that early (within 48 hours) application of decompressive craniectomy after \"malignant\" stroke may result in improved survival and functional outcome in patients under the age of 55, compared to conservative management alone. The procedure is recommended especially for young patients in whom ICP is not controllable by other methods. Age of greater than 50 years is associated with a poorer outcome after the surgery. Complications Infections such as meningitis or brain abscess can occur after decompressive craniectomy. Vasogenic Extracellular brain edema, or vasogenic edema, is caused by an increase in the permeability of the blood-brain barrier. The blood-brain barrier consists of astrocytes and pericytes joined together with adhesion proteins producing tight junctions. Return of blood flow to theses cells after an ischemic stroke can cause excitotoxicity and oxidative stress leading to dysfunction of the endothelial cells and disruption of the blood-brain barrier. The breakdown of the tight endothelial junctions that make up the blood–brain barrier causes extravasation of fluid, ions, and plasma proteins, such as albumin, into the brain parenchyma. Accumulation of extracellular fluid increases brain volume and then intracranial pressure causing the symptoms of cerebral edema. There are several clinical conditions in which vasogenic edema is present: Sixty-seven patients with severe head injury underwent intracranial pressure (ICP) monitoring (10 extradural and 57 intraventricular). All patients had Liege coma scale (LCS) score of 12 or less. Ventriculitis (E. Coli) occurred in one patient (1,8%). The intraventricular method allows C.S.F. drainage with lowering of I.C.P. even with slit ventricles. After 8 days, if an intracranial hypertension persists, we perform a ventriculo-atrial drainage. Pressure recording is a useful way of following the patient's evolution and a guide for prognosis of survival. If I.C.P. is constantly below 5 torr, then the probability of a bad outcome is great. The study also confirms the high mortality rate (93%) if I.C.P. is greater than 40 torr. Cerebral death occurs during reanimation as an isolated destruction of the entire brain. It is the result of a malignant and irreversible increase of the intracranial pressure. Continuous registration of the intracranial and systemic blood pressures which is done as a routine monitoring procedure in the majority of deep coma patients, allows to identify the moment when cerebral perfusion has come to a complete standstill, and also allows to confirm its irreversibility. At the end of an ischaemic period of 8 to 10 minutes, absolutely lethal to brain tissue, cerebral death is completed. To be on the safe side, the expiration of a 15 to 20 minute period of complete circulatory arrest within the cranial cavity is recommended before further diagnostic measures, especially cerebral arteriography, are undertaken as final proof of dissociated brain death, permitting the explantation of vital organs for grafting. At present, due to possible technical difficulties, reliance upon epidural intracranial pressure measurement alone must still be discouraged. Nevertheless, this investigation method can be most useful in the early timing of the so-called terminal angiography in order not to delay the diagnosis of brain death and its medical consequences. One of the most damaging aspects of brain trauma and other conditions, directly correlated with poor outcome, is an elevated intracranial pressure. ICP is very likely to cause severe harm if it rises too high. Very high intracranial pressures are usually fatal if prolonged, but children can tolerate higher pressures for longer periods. An increase in pressure, most commonly due to head injury leading to intracranial hematoma or cerebral edema, can crush brain tissue, shift brain structures, contribute to hydrocephalus, cause brain herniation, and restrict blood supply to the brain. It is a cause of reflex bradycardia. Low ICP Basic life support monitoring: Electrocardiography, pulse oximetry, blood pressure, assessment of comatose patients. Neurological monitoring : Serial neurologic examination, assessment of comatose patients (Glasgow Coma Scale plus pupil or four score), ICP (subarachnoid hemorrhages, TBI, Hydrocephalus, Stroke, CNS infection, Hepatic failure), multimodality monitoring to monitor disease and prevent secondary injury in states that are insensitive to neurological exam or conditions confounded by sedation, neuromuscular blockade and coma. Intracranial pressure (ICP) management: Ventricular catheter to monitor Brain oxygen and concentrations of glucose and PH. With treatment options of Hypertonic serum, barbiturates, hypothermia and decompressive hemi-craniotomy Common neurointensive care illnesses and treatments Traumatic brain injury: Sedation, ICP monitoring and management, Decompressive Craniectomy, Hyperosmolar therapy and maintain hemodynamic stability.\nHere is the question:\nNEUROLOGY: A 49-year-old man is admitted to the ICU for traumatic brain injury after an accident at work. In the physical examination he does not open his eyes, does not emit sounds before being intubated and presents extension of extremities to nociceptive stimulus. An intracranial pressure sensor is placed and a decompressive craniotomy must be performed due to intraparenchymal hemorrhage. Which of the following statements is correct?\nHere are the potential choices:\n1. On arrival she is in a Glasgow scale coma of 7.\n2. Cerebral perfusion pressure is mean arterial pressure plus intracranial pressure.\n3. Vasogenic cerebral edema is due to cellular edema, membrane rupture and cell death.\n4. Cerebral vascular flow increases with hypercapnia and acidosis.\nThe correct answer is: ",
        "gold_answer": "4 Cerebral vascular flow increases with hypercapnia and acidosis.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The effects of decompressive craniectomy in the treatment of severe head injury remain unclear. Only very few randomized studies relating to this topic exist in the literature, including a very small number of patients with no class I evidence. We rretrospectively reviewed a series of 221 patients operated on for a head injury during a 25-month period. Of these, 48 patients underwent a decompressive craniectomy. All data available on patients' Glasgow Coma Scale score, pupil size and reaction, and intracranial pressure were collected and analyzed. The patients' outcome was evaluated by the Glasgow Outcome Scale (GOS) and the results compared with the data available in the Traumatic Coma Data Bank. Furthermore, the results were analyzed in respect of the time of surgical intervention (early or late), age, and the preoperative Glasgow Coma Score. Decompressive craniectomy reduced the midline shift in all patients with monolateral diffuse brain edema and contusions having a median value of 7 mm; in the remaining, it ameliorated the basal cisterns effacement. At a mean follow-up of 14 months, 6 (12.5%) patients died, 7 (15%) were discharged home with a GOS of 5, 18 (40%) showed a favorable outcome after rehabilitation with a GOS of 4 and 5, 6 (12.5%) had a severe disability (GOS 3), 9 (20%) were in a vegetative state (GOS 2), and 2 were lost to follow-up. The younger age, earlier surgery, and higher preoperative Glasgow Coma Scale score were related to better outcome (P &lt; .001, P &lt; .05, and P &lt; .034, respectively). Our results seem to support the idea that decompressive craniectomy coupled with neurointensive care may be an effective way to reduce intractable raised intracranial pressure, and probably to improve patients outcome. However, it should be obvious that our results and those available in the literature can not be considered conclusive. Additionally, ventilation with use of positive pressure (PEEP) can improve oxygenation with the negative effect of decreasing cerebral venous drainage and increasing intracranial pressure (ICP), and thus, must be used with caution. Fluid management and cerebral perfusion Maintenance of cerebral perfusion pressure using appropriate fluid management is essential in patients with brain injury. Dehydration, or intravascular volume loss, and the use of hypotonic fluids, such as D5W or half normal saline, should be avoided. Blood serum ion concentration, or osmolality, should be maintained in the normo to hyperosmolar range. Judicial use of hypertonic saline can be used to increase serum osmolality and decrease cerebral edema, as discussed below. Intracranial pressure monitoring Intracranial pressure (ICP) and its management is a fundamental concept in traumatic brain injury (TBI). The Brain Trauma Foundation guidelines recommend ICP monitoring in individuals with TBI that have decreased Glasgow-Coma Scale (GCS) scores, abnormal CT scans, or additional risk factors such as older age and elevated blood pressure. However, no such guidelines exist for ICP monitoring in other brain injuries such as ischemic stroke, intracerebral hemorrhage, cerebral neoplasm. The treatment of cerebral edema depends on the cause and includes monitoring of the person's airway and intracranial pressure, proper positioning, controlled hyperventilation, medications, fluid management, steroids. Extensive cerebral edema can also be treated surgically with a decompressive craniectomy. Cerebral edema is a major cause of brain damage and contributes significantly to the mortality of ischemic strokes and traumatic brain injuries. As cerebral edema is present with many common cerebral pathologies, the epidemiology of the disease is not easily defined. The incidence of this disorder should be considered in terms of its potential causes and is present in most cases of traumatic brain injury, central nervous system tumors, brain ischemia, and intracerebral hemorrhage. For example, malignant brain edema was present in roughly 31% of people with ischemic strokes within 30 days after onset. The heart and lungs are vital organs for human life due to their ability to properly oxygenate human blood (lungs) and distribute this blood to all vital organs (heart). Hence failure of the heart to pump blood or the lungs to obtain oxygen can lead to a cardiopulmonary death where the heart stops pumping and there is no pulse. In the brain, this can be manifested by a hypoxic state which leads to cerebral edema and thus an increase in intracranial pressure. The rise in intracranial pressure can lead to further disruption in cerebral blood flow, leading to necrosis or tissue death. The aforementioned mechanism is the most common cause of brain death, however this increase in intracranial pressure does not always occur due to an arrest in cardiopulmonary function. Traumatic brain injuries and subarachnoid hemorrhages can also increase the intracranial pressure in the brain leading to a cessation of brain function and hence death. While cardiopulmonary death can be easily assessed by An increase in cerebral water content is called cerebral edema and it usually results from traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), subdural hematoma, ischemic stroke, brain tumors, infectious disorders and intracranial surgery. Cerebral edema may result in compromised regional cerebral blood flow (CBF) and intracranial pressure (ICP) gradients which could lead to death of the affected. Increased ICP leads to increased intracranial volume. Unmonitored ICP leads to brain damage by global hypoxic ischemic injury due to reduction in cerebral perfusion pressure (CPP) which is found by subtracting the ICP from mean arterial pressure (MAP), cerebral blood flow, and mechanical compression of brain tissue due to compartmentalized ICP gradients. Cerebral edema is mainly classified into cytotoxic edema, vasogenic edema and interstitial edema. It is important to note that prolonged hyperventilation in those with traumatic brain injuries has been shown to worsen outcomes. Barbiturates Induction of a coma via the use of barbiturates, most notably pentobarbital and thiopental, after brain injury is used for secondary treatment of refractory ICP. Yet their use is not without controversy and it is not clear whether barbiturates are favored over surgical decompression. In patients with traumatic brain injuries, barbiturates are effective in reducing ICP but have failed to show benefit to clinical outcomes. Evidence is limited for their use in cerebral disease that include tumor, intracranial hypertension, and ischemic stroke. There are several adverse effects of barbiturates that limit their use, such as lowering of systemic blood pressure and cerebral perfusion pressure, cardiodepression, immunosuppression, and systemic hypothermia. The aim of the study was to assess (i) a group of patients with established intracranial pressure (ICP) sensor in severe brain injuries scoring 3 points of Glasgow Coma Scale, (ii) mortality and survival of the patients within periods of 7, 30, 180 and 270 days; and (iii) predictive value of intracranial pressure and cerebral perfusion pressure for short and long-term survival of patients with traumatic brain injury. The group consisted of 61 patients with trauma brain injury scoring 3 points of Glasgow Coma Scale, continuously monitored for intracranial pressure cerebral perfusion pressure at the Intensive Care Unit setting in Nové Zámky. Follow-up period was between 7 and 270 days. Measured values and other recorded data were analysed using methods of descriptive and inferential statistics. ICP values below 20 mmHg were associated with a significantly lower risk of death of an individual patient at particular time. Accordingly, cerebral perfusion pressure values above 70 mmHg during 0-2 days were associated with a significantly higher long-term survival. Overall mortality rates within 30 days showed no peaks on survival curves. In the periods of 0-7 days, within 30 days, and between 30 and 180 days we recorded 24, 51 and 2 deaths, respectively. In the period between 180 and 270 days, mortality was zero. The survival of trauma brain injury patients depends on the speed and quality of pre-hospital care and adequate follow-up treatment at specialized intensive care units. High levels of intracranial pressure and low cerebral perfusion pressure values in the early period after brain injury are closely related to mortality of patients within 30 days. Intracranial pressure monitoring may help to avoid problems and allow intervention before they become life-threatening (Tab. 4, Fig. 4, Ref. 23). Text in PDF www.elis.sk. PRx and outcome prediction A high PRx indicating disturbed pressure autoregulation predicts poor outcome in traumatic brain injury. PRx as a treatment target PRx varies with the concurrent cerebral perfusion pressure (CPP) in a U-shaped way. It has been suggested that the CPP with the lowest PRx is optimal (CPPopt) and CPP-values close to optimal have been associated with better outcome. CPP values above CPPopt are believed to cause hyperemia, i.e. to high cerebral blood flow that may cause cerebral edema and intracranial hypertension, whereas CPP values below CPPopt are believed to cause hypoperfusion and ischemia resulting in tissue damage. See also Cerebral autoregulation Intracranial pressure Cushing's triad References Intensive care medicine Neurotrauma Neurophysiology Brain death occurs as a result of an acute catastrophic brain injury. Abrupt loss of cerebral perfusion occurs if a concomitant elevation of intracranial pressure is more than mean arterial pressure (cerebral perfusion pressure (CPP) = mean arterial pressure (MAP) - intracranial pressure (ICP). This process was studied by monitoring brain tissue oxygenation in patients with brain death and can occur via two different mechanisms: Clinical researches have recommended ICP and cerebral perfusion pressure (CPP) monitoring in any persons with cerebral injury who are at risk of elevated intracranial pressure based on clinical and neuroimaging features. Early monitoring can be used to guide medical and surgical decision making and to detect potentially life-threatening brain herniation. There was however, conflicting evidence on the threshold values of ICP that indicated the need for intervention. Researches also recommend that medical decisions should be tailored to the specific diagnosis (e.g. subarachnoid hemorrhage, TBI, encephalitis) and that ICP elevation should be used in conjunction with clinical and neuroimaging and not as an isolated prognostic marker. After severe head injury intracranial pressure (ICP) must be measured continuously for management to assess and maintain the cerebral perfusion. Therefore in our hospital epidural transducers are used. To prove the efficiency of this method in a 12-month period the clinical courses of 23 patients with intracranial pressure transducers were analysed retrospectively. Eighteen patients survived, 5 of them without residuals, 13 with residuals and 2 remained in coma. In 14 patients secondary rises of intracranial pressure were observed between days 3 and 6 post injury. The mean ICP value of the survivors revealed 25 mm Hg. whereas the expired showed 60 mm Hg. In 17 patients the measurements were considered as reliable, 6 measurements were not reliable, which included 1 of the 5 patients who died. One transduce was displaced, another one showed a hemorrhage at the drill hole. There was no infection. Secondary injury events include damage to the blood–brain barrier, release of factors that cause inflammation, free radical overload, excessive release of the neurotransmitter glutamate (excitotoxicity), influx of calcium and sodium ions into neurons, and dysfunction of mitochondria. Injured axons in the brain's white matter may separate from their cell bodies as a result of secondary injury, potentially killing those neurons. Other factors in secondary injury are changes in the blood flow to the brain; ischemia (insufficient blood flow); cerebral hypoxia (insufficient oxygen in the brain); cerebral edema (swelling of the brain); and raised intracranial pressure (the pressure within the skull). Intracranial pressure may rise due to swelling or a mass effect from a lesion, such as a hemorrhage. As a result, cerebral perfusion pressure (the pressure of blood flow in the brain) is reduced; ischemia results. When the pressure within the skull rises too high, it can cause brain death or To determine the influence of positive end-expiratory pressure (PEEP) on intracranial pressure and cerebral perfusion pressure. Neurosurgical intensive care patients requiring intracranial pressure monitoring and mechanical ventilation were studied in a randomized, controlled study. Tertiary care, neurosurgical intensive care unit. Eighteen patients were enrolled in the study. Patients had posttraumatic head injuries (n = 9), subarachnoid hemorrhage (n = 7), obstructive hydrocephalus (n = 1), and intracerebral hemorrhage of unknown cause (n = 1). Patients had PEEP levels of 5, 10, and 15 cm H2O applied to their lungs. Changes in intracranial pressure, mean arterial pressure, and cerebral perfusion pressure were measured. The results were analyzed separately for patients with normal and increased intracranial pressure (&gt; 15 mm Hg). PEEP at 5 cm H2O had no effect on intracranial pressure in the group with normal intracranial pressure. However, PEEP at 10 and 15 cm H2O produced a significant (p &lt; .05) increase in intracranial pressure (1.9 and 1.5 mm Hg, respectively). In the group with increased intracranial pressure, no significant change in intracranial pressure occurred at any of the PEEP levels used. In both groups, cerebral perfusion pressure was unchanged throughout. In patients with normal intracranial pressure, PEEP at 5 cm H2O did not significantly alter intracranial pressure. The clinical relevance of the intracranial pressure increase at PEEP levels of 10 and 15 cm H2O is questionable because cerebral perfusion pressure did not change and remained &gt; 60 mm Hg. In patients with increased intracranial pressure, higher levels of PEEP did not significantly change intracranial pressure or cerebral perfusion pressure. Most patients with more severe traumatic brain injury have of a combination of intracranial injuries, which can include diffuse axonal injury, cerebral contusions, and intracranial bleeding, including subarachnoid hemorrhage, subdural hematoma, epidural hematoma, and intraparenchymal hemorrhage. The recovery of brain function following a traumatic accident is highly variable and depends upon the specific intracranial injuries that occur, however there is significant correlation between the severity of the initial insult as well as the level of neurologic function during the initial assessment and the level of lasting neurologic deficits. Initial treatment may be targeted at reducing the intracranial pressure if there is concern for swelling or bleeding within this skull, which may require surgery such as a hemicraniectomy, in which part of the skull is removed. Blunt trauma to extremities There are several clinical conditions in which vasogenic edema is present: CNS tumors, like glioblastoma and meningioma Infections like meningitis, abscess, and encephalitis Inflammatory central nervous system disease such as multiple sclerosis Brain hemorrhage Traumatic brain injuries can lead to increased intracranial pressure, local damage, reduced cerebral blood flow, and focal ischemia secondary to vasogenic edema. Late stage of ischemic stroke after rapid recovery from cytotoxic edema Hypertensive encephalopathy Radiation injury Ionic (Osmotic) In ionic edema, the solute concentration (osmolality) of the brain exceeds that of the plasma and the abnormal pressure gradient leads to accumulation of water intake into the brain parenchyma through the process of osmosis. The blood-brain barrier is intact and maintains the osmotic gradient. The solute concentration of the blood plasma can be diluted by several mechanisms: Head injury is the main cause of death or disability among under-45-year-olds. This review covers the main pathophysiological aspects of head injury as well as initial treatment and management in the intensive care recovery ward. The chief therapeutic aim is to maintain adequate cerebral perfusion pressure rather than to maintain normal levels of intracranial pressure. An important challenge is to avoid development of secondary lesions, and in this context arterial hypotensive events that affect prognosis and the survival of such patients merit special attention. We reject treatment based on indiscriminate use of hyperventilation and mannitol and underline the importance of providing adequate sedation and analgesia while maintaining normal flow and pressure and adequate monitoring of such patients. Pathophysiology Cerebral perfusion pressure (CPP), the pressure of blood flowing to the brain, is normally fairly constant due to autoregulation, but for abnormal mean arterial pressure (MAP) or abnormal ICP the cerebral perfusion pressure is calculated by subtracting the intracranial pressure from the mean arterial pressure: CPP = MAP − ICP . One of the main dangers of increased ICP is that it can cause ischemia by decreasing CPP. Once the ICP approaches the level of the mean systemic pressure, cerebral perfusion falls. The body's response to a fall in CPP is to raise systemic blood pressure and dilate cerebral blood vessels. This results in increased cerebral blood volume, which increases ICP, lowering CPP further and causing a vicious cycle. This results in widespread reduction in cerebral flow and perfusion, eventually leading to ischemia and brain infarction. Increased blood pressure can also make intracranial hemorrhages bleed faster, also increasing ICP. Monitoring and management of intracranial pressure (ICP) are fundamental to modern neurotraumatology. Although never formally proven to independently improve outcome in prospective, randomized, placebo-controlled trials, there is such a predominance of indirect support for this modality that most neurotrauma protocols are impossible with-out its inclusion and ethical considerations virtually preclude placebo-controlled trials of its efficacy. In addition to the question of improving outcome, ICP monitoring is also useful in guiding the use of potentially harmful treatment modalities such as hyperventilation, mannitol, and barbiturates, and also provides important prognostic data. ICP monitoring provides information on the likelihood of cerebral herniation and allows calculation of the cerebral perfusion pressure (CPP). Although there is no constant threshold for herniation, the most commonly used treatment threshold is 20 to 25 mm Hg. In addition, ICP trends are indispensable in providing the earliest possible indication of critical intracranial mass effects when combined with other clinical indicators. CPP is the difference between mean arterial pressure and ICP. CPP is an important clinical indicator of cerebral blood flow (CBF). Cerebral autoregulation generally remains at least partially preserved after severe head injury, although the CPP value at which it is activated appears to be shifted upward. Therefore, maintaining adequate CBF appears to require using an elevated minimal CPP threshold when treating the injured brain. A generally accepted value of 70 mm Hg is suggested. Increased intracranial pressure (ICP) is a life-threatening surgical emergency marked by symptoms of headache, nausea, vomiting, decreased consciousness. Symptoms are frequently accompanied by visual disturbances such as gaze paresis, reduced vision, and dizziness. Increased pressures within the skull can cause a compensatory elevation of blood pressure to maintain cerebral blood flow, which, when associated with irregular breathing and a decreased heart rate, is called the Cushing reflex. The Cushing reflex often indicates compression of the brain on brain tissue and blood vessels, leading to decreased blood flow to the brain and eventually death. Causes Cerebral edema is frequently encountered in acute brain injuries from a variety of origins, including but not limited to: To explore the clinical application of intracranial pressure (ICP) monitoring and its prognostic correlation in patients with severe craniocerebral injury. A total of 216 severe craniocerebral injury patients with scores of Glasgow coma scale 3-8 underwent craniotomy at Affiliated Qilu Hospital, Shandong University.And 168 cases of ICP monitoring were divided into 3 treatment groups and another 48 cases without ICP monitoring selected as the control group.According to ICP, stepwise treatment was administered to control the level of ICP and maintain the cerebral perfusion pressure to analyze the relationship between ICP monitoring and prognosis. As compared with the control group, there were significant decreases of disability and mortality rate for patients with ICP monitoring (A, B, C group). Especially group C had a better prognosis than the other groups for statistical significance.In addition, the dose and duration of mannitol of group A, B or C were significantly lower than those of the control group (P &lt; 0.05). The application of ICP monitoring is capable of reducing mortality, improving prognosis and enhancing success rate of treating severe craniocerebral injury. Depending upon the location and severity of the occlusion, signs and symptoms may vary within the population affected with MCA syndrome. More distal blockages tend to produce milder deficits due to more extensive branching of the artery and less ischemic response. In contrast, the most proximal occlusions result in widespread effects that can lead to significant cerebral edema, increased intracranial pressure, loss of consciousness and could even be fatal. In such occasions, mannitol (osmotic diuretic) or hypertonic saline are given to draw fluid out of the edematous cerebrum to minimise secondary injury. Hypertonic saline is better than mannitol, as mannitol being a diuretic will decrease the mean arterial pressure and since cerebral perfusion is mean arterial pressure minus intracranial pressure, mannitol will also cause a decrease in cerebral perfusion. The treatment of head-injured patients has over the past 15 years become significantly more complex and involved. The rising interest in the treatment of these patients has been driven in large part by the growing body of evidence showing that there is a definite association between elevated ICP and increased mortality and long-term morbidity. The effective treatment of intracranial hypertension with hyperventilation, osmotic agents, and barbiturate therapy has been aided by the regular use of ICP monitoring in most neurosurgical centers. A continuing and ongoing record of ICP allows for the judicial and appropriate use of modern treatment modalities. On the basis of a series of 75 patients, the practical use of Icp continuous long-term recording in severe head injuries without mass lesions or remaining deeply comatose after surgical procedures is critically analyzed. ICP monitoring alone seems to be not essential for prognosis. Conversely it is of much greater use as a guide to management (respirator treatment, osmotics, CSF drainage). If the pros and cons of the procedure are carefully weighed, it would appear that, for the time being, ICP long-term monitoring is justified only in comatose patients on intensive care. Authors of recent studies have championed the importance of maintaining cerebral perfusion pressure (CPP) to prevent secondary brain injury following traumatic head injury. Data from these studies have provided little information regarding outcome following severe head injury in patients with an intracranial pressure (ICP) greater than 40 mm Hg, however, in July 1997 the authors instituted a protocol for the management of severe head injury in patients with a Glasgow Coma Scale score lower than 9. The protocol was focused on resuscitation from acidosis, maintenance of a CPP greater than 60 mm Hg through whatever means necessary as well as elevation of the head of the bed, mannitol infusion, and ventriculostomy with cerebrospinal fluid drainage for control of ICP. Since the institution of this protocol, nine patients had a sustained ICP greater than 40 mm Hg for 2 or more hours, and five of these had an ICP greater than 75 mm Hg on insertion of the ICP monitor and later experienced herniation and expired within 24 hours. Because of the severe nature of the injuries demonstrated on computerized tomography scans and their physical examinations, these patients were not aggressively treated under this protocol. The authors vigorously attempted to maintain a CPP greater than 60 mm Hg with intensive fluid resuscitation and the administration of pressor agents in the four remaining patients who had developed an ICP higher than 40 mm Hg after placement of the ICP monitor. Two patients had an episodic ICP greater than 40 mm Hg for more than 36 hours, the third patient had an episodic ICP greater than of 50 mm Hg for more than 36 hours, and the fourth patient had an episodic ICP greater than 50 mm Hg for more than 48 hours. On discharge, all four patients were able to perform normal activities of daily living with minimal assistance and experience ongoing improvement. Data from this preliminary study indicate that intense, aggressive management of CPP can lead to good neurological outcomes despite extremely high ICP. Aggressive CPP therapy should be performed and maintained even though apparently lethal ICP levels may be present. Further study is needed to support these encouraging results. Other effects In addition to reducing ICP, studies have found decompressive craniectomy to improve cerebral perfusion pressure and cerebral blood flow in head injured patients. Decompressive craniectomy is also used to manage major strokes, associated with \"malignant\" edema and intracranial hypertension. The pooled evidence from three randomised controlled trials in Europe supports the retrospective observations that early (within 48 hours) application of decompressive craniectomy after \"malignant\" stroke may result in improved survival and functional outcome in patients under the age of 55, compared to conservative management alone. The procedure is recommended especially for young patients in whom ICP is not controllable by other methods. Age of greater than 50 years is associated with a poorer outcome after the surgery. Complications Infections such as meningitis or brain abscess can occur after decompressive craniectomy. Vasogenic Extracellular brain edema, or vasogenic edema, is caused by an increase in the permeability of the blood-brain barrier. The blood-brain barrier consists of astrocytes and pericytes joined together with adhesion proteins producing tight junctions. Return of blood flow to theses cells after an ischemic stroke can cause excitotoxicity and oxidative stress leading to dysfunction of the endothelial cells and disruption of the blood-brain barrier. The breakdown of the tight endothelial junctions that make up the blood–brain barrier causes extravasation of fluid, ions, and plasma proteins, such as albumin, into the brain parenchyma. Accumulation of extracellular fluid increases brain volume and then intracranial pressure causing the symptoms of cerebral edema. There are several clinical conditions in which vasogenic edema is present: Sixty-seven patients with severe head injury underwent intracranial pressure (ICP) monitoring (10 extradural and 57 intraventricular). All patients had Liege coma scale (LCS) score of 12 or less. Ventriculitis (E. Coli) occurred in one patient (1,8%). The intraventricular method allows C.S.F. drainage with lowering of I.C.P. even with slit ventricles. After 8 days, if an intracranial hypertension persists, we perform a ventriculo-atrial drainage. Pressure recording is a useful way of following the patient's evolution and a guide for prognosis of survival. If I.C.P. is constantly below 5 torr, then the probability of a bad outcome is great. The study also confirms the high mortality rate (93%) if I.C.P. is greater than 40 torr. Cerebral death occurs during reanimation as an isolated destruction of the entire brain. It is the result of a malignant and irreversible increase of the intracranial pressure. Continuous registration of the intracranial and systemic blood pressures which is done as a routine monitoring procedure in the majority of deep coma patients, allows to identify the moment when cerebral perfusion has come to a complete standstill, and also allows to confirm its irreversibility. At the end of an ischaemic period of 8 to 10 minutes, absolutely lethal to brain tissue, cerebral death is completed. To be on the safe side, the expiration of a 15 to 20 minute period of complete circulatory arrest within the cranial cavity is recommended before further diagnostic measures, especially cerebral arteriography, are undertaken as final proof of dissociated brain death, permitting the explantation of vital organs for grafting. At present, due to possible technical difficulties, reliance upon epidural intracranial pressure measurement alone must still be discouraged. Nevertheless, this investigation method can be most useful in the early timing of the so-called terminal angiography in order not to delay the diagnosis of brain death and its medical consequences. One of the most damaging aspects of brain trauma and other conditions, directly correlated with poor outcome, is an elevated intracranial pressure. ICP is very likely to cause severe harm if it rises too high. Very high intracranial pressures are usually fatal if prolonged, but children can tolerate higher pressures for longer periods. An increase in pressure, most commonly due to head injury leading to intracranial hematoma or cerebral edema, can crush brain tissue, shift brain structures, contribute to hydrocephalus, cause brain herniation, and restrict blood supply to the brain. It is a cause of reflex bradycardia. Low ICP Basic life support monitoring: Electrocardiography, pulse oximetry, blood pressure, assessment of comatose patients. Neurological monitoring : Serial neurologic examination, assessment of comatose patients (Glasgow Coma Scale plus pupil or four score), ICP (subarachnoid hemorrhages, TBI, Hydrocephalus, Stroke, CNS infection, Hepatic failure), multimodality monitoring to monitor disease and prevent secondary injury in states that are insensitive to neurological exam or conditions confounded by sedation, neuromuscular blockade and coma. Intracranial pressure (ICP) management: Ventricular catheter to monitor Brain oxygen and concentrations of glucose and PH. With treatment options of Hypertonic serum, barbiturates, hypothermia and decompressive hemi-craniotomy Common neurointensive care illnesses and treatments Traumatic brain injury: Sedation, ICP monitoring and management, Decompressive Craniectomy, Hyperosmolar therapy and maintain hemodynamic stability.\nHere is the question:\nNEUROLOGY: A 49-year-old man is admitted to the ICU for traumatic brain injury after an accident at work. In the physical examination he does not open his eyes, does not emit sounds before being intubated and presents extension of extremities to nociceptive stimulus. An intracranial pressure sensor is placed and a decompressive craniotomy must be performed due to intraparenchymal hemorrhage. Which of the following statements is correct?\nHere are the potential choices:\n1. On arrival she is in a Glasgow scale coma of 7.\n2. Cerebral perfusion pressure is mean arterial pressure plus intracranial pressure.\n3. Vasogenic cerebral edema is due to cellular edema, membrane rupture and cell death.\n4. Cerebral vascular flow increases with hypercapnia and acidosis.\nThe correct answer is: 2. Cerebral perfusion pressure is mean arterial pressure plus intracranial pressure."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The incidence of surgical treatment of peptic ulcer decreased in the last two decades. The majority of procedures for surgical management of peptic disease impairs the ability of the stomach to receive and to store food. The intake of high protein-caloric content diets can improve some nutritional deficits expressed by loss of body weight and anemia. The mechanism responsible for diarrhea is unknown, but truncal vagotomy has the highest incidence. It is usually episodic, lessens over the first year after operation and rarely remains a severe problem. The decreasing levels of colecistokinin response after meal in gastrectomy and the division of hepatic branch of anterior vagus can cause gallbladder sludge and stone formation. Alkaline reflux explains gastritis and esophagitis after partial gastric resection. Surgical duodenal diversion, like a Roux-en-Y limb, have been successful in its control. The mechanism that leads to the dumping syndrome are loss of gastric reservoir function and rapid emptying of hyperosmolar meals into small intestine. Somatostatin analogues improve the symptoms caused by abnormal release of neurohormonal agents responsible of the behaviour of the gastrointestinal tract after meals. Cancer of gastric remanent may be due to increased bacterial overgrowth and nitrosation formation. The endoscopic follow-up is essential for early diagnosis of the stump cancer. In spite of all complications, the surgeon cannot have hesitations by carrying out radical approach meanly during catastrophic emergencies of peptic disease i.e. in elderly aged patients. Nowadays, the control of chronic sequelas is easy with conservative therapeutic. The Zollinger-Ellison syndrome is characterized pathophysiologically by a significant hypergastrinemia derived from a gastrin-secreting neuroendocrine tumor with a primary location in the pancreas or duodenum. Chronic hypergastrinemia in turn triggers gastric acid hypersecretion yielding in chronic or recurrent or refractory peptic ulcer disease and/or chronic diarrhea. One half of patients with ZES will have distant metastases in the liver by the time the diagnosis is established and one half of all patients with ZES will experience chronic diarrhea as chief complaint rather than peptic ulcer-related symptoms and signs. Gastrinomas have been reported to either manifest sporadically or to occur in conjunction with the genetic background of the MEN-I syndrome. Diagnosis is based on the patients history which is typically characterized by recurrent episodes of peptic ulcer disease or by severe reflux esophagitis and/or diarrhea or by acid-related symptoms which fail to respond to standard treatment regimens. Upper gastrointestinal tract endoscopy will provide evidence for peptic ulcer disease in anatomical regions located aborally the duodenal bulb within the descending part of the duodenum or even farther distally within the jejunum. Peptic ulcers frequently occur in groups indicating some substantial acid hypersecretion. A gastric pH &gt; 2 is mutually exclusive for ZES. Increased serum gastrin levels confirm the diagnosis biochemically. Gastrin secretion can be determined in the basal state or following stimulation with secretin or calcium. High sensitivity and specificity for the diagnosis of ZES is provided by determining the ratio of basal versus pentagastrin-stimulated gastric acid secretion: The ratio of BAO / MAO &gt; 0.6 is highly specific for gastrinoma. To localize the gastrin-secreting tumor computer-assisted tomography, endoscopic ultrasound, and somatostatin receptor scintigraphy provide useful help but most recently, endoscopic ultrasound with high resolution transducers appear to improve preoperative site localization. If modern imaging techniques fail to elucidate the site of the tumor, intraoperative diaphany may help to detect gastrinomas within the duodenal wall. Definitive treatment will only be achieved by total surgical resection of the gastrin-producing tumor in the pancreas or duodenum including dissection of the regional lymph nodes. Control of symptoms will have to be achieved by administration of highly potent proton pump inhibitors in up to 2-3-fold increased standard doses to inhibit gastric acid hypersecretion. Elevation of gastric pH &gt; 4 will be the therapeutic target to protect the mucosa of the upper gastrointestinal tract. Basal acid output should be reduced to less than 10 mEq H(+) per hour which requires administration of highly potent proton pump inhibitors with a recommended starting dose of 60 mg omeprazole equivalents per day. Dumping syndrome, or rapid gastric emptying, is a frequent complication after gastric surgery. In this case, the patient was a 47-year-old woman who 10 years previously had undergone distal gastrectomy with Billroth I reconstruction for early-stage gastric cancer. She presented with symptoms of weakness, headache, palpitation, sweating, dizziness and significant fatigue between one and two hours after a meal. Because a 75 g oral glucose tolerance test (75 g-OGTT) induced both acute postprandial tachycardia (within 1 hour) and postprandial hypoglycemia, we diagnosed this patient with early and late dumping syndrome. Dietary measures and acarbose improved symptoms of late dumping syndrome but did not prevent the symptoms of early dumping syndrome such as postprandial tachycardia, weakness, headache, palpitation, and dizziness. We therefore used the somatostatin analogue octreotide, which has been reported as an effective therapy for early dumping syndrome. Octreotide prevented the symptoms of early dumping syndrome, especially postprandial tachycardia, but caused postprandial hyperglycemia. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were completely suppressed during the 75 g-OGTT following subcutaneous injection of octreotide. No change was observed in vasoactive intestinal polypeptide (VIP), which is the gastrointestinal peptide hormone generally responsible for early dumping syndrome, suggesting possible contribution of incretins in early dumping syndrome of this patient. Post-vagotomy diarrhea is a form of diarrhea which occurs in 10% of people after a truncal vagotomy, which can range from severe to debilitating in approximately 2% to 4% of patients. However, the occurrence of post-vagotomy diarrhea is significantly reduced after proximal selective vagotomy, specifically when celiac and hepatic branches of the vagus are retained. Diagnosis Treatment Surgical treatment for refractory post-vagotomy diarrhea is rarely needed and at least one year from the occurrence of symptoms should be allotted to ensure all non-surgical treatments have been appropriately explored. Under severe cases, where surgical intervention does become necessary, a 10 cm reverse jejunal interposition is usually the procedure of choice. References Neurosurgery Diarrhea Treatment Treatment of gastric outlet obstruction depends on the cause, but is usually either surgical or medical. Medication In most people with peptic ulcer disease, the oedema will usually settle with conservative management with nasogastric suction, replacement of fluids and electrolytes and proton pump inhibitors. Surgery Surgery is indicated in cases of gastric outlet obstruction in which there is significant obstruction and in cases where medical therapy has failed. Endoscopic balloon therapy may be attempted as an alternative to surgery, with balloon dilation reporting success rates of 76% after repeat dilatons. The operation usually performed is an antrectomy, the removal of the antral portion of the stomach. Other surgical approaches include: vagotomy, the severing of the vagus nerve, the Billroth I, a procedure which involves anastomosing the duodenum to the distal stomach, or a bilateral truncal vagotomy with gastrojejunostomy. References External links Fourteen patients with severe and persistent postvagotomy/postgastrectomy symptoms were entered into a trial of treatment with the somatostatin analogue octreotide, 50 micrograms twice daily 30 min before meals being self-administered by subcutaneous injection. Six of the seven patients completing the 3-month trial showed sustained overall improvement of symptoms. The remaining patients were unhelped by treatment or developed unwanted effects. Six of eight patients with dumping syndrome showed sustained improvement of dumping symptoms during treatment. Bile vomiting was relieved in three of four patients with this complaint. Diarrhoea accompanying dumping showed a variable response to treatment, with improvement in three patients and no change or worsening of this symptom in five. Two patients with severe postvagotomy diarrhoea alone showed no improvement. Four patients with unwanted effects and three patients who found no benefit stopped the trial medication early. Four further patients reported mild or transient side-effects. For patients with severe postvagotomy/postgastrectomy symptoms, a trial of octreotide seems justified when significant dumping symptoms are present and other treatment options have been exhausted. All types of vagotomy can be performed at open surgery (laparotomy) or using minimally invasive surgery (laparoscopy). For the management of PUD, vagotomy is sometimes combined with antrectomy (removal of the distal half of the stomach) to reduce the rate of recurrence. Reconstruction is performed with gastroduodenostomy (Billroth I) or gastrojejunostomy (Billroth II). It is left intact in highly selective vagotomy so the function of gastric emptying remains intact. Applications Truncal vagotomy is a treatment option for chronic duodenal ulcers. It was once considered the gold standard, but is now usually reserved for patients who have failed the first-line \"triple therapy\" against Helicobacter pylori infection: two antibiotics (clarithromycin and amoxicillin or metronidazole) and a proton pump inhibitor (e.g., omeprazole). It is also used in the treatment of gastric outlet obstruction. We saw a 54-year-old patient who had been treated for gastrointestinal ulcerations with bleeding complications now presenting with nausea, vomiting and diarrhoea. The patient has been suffering from recurrent diarrhea for years. The suspicion of a neuroendocrine tumor had been made but could not be confirmed intraoperatively in the past. As suspicion was still high with high levels of chromogranin A and high gastrin levels the diagnosis now could be confirmed with a somatostatin scintigraphy. Finally the confirmed spot was identified to be a metastasis of a gastrinoma of still unknown primary localisation. The Roux-en-Y gastrojejunostomy has become an increasingly used method for gastrointestinal tract reconstruction, and is advocated in the treatment of alkaline reflux gastritis. Since 1979 we have used selective vagotomy, antrectomy and Roux-en-Y reconstruction as the primary method in treating gastric ulcer and complicated duodenal ulcer in 25 patients. In a follow-up study we have evaluated the postoperative course and the long term results. All patients were operated on between 1979 and 1984. Nine patients had a gastric ulcer (GU), 11 a prepyloric ulcer (PPU) and 5 patients had a complicated duodenal ulcer (DU). The clinical results showed a grade Visick I in 48%, Visick II in 44%, Visick III in 4% and a grade Visick IV in 4%. There were no postoperative deaths, but other early complications occurred in 9 patients (36%). At follow-up, endoscopy showed signs of delayed emptying in 5 patients, but only 1 had corresponding symptoms. Mild to moderate symptoms of dumping were found in 1 patient. There was no case of severe diarrhea. The overall results were satisfactory, indicating that selective vagotomy and antrectomy with Roux-en-Y reconstruction is a valuable alternative as a primary method in the surgical treatment of severe peptic ulcer disease. No cause had been found for chronic diarrhoea in a 57-year-old man. Up to 15 watery stools daily had been without relation to food intake and without blood admixture. But muscular cramps had developed, especially in the legs. The patient had a history of recurrent peptic ulcers for which a selective proximal vagotomy had been performed 13 years ago. Physical examination was unremarkable. Alkaline phosphatase activity (182 U/l) and C-reactive protein (9.3 mg/l) were slightly raised; serum iron was 42 micrograms/dl, while all other routine laboratory tests, including protein electrophoresis, blood picture and differential count were within normal limits. Gastroscopy revealed ulcerative duodenitis, gastritis with erosions and numerous ulcers and reflux oesophagitis, grade III-IV. Endosonography showed enlarged gastric mucosal relief as sign of foveolar hyperplasia and a ca. 4 x 3 cm tumour next to the duodenal bulb. Gastrin level was 7537 pg/ml (normal &lt; 150 pg/ml). Computed tomography and somatostatin receptor scintigraphy confirmed the site and size of the gastrinoma. Treatment with omeprazole (40 mg three times daily) slightly improved the symptoms. The tumour was excised a week after diagnosis. The patient has been symptom-free since then. Chronic diarrhoea of unknown aetiology can be caused by an endocrine tumour; endosonography can often provide information on the diagnosis and location of such a tumour. Cause Carcinoid syndrome involves multiple tumors in one out of five males. The incidence of gastric carcinoids is increased in achlorhydria, Hashimoto's thyroiditis, and pernicious anemia. Treatment Surgery, if feasible, is the only curative therapy. If the tumor has metastasized (most commonly, to the liver) and is considered incurable, there are some promising treatment modalities, such as radiolabeled octreotide (e.g. Lutetium (177Lu) DOTA-octreotate) or the radiopharmaceutical 131I-mIBG (meta iodo benzyl guanidine) for arresting the growth of the tumors and prolonging survival in patients with liver metastases, though these are currently experimental. Chemotherapy is of little benefit and is generally not indicated. Octreotide or lanreotide (somatostatin analogues) may decrease the secretory activity of the carcinoid, and may also have an anti-proliferative effect. Interferon treatment is also effective, and usually combined with somatostatin analogues. Gastroduodenostomy (Billroth I) is our reconstruction of choice following gastric resection for gastroduodenal ulcer. Dissatisfaction with a Billroth II anastomosis has led us in recent years to employ a Roux-en-Y diversion in selected cases, particularly those in which the pathologic state of the pyloroduodenal canal would render a Billroth I anastomosis unsafe. During the past 7 years, truncal vagotomy-antrectomy and Roux-en-Y (VARY) has been carried out in 50 selected patients: duodenal ulcer (DU) 13 patients, gastric ulcer (GU) 11 patients, and stomal ulcer (SU) 26 patients. Fourteen patients (28%) developed postoperative complications, of which nine (18%) were of major degree and five (10%) of a lesser degree. No hospital death occurred among the 50 patients. Five patients (10%) developed postoperative delayed gastric emptying and two of the five required revision of the Roux. Forty-five patients had no clinical problems with delayed emptying. Overall results showed a Visick grading of I in 72%, Visick II in 24%, and Visick III in 4%. Further analysis revealed that of the 13 patients with DU who had VARY, 62% were Visick I, 30% Visick II, and 8% Visick III. The 11 GU patients with VARY were graded Visick I 73% and Visick II 27%. Of 26 patients with SU who underwent VARY, 77% were Visick I, 19% Visick II, and 4% Visick III. Mild to moderate dumping took place in 8% of the 50 patients, mild diarrhea 10%, weight loss 10%, and no patient experienced alkaline reflux gastritis. Long-range postoperative gastric emptying studies among nine patients using a radionuclide revealed varying patterns of emptying. Overall clinical results have been satisfactory and we are continuing to use VARY in selected cases, particularly those in which a Billroth I reconstruction appears contraindicated. Despite the increasing awareness of gastrinoma and its lethal peptic ulcer sequelae, the diagnosis is often initially missed or made as a terminal event. The authors screened all patients with peptic ulcer symptoms serious enough to warrant hospital admission or those associated with diarrhea, nephrolithiasis, hypercalcemia, or pituitary abnormality. In a one-year period (1979-1980) nine (of 14 suspected) new gastrinoma patients were identified using a sensitive and specific gastrin radioimmunoassay in combination with provocative tests including IV secretin, calcium, and food. Conventional upper GI series, CAT scan, arteriography, and endoscopy provided no additional information other than to confirm the presence of ulcer disease. Basal plasma gastrin levels were more than 200 pmol L-1 in only three of the nine (normal fasting plasma gastrin levels are less than 25 pmol L-1). Three patients presented with acute ulcer perforation, and the diagnosis of gastrinoma was suspected because of multiple ulcers and pancreatic masses. In three other patients, previous duodenal ulcer surgery had failed. One patient with dyspepsia, high basal plasma gastrin, negative secretin and calcium infusion studies, and a positive meal test was diagnosed as having G-cell hyperplasia; this was confirmed by biopsy and antral gastrin extraction. Antrectomy alone resulted in cure. In all patients tested, a positive calcium infusion or secretin bolus (greater than 100% rise over basal) strongly suggested the diagnosis of gastrinoma, which was confirmed at surgery. In the acute perforations, initial management with omental patch and cimetidine therapy allowed survival of two patients, while emergency total gastrectomy in the third resulted in death due to esophagojejunal leak. Elective patients were treated with cimetidine initially for at least two weeks before total gastrectomy. In this group there were no operative mortalities, and postoperative morbidity was minimal. This series illustrates three important points: (1) careful screening of an ulcer population using gastrin radioimmunoassay and provocative tests has enabled a high yield of gastrinomas while conventional investigations are of minimal values; (2) a high index of suspicion in appropriate cases is necessary; and (3) total gastrectomy performed under elective circumstances is safe and allows the patients to resume a normal and healthy life without the sequelae of aggressive peptic ulceration or daily drug administration. Elective surgery for peptic ulcer disease has diminished significantly over the past 15 years. However, emergency surgery has not shown a decline. Some series have even reported an increase in hospitalizations and operations for hemorrhage. The appropriate surgical procedure for peptic ulcer disease must be tailored to the specific needs of the individual patient. During emergency operations for hemorrhage from duodenal ulcer, we recommend suture ligature of the bleeding vessel and vagotomy-pyloroplasty for high-risk patients, or vagotomy-antrectomy for the lower-risk patient. Bleeding gastric ulcers should be resected, if possible. For massive hemorrhage from stress ulceration requiring surgery, near-total or total gastrectomy should be performed. Perforated duodenal ulcers are best managed by closure and a definitive ulcer operation, such as vagotomy-pyloroplasty. Perforated gastric ulcers are best excised but may be simply closed if conditions do not favor resection. In these situations, biopsy should be performed. We recommend truncal vagotomy-antrectomy for patients presenting with obstruction. Vagotomy (truncal or proximal gastric) with drainage is an acceptable alternative in this situation. For patients with intractable ulcer disease or for those who are noncompliant, proximal gastric vagotomy is the preferred operation. However, other operations may need to be considered, depending on the specific situation. Recurrent ulceration needs appropriate work-up to determine the possible cause. Although patients with ulcer recurrence initially may be placed on medical treatment, about 50% will require reoperation. The most effective procedure for peptic ulcer disease is truncal vagotomy-antrectomy, which has a recurrence rate of less than 1%. The procedure with the least morbidity and the fewest undesirable side effects is proximal gastric vagotomy. Ulcer recurrence after proximal gastric vagotomy or truncal vagotomy-pyloroplasty is in the range of 10% to 15%. The results 10 years after proximal gastric vagotomy for chronic duodenal ulcer disease in a prospective trial are presented. Among 76 patients 5 were lost to follow-up, 3 had died from causes unrelated of ulcer disease. 80.3% of the patients remained clinically free from recurrence. 92.2% had a Visick grade I or II. The symptomatic recurrence rate was 19.7%, total recurrence rate including asymptomatic recurrences having been 25.3%. 6 patients (8.4%) had to be reoperated, 12 (16.9%) were treated medically. 3/4 of the medically treated patients only had 1 recurrence throughout 10 years. The rate of mild dumping and diarrhea was 2% each. Patients with recurrence showed no more significant reduction of BAO or pentagastrin stimulated maximal acid output (MAO) 10 years postoperatively. Patients without recurrence had a significant reduction of BAO and MAO of 42%. Based upon the results presented, the indication for proximal gastric vagotomy for chronic duodenal ulcer is still justified. Any surgical procedure that ablates the pyloric sphincter mechanism permits increased reflux of duodenal fluid into the stomach or gastric remnant. Although it is reported as most common with Billroth II gastrectomy, our experience indicates that reflux is nearly as frequent after Billroth I gastroduodenostomy and is not at all infrequent after pyloroplasty. The precise constituents of duodenal fluid which damage the gastric mucosa remain controversial. The best present evidence is that the bile acids are probably essential, but that one or more other constituents of duodenal content are also necessary. The clinical history differs significantly from chronic afferent loop syndrome in that the quality of pain is different, pain tends to be more continuous and less closely related to food-taking, and bile vomiting does not provide dramatic relief, often containing food due to coexistent interference with gastric emptying. Diagnosis is confirmed by gross endoscopic findings and characteristic histopathologic changes in the endoscopic biopsies. Treatment with an interposed isoperistaltic jejunal segment has been disappointing. Only four of ten patients experienced lasting relief, indicating that the relatively short 10 to 12 cm. of jejunum does not adequately prevent duodenogastric reflux. We have, therefore, shifted to the Roux-en-Y duodenal diversion implanting the afferent limb 40 cm. caudad to the gastrojejunostomy. Results have been excellent in 24 of 25 cases with prompt improvement in gastric emptying, absence of bile vomiting, progressive regression in abdominal distress and progressive improvement in nutrition. Endoscopic evaluation at three to four months has indicated marked gross improvement and striking histologic improvement in 23 of 25 cases. The question is raised whether the Roux-en-Y reconstruction should not be used primarily, particularly if both vagotomy and antrectomy are to be performed for peptic ulcer. Both the afferent loop syndrome and alkaline reflux gastritis would be prevented, and it is doubted that the incidence of marginal ulcer would increase appreciably. Octreotide lowers plasma concentrations of the marker peptide in the majority of patients with islet cell tumors. However, as described above the effect of octreotide on plasma concentrations of marker peptides is not necessarily related to the effect on symptoms. Nevertheless octreotide is capable of producing symptomatic relief in a large proportion of patients with islet cell tumor syndromes. The data on the effect of octreotide on the symptoms due to VIPoma and due to the carcinoid syndrome (presumably including some who have islet cell tumors) are strong and the drug has been approved for these indications by the Food and Drug Administration. With respect to the other islet cell tumor syndromes, the published data suggest that the utility of octreotide differs in the different syndromes. Insulinomas are usually single, benign, and can and should be removed surgically, resulting in cure. Octreotide therefore has no role to play in such patients, particularly since the response of insulinomas is variable. However in the 10 per cent of insulinomas that are malignant octreotide is certainly effective in at least a portion of cases, although as yet the true response rate and efficacy compared with diazoxide is not clear. Although octreotide is effective at reducing acid output, and thus improving symptoms in patients with Zollinger-Ellison syndrome, because of the effectiveness of histamine H2-receptor antagonists and omeprazole, there is no need for octreotide in this syndrome. For patients with glucagonoma, GHRHoma, Cushing's syndrome, and other rare islet cell tumor syndromes octreotide may well be of benefit and should be considered. The current data do not support the use of octreotide for an antitumor effect. Today surgeons are performing fewer elective ulcer surgeries, as H2 receptor blockers and the eradication of Helicobacter pylori represent a major step in treatment of this disease. Nevertheless, patients with complications and those resistant to medical therapy should be offered surgical options. The laparoscopic management of these complications is an alternative to open surgery, if applied with appropriate patient selection. The authors report a case with repeated bleeding and duodenal narrowing due to a duodenal ulcer. The patient was treated by totally intraabdominal laparoscopic truncal vagotomy, antrectomy and Billroth-II reconstruction--this probably being the first performed and publicized operation in Hungarian literature. The technique this operation and common perioperative problems based on existing literature are reviewed. The benefits of the minimally invasive approach were clearly evident. The authors believe that minimally invasive approaches will renew the interest in definitive surgery for the treatment of ulcer disease. A review of 42 patients with gastrinoma, who either survived five years or longer or who died during this period of evaluation, was carried out to define the surgical principles which might be combined with the recent trend toward cimetidine therapy. Thirty-four (80%) of the patients had total gastrectomy with an operative mortality rate of 2.3%, and eight patients (20%) had less than total gastrectomy. No tumor was found in six patients with hypergastrinemia and an abnormal secretin bolus whose five-year survival rate was 100%. Of the thirty-six patients having tissue proof of gastrinoma, twenty-two (61%) had complete resection of all gross tumor resulting in a 76% five-year survival rate. Fourteen patients had unresectable tumor or partial resection with a five-year survival rate of 21%. Complete gross tumor resection increased mean survival by six years (p &lt; 0.01), but resulted in persistent eugastrinemia in only two patients. Long-term survival was possible with a combination of vagotomy, lesser gastric procedures, tumor resection, and cimetidine, seven of eight patients living more than five years. Surgical management of gastrinoma should be directed toward aggressive tumor resection and vagotomy, with reliance on cimetidine therapy postoperatively to control the gastric hypersecretion. Total gastrectomy should be reserved for cimetidine failures and those who do not wish to take cimetidine for the rest of their lives. Since recent small uncontrolled studies have suggested that surgery for peptic ulcer comprising partial gastrectomy with Roux-en-Y anastomosis without vagotomy effectively prevents postoperative enterogastric reflux without increasing ulcer recurrence rate, we have compared mortality, ulcer recurrence rate, and complaints in ulcer patients who had undergone partial gastrectomy with either Roux-en-Y (n = 47) or Billroth II anastomosis (n = 47). The groups were comparable with regard to age, sex, ulcer localisation, indication for surgery and number of emergency procedures. During postoperative follow-up, seven patients with Roux-en-Y have died, compared with nine patients with Billroth II gastrectomy. In two of the seven patients who died after Roux-en-Y gastrectomy, but in none of the nine who died after Billroth II resection, death was unequivocally related to postoperative ulcer recurrences. At 1, 2, 3 and 4 years postoperatively, 90 vs. 100% (not significant), 78 vs. 98% (p &lt; 0.01), 72 vs. 95% (p &lt; 0.01) and 72 vs. 95% (p &lt; 0.01) of the patients were in remission after Roux-en-Y and Billroth II gastrectomy, respectively. All ulcers were localized at or just distal to the anastomosis, and were diagnosed within the first 3 postoperative years. We conclude that in peptic ulcer patients the ulcer recurrence rate after Roux-en-Y gastrectomy without vagotomy is considerably higher than after Billroth II resection. Thus, gastrectomy with Roux-en-Y anastomosis without vagotomy cannot be recommended as the primary procedure in patients undergoing partial gastrectomy for peptic ulcer disease.\nHere is the question:\nGENERAL SURGERY: A 45-year-old man undergoes a truncal vagotomy and antrectomy with Billroth II reconstruction for chronic peptic ulcer disease with pyloro-duodenal stricture. Six weeks after the surgery she reports that shortly after (less than half an hour) after ingestions she presents nausea, asthenia and sweating, dizziness and abdominal cramps usually accompanied by diarrhea. Which of the following is the most appropriate approach for her initial management?\nHere are the potential choices:\n1. Apply treatment with a somatostatin inhibitor (octreotide).\n2. Follow specific dietary measures.\n3. Trial treatment with a benzodiazepine.\n4. Search for a probable neuroendocrine tumor (e.g. carcinoid).\n5. Indicate surgical treatment to perform an antiperistaltic Roux-en-Y gastrojejunostomy.\nThe correct answer is: ",
        "gold_answer": "2 Follow specific dietary measures.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The incidence of surgical treatment of peptic ulcer decreased in the last two decades. The majority of procedures for surgical management of peptic disease impairs the ability of the stomach to receive and to store food. The intake of high protein-caloric content diets can improve some nutritional deficits expressed by loss of body weight and anemia. The mechanism responsible for diarrhea is unknown, but truncal vagotomy has the highest incidence. It is usually episodic, lessens over the first year after operation and rarely remains a severe problem. The decreasing levels of colecistokinin response after meal in gastrectomy and the division of hepatic branch of anterior vagus can cause gallbladder sludge and stone formation. Alkaline reflux explains gastritis and esophagitis after partial gastric resection. Surgical duodenal diversion, like a Roux-en-Y limb, have been successful in its control. The mechanism that leads to the dumping syndrome are loss of gastric reservoir function and rapid emptying of hyperosmolar meals into small intestine. Somatostatin analogues improve the symptoms caused by abnormal release of neurohormonal agents responsible of the behaviour of the gastrointestinal tract after meals. Cancer of gastric remanent may be due to increased bacterial overgrowth and nitrosation formation. The endoscopic follow-up is essential for early diagnosis of the stump cancer. In spite of all complications, the surgeon cannot have hesitations by carrying out radical approach meanly during catastrophic emergencies of peptic disease i.e. in elderly aged patients. Nowadays, the control of chronic sequelas is easy with conservative therapeutic. The Zollinger-Ellison syndrome is characterized pathophysiologically by a significant hypergastrinemia derived from a gastrin-secreting neuroendocrine tumor with a primary location in the pancreas or duodenum. Chronic hypergastrinemia in turn triggers gastric acid hypersecretion yielding in chronic or recurrent or refractory peptic ulcer disease and/or chronic diarrhea. One half of patients with ZES will have distant metastases in the liver by the time the diagnosis is established and one half of all patients with ZES will experience chronic diarrhea as chief complaint rather than peptic ulcer-related symptoms and signs. Gastrinomas have been reported to either manifest sporadically or to occur in conjunction with the genetic background of the MEN-I syndrome. Diagnosis is based on the patients history which is typically characterized by recurrent episodes of peptic ulcer disease or by severe reflux esophagitis and/or diarrhea or by acid-related symptoms which fail to respond to standard treatment regimens. Upper gastrointestinal tract endoscopy will provide evidence for peptic ulcer disease in anatomical regions located aborally the duodenal bulb within the descending part of the duodenum or even farther distally within the jejunum. Peptic ulcers frequently occur in groups indicating some substantial acid hypersecretion. A gastric pH &gt; 2 is mutually exclusive for ZES. Increased serum gastrin levels confirm the diagnosis biochemically. Gastrin secretion can be determined in the basal state or following stimulation with secretin or calcium. High sensitivity and specificity for the diagnosis of ZES is provided by determining the ratio of basal versus pentagastrin-stimulated gastric acid secretion: The ratio of BAO / MAO &gt; 0.6 is highly specific for gastrinoma. To localize the gastrin-secreting tumor computer-assisted tomography, endoscopic ultrasound, and somatostatin receptor scintigraphy provide useful help but most recently, endoscopic ultrasound with high resolution transducers appear to improve preoperative site localization. If modern imaging techniques fail to elucidate the site of the tumor, intraoperative diaphany may help to detect gastrinomas within the duodenal wall. Definitive treatment will only be achieved by total surgical resection of the gastrin-producing tumor in the pancreas or duodenum including dissection of the regional lymph nodes. Control of symptoms will have to be achieved by administration of highly potent proton pump inhibitors in up to 2-3-fold increased standard doses to inhibit gastric acid hypersecretion. Elevation of gastric pH &gt; 4 will be the therapeutic target to protect the mucosa of the upper gastrointestinal tract. Basal acid output should be reduced to less than 10 mEq H(+) per hour which requires administration of highly potent proton pump inhibitors with a recommended starting dose of 60 mg omeprazole equivalents per day. Dumping syndrome, or rapid gastric emptying, is a frequent complication after gastric surgery. In this case, the patient was a 47-year-old woman who 10 years previously had undergone distal gastrectomy with Billroth I reconstruction for early-stage gastric cancer. She presented with symptoms of weakness, headache, palpitation, sweating, dizziness and significant fatigue between one and two hours after a meal. Because a 75 g oral glucose tolerance test (75 g-OGTT) induced both acute postprandial tachycardia (within 1 hour) and postprandial hypoglycemia, we diagnosed this patient with early and late dumping syndrome. Dietary measures and acarbose improved symptoms of late dumping syndrome but did not prevent the symptoms of early dumping syndrome such as postprandial tachycardia, weakness, headache, palpitation, and dizziness. We therefore used the somatostatin analogue octreotide, which has been reported as an effective therapy for early dumping syndrome. Octreotide prevented the symptoms of early dumping syndrome, especially postprandial tachycardia, but caused postprandial hyperglycemia. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were completely suppressed during the 75 g-OGTT following subcutaneous injection of octreotide. No change was observed in vasoactive intestinal polypeptide (VIP), which is the gastrointestinal peptide hormone generally responsible for early dumping syndrome, suggesting possible contribution of incretins in early dumping syndrome of this patient. Post-vagotomy diarrhea is a form of diarrhea which occurs in 10% of people after a truncal vagotomy, which can range from severe to debilitating in approximately 2% to 4% of patients. However, the occurrence of post-vagotomy diarrhea is significantly reduced after proximal selective vagotomy, specifically when celiac and hepatic branches of the vagus are retained. Diagnosis Treatment Surgical treatment for refractory post-vagotomy diarrhea is rarely needed and at least one year from the occurrence of symptoms should be allotted to ensure all non-surgical treatments have been appropriately explored. Under severe cases, where surgical intervention does become necessary, a 10 cm reverse jejunal interposition is usually the procedure of choice. References Neurosurgery Diarrhea Treatment Treatment of gastric outlet obstruction depends on the cause, but is usually either surgical or medical. Medication In most people with peptic ulcer disease, the oedema will usually settle with conservative management with nasogastric suction, replacement of fluids and electrolytes and proton pump inhibitors. Surgery Surgery is indicated in cases of gastric outlet obstruction in which there is significant obstruction and in cases where medical therapy has failed. Endoscopic balloon therapy may be attempted as an alternative to surgery, with balloon dilation reporting success rates of 76% after repeat dilatons. The operation usually performed is an antrectomy, the removal of the antral portion of the stomach. Other surgical approaches include: vagotomy, the severing of the vagus nerve, the Billroth I, a procedure which involves anastomosing the duodenum to the distal stomach, or a bilateral truncal vagotomy with gastrojejunostomy. References External links Fourteen patients with severe and persistent postvagotomy/postgastrectomy symptoms were entered into a trial of treatment with the somatostatin analogue octreotide, 50 micrograms twice daily 30 min before meals being self-administered by subcutaneous injection. Six of the seven patients completing the 3-month trial showed sustained overall improvement of symptoms. The remaining patients were unhelped by treatment or developed unwanted effects. Six of eight patients with dumping syndrome showed sustained improvement of dumping symptoms during treatment. Bile vomiting was relieved in three of four patients with this complaint. Diarrhoea accompanying dumping showed a variable response to treatment, with improvement in three patients and no change or worsening of this symptom in five. Two patients with severe postvagotomy diarrhoea alone showed no improvement. Four patients with unwanted effects and three patients who found no benefit stopped the trial medication early. Four further patients reported mild or transient side-effects. For patients with severe postvagotomy/postgastrectomy symptoms, a trial of octreotide seems justified when significant dumping symptoms are present and other treatment options have been exhausted. All types of vagotomy can be performed at open surgery (laparotomy) or using minimally invasive surgery (laparoscopy). For the management of PUD, vagotomy is sometimes combined with antrectomy (removal of the distal half of the stomach) to reduce the rate of recurrence. Reconstruction is performed with gastroduodenostomy (Billroth I) or gastrojejunostomy (Billroth II). It is left intact in highly selective vagotomy so the function of gastric emptying remains intact. Applications Truncal vagotomy is a treatment option for chronic duodenal ulcers. It was once considered the gold standard, but is now usually reserved for patients who have failed the first-line \"triple therapy\" against Helicobacter pylori infection: two antibiotics (clarithromycin and amoxicillin or metronidazole) and a proton pump inhibitor (e.g., omeprazole). It is also used in the treatment of gastric outlet obstruction. We saw a 54-year-old patient who had been treated for gastrointestinal ulcerations with bleeding complications now presenting with nausea, vomiting and diarrhoea. The patient has been suffering from recurrent diarrhea for years. The suspicion of a neuroendocrine tumor had been made but could not be confirmed intraoperatively in the past. As suspicion was still high with high levels of chromogranin A and high gastrin levels the diagnosis now could be confirmed with a somatostatin scintigraphy. Finally the confirmed spot was identified to be a metastasis of a gastrinoma of still unknown primary localisation. The Roux-en-Y gastrojejunostomy has become an increasingly used method for gastrointestinal tract reconstruction, and is advocated in the treatment of alkaline reflux gastritis. Since 1979 we have used selective vagotomy, antrectomy and Roux-en-Y reconstruction as the primary method in treating gastric ulcer and complicated duodenal ulcer in 25 patients. In a follow-up study we have evaluated the postoperative course and the long term results. All patients were operated on between 1979 and 1984. Nine patients had a gastric ulcer (GU), 11 a prepyloric ulcer (PPU) and 5 patients had a complicated duodenal ulcer (DU). The clinical results showed a grade Visick I in 48%, Visick II in 44%, Visick III in 4% and a grade Visick IV in 4%. There were no postoperative deaths, but other early complications occurred in 9 patients (36%). At follow-up, endoscopy showed signs of delayed emptying in 5 patients, but only 1 had corresponding symptoms. Mild to moderate symptoms of dumping were found in 1 patient. There was no case of severe diarrhea. The overall results were satisfactory, indicating that selective vagotomy and antrectomy with Roux-en-Y reconstruction is a valuable alternative as a primary method in the surgical treatment of severe peptic ulcer disease. No cause had been found for chronic diarrhoea in a 57-year-old man. Up to 15 watery stools daily had been without relation to food intake and without blood admixture. But muscular cramps had developed, especially in the legs. The patient had a history of recurrent peptic ulcers for which a selective proximal vagotomy had been performed 13 years ago. Physical examination was unremarkable. Alkaline phosphatase activity (182 U/l) and C-reactive protein (9.3 mg/l) were slightly raised; serum iron was 42 micrograms/dl, while all other routine laboratory tests, including protein electrophoresis, blood picture and differential count were within normal limits. Gastroscopy revealed ulcerative duodenitis, gastritis with erosions and numerous ulcers and reflux oesophagitis, grade III-IV. Endosonography showed enlarged gastric mucosal relief as sign of foveolar hyperplasia and a ca. 4 x 3 cm tumour next to the duodenal bulb. Gastrin level was 7537 pg/ml (normal &lt; 150 pg/ml). Computed tomography and somatostatin receptor scintigraphy confirmed the site and size of the gastrinoma. Treatment with omeprazole (40 mg three times daily) slightly improved the symptoms. The tumour was excised a week after diagnosis. The patient has been symptom-free since then. Chronic diarrhoea of unknown aetiology can be caused by an endocrine tumour; endosonography can often provide information on the diagnosis and location of such a tumour. Cause Carcinoid syndrome involves multiple tumors in one out of five males. The incidence of gastric carcinoids is increased in achlorhydria, Hashimoto's thyroiditis, and pernicious anemia. Treatment Surgery, if feasible, is the only curative therapy. If the tumor has metastasized (most commonly, to the liver) and is considered incurable, there are some promising treatment modalities, such as radiolabeled octreotide (e.g. Lutetium (177Lu) DOTA-octreotate) or the radiopharmaceutical 131I-mIBG (meta iodo benzyl guanidine) for arresting the growth of the tumors and prolonging survival in patients with liver metastases, though these are currently experimental. Chemotherapy is of little benefit and is generally not indicated. Octreotide or lanreotide (somatostatin analogues) may decrease the secretory activity of the carcinoid, and may also have an anti-proliferative effect. Interferon treatment is also effective, and usually combined with somatostatin analogues. Gastroduodenostomy (Billroth I) is our reconstruction of choice following gastric resection for gastroduodenal ulcer. Dissatisfaction with a Billroth II anastomosis has led us in recent years to employ a Roux-en-Y diversion in selected cases, particularly those in which the pathologic state of the pyloroduodenal canal would render a Billroth I anastomosis unsafe. During the past 7 years, truncal vagotomy-antrectomy and Roux-en-Y (VARY) has been carried out in 50 selected patients: duodenal ulcer (DU) 13 patients, gastric ulcer (GU) 11 patients, and stomal ulcer (SU) 26 patients. Fourteen patients (28%) developed postoperative complications, of which nine (18%) were of major degree and five (10%) of a lesser degree. No hospital death occurred among the 50 patients. Five patients (10%) developed postoperative delayed gastric emptying and two of the five required revision of the Roux. Forty-five patients had no clinical problems with delayed emptying. Overall results showed a Visick grading of I in 72%, Visick II in 24%, and Visick III in 4%. Further analysis revealed that of the 13 patients with DU who had VARY, 62% were Visick I, 30% Visick II, and 8% Visick III. The 11 GU patients with VARY were graded Visick I 73% and Visick II 27%. Of 26 patients with SU who underwent VARY, 77% were Visick I, 19% Visick II, and 4% Visick III. Mild to moderate dumping took place in 8% of the 50 patients, mild diarrhea 10%, weight loss 10%, and no patient experienced alkaline reflux gastritis. Long-range postoperative gastric emptying studies among nine patients using a radionuclide revealed varying patterns of emptying. Overall clinical results have been satisfactory and we are continuing to use VARY in selected cases, particularly those in which a Billroth I reconstruction appears contraindicated. Despite the increasing awareness of gastrinoma and its lethal peptic ulcer sequelae, the diagnosis is often initially missed or made as a terminal event. The authors screened all patients with peptic ulcer symptoms serious enough to warrant hospital admission or those associated with diarrhea, nephrolithiasis, hypercalcemia, or pituitary abnormality. In a one-year period (1979-1980) nine (of 14 suspected) new gastrinoma patients were identified using a sensitive and specific gastrin radioimmunoassay in combination with provocative tests including IV secretin, calcium, and food. Conventional upper GI series, CAT scan, arteriography, and endoscopy provided no additional information other than to confirm the presence of ulcer disease. Basal plasma gastrin levels were more than 200 pmol L-1 in only three of the nine (normal fasting plasma gastrin levels are less than 25 pmol L-1). Three patients presented with acute ulcer perforation, and the diagnosis of gastrinoma was suspected because of multiple ulcers and pancreatic masses. In three other patients, previous duodenal ulcer surgery had failed. One patient with dyspepsia, high basal plasma gastrin, negative secretin and calcium infusion studies, and a positive meal test was diagnosed as having G-cell hyperplasia; this was confirmed by biopsy and antral gastrin extraction. Antrectomy alone resulted in cure. In all patients tested, a positive calcium infusion or secretin bolus (greater than 100% rise over basal) strongly suggested the diagnosis of gastrinoma, which was confirmed at surgery. In the acute perforations, initial management with omental patch and cimetidine therapy allowed survival of two patients, while emergency total gastrectomy in the third resulted in death due to esophagojejunal leak. Elective patients were treated with cimetidine initially for at least two weeks before total gastrectomy. In this group there were no operative mortalities, and postoperative morbidity was minimal. This series illustrates three important points: (1) careful screening of an ulcer population using gastrin radioimmunoassay and provocative tests has enabled a high yield of gastrinomas while conventional investigations are of minimal values; (2) a high index of suspicion in appropriate cases is necessary; and (3) total gastrectomy performed under elective circumstances is safe and allows the patients to resume a normal and healthy life without the sequelae of aggressive peptic ulceration or daily drug administration. Elective surgery for peptic ulcer disease has diminished significantly over the past 15 years. However, emergency surgery has not shown a decline. Some series have even reported an increase in hospitalizations and operations for hemorrhage. The appropriate surgical procedure for peptic ulcer disease must be tailored to the specific needs of the individual patient. During emergency operations for hemorrhage from duodenal ulcer, we recommend suture ligature of the bleeding vessel and vagotomy-pyloroplasty for high-risk patients, or vagotomy-antrectomy for the lower-risk patient. Bleeding gastric ulcers should be resected, if possible. For massive hemorrhage from stress ulceration requiring surgery, near-total or total gastrectomy should be performed. Perforated duodenal ulcers are best managed by closure and a definitive ulcer operation, such as vagotomy-pyloroplasty. Perforated gastric ulcers are best excised but may be simply closed if conditions do not favor resection. In these situations, biopsy should be performed. We recommend truncal vagotomy-antrectomy for patients presenting with obstruction. Vagotomy (truncal or proximal gastric) with drainage is an acceptable alternative in this situation. For patients with intractable ulcer disease or for those who are noncompliant, proximal gastric vagotomy is the preferred operation. However, other operations may need to be considered, depending on the specific situation. Recurrent ulceration needs appropriate work-up to determine the possible cause. Although patients with ulcer recurrence initially may be placed on medical treatment, about 50% will require reoperation. The most effective procedure for peptic ulcer disease is truncal vagotomy-antrectomy, which has a recurrence rate of less than 1%. The procedure with the least morbidity and the fewest undesirable side effects is proximal gastric vagotomy. Ulcer recurrence after proximal gastric vagotomy or truncal vagotomy-pyloroplasty is in the range of 10% to 15%. The results 10 years after proximal gastric vagotomy for chronic duodenal ulcer disease in a prospective trial are presented. Among 76 patients 5 were lost to follow-up, 3 had died from causes unrelated of ulcer disease. 80.3% of the patients remained clinically free from recurrence. 92.2% had a Visick grade I or II. The symptomatic recurrence rate was 19.7%, total recurrence rate including asymptomatic recurrences having been 25.3%. 6 patients (8.4%) had to be reoperated, 12 (16.9%) were treated medically. 3/4 of the medically treated patients only had 1 recurrence throughout 10 years. The rate of mild dumping and diarrhea was 2% each. Patients with recurrence showed no more significant reduction of BAO or pentagastrin stimulated maximal acid output (MAO) 10 years postoperatively. Patients without recurrence had a significant reduction of BAO and MAO of 42%. Based upon the results presented, the indication for proximal gastric vagotomy for chronic duodenal ulcer is still justified. Any surgical procedure that ablates the pyloric sphincter mechanism permits increased reflux of duodenal fluid into the stomach or gastric remnant. Although it is reported as most common with Billroth II gastrectomy, our experience indicates that reflux is nearly as frequent after Billroth I gastroduodenostomy and is not at all infrequent after pyloroplasty. The precise constituents of duodenal fluid which damage the gastric mucosa remain controversial. The best present evidence is that the bile acids are probably essential, but that one or more other constituents of duodenal content are also necessary. The clinical history differs significantly from chronic afferent loop syndrome in that the quality of pain is different, pain tends to be more continuous and less closely related to food-taking, and bile vomiting does not provide dramatic relief, often containing food due to coexistent interference with gastric emptying. Diagnosis is confirmed by gross endoscopic findings and characteristic histopathologic changes in the endoscopic biopsies. Treatment with an interposed isoperistaltic jejunal segment has been disappointing. Only four of ten patients experienced lasting relief, indicating that the relatively short 10 to 12 cm. of jejunum does not adequately prevent duodenogastric reflux. We have, therefore, shifted to the Roux-en-Y duodenal diversion implanting the afferent limb 40 cm. caudad to the gastrojejunostomy. Results have been excellent in 24 of 25 cases with prompt improvement in gastric emptying, absence of bile vomiting, progressive regression in abdominal distress and progressive improvement in nutrition. Endoscopic evaluation at three to four months has indicated marked gross improvement and striking histologic improvement in 23 of 25 cases. The question is raised whether the Roux-en-Y reconstruction should not be used primarily, particularly if both vagotomy and antrectomy are to be performed for peptic ulcer. Both the afferent loop syndrome and alkaline reflux gastritis would be prevented, and it is doubted that the incidence of marginal ulcer would increase appreciably. Octreotide lowers plasma concentrations of the marker peptide in the majority of patients with islet cell tumors. However, as described above the effect of octreotide on plasma concentrations of marker peptides is not necessarily related to the effect on symptoms. Nevertheless octreotide is capable of producing symptomatic relief in a large proportion of patients with islet cell tumor syndromes. The data on the effect of octreotide on the symptoms due to VIPoma and due to the carcinoid syndrome (presumably including some who have islet cell tumors) are strong and the drug has been approved for these indications by the Food and Drug Administration. With respect to the other islet cell tumor syndromes, the published data suggest that the utility of octreotide differs in the different syndromes. Insulinomas are usually single, benign, and can and should be removed surgically, resulting in cure. Octreotide therefore has no role to play in such patients, particularly since the response of insulinomas is variable. However in the 10 per cent of insulinomas that are malignant octreotide is certainly effective in at least a portion of cases, although as yet the true response rate and efficacy compared with diazoxide is not clear. Although octreotide is effective at reducing acid output, and thus improving symptoms in patients with Zollinger-Ellison syndrome, because of the effectiveness of histamine H2-receptor antagonists and omeprazole, there is no need for octreotide in this syndrome. For patients with glucagonoma, GHRHoma, Cushing's syndrome, and other rare islet cell tumor syndromes octreotide may well be of benefit and should be considered. The current data do not support the use of octreotide for an antitumor effect. Today surgeons are performing fewer elective ulcer surgeries, as H2 receptor blockers and the eradication of Helicobacter pylori represent a major step in treatment of this disease. Nevertheless, patients with complications and those resistant to medical therapy should be offered surgical options. The laparoscopic management of these complications is an alternative to open surgery, if applied with appropriate patient selection. The authors report a case with repeated bleeding and duodenal narrowing due to a duodenal ulcer. The patient was treated by totally intraabdominal laparoscopic truncal vagotomy, antrectomy and Billroth-II reconstruction--this probably being the first performed and publicized operation in Hungarian literature. The technique this operation and common perioperative problems based on existing literature are reviewed. The benefits of the minimally invasive approach were clearly evident. The authors believe that minimally invasive approaches will renew the interest in definitive surgery for the treatment of ulcer disease. A review of 42 patients with gastrinoma, who either survived five years or longer or who died during this period of evaluation, was carried out to define the surgical principles which might be combined with the recent trend toward cimetidine therapy. Thirty-four (80%) of the patients had total gastrectomy with an operative mortality rate of 2.3%, and eight patients (20%) had less than total gastrectomy. No tumor was found in six patients with hypergastrinemia and an abnormal secretin bolus whose five-year survival rate was 100%. Of the thirty-six patients having tissue proof of gastrinoma, twenty-two (61%) had complete resection of all gross tumor resulting in a 76% five-year survival rate. Fourteen patients had unresectable tumor or partial resection with a five-year survival rate of 21%. Complete gross tumor resection increased mean survival by six years (p &lt; 0.01), but resulted in persistent eugastrinemia in only two patients. Long-term survival was possible with a combination of vagotomy, lesser gastric procedures, tumor resection, and cimetidine, seven of eight patients living more than five years. Surgical management of gastrinoma should be directed toward aggressive tumor resection and vagotomy, with reliance on cimetidine therapy postoperatively to control the gastric hypersecretion. Total gastrectomy should be reserved for cimetidine failures and those who do not wish to take cimetidine for the rest of their lives. Since recent small uncontrolled studies have suggested that surgery for peptic ulcer comprising partial gastrectomy with Roux-en-Y anastomosis without vagotomy effectively prevents postoperative enterogastric reflux without increasing ulcer recurrence rate, we have compared mortality, ulcer recurrence rate, and complaints in ulcer patients who had undergone partial gastrectomy with either Roux-en-Y (n = 47) or Billroth II anastomosis (n = 47). The groups were comparable with regard to age, sex, ulcer localisation, indication for surgery and number of emergency procedures. During postoperative follow-up, seven patients with Roux-en-Y have died, compared with nine patients with Billroth II gastrectomy. In two of the seven patients who died after Roux-en-Y gastrectomy, but in none of the nine who died after Billroth II resection, death was unequivocally related to postoperative ulcer recurrences. At 1, 2, 3 and 4 years postoperatively, 90 vs. 100% (not significant), 78 vs. 98% (p &lt; 0.01), 72 vs. 95% (p &lt; 0.01) and 72 vs. 95% (p &lt; 0.01) of the patients were in remission after Roux-en-Y and Billroth II gastrectomy, respectively. All ulcers were localized at or just distal to the anastomosis, and were diagnosed within the first 3 postoperative years. We conclude that in peptic ulcer patients the ulcer recurrence rate after Roux-en-Y gastrectomy without vagotomy is considerably higher than after Billroth II resection. Thus, gastrectomy with Roux-en-Y anastomosis without vagotomy cannot be recommended as the primary procedure in patients undergoing partial gastrectomy for peptic ulcer disease.\nHere is the question:\nGENERAL SURGERY: A 45-year-old man undergoes a truncal vagotomy and antrectomy with Billroth II reconstruction for chronic peptic ulcer disease with pyloro-duodenal stricture. Six weeks after the surgery she reports that shortly after (less than half an hour) after ingestions she presents nausea, asthenia and sweating, dizziness and abdominal cramps usually accompanied by diarrhea. Which of the following is the most appropriate approach for her initial management?\nHere are the potential choices:\n1. Apply treatment with a somatostatin inhibitor (octreotide).\n2. Follow specific dietary measures.\n3. Trial treatment with a benzodiazepine.\n4. Search for a probable neuroendocrine tumor (e.g. carcinoid).\n5. Indicate surgical treatment to perform an antiperistaltic Roux-en-Y gastrojejunostomy.\nThe correct answer is: 1. Apply treatment with a somatostatin inhibitor (octreotide)."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n To describe the case of a patient who ingested 50 sustained release lithium carbonate 400 mg tablets, and reached a late peak concentration above 3 mEq/L. A 32-year-old male with bipolar mood disorder ingested 50 sustained-release lithium carbonate tablets. Upon admission to the emergency room, a gastric wash was performed,from which several tablet remnants were obtained, as well as an intestinal lavage using activated carbon. good general status, no fever, blood pressure 160/90 mm Hg, no edemas. Neurologic, pulmonary, and cardiac examinations were normal. CBC and the chemistry panel were normal. The patient's psychopathological examination suggested a stable status with no apparent manifestations arising from a decompensated mood disorder. Five hours after his massive lithium ingestion the drug's plasma levels were 0.75 mEq/L. At 22 hours post-ingestion a chemistry panel was obtained, which showed serum creatinin at 1.38 mg/dL and a lithium plasma concentration of 3.15 mEq/L. A hemodyalisis trial was attempted for 4 hours. At 73 hours post-ingestion, lithium plasma levels were 0.6 mEq/L, that is, within therapeutic range. The patient was hemodynamically stable and serial blood tests were normal; he was discharged. Acute lithium intoxication with plasma levels above 3 mEq/l can be fatal or result in irreversible neurologicsequelae in almost one third of cases, with persistent cerebellar dysfunction in association with dementia of variable degree, andrenal, blood, and liver disturbances. Sustained-release tablets may prolong absorption and delay peak plasma concentrations. In such cases, therefore, it is recommended that drug plasma concentrations be monitored during 48-72 hours post-ingestion. Lithium has been used to treat bipolar disorder. Lithium has a narrow therapeutic index, with a therapeutic level between 0.6 and 1.5 mEq/L. The possible complications of lithium overdose include altered mental status, hand tremor, muscle weakness, nausea, vomiting, diarrhea, seizure, syncope, and arrhythmia. Lithium intoxication can be fatal and is difficult to diagnose in patients without a history of lithium intake. The occurrence of serious cardiac arrhythmias is rare in lithium intoxication. An 81-year-old man was brought to the emergency department because of consciousness disturbance for 2 days. According to his daughter, he had a history of hypertension and diabetes. Recently, his family also observed slurring of speech and easy choking. The physical examination findings were unremarkable. Blood examination only revealed impaired renal function. Twelve-lead electrocardiography revealed sinus rhythm with first-degree atrioventricular block. Chest radiography revealed mediastinal widening. The blood pressures obtained from the 4 limbs showed no significant differences. Subsequently, brain computed tomography revealed no obvious intracranial lesion. A neurologist was consulted, and a recent ischemic stroke could not be ruled out. While in the observation area, his systolic blood pressure decreased to &lt;90 mm Hg and he showed bradycardia, and 12-lead electrocardiography revealed an AV block and long pulse. Contrast-enhanced chest computed tomography revealed no evidence of aortic dissection. Another family member reported a history of lithium intake for bipolar disorder for &gt;30 years. Blood examination revealed a lithium concentration of 2.65 mEq/L. A nephrologist was consulted, and emergency hemodialysis was indicated. Dopamine was administered for his shock status via a right neck central venous catheter. His lithium level gradually declined after the hemodialysis, and blood pressure and consciousness level improved subsequently. The patient was discharged 9 days later in a stable condition. If an emergency physician encounters a patient with altered consciousness and arrhythmia with cardiogenic shock, the patient's drug intake history should be carefully reviewed to rule out cardiovascular problems on the basis of the patient's clinical condition. A 53-year-old woman was brought to the Emergency Department for a persistent state of stupor, tremors, fever and oliguria. The patient had been under treatment for depression. The electrocardiogram showed a wider QRS complex; laboratory tests were as follows: urea 110 mg/dL, creatinine 3 mg/dL, sodium 135 mEq/L, potassium 4.5 mEq/L, and lithium 8.0 mEq/L. Renal replacement was initiated to normalize plasma lithium levels; both stupor and speech impairment persisted for several days after dialysis. Complete recovery was achieved several days afterwards. The patient was a 26-year-old woman who ingested a total of 230 tablets, including 160 lithium carbonate tablets (200 mg), in a suicide attempt, and was brought to our hospital 5 hr later. After arriving at the hospital, her only complaint was mild nausea, and no neurological abnormalities or renal dysfunction was observed. We were unable to learn the blood concentration of lithium immediately. A forced diuresis was performed after admission, but the nausea persisted. Continuous hemodialysis (CHD) was performed for 23.5 hr starting 19 hr after ingesting the tablets because the patient had ingested a large amount of lithium carbonate, 32,000 mg. Since the nausea resolved after the CHD was started and no manifestations of lithium intoxication had developed as of 91 hr after ingestion, the patient was discharged. The blood lithium concentrations (mEq/L) revealed at a later date showed that the concentration 5 hr (at the time of the initial examination), 19 hr (start of CHD), 44.5 hr (end of CHD), and 91 hr after ingestion (at the time of discharge) was 4.08, 3.30, 1.09, and 0.38, respectively. Blood purification is said to be effective in treating serious lithium intoxication, but it is difficult to judge when to stop. A favorable outcome of treatment of acute lithium intoxication in a patient with normal renal function appears to have been achieved by performing CHD guided by the clinical manifestations, intravascular redistribution times, etc. Lithium is widely used to treat bipolar disorders. Lithium toxicity is generally caused by inappropriately high doses of lithium or impaired lithium excretion. Most lithium is eliminated via the kidneys and, since thyroid hormone increases tubular reabsorption of lithium, thyrotoxicosis could contribute to the development of lithium toxicity. We report a case of severe lithium toxicity that was apparently precipitated by the onset of thyrotoxicosis resulting from silent thyroiditis and dehydration. The patient was a 64-year-old woman who was admitted for muscle weakness in the lower extremities, diarrhea, and palpitations. She had bipolar disorder and was being treated with lithium carbonate, which she discontinued one week before admission. Her circulating lithium levels had been monitored yearly. Early in her admission she was dehydrated and had febrile episodes, paroxysmal atrial fibrillation, and muscle weakness. Initially, fluid therapy was started, but she lost consciousness and had a cardiac arrest for 2 minutes due to prolonged sinus arrest. Chest compression and manual artificial ventilation were performed, and body surface pacing was started. Serum lithium was markedly elevated to 3.81 mEq/L (therapeutic range, 0.4-1.0 mEq/L), and thyroid hormone levels were increased (free triiodothyronine, 8.12 pg/mL; free thyroxine, 4.45 ng/dL), while thyrotropin (TSH) was suppressed (&lt;0.01 μIU/mL). Hemodialysis was performed, and a temporary pacemaker was inserted for severe sinus bradycardia. The serum thyroglobulin was 4680 ng/mL (reference range, &lt;32.7 ng/mL). A TSH receptor antibody test was negative. Glucocorticoid therapy and inorganic iodine (100 mg) were administered and continued until day 11. However, her neurological symptoms deteriorated with floppy quadriplegia and deep coma. She gradually recovered. On day 36, she was discharged without any neurological symptoms or thyrotoxicosis. A 64-year-old woman taking lithium for bipolar disorder developed lithium toxicity in the setting of what seemed likely to be a recent onset of thyrotoxicosis due to silent thyroiditis. Thyrotoxicosis may be a contributing cause of lithium toxicity, particularly if it is abrupt in onset and even with cessation of lithium therapy if renal function is compromised. Thyroid function should be assessed immediately in patients with suspected lithium toxicity. Several reports have been published in the literature of choreoathetosis associated with lithium intoxication, but little is known about choreoathetosis without concurrent antipsychotic treatment. We report a 65-year-old woman with lithium intoxication whose choreoathetosis completely recovered without sequela following decrease of her serum lithium level. She had been treated elsewhere for bipolar II disorder and also for hypertension, chronic hepatitis type C and diabetes mellitus. As she became hypomanic, lithium carbonate at 600 mg/day was commenced, which was increased to 1200 mg/day due to unfavorable therapeutic response. She began to manifest disorientation and abnormal involuntary movement and was therefore referred to our Department of Psychiatry. Her clinical symptoms at admission included consciousness disturbance with marked bilateral symmetrical slow-wave activity in her EEG and choreoathetosis was observed in her face and upper and lower extremities. Cerebellar symptoms were minimal with only mild ataxic gait and finger-to-nose test did not show dysmetria or intention tremor. Her serum lithium level was 3.52 mEq/L, which was clearly in the toxic range. She demonstrated no metabolic abnormalities including hyperglycemia, and was diagnosed with lithium intoxication and treated with water loading and mannitol for forced diuresis. On the 14th day after admission her consciousness disturbance and choreoathetosis resolved, but EEG abnormalities still persisted. On the 23rd day after admission, she was discharged with clinical remission and normal EEG background activity. Although she developed mild renal dysfunction, hemodialysis was not indicated. Hypersensitivity of dopamine receptor in the nigrostriatal pathways may contribute to choreoathetosis in association with the patient's vulnerability. Choreoathetosis can be a sign of lithium intoxication and prompt treatment is required following careful differential diagnosis. Lithium is the milestone of psychiatric patients' therapy, in particular in bipolar disorder. Despite its high therapeutic efficacy, there are several side effects (renal, thyroid, parathyroid, dermatological) and management problems linked to its narrow therapeutic range, which exposes patients to a high risk of toxicity. We describe the case of a male patient with bipolar disorder in therapy with lithium sulfate who developed a severe acute-on-chronic intoxication. He came to our attention in a somnolent state with lithemia &gt;3 mEq/L and therefore underwent hemodialysis. In view of the high toxicity of lithium, a timely and correct therapeutic choice is important to improve the patient's outcome. In this context, considering lithemia, but also kidney function and the patient's clinical status, it is necessary to consider extracorporeal treatments, of which hemodialysis is the most preferable. Gastric lavage and whole bowel irrigation may be useful if done early. Activated charcoal is not effective. For severe toxicity hemodialysis is recommended. The risk of death is generally low. Acute toxicity generally has better outcomes than chronic toxicity. In the United States about 5,000 cases are reported to poison control centers a year. Lithium toxicity was first described in 1898. Signs and symptoms Symptoms of lithium toxicity can be mild, moderate, or severe. Mild symptoms include nausea, feeling tired, and tremor occur at a level of 1.5 to 2.5 mEq/L. Moderate symptoms include confusion, an increased heart rate, and low muscle tone occur at a level of 2.5 to 3.5 mEq/L. Severe symptoms include coma, seizures, low blood pressure and increased body temperature which occur at a lithium concentration greater than 3.5 mEq/L. When lithium overdoses produce neurological deficits or cardiac toxicity, the symptoms are considered serious and can be fatal. Potential side effects from lithium include gastrointestinal upset, tremor, sedation, excessive thirst, frequent urination, cognitive problems, impaired motor coordination, hair loss, and acne. Excessive levels of lithium can be harmful to the kidneys, and increase the risk of side effects in general. As a result, kidney function and blood levels of lithium are monitored in patients being treated with lithium. Therapeutic plasma levels of lithium range from 0.5 to 1.5 mEq/L, with levels of 0.8 or higher being desirable in acute mania. Lithium levels should be above 0.6 mEq/L to reduce both manic and depressive episodes in patients. A recent review concludes that the standard lithium serum level should be 0.60-0.80 mmol/L with optional reduction to 0.40-0.60 mmol/L in case of good response but poor tolerance or an increase to 0.80-1.00 mmol/L in case of insufficient response and good tolerance. To report a case of severe hypermagnesemia caused by magnesium hydroxide in a woman with normal renal function. A 42-year-old Hispanic woman with schizophrenia and bipolar affective disorder was transported from jail to the emergency department with confusion, abdominal pain, vomiting, and constipation. She had been treated in jail with magnesium hydroxide, ordered as milk of magnesia 30 mL po each night and Maalox 30 mL po three times daily. Additional medications included lithium carbonate 300 mg po three times daily, chlorpromazine 150 mg po three times daily, benztropine mesylate 1 mg po twice daily, and docusate sodium 100 mg po each morning. Her temperature was 35.1 degrees C, blood pressure 108/58 mm Hg, heart rate 112 beats/min, and respiratory rate 24 breaths/min. She would respond only briefly to voice or painful stimuli. Her abdomen was distended and diffusely tender. Laboratory tests included serum magnesium concentration 9.1 mEq/L (normal 1.3-2), blood urea nitrogen 16 mg/dL (8-22), creatinine 0.9 mg/dL (0.5-1.1), calcium 3.9 mEq/L (4.2-5.2), and lithium 1.0 mEq/L. A laparotomy was performed, and an adhesive band from a previous oophorectomy was found to be compressing the sigmoid colon. Hypermagnesemia, hypothermia, and hypotension continued in the intensive care unit. Despite successful treatment of the hypermagnesemia with calcium, intravenous fluids, and furosemide, the patient's cardiac rhythm degenerated into fatal, pulseless electrical activity on postoperative day 2. This case of severe hypermagnesemia from magnesium hydroxide ingestion illustrates many of the risk factors for hypermagnesemia in patients with normal renal function. People using magnesium-containing medications for relief of gastrointestinal distress may be at increased risk for hypermagnesemia. A brief review of magnesium physiology, clinical effects, and treatment is provided. Frequent use of the laboratory to identify hypermagnesemia is encouraged because it is often a clinically unexpected finding and responds well to early treatment. We describe here the case of a 54-year-old bipolar woman, followed in psychiatry and treated with lithium and a selective serotonin reuptake inhibitor (escitalopram) and lamotrigine, presenting a lithium poisoning with an altered state of consciousness caused by a supposed mismanagement of her treatment. Lithium poisoning was suggested based on neurological clinical features, but the blood test brought out a lithium concentration within the therapeutic values at 1,2 mmol/L (N: 0,6-1,2 mmol/L). The classic biological complications related to lithium poisoning (hypercalcemia, diabetes insipidus) confirmed the diagnosis. The patient has been transferred to our nephrology department where she got two hemodialysis sessions conducting to clinical and biological improvement, confirming the diagnosis of lithium poisoning despite the normal blood levels. Later, she was transferred to the psychiatry department for follow-up and for treatment adjustment. A 63-year-old man was admitted to the intensive care unit (ICU) with a severe aspiration pneumonia. Past medical history included schizophrenia, for which he required institutional care; treatment had included neuroleptics and intermittent lithium, the latter restarted 6 months before admission. The patient was treated with antibiotics and intubated for several days, with the development of polyuria (3–5 L/d), hypernatremia, and acute renal insufficiency; the peak plasma Na+ concentration was 156 meq/L, and peak creatinine was 2.6 mg/dL. Urine osmolality was measured once and reported as 157 mOsm/kg, with a coincident plasma osmolality of 318 mOsm/kg. Lithium was stopped on admission to the ICU. On physical examination, the patient was alert, extubated, and thirsty. Weight was 97.5 kg. Urine output for the previous 24 h had been 3.4 L, with an IV intake of 2 L/d of D5W. To describe a patient with lithium intoxication presenting as acute parkinsonism, adverse metabolic effects and nephrogenic diabetes insipidus (DI). We report a case of a 67-year-old woman with a bipolar affective disorder who was treated with lithium for 10 years. Under concomitant renal insufficiency and urinary tract infarction, she experienced progressive hand tremor, bradykinesia, and unsteady gait. Laboratory results revealed hypercalcemia and hypermagnesiemia. A high serum lithium level (3.6 mEq/L) was found; thus lithium was discontinued. She was found to have a high serum level of intact parathyroid hormone: 135.0 pg/ml and a suspicious parathyroid adenoma. Polyuria with hypernatremia was also noted. A water deprivation test confirmed nephrogenic diabetes insipitces. After correction of electrolyte imbalance and reduction of lithium level, her consciousness recovered. Her parkinsonian features were responsive to levodopa 400 mg/day in 2 divided doses. One month later, apart from the residual extrapyramidal symptoms and mania, her condition was otherwise stationary. Tremor is the most frequent movement disorder associated with lithium therapy, while severe parkinsonism has been rarely reported. It should be kept in mind in differential diagnosis of acute parkinsonism especially in elder patients who receive a chronic lithium carbonate therapy. Treatment with lithium can cause several neurological side effects, even at therapeutic levels. We report the case of a 49-year-old woman, with bipolar disorder and depression, undergoing treatment with lithium, antidepressants and antipsychotics, who was admitted to hospital due to a clinical picture of visual hallucinations with an elevated lithaemia of 2.1 mEq/L (therapeutic range: 0.6-1.2 mEq/L). The patient developed a severe encephalopathy that required the use of assisted ventilation in the intensive care unit. Initial magnetic resonance imaging showed a reversible bilateral symmetrical hyperintensity in the dentate nuclei in T2 and T2-FLAIR sequences. Over the following months she gradually developed a pancerebellar syndrome with evidence of a marked loss of bilateral volume in the cerebellum, above all at the expense of the vermis, which was accompanied by a permanent and disabling cerebellar syndrome. Although treatment with lithium can cause a variety of neurological side effects, they are usually reversible. However, they occasionally give rise to permanent and disabling sequelae, as in the case of the patient reported here, with a marked and progressive cerebellar atrophy, accompanied by permanent sequelae in the form of a disabling cerebellar syndrome. The cerebellar neurotoxicity of lithium must be taken into account in the broad differential diagnosis of cerebellar ataxia in adults. A 35-year-old woman intentionally took 40,000 mg of lithium carbonate, and she was transferred to our hospital with nausea, vomiting, and diarrhea. She was diagnosed as having bipolar disorder 10 years ago and was receiving oral lithium therapy. Blood test results on arrival were remarkable for a negative anion gap of -2.1 and later, the serum lithium level turned out to be as high as 15.4 mEq/L. Intubation was required because of disrupted consciousness, and continuous hemodiafiltration (CHDF) was immediately started in the intensive care unit to obtain constant removal of lithium. After adding intermittent hemodialysis (IHD) twice during the daytime to accelerate the lithium clearance, CHDF became unnecessary on day 4, and she was extubated on day 6 with complete recovery of consciousness. Close monitoring of the patient data showed recovery of the decreased anion gap as indicator of the serum lithium level reduction. On day 36, she was discharged without any complication and sequela. The current case highlighted the effective use of CHDF between IHD sessions to prevent the rebound elevation of lithium and the role of the anion gap as a surrogate marker of serum lithium concentration during the treatment. Mineral Lithium – Lithium is the \"classic\" mood stabilizer, the first to be approved by the US FDA, and still popular in treatment. Therapeutic drug monitoring is required to ensure lithium levels remain in the therapeutic range: 0.6 or 0.8-1.2 mEq/L (or millimolar). Signs and symptoms of toxicity include nausea, vomiting, diarrhea, and ataxia. The most common side effects are lethargy and weight gain. The less common side effects of using lithium are blurred vision, a slight tremble in the hands, and a feeling of being mildly ill. In general, these side effects occur in the first few weeks after commencing lithium treatment. These symptoms can often be improved by lowering the dose. Lithium concentrations in whole blood, plasma, serum or urine may be measured using instrumental techniques as a guide to therapy, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Serum lithium concentrations are usually in the range of 0.5–1.3 mmol/L (0.5–1.3 mEq/L) in well-controlled people, but may increase to 1.8–2.5 mmol/L in those who accumulate the drug over time and to 3–10 mmol/L in acute overdose. Lithium salts have a narrow therapeutic/toxic ratio, so should not be prescribed unless facilities for monitoring plasma concentrations are available. Doses are adjusted to achieve plasma concentrations of 0.4 to 1.2 mmol /L on samples taken 12 hours after the preceding dose. Given the rates of thyroid dysfunction, thyroid parameters should be checked before lithium is instituted and monitored after 3–6 months and then every 6–12 months. Gastric lavage. A tube is placed through the nose or mouth into the stomach. The tube is used to remove lithium that has not been digested yet. It may also be used to put medicines directly into the stomach to help stop lithium from being absorbed. Use of an artificial kidney to clean the blood (dialysis). This is usually done only in the most severe cases. Diuretic medications such as furosemide and hydration via intravenous normal saline appear to be effective in speeding the removal of lithium and also rehydrate patients who've lost fluids. Hemodialysis. Hemodialysis is widely advocated as a means of reducing the risk of permanent neurological sequelae following lithium poisoning. Although hemodialysis clearly enhances the elimination of lithium, it is unclear whether this translates into improved patient outcomes. People may be sent home once their lithium level is less than 1.5 mEq/L and they have no symptoms. See also A stuporous 22-year-old man was admitted with a history of behaving strangely. His friends indicated he experienced recent emotional problems stemming from a failed relationship and had threatened suicide. There was a history of alcohol abuse, but his friends were unaware of recent alcohol consumption. The patient was obtunded on admission, with no evident focal neurologic deficits. The remainder of the physical examination was unremarkable. Na+ 140 meq/L K+ 5 meq/L Cl− 95 meq/L HCO3− 10 meq/L Glucose 125 mg/dL BUN 15 mg/dL Creatinine 0.9 mg/dL Ionized calcium 4.0 mg/dL Plasma osmolality 325 mOsm kg/H2O Urinalysis revealed crystalluria, with a mixture of envelope-shaped and needle-shaped crystals. With blood levels of lithium in the upper therapeutic range (therapeutic 0.6 to 1.2 mEq/L), it is not uncommon to observe a fast-frequency action tremor or asterixis, together with nausea, loose stools, fatigue, polydipsia, and polyuria. These symptoms usually subside with time. Above a level of 1.5 to 2 mEq/L, particularly in patients with impaired renal function or in those taking a thiazide diuretic, serious intoxication becomes manifest—clouding of consciousness, confusion, delirium, dizziness, nystagmus, ataxia, stammering, diffuse myoclonic twitching, and nephrogenic diabetes insipidus. Vertical (downbeating) nystagmus and opsoclonus (see Chap. 13) may also be prominent. A variety of skin problems is common including worsening of acne vulgaris. An uncommon toxic effect is the development of goiter but most patients remain euthyroid although the thyroid-stimulating hormone (TSH) levels may increase slightly. The goiter usually requires no treatment but it is possible to becomes effective, usually a matter of 4 or 5 days. The usual dosage of lithium is 1,200 to 2,400 mg daily in divided oral doses, which produces a desired serum level of 0.9 to 1.4 mEq/L. The serum level of lithium must be checked frequently, both to ensure that a therapeutic dose is being taken and to guard against toxicity (see later). In the treatment of acute mania, lithium is initiated at 300 mg bid or tid, and the dose is then increased by 300 mg every 2–3 days to achieve blood levels of 0.8–1.2 meq/L. Because the therapeutic effect of lithium may not appear until after 7–10 days of treatment, adjunctive usage of lorazepam (1–2 mg every 4 h) or clonazepam (0.5–1 mg every 4 h) may be beneficial to control agitation. Antipsychotics are indicated in patients with severe agitation who respond only partially to benzodiazepines. Patients using lithium should be monitored closely, since the blood levels required to achieve a therapeutic benefit are close to those associated with toxicity. Valproic acid may be better than lithium for patients who experience rapid cycling (i.e., more than four episodes a year) or who present with a mixed or dysphoric mania. Tremor and weight gain are the most common side effects; hepatotoxicity and pancreatitis are rare toxicities. A 32-year-old man was admitted to the hospital with weakness and hypokalemia. The patient had been very healthy until 2 months previously when he developed intermittent leg weakness. His review of systems was otherwise negative. He denied drug or laxative abuse and was on no medications. Past medical history was unremarkable, with no history of neuromuscular disease. Family history was notable for a sister with thyroid disease. Physical examination was notable only for reduced deep tendon reflexes. Sodium 139 143 meq/L Potassium 2.0 3.8 meq/L Chloride 105 107 meq/L Bicarbonate 26 29 meq/L BUN 11 16 mg/dL Creatinine 0.6 1.0 mg/dL Calcium 8.8 8.8 mg/dL Phosphate 1.2 mg/dL Albumin 3.8 meq/L TSH 0.08 μIU/L (normal 0.2–5.39) Free T4 41 pmol/L (normal 10–27) The abuse of laxatives and a prolonged treatment with diuretics has to be brought into consideration as the most common cause for renal or intestinal loss of potassium. Besides characteristical alterations at the E.C.G. and besides intestinal disturbances there do occur again and again acute, life-threatening aspects of cases connected with tetraplegias and a respiratory failure. By means of 3 cases from our hospital and 27 casuistics in literature symptomatology and dynamic in the development of hypokaliemia is discussed. The mean of potassium in the serum of the 16 patients, those having quadriplegias, ran up to 1,7 mval/l (range 1,4-2,5). Paralysis develops peracutely in 4 of the cases within hours and in 12 of the cases within days. In the anamnesis symptoms of adynamia could be traced with nearly every patient. A functional psychosis (reversible physically founded psychosis) couldn't be detected in any of the cases. With the help of a administration of potassium one could achieve a total retrogression of the symptoms. Besides this a normalisation of the acide-base equilibrium is required because of a metabolic alkalosis, detectable in most of the cases.\nHere is the question:\nPSYCHIATRY: A 46-year-old man with bipolar disorder is brought to the emergency department after an over-ingestion of lithium carbonate. Examination reveals severe tremor, ataxia, dysarthria, myoclonus and fasciculations. Lithemia is 4.1 mEq/L (toxicity > 1.6 mEq/L). Which of the following therapeutic options would be most indicated?\nHere are the potential choices:\n1. Aminophylline associated with a cathartic.\n2. Activated charcoal.\n3. Hemodialysis.\n4. Forced diuresis.\nThe correct answer is: ",
        "gold_answer": "3 Hemodialysis.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n To describe the case of a patient who ingested 50 sustained release lithium carbonate 400 mg tablets, and reached a late peak concentration above 3 mEq/L. A 32-year-old male with bipolar mood disorder ingested 50 sustained-release lithium carbonate tablets. Upon admission to the emergency room, a gastric wash was performed,from which several tablet remnants were obtained, as well as an intestinal lavage using activated carbon. good general status, no fever, blood pressure 160/90 mm Hg, no edemas. Neurologic, pulmonary, and cardiac examinations were normal. CBC and the chemistry panel were normal. The patient's psychopathological examination suggested a stable status with no apparent manifestations arising from a decompensated mood disorder. Five hours after his massive lithium ingestion the drug's plasma levels were 0.75 mEq/L. At 22 hours post-ingestion a chemistry panel was obtained, which showed serum creatinin at 1.38 mg/dL and a lithium plasma concentration of 3.15 mEq/L. A hemodyalisis trial was attempted for 4 hours. At 73 hours post-ingestion, lithium plasma levels were 0.6 mEq/L, that is, within therapeutic range. The patient was hemodynamically stable and serial blood tests were normal; he was discharged. Acute lithium intoxication with plasma levels above 3 mEq/l can be fatal or result in irreversible neurologicsequelae in almost one third of cases, with persistent cerebellar dysfunction in association with dementia of variable degree, andrenal, blood, and liver disturbances. Sustained-release tablets may prolong absorption and delay peak plasma concentrations. In such cases, therefore, it is recommended that drug plasma concentrations be monitored during 48-72 hours post-ingestion. Lithium has been used to treat bipolar disorder. Lithium has a narrow therapeutic index, with a therapeutic level between 0.6 and 1.5 mEq/L. The possible complications of lithium overdose include altered mental status, hand tremor, muscle weakness, nausea, vomiting, diarrhea, seizure, syncope, and arrhythmia. Lithium intoxication can be fatal and is difficult to diagnose in patients without a history of lithium intake. The occurrence of serious cardiac arrhythmias is rare in lithium intoxication. An 81-year-old man was brought to the emergency department because of consciousness disturbance for 2 days. According to his daughter, he had a history of hypertension and diabetes. Recently, his family also observed slurring of speech and easy choking. The physical examination findings were unremarkable. Blood examination only revealed impaired renal function. Twelve-lead electrocardiography revealed sinus rhythm with first-degree atrioventricular block. Chest radiography revealed mediastinal widening. The blood pressures obtained from the 4 limbs showed no significant differences. Subsequently, brain computed tomography revealed no obvious intracranial lesion. A neurologist was consulted, and a recent ischemic stroke could not be ruled out. While in the observation area, his systolic blood pressure decreased to &lt;90 mm Hg and he showed bradycardia, and 12-lead electrocardiography revealed an AV block and long pulse. Contrast-enhanced chest computed tomography revealed no evidence of aortic dissection. Another family member reported a history of lithium intake for bipolar disorder for &gt;30 years. Blood examination revealed a lithium concentration of 2.65 mEq/L. A nephrologist was consulted, and emergency hemodialysis was indicated. Dopamine was administered for his shock status via a right neck central venous catheter. His lithium level gradually declined after the hemodialysis, and blood pressure and consciousness level improved subsequently. The patient was discharged 9 days later in a stable condition. If an emergency physician encounters a patient with altered consciousness and arrhythmia with cardiogenic shock, the patient's drug intake history should be carefully reviewed to rule out cardiovascular problems on the basis of the patient's clinical condition. A 53-year-old woman was brought to the Emergency Department for a persistent state of stupor, tremors, fever and oliguria. The patient had been under treatment for depression. The electrocardiogram showed a wider QRS complex; laboratory tests were as follows: urea 110 mg/dL, creatinine 3 mg/dL, sodium 135 mEq/L, potassium 4.5 mEq/L, and lithium 8.0 mEq/L. Renal replacement was initiated to normalize plasma lithium levels; both stupor and speech impairment persisted for several days after dialysis. Complete recovery was achieved several days afterwards. The patient was a 26-year-old woman who ingested a total of 230 tablets, including 160 lithium carbonate tablets (200 mg), in a suicide attempt, and was brought to our hospital 5 hr later. After arriving at the hospital, her only complaint was mild nausea, and no neurological abnormalities or renal dysfunction was observed. We were unable to learn the blood concentration of lithium immediately. A forced diuresis was performed after admission, but the nausea persisted. Continuous hemodialysis (CHD) was performed for 23.5 hr starting 19 hr after ingesting the tablets because the patient had ingested a large amount of lithium carbonate, 32,000 mg. Since the nausea resolved after the CHD was started and no manifestations of lithium intoxication had developed as of 91 hr after ingestion, the patient was discharged. The blood lithium concentrations (mEq/L) revealed at a later date showed that the concentration 5 hr (at the time of the initial examination), 19 hr (start of CHD), 44.5 hr (end of CHD), and 91 hr after ingestion (at the time of discharge) was 4.08, 3.30, 1.09, and 0.38, respectively. Blood purification is said to be effective in treating serious lithium intoxication, but it is difficult to judge when to stop. A favorable outcome of treatment of acute lithium intoxication in a patient with normal renal function appears to have been achieved by performing CHD guided by the clinical manifestations, intravascular redistribution times, etc. Lithium is widely used to treat bipolar disorders. Lithium toxicity is generally caused by inappropriately high doses of lithium or impaired lithium excretion. Most lithium is eliminated via the kidneys and, since thyroid hormone increases tubular reabsorption of lithium, thyrotoxicosis could contribute to the development of lithium toxicity. We report a case of severe lithium toxicity that was apparently precipitated by the onset of thyrotoxicosis resulting from silent thyroiditis and dehydration. The patient was a 64-year-old woman who was admitted for muscle weakness in the lower extremities, diarrhea, and palpitations. She had bipolar disorder and was being treated with lithium carbonate, which she discontinued one week before admission. Her circulating lithium levels had been monitored yearly. Early in her admission she was dehydrated and had febrile episodes, paroxysmal atrial fibrillation, and muscle weakness. Initially, fluid therapy was started, but she lost consciousness and had a cardiac arrest for 2 minutes due to prolonged sinus arrest. Chest compression and manual artificial ventilation were performed, and body surface pacing was started. Serum lithium was markedly elevated to 3.81 mEq/L (therapeutic range, 0.4-1.0 mEq/L), and thyroid hormone levels were increased (free triiodothyronine, 8.12 pg/mL; free thyroxine, 4.45 ng/dL), while thyrotropin (TSH) was suppressed (&lt;0.01 μIU/mL). Hemodialysis was performed, and a temporary pacemaker was inserted for severe sinus bradycardia. The serum thyroglobulin was 4680 ng/mL (reference range, &lt;32.7 ng/mL). A TSH receptor antibody test was negative. Glucocorticoid therapy and inorganic iodine (100 mg) were administered and continued until day 11. However, her neurological symptoms deteriorated with floppy quadriplegia and deep coma. She gradually recovered. On day 36, she was discharged without any neurological symptoms or thyrotoxicosis. A 64-year-old woman taking lithium for bipolar disorder developed lithium toxicity in the setting of what seemed likely to be a recent onset of thyrotoxicosis due to silent thyroiditis. Thyrotoxicosis may be a contributing cause of lithium toxicity, particularly if it is abrupt in onset and even with cessation of lithium therapy if renal function is compromised. Thyroid function should be assessed immediately in patients with suspected lithium toxicity. Several reports have been published in the literature of choreoathetosis associated with lithium intoxication, but little is known about choreoathetosis without concurrent antipsychotic treatment. We report a 65-year-old woman with lithium intoxication whose choreoathetosis completely recovered without sequela following decrease of her serum lithium level. She had been treated elsewhere for bipolar II disorder and also for hypertension, chronic hepatitis type C and diabetes mellitus. As she became hypomanic, lithium carbonate at 600 mg/day was commenced, which was increased to 1200 mg/day due to unfavorable therapeutic response. She began to manifest disorientation and abnormal involuntary movement and was therefore referred to our Department of Psychiatry. Her clinical symptoms at admission included consciousness disturbance with marked bilateral symmetrical slow-wave activity in her EEG and choreoathetosis was observed in her face and upper and lower extremities. Cerebellar symptoms were minimal with only mild ataxic gait and finger-to-nose test did not show dysmetria or intention tremor. Her serum lithium level was 3.52 mEq/L, which was clearly in the toxic range. She demonstrated no metabolic abnormalities including hyperglycemia, and was diagnosed with lithium intoxication and treated with water loading and mannitol for forced diuresis. On the 14th day after admission her consciousness disturbance and choreoathetosis resolved, but EEG abnormalities still persisted. On the 23rd day after admission, she was discharged with clinical remission and normal EEG background activity. Although she developed mild renal dysfunction, hemodialysis was not indicated. Hypersensitivity of dopamine receptor in the nigrostriatal pathways may contribute to choreoathetosis in association with the patient's vulnerability. Choreoathetosis can be a sign of lithium intoxication and prompt treatment is required following careful differential diagnosis. Lithium is the milestone of psychiatric patients' therapy, in particular in bipolar disorder. Despite its high therapeutic efficacy, there are several side effects (renal, thyroid, parathyroid, dermatological) and management problems linked to its narrow therapeutic range, which exposes patients to a high risk of toxicity. We describe the case of a male patient with bipolar disorder in therapy with lithium sulfate who developed a severe acute-on-chronic intoxication. He came to our attention in a somnolent state with lithemia &gt;3 mEq/L and therefore underwent hemodialysis. In view of the high toxicity of lithium, a timely and correct therapeutic choice is important to improve the patient's outcome. In this context, considering lithemia, but also kidney function and the patient's clinical status, it is necessary to consider extracorporeal treatments, of which hemodialysis is the most preferable. Gastric lavage and whole bowel irrigation may be useful if done early. Activated charcoal is not effective. For severe toxicity hemodialysis is recommended. The risk of death is generally low. Acute toxicity generally has better outcomes than chronic toxicity. In the United States about 5,000 cases are reported to poison control centers a year. Lithium toxicity was first described in 1898. Signs and symptoms Symptoms of lithium toxicity can be mild, moderate, or severe. Mild symptoms include nausea, feeling tired, and tremor occur at a level of 1.5 to 2.5 mEq/L. Moderate symptoms include confusion, an increased heart rate, and low muscle tone occur at a level of 2.5 to 3.5 mEq/L. Severe symptoms include coma, seizures, low blood pressure and increased body temperature which occur at a lithium concentration greater than 3.5 mEq/L. When lithium overdoses produce neurological deficits or cardiac toxicity, the symptoms are considered serious and can be fatal. Potential side effects from lithium include gastrointestinal upset, tremor, sedation, excessive thirst, frequent urination, cognitive problems, impaired motor coordination, hair loss, and acne. Excessive levels of lithium can be harmful to the kidneys, and increase the risk of side effects in general. As a result, kidney function and blood levels of lithium are monitored in patients being treated with lithium. Therapeutic plasma levels of lithium range from 0.5 to 1.5 mEq/L, with levels of 0.8 or higher being desirable in acute mania. Lithium levels should be above 0.6 mEq/L to reduce both manic and depressive episodes in patients. A recent review concludes that the standard lithium serum level should be 0.60-0.80 mmol/L with optional reduction to 0.40-0.60 mmol/L in case of good response but poor tolerance or an increase to 0.80-1.00 mmol/L in case of insufficient response and good tolerance. To report a case of severe hypermagnesemia caused by magnesium hydroxide in a woman with normal renal function. A 42-year-old Hispanic woman with schizophrenia and bipolar affective disorder was transported from jail to the emergency department with confusion, abdominal pain, vomiting, and constipation. She had been treated in jail with magnesium hydroxide, ordered as milk of magnesia 30 mL po each night and Maalox 30 mL po three times daily. Additional medications included lithium carbonate 300 mg po three times daily, chlorpromazine 150 mg po three times daily, benztropine mesylate 1 mg po twice daily, and docusate sodium 100 mg po each morning. Her temperature was 35.1 degrees C, blood pressure 108/58 mm Hg, heart rate 112 beats/min, and respiratory rate 24 breaths/min. She would respond only briefly to voice or painful stimuli. Her abdomen was distended and diffusely tender. Laboratory tests included serum magnesium concentration 9.1 mEq/L (normal 1.3-2), blood urea nitrogen 16 mg/dL (8-22), creatinine 0.9 mg/dL (0.5-1.1), calcium 3.9 mEq/L (4.2-5.2), and lithium 1.0 mEq/L. A laparotomy was performed, and an adhesive band from a previous oophorectomy was found to be compressing the sigmoid colon. Hypermagnesemia, hypothermia, and hypotension continued in the intensive care unit. Despite successful treatment of the hypermagnesemia with calcium, intravenous fluids, and furosemide, the patient's cardiac rhythm degenerated into fatal, pulseless electrical activity on postoperative day 2. This case of severe hypermagnesemia from magnesium hydroxide ingestion illustrates many of the risk factors for hypermagnesemia in patients with normal renal function. People using magnesium-containing medications for relief of gastrointestinal distress may be at increased risk for hypermagnesemia. A brief review of magnesium physiology, clinical effects, and treatment is provided. Frequent use of the laboratory to identify hypermagnesemia is encouraged because it is often a clinically unexpected finding and responds well to early treatment. We describe here the case of a 54-year-old bipolar woman, followed in psychiatry and treated with lithium and a selective serotonin reuptake inhibitor (escitalopram) and lamotrigine, presenting a lithium poisoning with an altered state of consciousness caused by a supposed mismanagement of her treatment. Lithium poisoning was suggested based on neurological clinical features, but the blood test brought out a lithium concentration within the therapeutic values at 1,2 mmol/L (N: 0,6-1,2 mmol/L). The classic biological complications related to lithium poisoning (hypercalcemia, diabetes insipidus) confirmed the diagnosis. The patient has been transferred to our nephrology department where she got two hemodialysis sessions conducting to clinical and biological improvement, confirming the diagnosis of lithium poisoning despite the normal blood levels. Later, she was transferred to the psychiatry department for follow-up and for treatment adjustment. A 63-year-old man was admitted to the intensive care unit (ICU) with a severe aspiration pneumonia. Past medical history included schizophrenia, for which he required institutional care; treatment had included neuroleptics and intermittent lithium, the latter restarted 6 months before admission. The patient was treated with antibiotics and intubated for several days, with the development of polyuria (3–5 L/d), hypernatremia, and acute renal insufficiency; the peak plasma Na+ concentration was 156 meq/L, and peak creatinine was 2.6 mg/dL. Urine osmolality was measured once and reported as 157 mOsm/kg, with a coincident plasma osmolality of 318 mOsm/kg. Lithium was stopped on admission to the ICU. On physical examination, the patient was alert, extubated, and thirsty. Weight was 97.5 kg. Urine output for the previous 24 h had been 3.4 L, with an IV intake of 2 L/d of D5W. To describe a patient with lithium intoxication presenting as acute parkinsonism, adverse metabolic effects and nephrogenic diabetes insipidus (DI). We report a case of a 67-year-old woman with a bipolar affective disorder who was treated with lithium for 10 years. Under concomitant renal insufficiency and urinary tract infarction, she experienced progressive hand tremor, bradykinesia, and unsteady gait. Laboratory results revealed hypercalcemia and hypermagnesiemia. A high serum lithium level (3.6 mEq/L) was found; thus lithium was discontinued. She was found to have a high serum level of intact parathyroid hormone: 135.0 pg/ml and a suspicious parathyroid adenoma. Polyuria with hypernatremia was also noted. A water deprivation test confirmed nephrogenic diabetes insipitces. After correction of electrolyte imbalance and reduction of lithium level, her consciousness recovered. Her parkinsonian features were responsive to levodopa 400 mg/day in 2 divided doses. One month later, apart from the residual extrapyramidal symptoms and mania, her condition was otherwise stationary. Tremor is the most frequent movement disorder associated with lithium therapy, while severe parkinsonism has been rarely reported. It should be kept in mind in differential diagnosis of acute parkinsonism especially in elder patients who receive a chronic lithium carbonate therapy. Treatment with lithium can cause several neurological side effects, even at therapeutic levels. We report the case of a 49-year-old woman, with bipolar disorder and depression, undergoing treatment with lithium, antidepressants and antipsychotics, who was admitted to hospital due to a clinical picture of visual hallucinations with an elevated lithaemia of 2.1 mEq/L (therapeutic range: 0.6-1.2 mEq/L). The patient developed a severe encephalopathy that required the use of assisted ventilation in the intensive care unit. Initial magnetic resonance imaging showed a reversible bilateral symmetrical hyperintensity in the dentate nuclei in T2 and T2-FLAIR sequences. Over the following months she gradually developed a pancerebellar syndrome with evidence of a marked loss of bilateral volume in the cerebellum, above all at the expense of the vermis, which was accompanied by a permanent and disabling cerebellar syndrome. Although treatment with lithium can cause a variety of neurological side effects, they are usually reversible. However, they occasionally give rise to permanent and disabling sequelae, as in the case of the patient reported here, with a marked and progressive cerebellar atrophy, accompanied by permanent sequelae in the form of a disabling cerebellar syndrome. The cerebellar neurotoxicity of lithium must be taken into account in the broad differential diagnosis of cerebellar ataxia in adults. A 35-year-old woman intentionally took 40,000 mg of lithium carbonate, and she was transferred to our hospital with nausea, vomiting, and diarrhea. She was diagnosed as having bipolar disorder 10 years ago and was receiving oral lithium therapy. Blood test results on arrival were remarkable for a negative anion gap of -2.1 and later, the serum lithium level turned out to be as high as 15.4 mEq/L. Intubation was required because of disrupted consciousness, and continuous hemodiafiltration (CHDF) was immediately started in the intensive care unit to obtain constant removal of lithium. After adding intermittent hemodialysis (IHD) twice during the daytime to accelerate the lithium clearance, CHDF became unnecessary on day 4, and she was extubated on day 6 with complete recovery of consciousness. Close monitoring of the patient data showed recovery of the decreased anion gap as indicator of the serum lithium level reduction. On day 36, she was discharged without any complication and sequela. The current case highlighted the effective use of CHDF between IHD sessions to prevent the rebound elevation of lithium and the role of the anion gap as a surrogate marker of serum lithium concentration during the treatment. Mineral Lithium – Lithium is the \"classic\" mood stabilizer, the first to be approved by the US FDA, and still popular in treatment. Therapeutic drug monitoring is required to ensure lithium levels remain in the therapeutic range: 0.6 or 0.8-1.2 mEq/L (or millimolar). Signs and symptoms of toxicity include nausea, vomiting, diarrhea, and ataxia. The most common side effects are lethargy and weight gain. The less common side effects of using lithium are blurred vision, a slight tremble in the hands, and a feeling of being mildly ill. In general, these side effects occur in the first few weeks after commencing lithium treatment. These symptoms can often be improved by lowering the dose. Lithium concentrations in whole blood, plasma, serum or urine may be measured using instrumental techniques as a guide to therapy, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Serum lithium concentrations are usually in the range of 0.5–1.3 mmol/L (0.5–1.3 mEq/L) in well-controlled people, but may increase to 1.8–2.5 mmol/L in those who accumulate the drug over time and to 3–10 mmol/L in acute overdose. Lithium salts have a narrow therapeutic/toxic ratio, so should not be prescribed unless facilities for monitoring plasma concentrations are available. Doses are adjusted to achieve plasma concentrations of 0.4 to 1.2 mmol /L on samples taken 12 hours after the preceding dose. Given the rates of thyroid dysfunction, thyroid parameters should be checked before lithium is instituted and monitored after 3–6 months and then every 6–12 months. Gastric lavage. A tube is placed through the nose or mouth into the stomach. The tube is used to remove lithium that has not been digested yet. It may also be used to put medicines directly into the stomach to help stop lithium from being absorbed. Use of an artificial kidney to clean the blood (dialysis). This is usually done only in the most severe cases. Diuretic medications such as furosemide and hydration via intravenous normal saline appear to be effective in speeding the removal of lithium and also rehydrate patients who've lost fluids. Hemodialysis. Hemodialysis is widely advocated as a means of reducing the risk of permanent neurological sequelae following lithium poisoning. Although hemodialysis clearly enhances the elimination of lithium, it is unclear whether this translates into improved patient outcomes. People may be sent home once their lithium level is less than 1.5 mEq/L and they have no symptoms. See also A stuporous 22-year-old man was admitted with a history of behaving strangely. His friends indicated he experienced recent emotional problems stemming from a failed relationship and had threatened suicide. There was a history of alcohol abuse, but his friends were unaware of recent alcohol consumption. The patient was obtunded on admission, with no evident focal neurologic deficits. The remainder of the physical examination was unremarkable. Na+ 140 meq/L K+ 5 meq/L Cl− 95 meq/L HCO3− 10 meq/L Glucose 125 mg/dL BUN 15 mg/dL Creatinine 0.9 mg/dL Ionized calcium 4.0 mg/dL Plasma osmolality 325 mOsm kg/H2O Urinalysis revealed crystalluria, with a mixture of envelope-shaped and needle-shaped crystals. With blood levels of lithium in the upper therapeutic range (therapeutic 0.6 to 1.2 mEq/L), it is not uncommon to observe a fast-frequency action tremor or asterixis, together with nausea, loose stools, fatigue, polydipsia, and polyuria. These symptoms usually subside with time. Above a level of 1.5 to 2 mEq/L, particularly in patients with impaired renal function or in those taking a thiazide diuretic, serious intoxication becomes manifest—clouding of consciousness, confusion, delirium, dizziness, nystagmus, ataxia, stammering, diffuse myoclonic twitching, and nephrogenic diabetes insipidus. Vertical (downbeating) nystagmus and opsoclonus (see Chap. 13) may also be prominent. A variety of skin problems is common including worsening of acne vulgaris. An uncommon toxic effect is the development of goiter but most patients remain euthyroid although the thyroid-stimulating hormone (TSH) levels may increase slightly. The goiter usually requires no treatment but it is possible to becomes effective, usually a matter of 4 or 5 days. The usual dosage of lithium is 1,200 to 2,400 mg daily in divided oral doses, which produces a desired serum level of 0.9 to 1.4 mEq/L. The serum level of lithium must be checked frequently, both to ensure that a therapeutic dose is being taken and to guard against toxicity (see later). In the treatment of acute mania, lithium is initiated at 300 mg bid or tid, and the dose is then increased by 300 mg every 2–3 days to achieve blood levels of 0.8–1.2 meq/L. Because the therapeutic effect of lithium may not appear until after 7–10 days of treatment, adjunctive usage of lorazepam (1–2 mg every 4 h) or clonazepam (0.5–1 mg every 4 h) may be beneficial to control agitation. Antipsychotics are indicated in patients with severe agitation who respond only partially to benzodiazepines. Patients using lithium should be monitored closely, since the blood levels required to achieve a therapeutic benefit are close to those associated with toxicity. Valproic acid may be better than lithium for patients who experience rapid cycling (i.e., more than four episodes a year) or who present with a mixed or dysphoric mania. Tremor and weight gain are the most common side effects; hepatotoxicity and pancreatitis are rare toxicities. A 32-year-old man was admitted to the hospital with weakness and hypokalemia. The patient had been very healthy until 2 months previously when he developed intermittent leg weakness. His review of systems was otherwise negative. He denied drug or laxative abuse and was on no medications. Past medical history was unremarkable, with no history of neuromuscular disease. Family history was notable for a sister with thyroid disease. Physical examination was notable only for reduced deep tendon reflexes. Sodium 139 143 meq/L Potassium 2.0 3.8 meq/L Chloride 105 107 meq/L Bicarbonate 26 29 meq/L BUN 11 16 mg/dL Creatinine 0.6 1.0 mg/dL Calcium 8.8 8.8 mg/dL Phosphate 1.2 mg/dL Albumin 3.8 meq/L TSH 0.08 μIU/L (normal 0.2–5.39) Free T4 41 pmol/L (normal 10–27) The abuse of laxatives and a prolonged treatment with diuretics has to be brought into consideration as the most common cause for renal or intestinal loss of potassium. Besides characteristical alterations at the E.C.G. and besides intestinal disturbances there do occur again and again acute, life-threatening aspects of cases connected with tetraplegias and a respiratory failure. By means of 3 cases from our hospital and 27 casuistics in literature symptomatology and dynamic in the development of hypokaliemia is discussed. The mean of potassium in the serum of the 16 patients, those having quadriplegias, ran up to 1,7 mval/l (range 1,4-2,5). Paralysis develops peracutely in 4 of the cases within hours and in 12 of the cases within days. In the anamnesis symptoms of adynamia could be traced with nearly every patient. A functional psychosis (reversible physically founded psychosis) couldn't be detected in any of the cases. With the help of a administration of potassium one could achieve a total retrogression of the symptoms. Besides this a normalisation of the acide-base equilibrium is required because of a metabolic alkalosis, detectable in most of the cases.\nHere is the question:\nPSYCHIATRY: A 46-year-old man with bipolar disorder is brought to the emergency department after an over-ingestion of lithium carbonate. Examination reveals severe tremor, ataxia, dysarthria, myoclonus and fasciculations. Lithemia is 4.1 mEq/L (toxicity > 1.6 mEq/L). Which of the following therapeutic options would be most indicated?\nHere are the potential choices:\n1. Aminophylline associated with a cathartic.\n2. Activated charcoal.\n3. Hemodialysis.\n4. Forced diuresis.\nThe correct answer is: 3. Hemodialysis."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The present report describes the severe evolution of Kawasaki disease in a three-month-old infant. The ailment was initially atypical in its presentation, with the patient exhibiting only persistent fever in association with a progressive lethargy and maculopapular rash on the face, trunk and limbs erroneously diagnosed as roseola infantum. On the 10th day of the condition, mainly due to the unexplained persistence of fever, the infant was admitted to a local hospital. The typical features of KD appeared only on the 14th day of illness with the relapse of the maculopapular rash in association with non-purulent conjunctivitis; dry, reddish and fissured lips; tongue with reddish and hypertrophic papillae; erythema and edema of the palms and soles. During the following days, the ailment rapidly evolved to a catastrophic clinical picture characterized by generalized vasculitis, splenic infarction, pulmonary thrombosis, giant right and left coronary aneurysms, dilatation of common and internal iliac arteries and progressive ischemia of the distal third of the feet resulting in necrotic lesions of both halluces. Appropriate therapy was initiated, but repeated administration of intravenous immunoglobulin G (IVIG) followed by three days of administration of methylprednisolone did not abate the intense inflammatory activity. The remission of inflammation and regression of vascular lesions were only achieved during the following five weeks after the introduction of methotrexate associated with etanercept. The report of this case aims to draw attention to severe forms of KD that exhibit an unfavorable evolution and can be extremely refractory to the conventional therapy. While the diagnosis of typical form of Kawasaki disease (KD) is obvious, this multifaceted disease continues to surprise us. We report the case of a recurrent Kawasaki disease in an infant. At the age of 13 months, the infant was diagnosed with complete Kawasaki disease; he presented with prolonged fever, bilateral conjunctivitis, enanthem, exanthema, edema of the lower limb, peeling, and biological inflammatory syndrome. He was treated with intravenous immunoglobulin (IVIG) associated with a high dose of aspirin and then an antiplatelet dose with a good clinical-biological evolution. The echocardiography was normal. Seven months later, the patient was again admitted, in a similar picture: a prolonged fever evolving for 7 days, bilateral conjunctivitis, enanthem, cervical adenopathy of 1.5 cm/1 cm, scarlatiniform erythema, pruriginous of the trunk and limb, and peeling of the toes, with indurated edema of the hands and feet. The rest of the examination was normal except the irritability. The diagnosis of recurrent KD was made according the five criteria of the American Heart Association. The echocardiography was normal again. The infant received IVIG with good outcome. Despite its rarity, the possibility of recurrence of KD should be known by clinicians, so as not to delay the specific management of vasculitis whose stakes in terms of prevention of coronary artery lesions are well known. Our case confirms the possibility of this recurrence. The cutaneous eruption in Kawasaki disease (Chap. 385) is polymorphous, but the two most common forms are morbilliform and scarlatiniform. Additional mucocutaneous findings include bilateral conjunctival injection; erythema and edema of the hands and feet followed by desquamation; and diffuse erythema of the oropharynx, red strawberry tongue, and dry fissured lips. This clinical picture can resemble TSS and scarlet fever, but clues to the diagnosis of Kawasaki disease are cervical lymphadenopathy, cheilitis, and thrombocytosis. The most serious associated systemic finding in this disease is coronary aneurysms secondary to arteritis. Scarlatiniform eruptions are also seen in the early phase of SSSS (see “Vesicles/Bullae,” above), in young adults with Arcanobacterium haemolyticum infection, and as reactions to drugs. Kawasaki disease is an acute inflammatory condition characterized by various combinations of features but renal involvement is rare. This report is of a case of Kawasaki disease complicated by acute kidney failure. A 10 year-old girl was admitted because of acute renal failure with fever. She developed a high fever, and her general condition was poor; she had developed a macular erythematous rash 10 days earlier for which she was given cefadroxil. At admission, she remained febrile and had strawberry tongue, pharyngitis, dry erythematous lips, bilateral conjunctivitis, cervical lymphadenopathy and desquamation of the skin on her hands. She was anemic (hemoglobin = 9.6 g%), leukocytotic (33,100/mm3), but with no burr, fragmented red blood cells or thrombocytopenia. Her plasma C-reactive protein level was 236 mg/l; her blood urea was 9.5 mmol/l, her creatininemia 288 mumol/l and proteinuria was 0.5 g/l without hematuria. Urine cultures did not grow. Her blood transaminase and gammaglutamyltransferase activities were elevated. Ultrasonography of kidneys and coronary arteries was normal. Kidney biopsy performed one day after admission showed no vascular or glomerular changes, but renal tubular necrosis, indicating urinary excretion of pigments. Tests for myoglobinemia, myoglobinuria and blood muscle enzyme activities were all positive. The renal failure disappeared within 10 days but the fever and inflammatory manifestations persisted for 1 1/2-2 months despite two treatments of intravenous gammaglobulins and continuous salicylate administration. The patient developed arthralgias at the end of the first month of disease, but recovered without renal or vascular complications. Several cases of renal involvement have been reported during the course of Kawasaki disease. They have been rarely documented by histological examination so that the vascular origin of changes has not been demonstrated. Myoglobinuria, as seen in muscular crush injury, and in our case possibly due to malignant hyperthermia, may be responsible for the transient acute renal failure. In 2014, the American Heart Association (AHA) published the criteria needed to establish a diagnosis. [1] However, it is important to note that children who fall short of the full criteria but have cardiac abnormalities on echocardiogram meet the diagnosis of KD. [1] The patient must have fevers for five or more days, with at least four of the following criteria (either all at once or over a series of days): Bilateral painless bulbar conjunctival injection without exudate Erythematous mouth and pharynx, strawberry tongue or red, cracked lips Polymorphous exanthem (morbilliform, maculopapular, or scarlatiniform) Swelling of hands and feet with erythema of the palms and soles Cervical lymphadenopathy (over 1.5 cm in diameter) Arthritis is reported in one-third of cases with Kawasaki syndrome. It may have an early or a late onset form. We present a 15-month-old-girl who had been referred with complaints of pain and swelling in her left shoulder. Physical examination revealed bulbar conjunctival injection, erythematous lips and pharynx, strawberry tongue, erythematous rash, edema and erythema of the left shoulder, left knee, right elbow and right wrist, and moderate distress in the left shoulder and left hip. She was diagnosed with Kawasaki syndrome, and intravenous immunoglobulin infusion (IVIG) 2 g/kg and aspirin (100 mg/kg/day) were instituted. The patient had two additional episodes of arthritis involving the hip joint on the 8th day, and the shoulder and metacarpophalangeal (MCP) and interphalangeal (IP) joints of her right hand on the 15th day. Turbid material was aspirated in both instances; Gram and Wright's staining of this material showed many leukocytes but no bacteria. A second dose of IVIG (1 g/kg) was given. At the end of the third week all extremities were painless, with a normal range of motion. Arthritis in our patient was the presenting sign, having a 'septic arthritis mimicking' and 'biphasic' pattern. Although the patient presented with severe and recurrent arthritis, which is significantly correlated with severe multisystem disease and the presence or development of coronary artery aneurysm, the response to IVIG was excellent. Kawasaki disease (KD) is a systemic vasculitis of unknown cause and is associated with various digestive disorders, although only a few cases of intussusception associated with KD have been reported. We describe a case of intussusception followed by KD in a 3-year-old boy. The patient was admitted to our hospital for evaluation of severe abdominal pain. Because the target sign was seen on ultrasonography, intussusception was diagnosed and hydrostatic reduction was performed. On the second day after admission, he developed a high fever (38°C) and an irregular rash over his whole body. On the fourth day after admission, the high fever continued, and bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, strawberry tongue, indurated edema of the dorsa of the hands and feet, and diffuse erythema of the palms and soles appeared, and KD was ultimately diagnosed. He was treated with intravenous immunoglobulin 2 g/kg, aspirin 30 mg/kg/day, and prednisolone 2 mg/kg/day. The high fever and other clinical symptoms resolved immediately after the start of treatment. There was no relapse of KD symptoms after initial treatment, and periungual desquamation was observed on the 10th day after admission. He was discharged on the 15th day, without abnormalities such as coronary dilatation, 3 months after the onset of KD symptoms. Patients with intussusception and KD were older (≥3 years vs &lt;3 years) than those with intussusception alone. In addition, the site of intussusception in KD was mainly colonic rather than ileocolic. If intussusception precedes development of the characteristic clinical symptoms of KD, diagnosis of KD may be delayed. KD should be considered in children older than 3 years with intussusception at a colonic site. A 14-month-old girl presented with a 4-d history of fever and generalized exanthema. Four characteristic symptoms of incomplete Kawasaki disease (KD) were present on admission (fever, rash, non-purulent conjunctival injection, oropharyngeal changes) and then followed by oedema of the hands and feet and mild plantar desquamation. The typical laboratory features of KD, such as elevated erythrocyte sedimentation rate, leukocytosis, thrombocytosis, and positive C-reactive protein were also seen. Ultrasound examination of the mediastinum revealed the presence of a lymph node, 30 mm in diameter, below the tracheal carina. Thoracic CT scan confirmed the mediastinal lymph node. The patient was treated with aspirin and intravenous gamma-globulin. Ultrasound study of the mediastinum, which was carried out 6 weeks after hospital discharge, showed that the lymph node had disappeared. This case illustrates that lymph nodes other than cervical lymphadenopathy should be sought when the diagnosis of classical or atypical KD is suspected. We report a 3-year-old girl with Kawasaki disease who presented with retropharyngeal edema and shock syndrome. This is the first reported case in Taiwan. The patient initially presented with fever, cough, and pyuria followed by rapidly progressive enlarged bilateral cervical lymphadenopathy. On the third day of the fever, computed tomography for airway compression sign found widening of the retropharyngeal space mimicking a retropharyngeal abscess. Later, an endotracheal tube was inserted for respiratory distress. A skin rash over her trunk was also noted. On the fifth day of the fever, the clinical course progressed to hypotension and shock syndrome. Because of more swelling of bilateral neck lymph nodes, computed tomography was arranged again and revealed partial resolution of the edematous changes in the retropharyngeal space. Edema of the hands and feet, bilateral bulbar conjunctivitis, and fissured lips were subsequently found. The diagnosis of Kawasaki disease was confirmed on the eighth day of fever. There was no evidence of bacterial infection. She was administered intravenous immunoglobulin (2 mg/kg) and high dose aspirin (100 mg/kg/day). One day later, the fever subsided, and her blood pressure gradually became stable. Heart echocardiography on the Day 13 revealed dilated left coronary artery and mitral regurgitation. Follow-up echocardiography six months later showed normal coronary arteries. To date, the patient has not experienced any complications. This case illustrates that retropharyngeal edema and shock syndrome can be present in the same clinical course of Kawasaki disease. Clinicians and those who work in intensive care units should be aware of unusual presentations of Kawasaki disease to decrease rates of cardiovascular complications.  A 9-year-old girl developing fever and hyperemia of both bulbar conjunctiva 5 days before admission to the Saitama Children's Medical Center after antibiotics proved ineffective was found on admission to have general fatigue and a temperature of 39 degrees C. Physical examination showed hyperemia of the bulbar conjunctiva, fissures of the lips, redness of the pharynx, and swelling of the cervical lymph nodes. Laboratory tests detected neutrophilia (11,200/microL), mild anemia (11.4g/dL), thrombocytopenia (110,000/microL), and elevated serum aspartate aminotransferase (242IU/L), alanine aminotransferase (328IU/L), and C-rective protein (25.2 mg/dL). Autoantibodies such as anti-nuclear, anti-SS-A/Ro, and anti-Jo-1 were also found. Echocardiography showed no abnormality of the coronary arteries. She was diagnosed as having incomplete Kawasaki disease on day 7 of illness, necessitating that a high dose of immunoglobulin be given intravenously. Her temperature dropped temporarily to 37 degrees C, but she developed erythema of the cheek and fever. Intravenous immunoglobulin was restarted, and minocycline introduced because her daily contact with a pet cat indicated richettsial infection such as Q fever. Mild fever, muscle pain, and elevated C-reactive protein did not improve, but clinical signs and symptoms gradually lessened after ibuprofen was given, then disappeared. A definitive diagnosis of Q fever was made through an over 4-fold rise in phase II IgG antibody titers against Coxiella burnetii, titer of less than 1 : 16 on day 14 of illness, and titer of 1 : 256 on day 34. This case study describes on atypical case of Q fever with clinical manifestations mimicking Kawasaki disease. Erythema multiforme (EM) is an immune-mediated disease with mucocutaneous localization and plurietiologic determinism. The term \"multiforme\" refers to the variety of aspects that the lesions can take from patient to patient and during evolution in a single patient. We have selected 2 cases of small children diagnosed with different etiology of EM to illustrate the importance of a correct and fast diagnosis. Case 1 involves a 2-year-old girl from a rural area who presented with fever and pruritic erythematous papular eruption. The onset of the symptoms was 3 days before presentation with fever and ulcerative lesions on the oral and labial mucosa, followed by the appearance of erythematous macular lesions, with progressive confluence to intense pruritic patches. The 2nd involves a 2-year-old boy with fever, loss of appetite, productive cough, and petechiae. He had corticosensible immune thrombocytopenia from the age of 6 months, with many recurrences. The patient received treatment with ampicillin/sulbactam and symptomatics for an erythemato-pultaceous angina. During the 2nd day of treatment the patient developed an erythematous macular eruption on the face, scalp, trunk, and limbs, with bullae formation. The 1st patient was diagnosed based on biologic findings: positive inflammatory syndrome, elevated level of anti-Mycoplasma pneumoniae immunoglobulin M antibodies and immunoglobulin E. Histopathologic examination described papillary dermal edema, inflammatory infiltrate, and lymphocyte exocytosis. In the 2nd case, the hemoleucogram identified 12,000/mm platelets and the medulogram aspect was normal. Serology for Epstein-Barr virus was negative. The diagnosis was EM secondary to M pneumoniae infection in case 1 and secondary to administration of ampicillin/sulbactam in case 2. In both cases, etiopathogenic treatment consisting of steroidal antiinflammatory drugs, antihistamines was administered. Because of specific etiology, the 1st case received antibiotics. The evolution was favorable in 10 to 14 days; the patients were discharged after etiopathogenic treatment consisting of steroidal antiinflammatory drugs, antihistamines, and/or antibiotics. Performing a detailed clinical examination, medical history of drug use, infection or general diseases can establish a good diagnosis of EM. Histopathologic examination can help. The treatment is etiologic, pathogenic, and symptomatic. EM usually has a self-limited evolution. A previously healthy 11-month-old girl presented with fever and rash for 6 days. Physical examination revealed an irritable infant with a high fever, injected conjunctivae, red cracked lips, posterior auricular lymphadenopathy, hepatomegaly, generalized erythematous maculopapular rash and petechial hemorrhage on trunk, face and extremities. Complete blood count showed atypical lymphocytosis and thrombocytopenia. Dengue infection was initially diagnosed. The persistent fever and clinical manifestations of Kawasaki disease (KD) were observed on day 8 with high erythrocyte sedimentation rate (56 mm/hr). Treatment of KD included intravenous immunoglobulin on day 9 of the illness. Desquamation of the fingers was found on day 15 of the illness. Ectasia of left coronary artery with small aneurysmal dilatation was detected by echocardiography on day 15 of the illness. Hemagglutination-inhibition test and enzyme-linked immunosorbent assay for dengue virus eventually showed a four-fold rising. According to the literature review, this is the second reported case of dengue infection concomitant with KD. The natural course of each disease may be modified and causes some difficulties in diagnosis and management. Cervical lymphadenopathy (often painful and unilateral, with at least one node > 1.5 cm). Diffuse mucous membrane erythema (e.g., “strawberry tongue”); dry, red, chapped lips. Erythema of the palms and soles; indurative edema of the hands and feet; late desquamation of the fingertips (in the subacute phase). Other manifestations include sterile pyuria, gallbladder hydrops, hepatitis, and arthritis. Untreated Kawasaki disease can lead to coronary aneurysms and even myocardial infarction! Conjunctivitis Rash Adenopathy Strawberry tongue Hands and feet (red, swollen, f aky skin) BURN (fever > 40°C for ≥ 5 days) Subacute phase: Begins after the abatement of fever and typically lasts for an additional 2–3 weeks. Manifestations are thrombocytosis and elevated ESR. Untreated children may begin to develop coronary artery aneurysms (40%); all patients should be assessed by echocardiography at diagnosis. Kawasaki disease is an idiopathic medium-sized vasculitis that occurs primarily in infants and children younger than 5 years of age. Atypical Kawasaki disease applies to patients who do not fulfill the complete criteria of fever of 5 days or more with at least four of five features: bilateral conjunctival injection, changes in the lips and oral cavity, cervical lymphadenopathy, extremity changes, and polymorphous rash. Acute kidney injury is defined as a sudden decline in kidney function within hours, including structural injuries and loss of function. Acute kidney injury is extremely common in hospitalized pediatric patients. However, it is rarely documented in Kawasaki disease. Acute kidney injury is underestimated in Kawasaki disease due to the lack of a clear definition of age-specific normal serum creatinine levels and routine renal functions. This report describes a case who presented with clinical features suggestive of atypical Kawasaki disease and developed acute kidney injury. A 2-year-old Saudi girl had a history of high-grade fever for 5 days, moderate dehydration, dry cracked lips, poor appetite, and generalized erythematous rash; therefore, she was diagnosed to have incomplete Kawasaki disease. Laboratory investigations revealed normochromic normocytic anemia, leukocytosis, thrombocytosis, high inflammatory markers, and acute kidney injury stage III. An echocardiogram showed a 4-mm dilatation on the left main coronary artery and a 3-mm dilatation on the right. A renal biopsy was not performed to identify the cause of the injury as it showed improvements after the start of the specific therapy for Kawasaki disease; intravenous immune globulin at a dose of 2 g/kg, aspirin at a high dosage of 80 mg/kg/day, and prednisolone at 2 mg/kg. In addition to the acute kidney injury management, normal saline boluses were followed by furosemide at a 2 mg/kg dose. Her urine output increased, and her renal functions normalized. She was discharged in good condition after 10 days. It is valuable to check renal function tests in a confirmed case of Kawasaki disease to reduce the negative consequences of late acute kidney injury discovery. Early detection and intervention make a substantial difference in acute kidney injury management. Measles should be distinguished from similar presenting exanthemic diseases of childhood, autoimmune processes, and adverse drug reactions. Rubella causes a rash similar to measles with head to caudal distribution, mild respiratory symptoms, the absence of conjunctivitis. Still, it is accompanied by the presence of adenopathies - which is characteristic of this disease. Roseola is characterized by an illness beginning with a high fever, which subsides after a few days, accompanied by the appearance of a rash in the central part of the body, without the presence of Koplik's points. Mononucleosis is a febrile viral disease, a characteristic course with few symptoms during childhood, contrary to what happens in more advanced ages.  Mononucleosis manifests itself by pharyngeal compromise, polyadenopathy, and hepatosplenomegaly, and the rash can have different forms of presentation. In Kawasaki disease, there is an ocular compromise with the presence of conjunctivitis without exudate, and the respiratory compromise is not part of this pathology. Group A Streptococcus (particularly Scarlet fever) may present with a similar rash (a coarse, sandpaper-like, blanching, erythematous) to measles in association with pharyngitis. [5] [14] Kawasaki disease (KD) is a common vasculitic disorder usually seen in children below 5 years of age. The disease can present with protean clinical manifestations which include high grade fever (for at least 5 days), rash, redness of the lips and a typical strawberry tongue, cervical lymph node enlargement (often unilateral), swelling over the hands/feet and, later a characteristic peripheral desquamation over the fingers and toes. These clinical features appear sequentially and the findings may change from day-to-day. Thus, all these features may not be seen together at any one point of time. The diagnosis rests on the recognition of this characteristic temporal sequence of clinical events, none of which are, by themselves, pathognomonic. Establishing a diagnosis of KD may be further complicated by the occurrence of several other, seemingly unrelated, clinical features. These include irritability, neck stiffness, sterile pyuria, pneumonitis, hydrops of the gallbladder and hepatitis among many others. There is no laboratory test that can help in confirming a diagnosis of KD. Left untreated, up to 20% of children with KD can develop coronary aneurysms with catastrophic long term sequelae. It is important to diagnose KD in the first 10 days of the illness so that appropriate therapy with intravenous immunoglobulin and aspirin can be Initiated. All paediatricians, and physicians looking after children, need to be aware of this condition which is now being increasingly recognized in India. Kawasaki syndrome, also known as mucocutaneous lymph node syndrome, is an acute vasculitis of infants and young children. We describe a four-year-old girl who presented with fever, a diffuse erythematous maculopapular rash, bilateral nonpurulent bulbar conjunctivitis, dry, red, fissured lips, a tongue with a strawberry \"appearance\", an erythematous pharynx, indurative erythema, and edema and desquamation of the face, hands and feet. She probably developed mitral valve prolapse during the course of the disease. The diagnosis of Kawasaki syndrome was arrived at by excluding other diseases and by the presence of all the clinical criteria for Kawasaki syndrome. Since this syndrome is rarely encountered in Turkey, this case is presented and the literature regarding the syndrome is reviewed. Classically, five days of fever plus four of five diagnostic criteria must be met to establish the diagnosis. The criteria are: erythema of the lips or oral cavity or cracking of the lips rash on the trunk swelling or erythema of the hands or feet red eyes (conjunctival injection) swollen lymph node in the neck of at least 15 mm Many children, especially infants, eventually diagnosed with Kawasaki disease, do not exhibit all of the above criteria. In fact, many experts now recommend treating for Kawasaki disease even if only three days of fever have passed and at least three diagnostic criteria are present, especially if other tests reveal abnormalities consistent with Kawasaki disease. In addition, the diagnosis can be made purely by the detection of coronary artery aneurysms in the proper clinical setting. Investigations A physical examination will demonstrate many of the features listed above. This report describes a 26-year-old woman who fulfills the criteria for the diagnosis of Kawasaki disease or mucocutaneous lymph node syndrome, an acute febrile illness that usually afflicts young children. The diagnosis is made in persons with fever lasting 5 or more days when four of the following criteria are met: bilateral injection of ocular conjunctivae; the involvement of the mucous membranes of the upper respiratory tract consisting of any combination of the following--redness and fissuring of lips; \"strawberry tongue,\" or erythema of the pharynx; involvement of the peripheral extremities characterized in the early stages by an indurative erythematous rash of palms and soles followed by membranous desquamation; polymorphous nonvesicular truncal exanthem; and acute nonsuppurative enlargement of cervical lymph nodes. An added stipulation is that the illness must not be attributable to a known disease process. A 4-year-old boy experienced sudden fever, followed by a rash on the trunk and extremities and erythema of the pharynx. Five days later, the fever remained and erythema appeared on the oropharynx, tongue, and lips. The skin of the palms and soles became erythematous and indurated, and both conjunctivae became injected. Desquamation of the skin occurred on both thumbs and one finger, and an anterior cervical lymph node was found to be enlarged. The patient was diagnosed as having Kawasaki disease, and treatment with aspirin was started. The desquamation progressed to involve the entire surface of the palms and soles, and then symptoms resolved. Twenty years after recognition of Kawasaki disease, this enigmatic illness continues to defy attempts to understand its etiology and pathogenesis. Most experts agree that the cause is either an environmental toxin or an infectious agent, but other possible causative agents may need to be proposed and investigated. We describe adult-onset Kawasaki disease (KD) and review clinical manifestations and treatment guidelines. Our patient is a 20-year-old female who initially presented to an outside hospital for fever, cervical lymphadenopathy, malaise, exudative tonsillitis, and skin eruption. She received antibiotics for suspected exudative pharyngitis, but experienced continued fevers and presented to the UCLA emergency room one week later. She had diffuse petechial macules coalescing into reticulated patches, fingertip peeling, conjunctival injection, oral erosions, and tongue swelling. Despite her age, given her constellation of symptoms, a diagnosis of typical KD was favored. She was started on high dose aspirin and IVIG, with improvement of rash and conjunctivitis. She was discharged on 325mg of aspirin daily with close follow-up. This case highlights the challenge of diagnosing KD in adults. Although this patient had classic symptoms, she was likely misdiagnosed because KD is rare in adults and without validated criteria. Our patient met the pediatric criteria, suggesting these should be considered when clinical suspicion for adult-onset KD is high. Adult-onset KD is most commonly misdiagnosed as toxic shock syndrome or drug-induced hypersensitivity syndrome and these are important to rule-out. Treatment with high-dose aspirin and IVIG is well established and should be initiated promptly.\nHere is the question:\nDERMATOLOGY: A 4-year-old girl presenting with a high fever of 6 days' evolution. On clinical examination she presents an erythematous maculopapular rash on the trunk and genital area, with a tendency to confluence, without becoming scarlatiniform; conjunctival injection without secretions and red lips with raspberry tongue. She also presents erythema with edema in hands and feet and a unilateral cervical adenopathy of 2 cm in diameter. The most likely clinical diagnosis of suspicion is:\nHere are the potential choices:\n1. Kawasaki disease.\n2. Measles.\n3. Rubella.\n4. Scarlet fever.\nThe correct answer is: ",
        "gold_answer": "1 Kawasaki disease.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The present report describes the severe evolution of Kawasaki disease in a three-month-old infant. The ailment was initially atypical in its presentation, with the patient exhibiting only persistent fever in association with a progressive lethargy and maculopapular rash on the face, trunk and limbs erroneously diagnosed as roseola infantum. On the 10th day of the condition, mainly due to the unexplained persistence of fever, the infant was admitted to a local hospital. The typical features of KD appeared only on the 14th day of illness with the relapse of the maculopapular rash in association with non-purulent conjunctivitis; dry, reddish and fissured lips; tongue with reddish and hypertrophic papillae; erythema and edema of the palms and soles. During the following days, the ailment rapidly evolved to a catastrophic clinical picture characterized by generalized vasculitis, splenic infarction, pulmonary thrombosis, giant right and left coronary aneurysms, dilatation of common and internal iliac arteries and progressive ischemia of the distal third of the feet resulting in necrotic lesions of both halluces. Appropriate therapy was initiated, but repeated administration of intravenous immunoglobulin G (IVIG) followed by three days of administration of methylprednisolone did not abate the intense inflammatory activity. The remission of inflammation and regression of vascular lesions were only achieved during the following five weeks after the introduction of methotrexate associated with etanercept. The report of this case aims to draw attention to severe forms of KD that exhibit an unfavorable evolution and can be extremely refractory to the conventional therapy. While the diagnosis of typical form of Kawasaki disease (KD) is obvious, this multifaceted disease continues to surprise us. We report the case of a recurrent Kawasaki disease in an infant. At the age of 13 months, the infant was diagnosed with complete Kawasaki disease; he presented with prolonged fever, bilateral conjunctivitis, enanthem, exanthema, edema of the lower limb, peeling, and biological inflammatory syndrome. He was treated with intravenous immunoglobulin (IVIG) associated with a high dose of aspirin and then an antiplatelet dose with a good clinical-biological evolution. The echocardiography was normal. Seven months later, the patient was again admitted, in a similar picture: a prolonged fever evolving for 7 days, bilateral conjunctivitis, enanthem, cervical adenopathy of 1.5 cm/1 cm, scarlatiniform erythema, pruriginous of the trunk and limb, and peeling of the toes, with indurated edema of the hands and feet. The rest of the examination was normal except the irritability. The diagnosis of recurrent KD was made according the five criteria of the American Heart Association. The echocardiography was normal again. The infant received IVIG with good outcome. Despite its rarity, the possibility of recurrence of KD should be known by clinicians, so as not to delay the specific management of vasculitis whose stakes in terms of prevention of coronary artery lesions are well known. Our case confirms the possibility of this recurrence. The cutaneous eruption in Kawasaki disease (Chap. 385) is polymorphous, but the two most common forms are morbilliform and scarlatiniform. Additional mucocutaneous findings include bilateral conjunctival injection; erythema and edema of the hands and feet followed by desquamation; and diffuse erythema of the oropharynx, red strawberry tongue, and dry fissured lips. This clinical picture can resemble TSS and scarlet fever, but clues to the diagnosis of Kawasaki disease are cervical lymphadenopathy, cheilitis, and thrombocytosis. The most serious associated systemic finding in this disease is coronary aneurysms secondary to arteritis. Scarlatiniform eruptions are also seen in the early phase of SSSS (see “Vesicles/Bullae,” above), in young adults with Arcanobacterium haemolyticum infection, and as reactions to drugs. Kawasaki disease is an acute inflammatory condition characterized by various combinations of features but renal involvement is rare. This report is of a case of Kawasaki disease complicated by acute kidney failure. A 10 year-old girl was admitted because of acute renal failure with fever. She developed a high fever, and her general condition was poor; she had developed a macular erythematous rash 10 days earlier for which she was given cefadroxil. At admission, she remained febrile and had strawberry tongue, pharyngitis, dry erythematous lips, bilateral conjunctivitis, cervical lymphadenopathy and desquamation of the skin on her hands. She was anemic (hemoglobin = 9.6 g%), leukocytotic (33,100/mm3), but with no burr, fragmented red blood cells or thrombocytopenia. Her plasma C-reactive protein level was 236 mg/l; her blood urea was 9.5 mmol/l, her creatininemia 288 mumol/l and proteinuria was 0.5 g/l without hematuria. Urine cultures did not grow. Her blood transaminase and gammaglutamyltransferase activities were elevated. Ultrasonography of kidneys and coronary arteries was normal. Kidney biopsy performed one day after admission showed no vascular or glomerular changes, but renal tubular necrosis, indicating urinary excretion of pigments. Tests for myoglobinemia, myoglobinuria and blood muscle enzyme activities were all positive. The renal failure disappeared within 10 days but the fever and inflammatory manifestations persisted for 1 1/2-2 months despite two treatments of intravenous gammaglobulins and continuous salicylate administration. The patient developed arthralgias at the end of the first month of disease, but recovered without renal or vascular complications. Several cases of renal involvement have been reported during the course of Kawasaki disease. They have been rarely documented by histological examination so that the vascular origin of changes has not been demonstrated. Myoglobinuria, as seen in muscular crush injury, and in our case possibly due to malignant hyperthermia, may be responsible for the transient acute renal failure. In 2014, the American Heart Association (AHA) published the criteria needed to establish a diagnosis. [1] However, it is important to note that children who fall short of the full criteria but have cardiac abnormalities on echocardiogram meet the diagnosis of KD. [1] The patient must have fevers for five or more days, with at least four of the following criteria (either all at once or over a series of days): Bilateral painless bulbar conjunctival injection without exudate Erythematous mouth and pharynx, strawberry tongue or red, cracked lips Polymorphous exanthem (morbilliform, maculopapular, or scarlatiniform) Swelling of hands and feet with erythema of the palms and soles Cervical lymphadenopathy (over 1.5 cm in diameter) Arthritis is reported in one-third of cases with Kawasaki syndrome. It may have an early or a late onset form. We present a 15-month-old-girl who had been referred with complaints of pain and swelling in her left shoulder. Physical examination revealed bulbar conjunctival injection, erythematous lips and pharynx, strawberry tongue, erythematous rash, edema and erythema of the left shoulder, left knee, right elbow and right wrist, and moderate distress in the left shoulder and left hip. She was diagnosed with Kawasaki syndrome, and intravenous immunoglobulin infusion (IVIG) 2 g/kg and aspirin (100 mg/kg/day) were instituted. The patient had two additional episodes of arthritis involving the hip joint on the 8th day, and the shoulder and metacarpophalangeal (MCP) and interphalangeal (IP) joints of her right hand on the 15th day. Turbid material was aspirated in both instances; Gram and Wright's staining of this material showed many leukocytes but no bacteria. A second dose of IVIG (1 g/kg) was given. At the end of the third week all extremities were painless, with a normal range of motion. Arthritis in our patient was the presenting sign, having a 'septic arthritis mimicking' and 'biphasic' pattern. Although the patient presented with severe and recurrent arthritis, which is significantly correlated with severe multisystem disease and the presence or development of coronary artery aneurysm, the response to IVIG was excellent. Kawasaki disease (KD) is a systemic vasculitis of unknown cause and is associated with various digestive disorders, although only a few cases of intussusception associated with KD have been reported. We describe a case of intussusception followed by KD in a 3-year-old boy. The patient was admitted to our hospital for evaluation of severe abdominal pain. Because the target sign was seen on ultrasonography, intussusception was diagnosed and hydrostatic reduction was performed. On the second day after admission, he developed a high fever (38°C) and an irregular rash over his whole body. On the fourth day after admission, the high fever continued, and bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, strawberry tongue, indurated edema of the dorsa of the hands and feet, and diffuse erythema of the palms and soles appeared, and KD was ultimately diagnosed. He was treated with intravenous immunoglobulin 2 g/kg, aspirin 30 mg/kg/day, and prednisolone 2 mg/kg/day. The high fever and other clinical symptoms resolved immediately after the start of treatment. There was no relapse of KD symptoms after initial treatment, and periungual desquamation was observed on the 10th day after admission. He was discharged on the 15th day, without abnormalities such as coronary dilatation, 3 months after the onset of KD symptoms. Patients with intussusception and KD were older (≥3 years vs &lt;3 years) than those with intussusception alone. In addition, the site of intussusception in KD was mainly colonic rather than ileocolic. If intussusception precedes development of the characteristic clinical symptoms of KD, diagnosis of KD may be delayed. KD should be considered in children older than 3 years with intussusception at a colonic site. A 14-month-old girl presented with a 4-d history of fever and generalized exanthema. Four characteristic symptoms of incomplete Kawasaki disease (KD) were present on admission (fever, rash, non-purulent conjunctival injection, oropharyngeal changes) and then followed by oedema of the hands and feet and mild plantar desquamation. The typical laboratory features of KD, such as elevated erythrocyte sedimentation rate, leukocytosis, thrombocytosis, and positive C-reactive protein were also seen. Ultrasound examination of the mediastinum revealed the presence of a lymph node, 30 mm in diameter, below the tracheal carina. Thoracic CT scan confirmed the mediastinal lymph node. The patient was treated with aspirin and intravenous gamma-globulin. Ultrasound study of the mediastinum, which was carried out 6 weeks after hospital discharge, showed that the lymph node had disappeared. This case illustrates that lymph nodes other than cervical lymphadenopathy should be sought when the diagnosis of classical or atypical KD is suspected. We report a 3-year-old girl with Kawasaki disease who presented with retropharyngeal edema and shock syndrome. This is the first reported case in Taiwan. The patient initially presented with fever, cough, and pyuria followed by rapidly progressive enlarged bilateral cervical lymphadenopathy. On the third day of the fever, computed tomography for airway compression sign found widening of the retropharyngeal space mimicking a retropharyngeal abscess. Later, an endotracheal tube was inserted for respiratory distress. A skin rash over her trunk was also noted. On the fifth day of the fever, the clinical course progressed to hypotension and shock syndrome. Because of more swelling of bilateral neck lymph nodes, computed tomography was arranged again and revealed partial resolution of the edematous changes in the retropharyngeal space. Edema of the hands and feet, bilateral bulbar conjunctivitis, and fissured lips were subsequently found. The diagnosis of Kawasaki disease was confirmed on the eighth day of fever. There was no evidence of bacterial infection. She was administered intravenous immunoglobulin (2 mg/kg) and high dose aspirin (100 mg/kg/day). One day later, the fever subsided, and her blood pressure gradually became stable. Heart echocardiography on the Day 13 revealed dilated left coronary artery and mitral regurgitation. Follow-up echocardiography six months later showed normal coronary arteries. To date, the patient has not experienced any complications. This case illustrates that retropharyngeal edema and shock syndrome can be present in the same clinical course of Kawasaki disease. Clinicians and those who work in intensive care units should be aware of unusual presentations of Kawasaki disease to decrease rates of cardiovascular complications.  A 9-year-old girl developing fever and hyperemia of both bulbar conjunctiva 5 days before admission to the Saitama Children's Medical Center after antibiotics proved ineffective was found on admission to have general fatigue and a temperature of 39 degrees C. Physical examination showed hyperemia of the bulbar conjunctiva, fissures of the lips, redness of the pharynx, and swelling of the cervical lymph nodes. Laboratory tests detected neutrophilia (11,200/microL), mild anemia (11.4g/dL), thrombocytopenia (110,000/microL), and elevated serum aspartate aminotransferase (242IU/L), alanine aminotransferase (328IU/L), and C-rective protein (25.2 mg/dL). Autoantibodies such as anti-nuclear, anti-SS-A/Ro, and anti-Jo-1 were also found. Echocardiography showed no abnormality of the coronary arteries. She was diagnosed as having incomplete Kawasaki disease on day 7 of illness, necessitating that a high dose of immunoglobulin be given intravenously. Her temperature dropped temporarily to 37 degrees C, but she developed erythema of the cheek and fever. Intravenous immunoglobulin was restarted, and minocycline introduced because her daily contact with a pet cat indicated richettsial infection such as Q fever. Mild fever, muscle pain, and elevated C-reactive protein did not improve, but clinical signs and symptoms gradually lessened after ibuprofen was given, then disappeared. A definitive diagnosis of Q fever was made through an over 4-fold rise in phase II IgG antibody titers against Coxiella burnetii, titer of less than 1 : 16 on day 14 of illness, and titer of 1 : 256 on day 34. This case study describes on atypical case of Q fever with clinical manifestations mimicking Kawasaki disease. Erythema multiforme (EM) is an immune-mediated disease with mucocutaneous localization and plurietiologic determinism. The term \"multiforme\" refers to the variety of aspects that the lesions can take from patient to patient and during evolution in a single patient. We have selected 2 cases of small children diagnosed with different etiology of EM to illustrate the importance of a correct and fast diagnosis. Case 1 involves a 2-year-old girl from a rural area who presented with fever and pruritic erythematous papular eruption. The onset of the symptoms was 3 days before presentation with fever and ulcerative lesions on the oral and labial mucosa, followed by the appearance of erythematous macular lesions, with progressive confluence to intense pruritic patches. The 2nd involves a 2-year-old boy with fever, loss of appetite, productive cough, and petechiae. He had corticosensible immune thrombocytopenia from the age of 6 months, with many recurrences. The patient received treatment with ampicillin/sulbactam and symptomatics for an erythemato-pultaceous angina. During the 2nd day of treatment the patient developed an erythematous macular eruption on the face, scalp, trunk, and limbs, with bullae formation. The 1st patient was diagnosed based on biologic findings: positive inflammatory syndrome, elevated level of anti-Mycoplasma pneumoniae immunoglobulin M antibodies and immunoglobulin E. Histopathologic examination described papillary dermal edema, inflammatory infiltrate, and lymphocyte exocytosis. In the 2nd case, the hemoleucogram identified 12,000/mm platelets and the medulogram aspect was normal. Serology for Epstein-Barr virus was negative. The diagnosis was EM secondary to M pneumoniae infection in case 1 and secondary to administration of ampicillin/sulbactam in case 2. In both cases, etiopathogenic treatment consisting of steroidal antiinflammatory drugs, antihistamines was administered. Because of specific etiology, the 1st case received antibiotics. The evolution was favorable in 10 to 14 days; the patients were discharged after etiopathogenic treatment consisting of steroidal antiinflammatory drugs, antihistamines, and/or antibiotics. Performing a detailed clinical examination, medical history of drug use, infection or general diseases can establish a good diagnosis of EM. Histopathologic examination can help. The treatment is etiologic, pathogenic, and symptomatic. EM usually has a self-limited evolution. A previously healthy 11-month-old girl presented with fever and rash for 6 days. Physical examination revealed an irritable infant with a high fever, injected conjunctivae, red cracked lips, posterior auricular lymphadenopathy, hepatomegaly, generalized erythematous maculopapular rash and petechial hemorrhage on trunk, face and extremities. Complete blood count showed atypical lymphocytosis and thrombocytopenia. Dengue infection was initially diagnosed. The persistent fever and clinical manifestations of Kawasaki disease (KD) were observed on day 8 with high erythrocyte sedimentation rate (56 mm/hr). Treatment of KD included intravenous immunoglobulin on day 9 of the illness. Desquamation of the fingers was found on day 15 of the illness. Ectasia of left coronary artery with small aneurysmal dilatation was detected by echocardiography on day 15 of the illness. Hemagglutination-inhibition test and enzyme-linked immunosorbent assay for dengue virus eventually showed a four-fold rising. According to the literature review, this is the second reported case of dengue infection concomitant with KD. The natural course of each disease may be modified and causes some difficulties in diagnosis and management. Cervical lymphadenopathy (often painful and unilateral, with at least one node > 1.5 cm). Diffuse mucous membrane erythema (e.g., “strawberry tongue”); dry, red, chapped lips. Erythema of the palms and soles; indurative edema of the hands and feet; late desquamation of the fingertips (in the subacute phase). Other manifestations include sterile pyuria, gallbladder hydrops, hepatitis, and arthritis. Untreated Kawasaki disease can lead to coronary aneurysms and even myocardial infarction! Conjunctivitis Rash Adenopathy Strawberry tongue Hands and feet (red, swollen, f aky skin) BURN (fever > 40°C for ≥ 5 days) Subacute phase: Begins after the abatement of fever and typically lasts for an additional 2–3 weeks. Manifestations are thrombocytosis and elevated ESR. Untreated children may begin to develop coronary artery aneurysms (40%); all patients should be assessed by echocardiography at diagnosis. Kawasaki disease is an idiopathic medium-sized vasculitis that occurs primarily in infants and children younger than 5 years of age. Atypical Kawasaki disease applies to patients who do not fulfill the complete criteria of fever of 5 days or more with at least four of five features: bilateral conjunctival injection, changes in the lips and oral cavity, cervical lymphadenopathy, extremity changes, and polymorphous rash. Acute kidney injury is defined as a sudden decline in kidney function within hours, including structural injuries and loss of function. Acute kidney injury is extremely common in hospitalized pediatric patients. However, it is rarely documented in Kawasaki disease. Acute kidney injury is underestimated in Kawasaki disease due to the lack of a clear definition of age-specific normal serum creatinine levels and routine renal functions. This report describes a case who presented with clinical features suggestive of atypical Kawasaki disease and developed acute kidney injury. A 2-year-old Saudi girl had a history of high-grade fever for 5 days, moderate dehydration, dry cracked lips, poor appetite, and generalized erythematous rash; therefore, she was diagnosed to have incomplete Kawasaki disease. Laboratory investigations revealed normochromic normocytic anemia, leukocytosis, thrombocytosis, high inflammatory markers, and acute kidney injury stage III. An echocardiogram showed a 4-mm dilatation on the left main coronary artery and a 3-mm dilatation on the right. A renal biopsy was not performed to identify the cause of the injury as it showed improvements after the start of the specific therapy for Kawasaki disease; intravenous immune globulin at a dose of 2 g/kg, aspirin at a high dosage of 80 mg/kg/day, and prednisolone at 2 mg/kg. In addition to the acute kidney injury management, normal saline boluses were followed by furosemide at a 2 mg/kg dose. Her urine output increased, and her renal functions normalized. She was discharged in good condition after 10 days. It is valuable to check renal function tests in a confirmed case of Kawasaki disease to reduce the negative consequences of late acute kidney injury discovery. Early detection and intervention make a substantial difference in acute kidney injury management. Measles should be distinguished from similar presenting exanthemic diseases of childhood, autoimmune processes, and adverse drug reactions. Rubella causes a rash similar to measles with head to caudal distribution, mild respiratory symptoms, the absence of conjunctivitis. Still, it is accompanied by the presence of adenopathies - which is characteristic of this disease. Roseola is characterized by an illness beginning with a high fever, which subsides after a few days, accompanied by the appearance of a rash in the central part of the body, without the presence of Koplik's points. Mononucleosis is a febrile viral disease, a characteristic course with few symptoms during childhood, contrary to what happens in more advanced ages.  Mononucleosis manifests itself by pharyngeal compromise, polyadenopathy, and hepatosplenomegaly, and the rash can have different forms of presentation. In Kawasaki disease, there is an ocular compromise with the presence of conjunctivitis without exudate, and the respiratory compromise is not part of this pathology. Group A Streptococcus (particularly Scarlet fever) may present with a similar rash (a coarse, sandpaper-like, blanching, erythematous) to measles in association with pharyngitis. [5] [14] Kawasaki disease (KD) is a common vasculitic disorder usually seen in children below 5 years of age. The disease can present with protean clinical manifestations which include high grade fever (for at least 5 days), rash, redness of the lips and a typical strawberry tongue, cervical lymph node enlargement (often unilateral), swelling over the hands/feet and, later a characteristic peripheral desquamation over the fingers and toes. These clinical features appear sequentially and the findings may change from day-to-day. Thus, all these features may not be seen together at any one point of time. The diagnosis rests on the recognition of this characteristic temporal sequence of clinical events, none of which are, by themselves, pathognomonic. Establishing a diagnosis of KD may be further complicated by the occurrence of several other, seemingly unrelated, clinical features. These include irritability, neck stiffness, sterile pyuria, pneumonitis, hydrops of the gallbladder and hepatitis among many others. There is no laboratory test that can help in confirming a diagnosis of KD. Left untreated, up to 20% of children with KD can develop coronary aneurysms with catastrophic long term sequelae. It is important to diagnose KD in the first 10 days of the illness so that appropriate therapy with intravenous immunoglobulin and aspirin can be Initiated. All paediatricians, and physicians looking after children, need to be aware of this condition which is now being increasingly recognized in India. Kawasaki syndrome, also known as mucocutaneous lymph node syndrome, is an acute vasculitis of infants and young children. We describe a four-year-old girl who presented with fever, a diffuse erythematous maculopapular rash, bilateral nonpurulent bulbar conjunctivitis, dry, red, fissured lips, a tongue with a strawberry \"appearance\", an erythematous pharynx, indurative erythema, and edema and desquamation of the face, hands and feet. She probably developed mitral valve prolapse during the course of the disease. The diagnosis of Kawasaki syndrome was arrived at by excluding other diseases and by the presence of all the clinical criteria for Kawasaki syndrome. Since this syndrome is rarely encountered in Turkey, this case is presented and the literature regarding the syndrome is reviewed. Classically, five days of fever plus four of five diagnostic criteria must be met to establish the diagnosis. The criteria are: erythema of the lips or oral cavity or cracking of the lips rash on the trunk swelling or erythema of the hands or feet red eyes (conjunctival injection) swollen lymph node in the neck of at least 15 mm Many children, especially infants, eventually diagnosed with Kawasaki disease, do not exhibit all of the above criteria. In fact, many experts now recommend treating for Kawasaki disease even if only three days of fever have passed and at least three diagnostic criteria are present, especially if other tests reveal abnormalities consistent with Kawasaki disease. In addition, the diagnosis can be made purely by the detection of coronary artery aneurysms in the proper clinical setting. Investigations A physical examination will demonstrate many of the features listed above. This report describes a 26-year-old woman who fulfills the criteria for the diagnosis of Kawasaki disease or mucocutaneous lymph node syndrome, an acute febrile illness that usually afflicts young children. The diagnosis is made in persons with fever lasting 5 or more days when four of the following criteria are met: bilateral injection of ocular conjunctivae; the involvement of the mucous membranes of the upper respiratory tract consisting of any combination of the following--redness and fissuring of lips; \"strawberry tongue,\" or erythema of the pharynx; involvement of the peripheral extremities characterized in the early stages by an indurative erythematous rash of palms and soles followed by membranous desquamation; polymorphous nonvesicular truncal exanthem; and acute nonsuppurative enlargement of cervical lymph nodes. An added stipulation is that the illness must not be attributable to a known disease process. A 4-year-old boy experienced sudden fever, followed by a rash on the trunk and extremities and erythema of the pharynx. Five days later, the fever remained and erythema appeared on the oropharynx, tongue, and lips. The skin of the palms and soles became erythematous and indurated, and both conjunctivae became injected. Desquamation of the skin occurred on both thumbs and one finger, and an anterior cervical lymph node was found to be enlarged. The patient was diagnosed as having Kawasaki disease, and treatment with aspirin was started. The desquamation progressed to involve the entire surface of the palms and soles, and then symptoms resolved. Twenty years after recognition of Kawasaki disease, this enigmatic illness continues to defy attempts to understand its etiology and pathogenesis. Most experts agree that the cause is either an environmental toxin or an infectious agent, but other possible causative agents may need to be proposed and investigated. We describe adult-onset Kawasaki disease (KD) and review clinical manifestations and treatment guidelines. Our patient is a 20-year-old female who initially presented to an outside hospital for fever, cervical lymphadenopathy, malaise, exudative tonsillitis, and skin eruption. She received antibiotics for suspected exudative pharyngitis, but experienced continued fevers and presented to the UCLA emergency room one week later. She had diffuse petechial macules coalescing into reticulated patches, fingertip peeling, conjunctival injection, oral erosions, and tongue swelling. Despite her age, given her constellation of symptoms, a diagnosis of typical KD was favored. She was started on high dose aspirin and IVIG, with improvement of rash and conjunctivitis. She was discharged on 325mg of aspirin daily with close follow-up. This case highlights the challenge of diagnosing KD in adults. Although this patient had classic symptoms, she was likely misdiagnosed because KD is rare in adults and without validated criteria. Our patient met the pediatric criteria, suggesting these should be considered when clinical suspicion for adult-onset KD is high. Adult-onset KD is most commonly misdiagnosed as toxic shock syndrome or drug-induced hypersensitivity syndrome and these are important to rule-out. Treatment with high-dose aspirin and IVIG is well established and should be initiated promptly.\nHere is the question:\nDERMATOLOGY: A 4-year-old girl presenting with a high fever of 6 days' evolution. On clinical examination she presents an erythematous maculopapular rash on the trunk and genital area, with a tendency to confluence, without becoming scarlatiniform; conjunctival injection without secretions and red lips with raspberry tongue. She also presents erythema with edema in hands and feet and a unilateral cervical adenopathy of 2 cm in diameter. The most likely clinical diagnosis of suspicion is:\nHere are the potential choices:\n1. Kawasaki disease.\n2. Measles.\n3. Rubella.\n4. Scarlet fever.\nThe correct answer is: 1. Kawasaki disease."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Medium vessel vasculitis These conditions are sometimes considered together with the small vessel vasculitides. Polyarteritis nodosa (PAN). Systemic necrotizing vasculitis and aneurysm formation affecting both medium and small arteries. If only small vessels are affected, it is called microscopic polyangiitis, although it is more associated with granulomatosis with polyangiitis than to classic PAN. At least 3 out of 10 criteria yields sensitivity and specificity of 82 and 87%: Unexplained weight loss > 4 kg Livedo reticularis Testicular pain Myalgias, weakness Abdominal pain, diarrhea, and GI bleeding Mononeuropathy or polyneuropathy New onset diastolic blood pressure > 90 mmHg Elevated serum blood urea nitrogen (> 40 mg/dL) or serum creatinine (> 1.5 mg/dL) Hepatitis B infection Arteriographic abnormalities Arterial biopsy showing polymorphonuclear cells Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome) is a rare multisystem necrotizing vasculitis that involves small- to medium-sized blood vessels. We report a rare case of syndrome of the inappropriate antidiuretic hormone (ADH) secretion (SIADH) secondary to EGPA. A 53-year-old man applied with complaints of pain in the large joints and morning stiffness in knee for 2 months. The patient had the history of impaired fasting glucose, asthma, nasal polyps, and urticaria. Physical examination revealed intrinsic muscle atrophy and weakness in the right hand. Peripheral eosinophil count was 9.78 × 109/L (0.02-0.5), erythrocyte sedimentation rate 39 mm/h (0-20), and C-reactive protein 5.77 mg/dL (0-0.5). Migratory ground-glass pulmonary opacities had been reported in previous chest computed tomography scans. Echocardiography revealed findings compatible with eosinophilic involvement. Electroneuromyographic evaluation showed acute distal axonal neuropathy of right ulnar nerve. EGPA was considered. Oral methylprednisolone treatment was initiated. Intravenous immunoglobulin (IVIG) and cyclophosphamide treatment and gradual tapering of oral steroids were planned. In 24-h urine analysis, sodium was 387 mEq, creatinine was 1156 mg, and volume was 3000 mL. When his medical records were investigated, it was observed that hyponatremia was present for nearly 2 years. While serum osmolality was 270, urine osmolality was 604 mOsm/kg H<sub2</subO. So, SIADH diagnosis was made. Fluid intake was restricted. Although the patient's sodium level did not return to normal, it rose up to 130 mEq/L. After second cycle of EGPA treatment (cyclophosphamide and IVIG), serum sodium was normal. There is only four other documented cases of SIADH associated with EGPA. We hypothesized that blood supply to the hypothalamus and/or posterior hypophysis might be affected from EGPA vasculitis. Here, in this case, with effective treatment of EGPA, SIADH was resolved which implies a causality between two conditions. Churg-Strauss syndrome, Eosinophilic granulomatosis with polyangiitis (EGPA), is a systemic vasculitis that affects small- to medium-sized vessels. It is rare and part of the Anti-neutrophil cytoplasm antibody-associated vasculitis (ANCA) group. We present a 37-year-old man, with a previous history of asthma, that was sent to the ED due to 2 weeks of productive cough, occasional dyspnea on exertion, fever (one week), asthenia, and anorexia. Upon physical examination, he was subfebrile and tachycardic. He had leukocytosis (17.00 x10^9/L) and eosinophilia of 20.0 % (3.4 X10^9/L), creatinine level of 1.5 mg/dL, subtle elevation on liver function tests and CRP of 10.82mg/dL. On Chest X-Ray, there was infiltrate on the right pulmonary base. Due to a strong suspicion of EGPA, he was started on 80mg of prednisolone from admission. ANCA MPO was positive, with the remaining auto-immune study negative. He underwent Thorax CT (under corticotherapy) without relevant changes, as well as bronchoalveolar lavage, without macroscopic signs of alveolar hemorrhage. Because of active urinary sediment, nephrotic proteinuria (6.5g/24h), and acute renal failure he underwent a renal biopsy, which revealed pauci-immune crescentic glomerulonephritis, with predominantly acute findings (in the context of ANCA-MPO Vasculitis - EGPA). After the biopsy, he received three 1g methylprednisolone pulses and was started on Cyclophosphamide. He remained asymptomatic and renal function was restored. This case highlights the importance of integrating all findings in one clinical scenario to prevent a more complex disease diagnosis, with a specific treatment, from being missed. A 41-year-old woman presented to her primary doctor with nausea, back pain and lower extremity oedema. Initial labs showed elevated serum creatinine and white blood cell count (WBC), which her doctor attributed to ibuprofen use and a recent upper respiratory infection. Five days later, she presented to the eye clinic with eye pain, redness and blurred vision. She was diagnosed with iritis, conjunctivitis and keratitis. The inflammatory eye disease with decreased renal function prompted the ophthalmologist to initiate systemic autoimmune and infectious disease work-up. Before laboratory testing was complete, she developed severe haemoptysis. Diagnosis of granulomatosis with polyangiitis (GPA) was confirmed using blood testing, radiological imaging and kidney biopsy. She received plasmapheresis, then cyclophosphamide and prednisone with good effect. This case highlights the need to consider GPA in the differential when patients present with inflammatory eye disease with decreased renal function and the need for multispecialty collaboration including ophthalmologists in the diagnosis of GPA. Lab tests. Basic lab tests may include a complete blood count, chemiestries (look for creatinine), creatine phosphokinase level, liver function tests, erythrocyte sedimentation rate, hepatitis serologies, urinalysis, chest X-ray, and an electrocardiogram. Additional, more specific tests include: Antinuclear antibody test can detect an underlying connective tissue disorder, especially lupus erythematosus Complement levels that are low can suggest mixed cryoglobulinemia, hepatitis C infection, and lupus erythematosus], but not most other vasculitides. Antineutrophil cytoplasmic antibody may suggest granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, or drug-induced vasculitis, but is not diagnostic. Electromyography. It is useful if a systemic vasculitis is suspected and neuromuscular symptoms are present. To describe a case of anterior ischemic optic neuropathy as a presenting sign of granulomatosis with polyangiitis. A previously healthy 50-year-old female developed right eye, then left eye, redness and pruritis and was diagnosed with allergic versus viral conjunctivitis. Five days later, she noted an acute decline in vision in the right eye, corresponding with a decrease on Snellen testing from 20/30 to 20/100 with correction. She was noted to have a right relative afferent pupillary defect, 2+ pallid disc edema, and OCT (Spectralis, Heidelberg Engineering, Carlsbad, CA) findings of significant retinal nerve fiber thickening. Review of systems revealed a three-month history fatigue, right-sided headaches, jaw claudication, bronchitis, cough without hemoptysis, and epistaxis, as well as interval development of a petechial rash across her body, migratory polyarthralgias, fevers, and tachycardia. ESR and CRP were markedly elevated, and the patient was admitted to the hospital for a systemic vasculitis workup. She was started on IV methylprednisolone. Her vision improved dramatically with steroids, measuring 20/50 with correction in the right eye after 24 hours and returning to baseline after five days. An extensive workup including imaging, bloodwork, and biopsies led to a diagnosis of granulomatosis with polyangiitis, with PR3-positive ANCA. Ocular findings, including anterior ischemic optic neuropathy, may be the presenting signs for patients with granulomatosis with polyangiitis. Prompt recognition and treatment with high-dose steroids and immunomodulatory therapy is important for visual recovery. Prompt recognition of potential vasculitis-related vision loss can lead to timely initiation of vision-saving treatment. Granulomatosis with polyangiitis, also known as Wegener's granulomatosis, is a chronic systemic inflammatory disease that can also involve the eyes. We report a case of massive retinal and preretinal hemorrhages with perivascular changes as the initial signs in granulomatosis with polyangiitis (Wegener's granulomatosis). A 39-year-old Caucasian male presented with blurred vision in his right eye, myalgia and arthralgia, recurrent nose bleeds and anosmia. Fundus image of his right eye showed massive retinal hemorrhages and vasculitis-like angiopathy, although no fluorescein extravasation was present in fluorescein angiography. Laboratory investigations revealed an inflammation with increased C-reactive protein, elevated erythrocyte sedimentation rate and neutrophil count. Tests for antineutrophil cytoplasmic antibodies (ANCA) were positive for c-ANCA (cytoplasmatic ANCA) and PR3-ANCA (proteinase 3-ANCA). Renal biopsy demonstrated a focal segmental necrotizing glomerulonephritis. Granulomatosis with polyangiitis (Wegener's granulomatosis) was diagnosed and a combined systemic therapy of cyclophosphamide and corticosteroids was initiated. During 3 months of follow-up, complete resorption of retinal hemorrhages was seen and general complaints as well as visual acuity improved during therapy. Vasculitis-like retinal changes can occur in Wegener's granulomatosis. Despite massive retinal and preretinal hemorrhages that cause visual impairment, immunosuppressive therapy can improve ocular symptoms. Diagnosis No specific lab tests exist for diagnosing polyarteritis nodosa. Diagnosis is generally based on the physical examination and a few laboratory studies that help confirm the diagnosis: CBC (may demonstrate an elevated white blood count) ESR (elevated) Perinuclear pattern of antineutrophil cytoplasmic antibodies (p-ANCA) - not associated with \"classic\" polyarteritis nodosa, but is present in a form of the disease affecting smaller blood vessels, known as microscopic polyangiitis or leukocytoclastic angiitis Tissue biopsy (reveals inflammation in small arteries, called arteritis) Elevated C-reactive protein Diagnosis Laboratory tests may reveal an increased sedimentation rate, elevated CRP, anemia and elevated creatinine due to kidney impairment. An important diagnostic test is the presence of perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) with myeloperoxidase specificity (a constituent of neutrophil granules), and protein and red blood cells in the urine. In patients with neuropathy, electromyography may reveal a sensorimotor peripheral neuropathy. Differential diagnosis The signs and symptoms of microscopic polyangiitis may resemble those of granulomatosis with polyangiitis (GPA) (another form of small-vessel vasculitis) but typically lacks the significant upper respiratory tract involvement (e.g., sinusitis) frequently seen in people affected by GPA. Systemic histoplasmosis is an invasive fungal infection that may mimic primary vasculitis, particularly granulomatosis with polyangiitis (GPA), and was rarely described in adult patients. We reported an immunocompetent patient with disseminated histoplasmosis mimicking GPA who fulfilled European League Against Rheumatism (EULAR)/Pediatric Rheumatology International Trials Organisation (PRINTO)/Pediatric Rheumatology European Society (PRES) validated classification criteria. A 6-year old boy presented acute migratory polyarthritis with spontaneous improvement, sinus inflammation, fever, headache and abdominal pain. Serologic test for hepatitis, cytomegalovirus, human immunodeficiency virus, Epstein-Barr virus, toxoplasmosis, dengue virus and antistreptolysin O were all negative. Magnetic resonance imaging (MRI) showed moderate ascites in pelvis and pansinusitis. Antineutrophil cytoplasmic antibodies (c-ANCA) were positive. He had spontaneous remission of the symptoms including fever. At the age of 11 years and 11 months, he had sinusitis, pneumonia and epididymitis. A month later, he was hospitalized and MRI showed left eye proptosis. Cerebrospinal fluid was normal and indirect tests of fungi were negative. Two months later, he had lumbar pain and computer tomography showed a mass in the right kidney and pulmonary nodule in the right lung. He fulfilled EULAR/PRINTO/PRES criteria for GPA, however the renal biopsy showed a focal granulomatous interstitial nephritis with yeast fungal cells compatible with Histoplasma sp. He was treated with liposomal amphotericin B and itraconazole with improvement of signs and symptoms. We reported a progressive disseminated histoplasmosis case mimicking GPA. Histoplasmosis infection should be considered in immunocompetent subjects with uncommon clinical manifestations, such as arthritis, nephritis and epididymitis. The purpose of this study is to describe a patient who was diagnosed with granulomatosis with polyangiitis based on conjunctival biopsy. This study is a case report and review of the literature. A 48-year-old Caucasian woman presented with a 2-week history of a left eye peripheral corneal ulcer with adjacent conjunctivitis and a 4-month history of a non-resolving productive cough. Given her elevated serum perinuclear antineutrophil cytoplasmic antibody (P-ANCA) and erythrocyte sedimentation rate (ESR) levels as well as a chest computed topography (CT) that showed bilateral patchy infiltrates, suspicion of limited granulomatosis with polyangiitis with lung and ocular involvement was high. Because bronchoalveolar lavage was nondiagnostic for granulomatous disease, conjunctival biopsy was initially attempted in order to avoid a more invasive lung biopsy. The conjunctival biopsy revealed mixed subacute inflammatory mediators and vasculitis consistent with granulomatosis with polyangiitis. Conjunctival biopsy may be a valuable, minimally invasive method for diagnosing systemic granulomatosis with polyangiitis. A 51-year-old woman had been suffering from blood-stained purulent sinusitis and antibiotic-resistant bouts of fever for 4 months. She had microhematuria and serological evidence of inflammation (erythrocyte sedimentation rate [ESR] 92/135 mm, C-reactive protein 5.0 mg/dl). When she was admitted to hospital suspected of having postinfectious glomerulonephritis she complained of spontaneous colic-like pains in the left flank. Within one day the haemoglobin concentration fell from 10 to 6.5 g/dl. Ultrasound and computed tomography demonstrated a large space-occupying lesion around the left kidney. At operation this was found to be a rupture of the kidney with perirenal bleeding which was treated without removing the kidney. No biopsy was taken, but serological tests showed antineutrophil cytoplasmatic antibodies (cANCA), indicating Wegener's granulomatosis as the cause of the compensated renal insufficiency and spontaneous renal rupture. Under immunosuppressive treatment the inflammatory signs (ESR 18/44 mm), fever, chronic maxillary sinusitis, raised serum creatinine concentration and the ANCA titre all regressed, while proteinuria of about 4 g/24 h persisted. There was no recurrence during a follow-up period of 15 months. Serological signs of marked inflammatory activity, urinary sediments of nephritis and spontaneous retroperitoneal bleeding should suggest that, in addition to lupus erythematodes and panarteritis nodosa, Wegener's granulomatosis be included in the differential diagnosis. Palpable purpura is a condition where purpura, which constitutes visible non-blanching hemorrhages, are raised and able to be touched or felt upon palpation. It indicates some sort of vasculitis secondary to a serious disease. Causes Rocky mountain spotted fever Acute meningococcemia Disseminated gonococcal infection Ecthyma gangrenosum Henoch–Schönlein purpura Eosinophilic granulomatosis with polyangiitis Polyarteritis nodosa Leucocytoclastic vasculitis Microscopic polyangiitis Mixed essential cryoglobulinemia Subacute bacterial endocarditis Diagnosis Identification of underlying cause. Treatment Treat the underlying disease. References Further reading Vascular-related cutaneous conditions Dysthyroid optic neuropathy is the most commonly suspected diagnosis of optic neuropathy in Graves' patients; however, other causes need to be ruled out. We present a unique case of optic neuropathy secondary to hypertrophic pachymeningitis with antineutrophil cytoplasmic antibody-associated vasculitis, which was suspected to be antithyroid drug related. A 79-year-old Japanese male presented with acute visual loss in the left eye. He had a 24-year history of Graves' disease and was taking methimazole. Best-corrected visual acuity was 0.8 in the right eye and light perception in the left eye, and relative afferent pupillary defect in the left eye was seen. Ocular movement was normal, and there were no findings explaining visual loss in intermediate optic media and fundus in the left eye. Contrast-enhanced magnetic resonance imaging demonstrated thickened dura mater. Tests for myeloperoxidase-antineutrophil cytoplasmic antibody, proteinuria, and hematuria were positive; pulmonary nodule lesions and a blood clot in the left lower leg were also found. After excluding the presence of diseases that could lead to hypertrophic pachymeningitis, we diagnosed optic neuropathy due to hypertrophic pachymeningitis with granulomatosis with polyangiitis-a subtype of antineutrophil cytoplasmic antibody-associated vasculitis. Since he had history of using methimazole, antineutrophil cytoplasmic antibody-associated vasculitis was considered as drug related. We started high-dosage steroid pulse therapy followed by 1 mg/kg body weight daily of oral prednisolone, and subsequently tapered. Methimazole was stopped. Best-corrected visual acuity recovered to 0.9, 2 weeks after starting treatment. Though myeloperoxidase-antineutrophil cytoplasmic antibody remained negative, the symptom relapsed 6 months after treatment initiation. We gave a second high-dose steroid pulse therapy followed by prednisolone tapered together with methotrexate. Remission remained, and using 4 mg/week methotrexate without prednisolone, myeloperoxidase-antineutrophil cytoplasmic antibody was kept within the normal limit until now, 4 years after onset. We present a case of optic neuropathy with hypertrophic pachymeningitis related to antineutrophil cytoplasmic antibody-associated vasculitis, which was suspected to be drug related. The patient had good visual recovery after quitting the drug and receiving immunosuppressive therapy with systemic steroids. Hypertrophic pachymeningitis with antineutrophil cytoplasmic antibody-associated vasculitis related to antithyroid drugs should be considered as a differential diagnosis for optic neuropathy in Graves' patients in whom optic nerve compression is not obvious. Differential diagnosis Polyarteritis nodosa rarely affects the blood vessels of the lungs and this feature can help to differentiate it from other vasculitides that may have similar signs and symptoms (e.g., granulomatosis with polyangiitis or microscopic polyangiitis). Treatment Treatment involves medications to suppress the immune system, including prednisone and cyclophosphamide. When present, underlying hepatitis B virus infection should be immediately treated. In some cases, methotrexate or leflunomide may be helpful. Some patients have entered a remission phase when a four-dose infusion of rituximab is used before the leflunomide treatment is begun. Therapy results in remissions or cures in 90% of cases. Untreated, the disease is fatal in most cases. The most serious associated conditions generally involve the kidneys and gastrointestinal tract. A fatal course usually involves gastrointestinal bleeding, infection, myocardial infarction, and/or kidney failure. Diagnosis Granulomatosis with polyangiitis is usually suspected only when a person has had unexplained symptoms for a long period of time. Determination of anti-neutrophil cytoplasmic antibodies (ANCAs) can aid in the diagnosis, but positivity is not conclusive and negative ANCAs are not sufficient to reject the diagnosis. More than 90% of people who have GPA test positive for ANCA. Cytoplasmic-staining ANCAs that react with the enzyme proteinase 3 (cANCA) in neutrophils (a type of white blood cell) are associated with GPA. Involvement of the ears, nose, and throat is more common in granulomatosis with polyangiitis than in the similar condition microscopic polyangiitis. Granulomatosis with polyangiitis (GPA), a necrotizing granulomatous disease, very rarely involves the central nervous system (CNS), particularly the pituitary. Delayed treatment may cause permanent bilateral blindness. We report an isolated case of pituitary GPA that manifested as a progressive bilateral temporal visual field (VF) defect and was diagnosed via pituitary biopsy. Additionally, we review ocular, chiasmal and cranial nerve involvement in pituitary GPA. A 20-year-old Chinese man was referred for repeated fever, sudden headache, diplopia with a bilateral best-corrected visual acuity (BCVA) of 10/20, ptosis in both eyes and restricted abduction on the right side. VF tests showed bitemporal hemianopsia. Laboratory tests revealed hypothyroidism and were negative for autoimmune markers. Enhanced magnetic resonance imaging (MRI) showed pituitary enlargement. The diagnosis was lymphocytic pituitaritis. After intravenous (IV) dexamethasone treatment, full recovery occurred within 2 months. Two years later, the patient was readmitted for headache recurrence. With oral prednisone, the visual acuity in his right eye rapidly decreased to hand motion (HM) within one month. Enhanced MRI showed pituitary enlargement and a new, invasive suprasellar CNS lesion. All infection- and autoimmune-related tests were negative. The visual acuity in his right and left eye decreased to no light perception (NLP) after 6 days and 2 weeks, respectively. The biopsy results suggested GPA. After IV methylprednisolone treatment, complete remission of the symptoms occurred and was confirmed by MRI. The 15-month follow-up showed no signs of recurrence. GPA typically affects the respiratory tract, lungs and kidneys. To date, 50 cases with pituitary involvement have been reported. Chiasmal and cranial nerve involvement leading to visual acuity impairment are common. We found 2 cases with severe visual loss resembling our case and discuss certain similarities. Risk stratification The French Vasculitis Study Group has developed a five-point system (\"five-factor score\") that predicts the risk of death in Churg–Strauss syndrome using clinical presentations. These factors are: Reduced renal function (creatinine >1.58 mg/dl or 140 μmol/l) Proteinuria (>1 g/24h) Gastrointestinal hemorrhage, infarction, or pancreatitis Involvement of the central nervous system Cardiomyopathy Having none of these factors indicates milder case, with a five-year mortality rate of 11.9%. The presence of one factor indicates severe disease, with a five-year mortality rate of 26%, and three or more indicate very severe disease: 46% five-year mortality rate. In the setting of systemic vasculitis as described above, proliferative nephritis is associated with antineutrophil cytoplasmic antibodies (ANCA). Because of this, an ANCA test should always follow a negative immunofluorescence result to have the highest accuracy for confirming pauci-immune vasculitis-driven proliferative nephritis. Some cases of pauci-immune proliferative nephritis have no explanation and are thus deemed \"idiopathic.\" Peak incidences in 50- to 60-year-olds symptoms include intermittent fever / weight loss / shortness of breath / joint pain. See also Systemic vasculitis#Pauci-immune Goodpasture Syndrome and Poststrep Glomerulonephritis Microscopic polyangiitis, Eosinophilic granulomatosis with polyangiitis or Granulomatosis with polyangiitis References External links wikt:paucity Vascular-related cutaneous conditions Upon presentation, renal involvement is noted in only 10%-20%, but glomerulonephritis eventually develops in 80% of patients within two years of disease onset. The most common manifestation is rapidly progressive crescentic glomerulonephritis leading to chronic kidney disease or end-stage renal disease. Eye involvement: A 55-year-old male was admitted with non productive cough and fever which had continued for 6 weeks. The patient had symptoms of peripheral neuralgia. Chest X-ray revealed bilateral hilar lymphadenopathy (BHL) and reticular shadows in both lung fields. Other laboratory abnormalities included hematuria, RBC cast, high BUN, leukocytosis and thrombocytosis. Destruction of the internal membrane of arterioles was observed in a livedo reticularis on the right lower extremity. Renal angiography showed irregularity in the diameter, discontinuation and narrowing of peripheral arteries of both kidneys. These findings suggested the existence of \"angiitis\". These data were compatible with the diagnosis of polyarteritis nodosa (PN). Prednisolone (60 mg/day) administration resulted in the improvement of his symptoms and laboratory findings. A case of PN with lymph node swelling has been reported, however PN with BHL has not yet been reported. This is the first report of PN with BHL.\nHere is the question:\nRHEUMATOLOGY: A 67-year-old man presents with 3 months of asthenia and febrile fever, with nasal obstruction and mucus emission with some clots in the last month. In the last few days she noticed pain in the right eye and asymmetry with respect to the contralateral eye. Physical examination reveals proptosis of the right eyeball and inspection of the nostrils reveals an erythematous mucosa with serohematic crusts. The rest of the examination was normal. Blood tests (hemogram, renal and hepatic function) are normal, except for an ESR of 65 mm/h; urinalysis shows microhematuria and proteinuria of 520 mg/24h. What is the most probable initial diagnosis?\nHere are the potential choices:\n1. Eosinophilic granulomatosis with polyangiitis.\n2. Microscopic polyangiitis.\n3. Granulomatosis with polyangiitis.\n4. Polyarteritis nodosa.\nThe correct answer is: ",
        "gold_answer": "3 Granulomatosis with polyangiitis.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Medium vessel vasculitis These conditions are sometimes considered together with the small vessel vasculitides. Polyarteritis nodosa (PAN). Systemic necrotizing vasculitis and aneurysm formation affecting both medium and small arteries. If only small vessels are affected, it is called microscopic polyangiitis, although it is more associated with granulomatosis with polyangiitis than to classic PAN. At least 3 out of 10 criteria yields sensitivity and specificity of 82 and 87%: Unexplained weight loss > 4 kg Livedo reticularis Testicular pain Myalgias, weakness Abdominal pain, diarrhea, and GI bleeding Mononeuropathy or polyneuropathy New onset diastolic blood pressure > 90 mmHg Elevated serum blood urea nitrogen (> 40 mg/dL) or serum creatinine (> 1.5 mg/dL) Hepatitis B infection Arteriographic abnormalities Arterial biopsy showing polymorphonuclear cells Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome) is a rare multisystem necrotizing vasculitis that involves small- to medium-sized blood vessels. We report a rare case of syndrome of the inappropriate antidiuretic hormone (ADH) secretion (SIADH) secondary to EGPA. A 53-year-old man applied with complaints of pain in the large joints and morning stiffness in knee for 2 months. The patient had the history of impaired fasting glucose, asthma, nasal polyps, and urticaria. Physical examination revealed intrinsic muscle atrophy and weakness in the right hand. Peripheral eosinophil count was 9.78 × 109/L (0.02-0.5), erythrocyte sedimentation rate 39 mm/h (0-20), and C-reactive protein 5.77 mg/dL (0-0.5). Migratory ground-glass pulmonary opacities had been reported in previous chest computed tomography scans. Echocardiography revealed findings compatible with eosinophilic involvement. Electroneuromyographic evaluation showed acute distal axonal neuropathy of right ulnar nerve. EGPA was considered. Oral methylprednisolone treatment was initiated. Intravenous immunoglobulin (IVIG) and cyclophosphamide treatment and gradual tapering of oral steroids were planned. In 24-h urine analysis, sodium was 387 mEq, creatinine was 1156 mg, and volume was 3000 mL. When his medical records were investigated, it was observed that hyponatremia was present for nearly 2 years. While serum osmolality was 270, urine osmolality was 604 mOsm/kg H<sub2</subO. So, SIADH diagnosis was made. Fluid intake was restricted. Although the patient's sodium level did not return to normal, it rose up to 130 mEq/L. After second cycle of EGPA treatment (cyclophosphamide and IVIG), serum sodium was normal. There is only four other documented cases of SIADH associated with EGPA. We hypothesized that blood supply to the hypothalamus and/or posterior hypophysis might be affected from EGPA vasculitis. Here, in this case, with effective treatment of EGPA, SIADH was resolved which implies a causality between two conditions. Churg-Strauss syndrome, Eosinophilic granulomatosis with polyangiitis (EGPA), is a systemic vasculitis that affects small- to medium-sized vessels. It is rare and part of the Anti-neutrophil cytoplasm antibody-associated vasculitis (ANCA) group. We present a 37-year-old man, with a previous history of asthma, that was sent to the ED due to 2 weeks of productive cough, occasional dyspnea on exertion, fever (one week), asthenia, and anorexia. Upon physical examination, he was subfebrile and tachycardic. He had leukocytosis (17.00 x10^9/L) and eosinophilia of 20.0 % (3.4 X10^9/L), creatinine level of 1.5 mg/dL, subtle elevation on liver function tests and CRP of 10.82mg/dL. On Chest X-Ray, there was infiltrate on the right pulmonary base. Due to a strong suspicion of EGPA, he was started on 80mg of prednisolone from admission. ANCA MPO was positive, with the remaining auto-immune study negative. He underwent Thorax CT (under corticotherapy) without relevant changes, as well as bronchoalveolar lavage, without macroscopic signs of alveolar hemorrhage. Because of active urinary sediment, nephrotic proteinuria (6.5g/24h), and acute renal failure he underwent a renal biopsy, which revealed pauci-immune crescentic glomerulonephritis, with predominantly acute findings (in the context of ANCA-MPO Vasculitis - EGPA). After the biopsy, he received three 1g methylprednisolone pulses and was started on Cyclophosphamide. He remained asymptomatic and renal function was restored. This case highlights the importance of integrating all findings in one clinical scenario to prevent a more complex disease diagnosis, with a specific treatment, from being missed. A 41-year-old woman presented to her primary doctor with nausea, back pain and lower extremity oedema. Initial labs showed elevated serum creatinine and white blood cell count (WBC), which her doctor attributed to ibuprofen use and a recent upper respiratory infection. Five days later, she presented to the eye clinic with eye pain, redness and blurred vision. She was diagnosed with iritis, conjunctivitis and keratitis. The inflammatory eye disease with decreased renal function prompted the ophthalmologist to initiate systemic autoimmune and infectious disease work-up. Before laboratory testing was complete, she developed severe haemoptysis. Diagnosis of granulomatosis with polyangiitis (GPA) was confirmed using blood testing, radiological imaging and kidney biopsy. She received plasmapheresis, then cyclophosphamide and prednisone with good effect. This case highlights the need to consider GPA in the differential when patients present with inflammatory eye disease with decreased renal function and the need for multispecialty collaboration including ophthalmologists in the diagnosis of GPA. Lab tests. Basic lab tests may include a complete blood count, chemiestries (look for creatinine), creatine phosphokinase level, liver function tests, erythrocyte sedimentation rate, hepatitis serologies, urinalysis, chest X-ray, and an electrocardiogram. Additional, more specific tests include: Antinuclear antibody test can detect an underlying connective tissue disorder, especially lupus erythematosus Complement levels that are low can suggest mixed cryoglobulinemia, hepatitis C infection, and lupus erythematosus], but not most other vasculitides. Antineutrophil cytoplasmic antibody may suggest granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, or drug-induced vasculitis, but is not diagnostic. Electromyography. It is useful if a systemic vasculitis is suspected and neuromuscular symptoms are present. To describe a case of anterior ischemic optic neuropathy as a presenting sign of granulomatosis with polyangiitis. A previously healthy 50-year-old female developed right eye, then left eye, redness and pruritis and was diagnosed with allergic versus viral conjunctivitis. Five days later, she noted an acute decline in vision in the right eye, corresponding with a decrease on Snellen testing from 20/30 to 20/100 with correction. She was noted to have a right relative afferent pupillary defect, 2+ pallid disc edema, and OCT (Spectralis, Heidelberg Engineering, Carlsbad, CA) findings of significant retinal nerve fiber thickening. Review of systems revealed a three-month history fatigue, right-sided headaches, jaw claudication, bronchitis, cough without hemoptysis, and epistaxis, as well as interval development of a petechial rash across her body, migratory polyarthralgias, fevers, and tachycardia. ESR and CRP were markedly elevated, and the patient was admitted to the hospital for a systemic vasculitis workup. She was started on IV methylprednisolone. Her vision improved dramatically with steroids, measuring 20/50 with correction in the right eye after 24 hours and returning to baseline after five days. An extensive workup including imaging, bloodwork, and biopsies led to a diagnosis of granulomatosis with polyangiitis, with PR3-positive ANCA. Ocular findings, including anterior ischemic optic neuropathy, may be the presenting signs for patients with granulomatosis with polyangiitis. Prompt recognition and treatment with high-dose steroids and immunomodulatory therapy is important for visual recovery. Prompt recognition of potential vasculitis-related vision loss can lead to timely initiation of vision-saving treatment. Granulomatosis with polyangiitis, also known as Wegener's granulomatosis, is a chronic systemic inflammatory disease that can also involve the eyes. We report a case of massive retinal and preretinal hemorrhages with perivascular changes as the initial signs in granulomatosis with polyangiitis (Wegener's granulomatosis). A 39-year-old Caucasian male presented with blurred vision in his right eye, myalgia and arthralgia, recurrent nose bleeds and anosmia. Fundus image of his right eye showed massive retinal hemorrhages and vasculitis-like angiopathy, although no fluorescein extravasation was present in fluorescein angiography. Laboratory investigations revealed an inflammation with increased C-reactive protein, elevated erythrocyte sedimentation rate and neutrophil count. Tests for antineutrophil cytoplasmic antibodies (ANCA) were positive for c-ANCA (cytoplasmatic ANCA) and PR3-ANCA (proteinase 3-ANCA). Renal biopsy demonstrated a focal segmental necrotizing glomerulonephritis. Granulomatosis with polyangiitis (Wegener's granulomatosis) was diagnosed and a combined systemic therapy of cyclophosphamide and corticosteroids was initiated. During 3 months of follow-up, complete resorption of retinal hemorrhages was seen and general complaints as well as visual acuity improved during therapy. Vasculitis-like retinal changes can occur in Wegener's granulomatosis. Despite massive retinal and preretinal hemorrhages that cause visual impairment, immunosuppressive therapy can improve ocular symptoms. Diagnosis No specific lab tests exist for diagnosing polyarteritis nodosa. Diagnosis is generally based on the physical examination and a few laboratory studies that help confirm the diagnosis: CBC (may demonstrate an elevated white blood count) ESR (elevated) Perinuclear pattern of antineutrophil cytoplasmic antibodies (p-ANCA) - not associated with \"classic\" polyarteritis nodosa, but is present in a form of the disease affecting smaller blood vessels, known as microscopic polyangiitis or leukocytoclastic angiitis Tissue biopsy (reveals inflammation in small arteries, called arteritis) Elevated C-reactive protein Diagnosis Laboratory tests may reveal an increased sedimentation rate, elevated CRP, anemia and elevated creatinine due to kidney impairment. An important diagnostic test is the presence of perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) with myeloperoxidase specificity (a constituent of neutrophil granules), and protein and red blood cells in the urine. In patients with neuropathy, electromyography may reveal a sensorimotor peripheral neuropathy. Differential diagnosis The signs and symptoms of microscopic polyangiitis may resemble those of granulomatosis with polyangiitis (GPA) (another form of small-vessel vasculitis) but typically lacks the significant upper respiratory tract involvement (e.g., sinusitis) frequently seen in people affected by GPA. Systemic histoplasmosis is an invasive fungal infection that may mimic primary vasculitis, particularly granulomatosis with polyangiitis (GPA), and was rarely described in adult patients. We reported an immunocompetent patient with disseminated histoplasmosis mimicking GPA who fulfilled European League Against Rheumatism (EULAR)/Pediatric Rheumatology International Trials Organisation (PRINTO)/Pediatric Rheumatology European Society (PRES) validated classification criteria. A 6-year old boy presented acute migratory polyarthritis with spontaneous improvement, sinus inflammation, fever, headache and abdominal pain. Serologic test for hepatitis, cytomegalovirus, human immunodeficiency virus, Epstein-Barr virus, toxoplasmosis, dengue virus and antistreptolysin O were all negative. Magnetic resonance imaging (MRI) showed moderate ascites in pelvis and pansinusitis. Antineutrophil cytoplasmic antibodies (c-ANCA) were positive. He had spontaneous remission of the symptoms including fever. At the age of 11 years and 11 months, he had sinusitis, pneumonia and epididymitis. A month later, he was hospitalized and MRI showed left eye proptosis. Cerebrospinal fluid was normal and indirect tests of fungi were negative. Two months later, he had lumbar pain and computer tomography showed a mass in the right kidney and pulmonary nodule in the right lung. He fulfilled EULAR/PRINTO/PRES criteria for GPA, however the renal biopsy showed a focal granulomatous interstitial nephritis with yeast fungal cells compatible with Histoplasma sp. He was treated with liposomal amphotericin B and itraconazole with improvement of signs and symptoms. We reported a progressive disseminated histoplasmosis case mimicking GPA. Histoplasmosis infection should be considered in immunocompetent subjects with uncommon clinical manifestations, such as arthritis, nephritis and epididymitis. The purpose of this study is to describe a patient who was diagnosed with granulomatosis with polyangiitis based on conjunctival biopsy. This study is a case report and review of the literature. A 48-year-old Caucasian woman presented with a 2-week history of a left eye peripheral corneal ulcer with adjacent conjunctivitis and a 4-month history of a non-resolving productive cough. Given her elevated serum perinuclear antineutrophil cytoplasmic antibody (P-ANCA) and erythrocyte sedimentation rate (ESR) levels as well as a chest computed topography (CT) that showed bilateral patchy infiltrates, suspicion of limited granulomatosis with polyangiitis with lung and ocular involvement was high. Because bronchoalveolar lavage was nondiagnostic for granulomatous disease, conjunctival biopsy was initially attempted in order to avoid a more invasive lung biopsy. The conjunctival biopsy revealed mixed subacute inflammatory mediators and vasculitis consistent with granulomatosis with polyangiitis. Conjunctival biopsy may be a valuable, minimally invasive method for diagnosing systemic granulomatosis with polyangiitis. A 51-year-old woman had been suffering from blood-stained purulent sinusitis and antibiotic-resistant bouts of fever for 4 months. She had microhematuria and serological evidence of inflammation (erythrocyte sedimentation rate [ESR] 92/135 mm, C-reactive protein 5.0 mg/dl). When she was admitted to hospital suspected of having postinfectious glomerulonephritis she complained of spontaneous colic-like pains in the left flank. Within one day the haemoglobin concentration fell from 10 to 6.5 g/dl. Ultrasound and computed tomography demonstrated a large space-occupying lesion around the left kidney. At operation this was found to be a rupture of the kidney with perirenal bleeding which was treated without removing the kidney. No biopsy was taken, but serological tests showed antineutrophil cytoplasmatic antibodies (cANCA), indicating Wegener's granulomatosis as the cause of the compensated renal insufficiency and spontaneous renal rupture. Under immunosuppressive treatment the inflammatory signs (ESR 18/44 mm), fever, chronic maxillary sinusitis, raised serum creatinine concentration and the ANCA titre all regressed, while proteinuria of about 4 g/24 h persisted. There was no recurrence during a follow-up period of 15 months. Serological signs of marked inflammatory activity, urinary sediments of nephritis and spontaneous retroperitoneal bleeding should suggest that, in addition to lupus erythematodes and panarteritis nodosa, Wegener's granulomatosis be included in the differential diagnosis. Palpable purpura is a condition where purpura, which constitutes visible non-blanching hemorrhages, are raised and able to be touched or felt upon palpation. It indicates some sort of vasculitis secondary to a serious disease. Causes Rocky mountain spotted fever Acute meningococcemia Disseminated gonococcal infection Ecthyma gangrenosum Henoch–Schönlein purpura Eosinophilic granulomatosis with polyangiitis Polyarteritis nodosa Leucocytoclastic vasculitis Microscopic polyangiitis Mixed essential cryoglobulinemia Subacute bacterial endocarditis Diagnosis Identification of underlying cause. Treatment Treat the underlying disease. References Further reading Vascular-related cutaneous conditions Dysthyroid optic neuropathy is the most commonly suspected diagnosis of optic neuropathy in Graves' patients; however, other causes need to be ruled out. We present a unique case of optic neuropathy secondary to hypertrophic pachymeningitis with antineutrophil cytoplasmic antibody-associated vasculitis, which was suspected to be antithyroid drug related. A 79-year-old Japanese male presented with acute visual loss in the left eye. He had a 24-year history of Graves' disease and was taking methimazole. Best-corrected visual acuity was 0.8 in the right eye and light perception in the left eye, and relative afferent pupillary defect in the left eye was seen. Ocular movement was normal, and there were no findings explaining visual loss in intermediate optic media and fundus in the left eye. Contrast-enhanced magnetic resonance imaging demonstrated thickened dura mater. Tests for myeloperoxidase-antineutrophil cytoplasmic antibody, proteinuria, and hematuria were positive; pulmonary nodule lesions and a blood clot in the left lower leg were also found. After excluding the presence of diseases that could lead to hypertrophic pachymeningitis, we diagnosed optic neuropathy due to hypertrophic pachymeningitis with granulomatosis with polyangiitis-a subtype of antineutrophil cytoplasmic antibody-associated vasculitis. Since he had history of using methimazole, antineutrophil cytoplasmic antibody-associated vasculitis was considered as drug related. We started high-dosage steroid pulse therapy followed by 1 mg/kg body weight daily of oral prednisolone, and subsequently tapered. Methimazole was stopped. Best-corrected visual acuity recovered to 0.9, 2 weeks after starting treatment. Though myeloperoxidase-antineutrophil cytoplasmic antibody remained negative, the symptom relapsed 6 months after treatment initiation. We gave a second high-dose steroid pulse therapy followed by prednisolone tapered together with methotrexate. Remission remained, and using 4 mg/week methotrexate without prednisolone, myeloperoxidase-antineutrophil cytoplasmic antibody was kept within the normal limit until now, 4 years after onset. We present a case of optic neuropathy with hypertrophic pachymeningitis related to antineutrophil cytoplasmic antibody-associated vasculitis, which was suspected to be drug related. The patient had good visual recovery after quitting the drug and receiving immunosuppressive therapy with systemic steroids. Hypertrophic pachymeningitis with antineutrophil cytoplasmic antibody-associated vasculitis related to antithyroid drugs should be considered as a differential diagnosis for optic neuropathy in Graves' patients in whom optic nerve compression is not obvious. Differential diagnosis Polyarteritis nodosa rarely affects the blood vessels of the lungs and this feature can help to differentiate it from other vasculitides that may have similar signs and symptoms (e.g., granulomatosis with polyangiitis or microscopic polyangiitis). Treatment Treatment involves medications to suppress the immune system, including prednisone and cyclophosphamide. When present, underlying hepatitis B virus infection should be immediately treated. In some cases, methotrexate or leflunomide may be helpful. Some patients have entered a remission phase when a four-dose infusion of rituximab is used before the leflunomide treatment is begun. Therapy results in remissions or cures in 90% of cases. Untreated, the disease is fatal in most cases. The most serious associated conditions generally involve the kidneys and gastrointestinal tract. A fatal course usually involves gastrointestinal bleeding, infection, myocardial infarction, and/or kidney failure. Diagnosis Granulomatosis with polyangiitis is usually suspected only when a person has had unexplained symptoms for a long period of time. Determination of anti-neutrophil cytoplasmic antibodies (ANCAs) can aid in the diagnosis, but positivity is not conclusive and negative ANCAs are not sufficient to reject the diagnosis. More than 90% of people who have GPA test positive for ANCA. Cytoplasmic-staining ANCAs that react with the enzyme proteinase 3 (cANCA) in neutrophils (a type of white blood cell) are associated with GPA. Involvement of the ears, nose, and throat is more common in granulomatosis with polyangiitis than in the similar condition microscopic polyangiitis. Granulomatosis with polyangiitis (GPA), a necrotizing granulomatous disease, very rarely involves the central nervous system (CNS), particularly the pituitary. Delayed treatment may cause permanent bilateral blindness. We report an isolated case of pituitary GPA that manifested as a progressive bilateral temporal visual field (VF) defect and was diagnosed via pituitary biopsy. Additionally, we review ocular, chiasmal and cranial nerve involvement in pituitary GPA. A 20-year-old Chinese man was referred for repeated fever, sudden headache, diplopia with a bilateral best-corrected visual acuity (BCVA) of 10/20, ptosis in both eyes and restricted abduction on the right side. VF tests showed bitemporal hemianopsia. Laboratory tests revealed hypothyroidism and were negative for autoimmune markers. Enhanced magnetic resonance imaging (MRI) showed pituitary enlargement. The diagnosis was lymphocytic pituitaritis. After intravenous (IV) dexamethasone treatment, full recovery occurred within 2 months. Two years later, the patient was readmitted for headache recurrence. With oral prednisone, the visual acuity in his right eye rapidly decreased to hand motion (HM) within one month. Enhanced MRI showed pituitary enlargement and a new, invasive suprasellar CNS lesion. All infection- and autoimmune-related tests were negative. The visual acuity in his right and left eye decreased to no light perception (NLP) after 6 days and 2 weeks, respectively. The biopsy results suggested GPA. After IV methylprednisolone treatment, complete remission of the symptoms occurred and was confirmed by MRI. The 15-month follow-up showed no signs of recurrence. GPA typically affects the respiratory tract, lungs and kidneys. To date, 50 cases with pituitary involvement have been reported. Chiasmal and cranial nerve involvement leading to visual acuity impairment are common. We found 2 cases with severe visual loss resembling our case and discuss certain similarities. Risk stratification The French Vasculitis Study Group has developed a five-point system (\"five-factor score\") that predicts the risk of death in Churg–Strauss syndrome using clinical presentations. These factors are: Reduced renal function (creatinine >1.58 mg/dl or 140 μmol/l) Proteinuria (>1 g/24h) Gastrointestinal hemorrhage, infarction, or pancreatitis Involvement of the central nervous system Cardiomyopathy Having none of these factors indicates milder case, with a five-year mortality rate of 11.9%. The presence of one factor indicates severe disease, with a five-year mortality rate of 26%, and three or more indicate very severe disease: 46% five-year mortality rate. In the setting of systemic vasculitis as described above, proliferative nephritis is associated with antineutrophil cytoplasmic antibodies (ANCA). Because of this, an ANCA test should always follow a negative immunofluorescence result to have the highest accuracy for confirming pauci-immune vasculitis-driven proliferative nephritis. Some cases of pauci-immune proliferative nephritis have no explanation and are thus deemed \"idiopathic.\" Peak incidences in 50- to 60-year-olds symptoms include intermittent fever / weight loss / shortness of breath / joint pain. See also Systemic vasculitis#Pauci-immune Goodpasture Syndrome and Poststrep Glomerulonephritis Microscopic polyangiitis, Eosinophilic granulomatosis with polyangiitis or Granulomatosis with polyangiitis References External links wikt:paucity Vascular-related cutaneous conditions Upon presentation, renal involvement is noted in only 10%-20%, but glomerulonephritis eventually develops in 80% of patients within two years of disease onset. The most common manifestation is rapidly progressive crescentic glomerulonephritis leading to chronic kidney disease or end-stage renal disease. Eye involvement: A 55-year-old male was admitted with non productive cough and fever which had continued for 6 weeks. The patient had symptoms of peripheral neuralgia. Chest X-ray revealed bilateral hilar lymphadenopathy (BHL) and reticular shadows in both lung fields. Other laboratory abnormalities included hematuria, RBC cast, high BUN, leukocytosis and thrombocytosis. Destruction of the internal membrane of arterioles was observed in a livedo reticularis on the right lower extremity. Renal angiography showed irregularity in the diameter, discontinuation and narrowing of peripheral arteries of both kidneys. These findings suggested the existence of \"angiitis\". These data were compatible with the diagnosis of polyarteritis nodosa (PN). Prednisolone (60 mg/day) administration resulted in the improvement of his symptoms and laboratory findings. A case of PN with lymph node swelling has been reported, however PN with BHL has not yet been reported. This is the first report of PN with BHL.\nHere is the question:\nRHEUMATOLOGY: A 67-year-old man presents with 3 months of asthenia and febrile fever, with nasal obstruction and mucus emission with some clots in the last month. In the last few days she noticed pain in the right eye and asymmetry with respect to the contralateral eye. Physical examination reveals proptosis of the right eyeball and inspection of the nostrils reveals an erythematous mucosa with serohematic crusts. The rest of the examination was normal. Blood tests (hemogram, renal and hepatic function) are normal, except for an ESR of 65 mm/h; urinalysis shows microhematuria and proteinuria of 520 mg/24h. What is the most probable initial diagnosis?\nHere are the potential choices:\n1. Eosinophilic granulomatosis with polyangiitis.\n2. Microscopic polyangiitis.\n3. Granulomatosis with polyangiitis.\n4. Polyarteritis nodosa.\nThe correct answer is: 3. Granulomatosis with polyangiitis."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Macular diseases in the elderly, such as age-related macular degeneration, idiopathic senile macular hole and epiretinal membrane of the macular area were studied. In 75 normal subjects aged from 20 to 78 years, retinal sensitivity in the central 10 degree visual field were examined using automated static quantitative perimetry. For background luminance of 31.5 asb, a significant reciprocal correlation was demonstrated between individual mean sensitivity and age. The influence of age on the decrease in sensitivity was proved to differ according to different test locations. To enhance contrast, an image processing procedure was applied for fluorescein angiographs of age-related pathologies which resulted in better recognition of age-related RPE pathologies were recognized. The senile disciform macular degeneration (SDMD) study group sponsored by the Ministry of Health and Welfare performed an epidemiological survey to estimate the number of patients with SDMD. The epidemiological estimation was 6,000 to 13,000 patients in the entire Japanese population. 133 eyes of uni- or bi-lateral senile macular degeneration without choroidal neovascularization and 156 opposite eyes of patients with unilateral SDMD were followed-up for choroidal neovascularization development. Choroidal neovascularization development was confirmed in 15 eyes, 5.2%. In 13 of the 15 eyes, choroidal neovascularization was proved to develop through serous RPE detachment. Also, serous drusen were shown to be to predisposed to choroidal neovascularization through serous RPE detachment. Therefore, it was concluded that senile macular degeneration should be classified into the atrophic form, predisciform or intermediate form and disciform form. In the author's previous paper, it was reported that the navel-like lesion would be a macular lesion predisposing to a senile macular hole. 49 opposite eye of patients with one eye affected by a macular hole were follow-up for macular hole development. At the initial examination, the navel-like lesion was observed in 5 of the 49 eyes. During the course of observation, navel-like lesions developed in one of the other 27 eyes with other abnormalities and in 4 of the 17 eyes without any abnormality. Finally, macular holes developed in 11 of the 49 eyes; in 10 eyes with a navel-like lesion and one eye with another abnormality. We found a 17 year old female Japanese monkey with pre-macular holes in both eyes and clinicopathological correlative study was carried out. In her right eye, photoreceptor cell loss at the foveola, circumferential retinal detachment around the area of cell loss, cystoid spaces in the detached retina, and very thin residual tissue covering the foveolar lesion were observed.(ABSTRACT TRUNCATED AT 400 WORDS) Drusen are important risk factor for neovascular age-related macular degeneration (AMD) and have a dynamic nature as they can enlarge, newly form, or disappear over time. There have been few reports on drusen regression or choroidal neovascularization (CNV) development after macular hole surgery. We report, to our knowledge, the first case of both drusen regression and subsequent CNV development within 7 months of successful macular hole surgery. A 73-year-old woman presented with a stage 3 full-thickness macular hole and large, confluent soft macular drusen in the right eye and a neovascular age-related macular degeneration (AMD) in the fellow eye. Four months after the successful macular hole surgery, significant regression of drusen was seen, especially in the temporal area to the fovea. Three months later, the patient developed CNV and her best-corrected visual acuity decreased to 20/100, despite further regression of macular drusen. Macular hole patients with macular soft drusen need to be carefully followed up after surgery for possible drusen regression and CNV development. To describe functional and anatomic results obtained by treatment with photodynamic therapy (PDT) or intravitreal bevacizumab (Avastin, Roche) in macular serous retinal detachment associated with tilted disk syndrome. Three eyes of 3 patients with symptomatic macular serous detachment associated with tilted disc syndrome (optic disc with an oblique axis, inferonasal crescent, and inferior staphyloma) were treated. In all patients, best-corrected visual acuity (BCVA) was tested and fluorescein angiography (FA) and optical coherence tomography (OCT) were performed before and about 45 days after treatment. All patients underwent a complete ophthalmologic examination including OCT at least 6 months after treatment. The first patient was treated with one low fluence (300 mW/cm2 for 83 seconds) PDT (6 months follow-up). The second patient was treated with 3 intravitreal injections of bevacizumab 1.25 mg (33 months follow-up) and the third patient was treated with 2 low fluence PDTs at 4 months and, after 1 year, 3 intravitreal injections of bevacizumab 1.25 mg (37 months follow-up). Before treatment, all patients complained of visual loss and metamorphopsia. The OCT showed in the macular area a focal neurosensory detachment with foveal involvement. The FA showed in the macular area multiple focal areas of hyperfluorescence due to pigment epithelium atrophy and in the second and third patient also a hyperfluorescent pinpoint with minimal leakage. After treatment in all eyes, symptoms did not change, BCVA remained stable, and in OCT the foveal neuroretinal detachment was changeless. In FA, no noticeable variation of the hyperfluorescence areas was appreciated. In the second patient, the hyperfluorescent point remained unvaried, and the same occurred in the third patient after the first PDT, while after the second PDT a new leaking dot disappeared. Macular serous retinal detachment was first described in 1998 as an uncommon complication of tilted disc syndrome showing angiographic and OCT features similar to a chronic central serous chorioretinopathy. In contrast to this pathology, in our patients treatment with PDT or intravitreal bevacizumab did not succeed, probably because of a different pathogenesis of macular serous detachment. Further investigations are needed to clarify the proper therapy of this disease. Acquired vitelliform lesions (AVLs) are associated with age-related macular degeneration and other variable macular disorders. AVLs often lead to outer retinal atrophy, sometimes accompanying a macular hole and choroidal neovascularization. The purpose of this study was to report a rare case with bilateral AVLs, in which one eye had accompanied a macular hole and the second eye a serous pigment epithelial detachment (sPED). A 66-year-old woman complained of bilateral metamorphopsia. AVLs were observed in the right eye and a flat sPED in the left eye. The best-corrected visual acuity (BCVA) was 20/17 in both eyes. Fluorescein angiography revealed local leakage in the right eye and pattern dystrophy-like hypofluorescence in both eyes. The sPED progressed with AVLs in the left eye and was treated with a combination therapy of intravitreal aflibercept, a sub-Tenon's injection of triamcinolone acetonide, and photodynamic therapy (IVA/STTA/PDT), which successfully flattened the sPED and sustained good vision for 4 years. The right eye was treated with intravitreal ranibizumab and tissue plasminogen activator, which enhanced absorption of the vitelliform material. However, 14 months later, a macular hole with typical metamorphopsia formed above a subretinal fibrotic scar at the vitelliruptive stage. Although pars plana vitrectomy closed the macular hole, enlargement of the outer retinal atrophy worsened the BCVA to 20/100. We successfully treated one eye with a sPED with AVLs using the combination therapy of IVA/STTA/PDT, while the second eye with a macular hole secondary to AVLs ultimately developed outer retinal atrophy with visual loss. Clinical significance Amsler grid can be used in detecting central visual field defects in following conditions: Age-related macular degeneration: The grid will help detecting the progression of AMD from dry form to wet form. Chance of metamorphopsia is more in wet AMD compared to dry form. Choroidal neovascular membranes: Choroidal neovascular membranes cause scotoma and metamorphopsia. It may be associated with many diseases like macular degeneration, POHS, myopic macular degeneration, trauma etc. Central serous chorioretinopathy: CSCR Causes round or oval scotoma. Macular pucker: Macular pucker also known as an epiretinal membrane cause metamorphopsia and distortions in central field of vision. Cystoid macular edema: Due to macular edema, micropsia may occur. Glaucoma: Amsler grid is useful in detecting central field defects in moderate to severe glaucoma. Macular sparing: Amsler Grid can be used to detect and accurately measure macular sparing. Types Recent advancement in OCT has made it simpler to differentiate a macular hole from other similar types of smaller diameter macular pathologies of old age. From history and physical examination, round central small reddish lesions with dimness of central vision, probable differential diagnosis include: Epiretinal membrane (ERM) with a macular pseudo hole Central foveal dot hemorrhage Lamellar (aborted) macular hole Vitreomacular traction syndrome (VMTS) Foveal drusen Central areolar pigment epitheliopathy Solar retinopathy Small choroidal neovascular membrane involving center Small central serous chorioretinopathy involving center Cystoid macular edema (CME) Other types There are a few other (rare) kinds of macular degeneration with similar symptoms but unrelated in etiology to Wet or Dry age-related macular degeneration. They are all genetic disorders that may occur in childhood or middle age. Vitelliform macular dystrophy Sorsby's fundus dystrophy is an autosomal dominant, retinal disease characterized by sudden acuity loss resulting from untreatable submacular neovascularisation Stargardt's disease (juvenile macular degeneration, STGD) is an autosomal recessive retinal disorder characterized by juvenile-onset macular dystrophy, alterations of the peripheral retina, and subretinal deposition of lipofuscin-like material. Similar symptoms with a very different etiology and different treatment can be caused by epiretinal membrane or macular pucker or any other condition affecting the macula, such as central serous retinopathy. Notable cases Judi Dench Joan Plowright Peter Sallis June Brown S. Robert Morgan See also Treatment and Prognosis Metamorphopsia is a symptom of several common retinal and macular diseases, therefore treating the underlying disorder can improve symptoms. For people who have conditions such as Epiretinal membrane (ERM), Macular Holes and Retinal Detachment, decreased metamorphopsia is associated with an increase in visual acuity. Quantitative evaluation of metamorphopsia is an important step in understanding visual functions of individuals with macular disorders and is an essential tool for physicians in evaluating treatment results. Types Dry (non-exudative, > 80%)—deposition of yellowish extracellular material in and between Bruch's membrane and retinal pigment epithelium (“drusen”) with gradual loss in vision. Wet (exudative, 10–15%)—rapid loss of vision due to bleeding secondary to choroidal neovascularization. Etymology Gk, meta + morphe, form, opsis, sight See also Dysmorphopsia Hallucination References Visual disturbances and blindness Purpose. Myopic macular holes can be difficult to close with surgery and are frequently associated with retinal detachment. We report on a case of a macular hole in a severely myopic eye that underwent spontaneous closure. Methods. An observational case study. Results. A 55-year-old female was referred to Ophthalmology for a central scotoma and metamorphopsia in the right eye. Visual acuity was 1/20 in both eyes. Fundus examination showed loss of the foveal depression, with a small yellow ring in the center of the fovea in the right eye, and a tilted optic disc and peripapillary staphyloma bilaterally. Spectral domain optical coherence tomography (SD-OCT) revealed a fully developed macular hole with a rim of thickened and slightly elevated retina in the right eye. The patient refused surgery. After 4 years of follow-up, her visual acuity improved to 20/40 in the right eye, and SD-OCT revealed spontaneous sealing of the macular hole without bare retinal pigment epithelium. Conclusions. Myopic macular holes represent a challenge regarding their management, and the prognosis is often poor.  To characterize retinal and fluorescein angiographic findings of Asian patients with symptoms secondary to age-related macular degeneration (ARMD). We retrospectively reviewed 453 consecutive medical records corresponding to fluorescein angiograms performed between November 1992 and November 1995 to identify Asian patients with symptomatic ARMD. Presenting visual symptoms, best-corrected Snellen visual acuities, and retinal examination findings were determined from the medical records. Fundus photos and fluorescein angiograms were reviewed. There were 26 symptomatic eyes in 19 Asian patients with a median age of 73 years. Presenting visual symptoms included decreased visual acuity (19 eyes), metamorphopsia (5 eyes), or scotoma (2 eyes). Retinal findings included occult choroidal neovascularization (CNV) in 5 (19%) eyes, serous pigment epithelial detachment (PED) in 8 (31%) eyes, PED with CNV in 5 (19%) eyes, drusen in 5 (19%) eyes, retinal pigment epithelial atrophy in 1 (4%) eye, vitreous hemorrhage in 1 (4%) eye, and a disciform scar in 1 (4%) eye. In this cohort of Asian patients with ARMD, the majority of symptomatic eyes had either CNV (46%) or serous PED (31%). To study the clinical features and the pathogenesis of macular hole with and without retina detachment (RD) in high myopic eyes. It was a retrospective series case study. The charts of high myopic patients with macular hole at our hospital from June 2006 to February 2007 were retrospectively reviewed and analyzed. Patients were divided into two groups (the RD group and non-RD group) depending on the presence of RD or not. Their clinical data and optic coherence tomography (OCT) results were further analyzed. SPSS 13.0 was used for the statistic analysis. When comparing the quantitative aspects like age, axial length and refraction, t-test was used. Categorical data, such as sex ratio, occurrence of vitreous traction, posterior staphyloma and retinoschisis were compared by using χ(2) test. Fisher's test was used in comparing eye laterality, incidence of white hole, visual acuity and posterior vitreous detachment (PVD). During this period, there were 43 patients fitting the including criteria. Among them, 36 patents (37 eyes) were in the RD group and 7 patients (7 eyes) in the no-RD group. In the RD group, the average age was 56.1, 24.3% of them (9/37) were male; percentage of left and right eyes was (11/37) and 70.3% (26/37), respectively; average refraction was (-8.9 ± 2.2) D; average axial length was (28.7 ± 2.0) mm. Visual acuity was ≤ 0.05 (72.2%) in 26 eyes and 0.05 - 0.2 (27.8%) in 10 patients. The incidence of complete and non-complete PVD was 89.2% (33/37) and 10.8% (4/37), respectively. White hole presented in 35.1% (3/37) patients. Vitreous traction and retinoschisis presented in 27.0% (10/37) and 35.1% (13/37) patients, respectively. In the non-RD group, the average age was 47.6; 16.7% of them (1/7) were male; left and right eyes were involved in 42.9% (3/7) and 57.1% (4/7), respectively. Average refraction was (-9.0 ± 1.9) D; average axial length was (28.9 ± 1.5) mm. Vision acuity was ≤ 0.05 in 3 patients (42.9%); between 0.05 - 0.2 in 3 eyes (42.9%) and ≥ 0.2 in 1 eye (14.3%). Incidence of complete and non-complete PVD was 85.7% (6/7) and 14.3% (1/7), respectively. White hole was observed in 14.3% (1/7) patients; 42.9% (3/7) patients were accompanied with vitreous traction and 71.4% (5/7) with retinoschisis. B-scan ultrasonography showed posterior staphyloma in all 44 eyes. The results of statistical analysis showed that the gender (χ(2) = 0.008) and eye laterality (χ(2) = 0.449) as well as refraction (t = 0.193), axial length (t = -0.25) and visual acuity (χ(2) = 4.509) of these two groups were similar (P &gt; 0.05). The incidences of vitreous traction (χ(2) = 0.709), white hole (χ(2) = 1.179), PVD (χ(2) = 0.071) and retinoschisis (χ(2) = 3.207) were also similar (P &gt; 0.05). But the age of the non-RD group is significantly younger than the RD group (t = 1.66, P &lt; 0.05). Various pathogenesis may involved in the occurrence of retinal detachment in highly myopic eyes with macular hole. Further study is required to improve our understanding of this entity. The aim of this case report is to describe a case of atypical central serous chorioretinopathy (CSCR) definitively diagnosed after 8 years. A 44-year-old woman presented with reduced visual acuity in her left eye. Her visual acuity was light perception with projection in the right eye and 0.15 in the left. She described a similar decline in vision in her right eye 8 years ago. At that time, she had exudative retinal detachment and was treated with systemic immunosuppressive therapy for a presumed diagnosis of Vogt-Koyanagi-Harada disease. Despite resolution of the exudative retinal detachment, macular scarring developed. Eight years later, she developed inferior exudative retinal detachment in the left eye. A diagnosis of atypical CSCR was made with the help of multimodal imaging and her left eye was successfully treated with eplerenone and half-fluence photodynamic therapy (hf-PDT). In conclusion, early diagnosis and treatment of atypical CSCR may prevent subretinal fibrosis formation and permanent vision loss. Hf-PDT and eplerenone are successful treatment options for atypical CSCR. Self-separation or peeling of an idiopathic epiretinal membrane (ERM) in an eye with partial posterior vitreous detachment (PVD) is a rare event. A 56-year-old woman presented to our clinic with complaints of floaters in her right eye. Best-corrected visual acuity (BCVA) was 9/10 in this eye. Fundus examination and Spectral domain optical coherence tomography (SD-OCT) revealed an idiopathic ERM and Grade 3 PVD in this eye. Four months later, she had complaints of metamorphopsia in her right eye. BCVA was 7/10, while SD-OCT images of the right macula were similar to previous images. One week after the last visit, she presented again due to the sudden disappearance of her metamorphopsia complaints. BCVA had improved to 10/10. Fundus examination demonstrated that the ERM had spontaneously separated from the retinal surface as a flap floating in the vitreous and the foveal contour had returned to normal. The etiologic mechanism may be explained as the contracting forces within an immature ERM being stronger than its adhesion to the retina. The pathogenesis of the macular serous retinal detachment (SRD) associated with congenital optic disc pit remains controversial. The treatment is also discussed. Through this study, which includes the majority of the techniques available, we report our experiment in the treatment of this pathology. This was a retrospective single-centre study of 20 patients who presented with macular SRD associated with optic disc pit between 1983 and 2009. Various treatments were provided. At the beginning of the study, patients were treated only by juxtapapillary laser photocoagulation. After laser failure then as first-line treatment, laser photocoagulation was associated with intravitreal gas (C3F8) injection with postoperative facedown positioning for 2 weeks. During the past few years, all patients have been systematically treated with vitrectomy with or without internal limiting membrane (ILM) peeling, laser, and gas (C2F6) tamponade. This series consisted of 20 patients: nine men and 11 women. The patients' mean age at presentation was 29 years (range, 9-60 years). The mean time between the onset of the decrease in visual acuity (VA) and treatment was 6.1 months. None of these patients had a posterior vitreous detachment at the time of diagnosis. Six patients were treated by laser photocoagulation alone, which was successful only in two cases. Eleven patients (with laser treatment failure in three) were treated by laser and intravitreal gas injection, with a 72% success rate. We performed vitrectomy with posterior hyaloid dissection, laser, and gas tamponade in eight cases (with laser-gas treatment failure in two) with 87% success rate and no recurrence. Five of these patients had ILM peeling during the vitrectomy. The mean follow-up period was 60 months (range, 2 months to 17 years). This study shows that early treatment of macular SRD associated with optic disc pit by vitrectomy, ILM peeling, juxtapapillary photocoagulation, and gas tamponade is followed by good anatomical and functional results. This treatment is superior to the other less invasive procedures. Optical coherence tomography is an important exam for diagnosis and postoperative follow-up of patients. Central serous choroidopathy is a macular disease, usually with a self-limited and benign course, and predominantly affects male patients between 20 and 45 years old. A 68 year-old female patient complained of decreased visual acuity of her right eye of approximately 3 weeks of onset. Best corrected visual acuity in her right eye was 20/100. Fundus examination revealed a macular serous detachment involving its centre, as well as the presence of multiple calcified drusen. Fluorescein angiography showed late parafoveal leakage in a \"smokestack\" pattern in the right macular area. Optical coherence tomography showed a dome-shape macular detachment, also in the right eye. The patient was observed every 2 weeks and spontaneous resolution of the macular detachment was seen a month later. Based on these clinical features, a diagnosis was made of central serous choroidopathy of atypical presentation. Atypical presentation cases of serous central choroidopathy might be seen occasionally. Hence, it is an important differential diagnosis of age related macular degeneration in patients older than 60 years. To evaluate a macular buckle for exudative choroidal neovascularization secondary to age-related macular degeneration (ARMD). Forty-two eyes with choroidal neovascular membranes (CNVM) secondary to ARMD underwent surgical placement of a macular buckle. A Gore-Tex strip (2.0-2.5 mm wide) was button-holed through a 5 mm diameter silicone sponge (9 mm long) and placed behind the macula underneath the CNVM by the same surgeon (Dr Peyman) in all cases. Follow-up ranged from 7-76 months (mean, 20.9 months). Of 12 eyes with classic subfoveal CNVM: 4 (33%) gained 2 or more lines of Snellen visual acuity; 3 (25%) gained 1 line, remained the same, or lost 1 line; and 5 (42%) lost 2 or more lines (range + 6 to - 6 lines). Of 22 eyes with ill-defined subfoveal CNVM: 12 (54%) gained 1 line, remained the same, or lost 1 line; and 10 (46%) lost 2 or more lines (range + 1 to - 8 lines). Eight eyes with ill-defined juxtafoveal CNVM had the following visual acuity outcomes: 5 eyes (62%) maintained the same level of Snellen visual acuity (gained 1, 0, or lost 1 line); and 3 (38%) got worse (lost 2 or more lines of Snellen visual acuity, range + 1 to - 6 lines). Ten eyes (24%) bled subretinally during the follow-up period (average 11.5 months, range 14 days to 27 months), all outside the area of indentation of the macular buckle. The macular buckle treatment for exudative subretinal choroidal neovascular membranes in ARMD stabilized visual decline and displaced significant subfoveal hemorrhage. To report the pathogenic factors that account for cystoid macular edema and cystoid macular degeneration in chronic central serous chorioretinopathy (CSC). The clinical course and multimodal imaging findings, including fundus color photography, fundus autofluorescence, spectral-domain optical coherence tomography, and fluorescein angiography, of one eye with cystoid macular edema due to chronic CSC was documented. A 44-year old woman with a history of chronic CSC presented with progressive visual decline in the right eye. Best-corrected visual acuity was 20/40. Funduscopic examination revealed diffuse retinal pigment epithelial changes and macular edema. Fluorescein angiography demonstrated perifoveal microaneurysms and leakage in a petaloid configuration. Spectral-domain optical coherence tomography demonstrated cysts at the level of the inner nuclear layer, an epiretinal membrane, vitreomacular traction, and an attenuated retinal pigment epithelial band. Central subfield thickness was 486 μm. Three intravitreal injections of aflibercept were administered over 16 weeks following which there was resolution of leakage, release of vitreomacular traction, and resolution of microaneurysms. Central subfield thickness reduced to 379 μm, but persistent intraretinal cysts were observed. There was subjective improvement in visual symptoms, but Snellen acuity remained at 20/40. Intraretinal cystic changes in chronic CSC may be the result of multifactorial pathogenic factors and may represent the coexistence of cystoid macular edema and cystoid macular degeneration. Anti-vascular endothelial growth factor may play an important role in the treatment of cystoid macular edema caused by CSC. A patient developed choroidal neovascularization (CNV) in one eye during treatment for bilateral recurrent central serous chorioretinopathy (CSC) and was intravitreously injected with bevacizumab; she developed multiple evanescent white dots and serous retinal detachment(SRD). A 50-year-old women had a history of CSC OD at the age of 29 years. On initial examination, CSC OD was noted, and multiple detachments of the retinal pigment epithelium OU were observed. While the CSC in the right eye was successfully treated by laser photocoagulation, it spread to both eyes following this episode. Examination of the right eye by optical coherence tomography (OCT) following the recurrence of the CSC showed slight elevation of the retinal pigment epithelial layer in the central fovea, but this finding disappeared with the resolution of the CSC. However, as the CSC combined with CNV (Gass type 2) recurred within 1 year, the patient was intravitreously injected with bevacizumab. On the day following the injection, SRD OD occurred, and on the 7th day following the injection many white lesions varying in size appeared in the deep layer of the retina, but they healed 3 weeks later, leaving only the CNV. The CNV was cured later by additional photodynamic therapy. Since the lesions of the fundus observed immediately after the bevacizumab administration resolved spontaneously without sequelae, they were retrospectively diagnosed as a white dot syndrome-like disease. The white dot syndrome-like disease is suggested as a rare complication of bevacizumab. Central serous chorioretinopathy (CSCR) is an idiopathic condition characterized by serous detachment of the neurosensory retina in the macular region. It is relatively uncommon in Africans and though pregnancy is a known risk factor, there are no previous reports of CSCR in pregnant African women. We report the case of a 35-year-old pregnant woman who presented to our clinic at gestational age of 29 weeks with a 4 months history of blurring of vision in her left eye. Examination revealed visual acuity of 6/4 on the right eye and 6/9 on the left eye. She had normal anterior segments bilaterally and a normal posterior segment on the right. However, she had left macular edema with exudates. There was no significant refractive error. Her blood pressure was normal. Investigations including electrolytes and urea, urinalysis, and blood sugar profile were all normal. She was managed conservatively, and symptoms resolved 2 weeks prior to delivery. This is a case report of CSCR in a pregnant Nigerian woman with spontaneous resolution of symptoms prior to delivery. Pregnant women should be educated about the possibility of visual problems accompanying pregnancy. \nHere is the question:\nOPHTHALMOLOGY: 75-year-old woman diagnosed 3 years ago with soft drusen in the fundus. She reports presenting, since 2 weeks ago, metamorphopsia and significant visual loss in her right eye that prevents her from reading. Indicate the most probable diagnosis:\nHere are the potential choices:\n1. Macular epiretinal membrane.\n2. Macular hole.\n3. Thrombosis of the central retinal vein.\n4. Senile macular degeneration.\n5. Central serous chorioretinopathy.\nThe correct answer is: ",
        "gold_answer": "4 Senile macular degeneration.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Macular diseases in the elderly, such as age-related macular degeneration, idiopathic senile macular hole and epiretinal membrane of the macular area were studied. In 75 normal subjects aged from 20 to 78 years, retinal sensitivity in the central 10 degree visual field were examined using automated static quantitative perimetry. For background luminance of 31.5 asb, a significant reciprocal correlation was demonstrated between individual mean sensitivity and age. The influence of age on the decrease in sensitivity was proved to differ according to different test locations. To enhance contrast, an image processing procedure was applied for fluorescein angiographs of age-related pathologies which resulted in better recognition of age-related RPE pathologies were recognized. The senile disciform macular degeneration (SDMD) study group sponsored by the Ministry of Health and Welfare performed an epidemiological survey to estimate the number of patients with SDMD. The epidemiological estimation was 6,000 to 13,000 patients in the entire Japanese population. 133 eyes of uni- or bi-lateral senile macular degeneration without choroidal neovascularization and 156 opposite eyes of patients with unilateral SDMD were followed-up for choroidal neovascularization development. Choroidal neovascularization development was confirmed in 15 eyes, 5.2%. In 13 of the 15 eyes, choroidal neovascularization was proved to develop through serous RPE detachment. Also, serous drusen were shown to be to predisposed to choroidal neovascularization through serous RPE detachment. Therefore, it was concluded that senile macular degeneration should be classified into the atrophic form, predisciform or intermediate form and disciform form. In the author's previous paper, it was reported that the navel-like lesion would be a macular lesion predisposing to a senile macular hole. 49 opposite eye of patients with one eye affected by a macular hole were follow-up for macular hole development. At the initial examination, the navel-like lesion was observed in 5 of the 49 eyes. During the course of observation, navel-like lesions developed in one of the other 27 eyes with other abnormalities and in 4 of the 17 eyes without any abnormality. Finally, macular holes developed in 11 of the 49 eyes; in 10 eyes with a navel-like lesion and one eye with another abnormality. We found a 17 year old female Japanese monkey with pre-macular holes in both eyes and clinicopathological correlative study was carried out. In her right eye, photoreceptor cell loss at the foveola, circumferential retinal detachment around the area of cell loss, cystoid spaces in the detached retina, and very thin residual tissue covering the foveolar lesion were observed.(ABSTRACT TRUNCATED AT 400 WORDS) Drusen are important risk factor for neovascular age-related macular degeneration (AMD) and have a dynamic nature as they can enlarge, newly form, or disappear over time. There have been few reports on drusen regression or choroidal neovascularization (CNV) development after macular hole surgery. We report, to our knowledge, the first case of both drusen regression and subsequent CNV development within 7 months of successful macular hole surgery. A 73-year-old woman presented with a stage 3 full-thickness macular hole and large, confluent soft macular drusen in the right eye and a neovascular age-related macular degeneration (AMD) in the fellow eye. Four months after the successful macular hole surgery, significant regression of drusen was seen, especially in the temporal area to the fovea. Three months later, the patient developed CNV and her best-corrected visual acuity decreased to 20/100, despite further regression of macular drusen. Macular hole patients with macular soft drusen need to be carefully followed up after surgery for possible drusen regression and CNV development. To describe functional and anatomic results obtained by treatment with photodynamic therapy (PDT) or intravitreal bevacizumab (Avastin, Roche) in macular serous retinal detachment associated with tilted disk syndrome. Three eyes of 3 patients with symptomatic macular serous detachment associated with tilted disc syndrome (optic disc with an oblique axis, inferonasal crescent, and inferior staphyloma) were treated. In all patients, best-corrected visual acuity (BCVA) was tested and fluorescein angiography (FA) and optical coherence tomography (OCT) were performed before and about 45 days after treatment. All patients underwent a complete ophthalmologic examination including OCT at least 6 months after treatment. The first patient was treated with one low fluence (300 mW/cm2 for 83 seconds) PDT (6 months follow-up). The second patient was treated with 3 intravitreal injections of bevacizumab 1.25 mg (33 months follow-up) and the third patient was treated with 2 low fluence PDTs at 4 months and, after 1 year, 3 intravitreal injections of bevacizumab 1.25 mg (37 months follow-up). Before treatment, all patients complained of visual loss and metamorphopsia. The OCT showed in the macular area a focal neurosensory detachment with foveal involvement. The FA showed in the macular area multiple focal areas of hyperfluorescence due to pigment epithelium atrophy and in the second and third patient also a hyperfluorescent pinpoint with minimal leakage. After treatment in all eyes, symptoms did not change, BCVA remained stable, and in OCT the foveal neuroretinal detachment was changeless. In FA, no noticeable variation of the hyperfluorescence areas was appreciated. In the second patient, the hyperfluorescent point remained unvaried, and the same occurred in the third patient after the first PDT, while after the second PDT a new leaking dot disappeared. Macular serous retinal detachment was first described in 1998 as an uncommon complication of tilted disc syndrome showing angiographic and OCT features similar to a chronic central serous chorioretinopathy. In contrast to this pathology, in our patients treatment with PDT or intravitreal bevacizumab did not succeed, probably because of a different pathogenesis of macular serous detachment. Further investigations are needed to clarify the proper therapy of this disease. Acquired vitelliform lesions (AVLs) are associated with age-related macular degeneration and other variable macular disorders. AVLs often lead to outer retinal atrophy, sometimes accompanying a macular hole and choroidal neovascularization. The purpose of this study was to report a rare case with bilateral AVLs, in which one eye had accompanied a macular hole and the second eye a serous pigment epithelial detachment (sPED). A 66-year-old woman complained of bilateral metamorphopsia. AVLs were observed in the right eye and a flat sPED in the left eye. The best-corrected visual acuity (BCVA) was 20/17 in both eyes. Fluorescein angiography revealed local leakage in the right eye and pattern dystrophy-like hypofluorescence in both eyes. The sPED progressed with AVLs in the left eye and was treated with a combination therapy of intravitreal aflibercept, a sub-Tenon's injection of triamcinolone acetonide, and photodynamic therapy (IVA/STTA/PDT), which successfully flattened the sPED and sustained good vision for 4 years. The right eye was treated with intravitreal ranibizumab and tissue plasminogen activator, which enhanced absorption of the vitelliform material. However, 14 months later, a macular hole with typical metamorphopsia formed above a subretinal fibrotic scar at the vitelliruptive stage. Although pars plana vitrectomy closed the macular hole, enlargement of the outer retinal atrophy worsened the BCVA to 20/100. We successfully treated one eye with a sPED with AVLs using the combination therapy of IVA/STTA/PDT, while the second eye with a macular hole secondary to AVLs ultimately developed outer retinal atrophy with visual loss. Clinical significance Amsler grid can be used in detecting central visual field defects in following conditions: Age-related macular degeneration: The grid will help detecting the progression of AMD from dry form to wet form. Chance of metamorphopsia is more in wet AMD compared to dry form. Choroidal neovascular membranes: Choroidal neovascular membranes cause scotoma and metamorphopsia. It may be associated with many diseases like macular degeneration, POHS, myopic macular degeneration, trauma etc. Central serous chorioretinopathy: CSCR Causes round or oval scotoma. Macular pucker: Macular pucker also known as an epiretinal membrane cause metamorphopsia and distortions in central field of vision. Cystoid macular edema: Due to macular edema, micropsia may occur. Glaucoma: Amsler grid is useful in detecting central field defects in moderate to severe glaucoma. Macular sparing: Amsler Grid can be used to detect and accurately measure macular sparing. Types Recent advancement in OCT has made it simpler to differentiate a macular hole from other similar types of smaller diameter macular pathologies of old age. From history and physical examination, round central small reddish lesions with dimness of central vision, probable differential diagnosis include: Epiretinal membrane (ERM) with a macular pseudo hole Central foveal dot hemorrhage Lamellar (aborted) macular hole Vitreomacular traction syndrome (VMTS) Foveal drusen Central areolar pigment epitheliopathy Solar retinopathy Small choroidal neovascular membrane involving center Small central serous chorioretinopathy involving center Cystoid macular edema (CME) Other types There are a few other (rare) kinds of macular degeneration with similar symptoms but unrelated in etiology to Wet or Dry age-related macular degeneration. They are all genetic disorders that may occur in childhood or middle age. Vitelliform macular dystrophy Sorsby's fundus dystrophy is an autosomal dominant, retinal disease characterized by sudden acuity loss resulting from untreatable submacular neovascularisation Stargardt's disease (juvenile macular degeneration, STGD) is an autosomal recessive retinal disorder characterized by juvenile-onset macular dystrophy, alterations of the peripheral retina, and subretinal deposition of lipofuscin-like material. Similar symptoms with a very different etiology and different treatment can be caused by epiretinal membrane or macular pucker or any other condition affecting the macula, such as central serous retinopathy. Notable cases Judi Dench Joan Plowright Peter Sallis June Brown S. Robert Morgan See also Treatment and Prognosis Metamorphopsia is a symptom of several common retinal and macular diseases, therefore treating the underlying disorder can improve symptoms. For people who have conditions such as Epiretinal membrane (ERM), Macular Holes and Retinal Detachment, decreased metamorphopsia is associated with an increase in visual acuity. Quantitative evaluation of metamorphopsia is an important step in understanding visual functions of individuals with macular disorders and is an essential tool for physicians in evaluating treatment results. Types Dry (non-exudative, > 80%)—deposition of yellowish extracellular material in and between Bruch's membrane and retinal pigment epithelium (“drusen”) with gradual loss in vision. Wet (exudative, 10–15%)—rapid loss of vision due to bleeding secondary to choroidal neovascularization. Etymology Gk, meta + morphe, form, opsis, sight See also Dysmorphopsia Hallucination References Visual disturbances and blindness Purpose. Myopic macular holes can be difficult to close with surgery and are frequently associated with retinal detachment. We report on a case of a macular hole in a severely myopic eye that underwent spontaneous closure. Methods. An observational case study. Results. A 55-year-old female was referred to Ophthalmology for a central scotoma and metamorphopsia in the right eye. Visual acuity was 1/20 in both eyes. Fundus examination showed loss of the foveal depression, with a small yellow ring in the center of the fovea in the right eye, and a tilted optic disc and peripapillary staphyloma bilaterally. Spectral domain optical coherence tomography (SD-OCT) revealed a fully developed macular hole with a rim of thickened and slightly elevated retina in the right eye. The patient refused surgery. After 4 years of follow-up, her visual acuity improved to 20/40 in the right eye, and SD-OCT revealed spontaneous sealing of the macular hole without bare retinal pigment epithelium. Conclusions. Myopic macular holes represent a challenge regarding their management, and the prognosis is often poor.  To characterize retinal and fluorescein angiographic findings of Asian patients with symptoms secondary to age-related macular degeneration (ARMD). We retrospectively reviewed 453 consecutive medical records corresponding to fluorescein angiograms performed between November 1992 and November 1995 to identify Asian patients with symptomatic ARMD. Presenting visual symptoms, best-corrected Snellen visual acuities, and retinal examination findings were determined from the medical records. Fundus photos and fluorescein angiograms were reviewed. There were 26 symptomatic eyes in 19 Asian patients with a median age of 73 years. Presenting visual symptoms included decreased visual acuity (19 eyes), metamorphopsia (5 eyes), or scotoma (2 eyes). Retinal findings included occult choroidal neovascularization (CNV) in 5 (19%) eyes, serous pigment epithelial detachment (PED) in 8 (31%) eyes, PED with CNV in 5 (19%) eyes, drusen in 5 (19%) eyes, retinal pigment epithelial atrophy in 1 (4%) eye, vitreous hemorrhage in 1 (4%) eye, and a disciform scar in 1 (4%) eye. In this cohort of Asian patients with ARMD, the majority of symptomatic eyes had either CNV (46%) or serous PED (31%). To study the clinical features and the pathogenesis of macular hole with and without retina detachment (RD) in high myopic eyes. It was a retrospective series case study. The charts of high myopic patients with macular hole at our hospital from June 2006 to February 2007 were retrospectively reviewed and analyzed. Patients were divided into two groups (the RD group and non-RD group) depending on the presence of RD or not. Their clinical data and optic coherence tomography (OCT) results were further analyzed. SPSS 13.0 was used for the statistic analysis. When comparing the quantitative aspects like age, axial length and refraction, t-test was used. Categorical data, such as sex ratio, occurrence of vitreous traction, posterior staphyloma and retinoschisis were compared by using χ(2) test. Fisher's test was used in comparing eye laterality, incidence of white hole, visual acuity and posterior vitreous detachment (PVD). During this period, there were 43 patients fitting the including criteria. Among them, 36 patents (37 eyes) were in the RD group and 7 patients (7 eyes) in the no-RD group. In the RD group, the average age was 56.1, 24.3% of them (9/37) were male; percentage of left and right eyes was (11/37) and 70.3% (26/37), respectively; average refraction was (-8.9 ± 2.2) D; average axial length was (28.7 ± 2.0) mm. Visual acuity was ≤ 0.05 (72.2%) in 26 eyes and 0.05 - 0.2 (27.8%) in 10 patients. The incidence of complete and non-complete PVD was 89.2% (33/37) and 10.8% (4/37), respectively. White hole presented in 35.1% (3/37) patients. Vitreous traction and retinoschisis presented in 27.0% (10/37) and 35.1% (13/37) patients, respectively. In the non-RD group, the average age was 47.6; 16.7% of them (1/7) were male; left and right eyes were involved in 42.9% (3/7) and 57.1% (4/7), respectively. Average refraction was (-9.0 ± 1.9) D; average axial length was (28.9 ± 1.5) mm. Vision acuity was ≤ 0.05 in 3 patients (42.9%); between 0.05 - 0.2 in 3 eyes (42.9%) and ≥ 0.2 in 1 eye (14.3%). Incidence of complete and non-complete PVD was 85.7% (6/7) and 14.3% (1/7), respectively. White hole was observed in 14.3% (1/7) patients; 42.9% (3/7) patients were accompanied with vitreous traction and 71.4% (5/7) with retinoschisis. B-scan ultrasonography showed posterior staphyloma in all 44 eyes. The results of statistical analysis showed that the gender (χ(2) = 0.008) and eye laterality (χ(2) = 0.449) as well as refraction (t = 0.193), axial length (t = -0.25) and visual acuity (χ(2) = 4.509) of these two groups were similar (P &gt; 0.05). The incidences of vitreous traction (χ(2) = 0.709), white hole (χ(2) = 1.179), PVD (χ(2) = 0.071) and retinoschisis (χ(2) = 3.207) were also similar (P &gt; 0.05). But the age of the non-RD group is significantly younger than the RD group (t = 1.66, P &lt; 0.05). Various pathogenesis may involved in the occurrence of retinal detachment in highly myopic eyes with macular hole. Further study is required to improve our understanding of this entity. The aim of this case report is to describe a case of atypical central serous chorioretinopathy (CSCR) definitively diagnosed after 8 years. A 44-year-old woman presented with reduced visual acuity in her left eye. Her visual acuity was light perception with projection in the right eye and 0.15 in the left. She described a similar decline in vision in her right eye 8 years ago. At that time, she had exudative retinal detachment and was treated with systemic immunosuppressive therapy for a presumed diagnosis of Vogt-Koyanagi-Harada disease. Despite resolution of the exudative retinal detachment, macular scarring developed. Eight years later, she developed inferior exudative retinal detachment in the left eye. A diagnosis of atypical CSCR was made with the help of multimodal imaging and her left eye was successfully treated with eplerenone and half-fluence photodynamic therapy (hf-PDT). In conclusion, early diagnosis and treatment of atypical CSCR may prevent subretinal fibrosis formation and permanent vision loss. Hf-PDT and eplerenone are successful treatment options for atypical CSCR. Self-separation or peeling of an idiopathic epiretinal membrane (ERM) in an eye with partial posterior vitreous detachment (PVD) is a rare event. A 56-year-old woman presented to our clinic with complaints of floaters in her right eye. Best-corrected visual acuity (BCVA) was 9/10 in this eye. Fundus examination and Spectral domain optical coherence tomography (SD-OCT) revealed an idiopathic ERM and Grade 3 PVD in this eye. Four months later, she had complaints of metamorphopsia in her right eye. BCVA was 7/10, while SD-OCT images of the right macula were similar to previous images. One week after the last visit, she presented again due to the sudden disappearance of her metamorphopsia complaints. BCVA had improved to 10/10. Fundus examination demonstrated that the ERM had spontaneously separated from the retinal surface as a flap floating in the vitreous and the foveal contour had returned to normal. The etiologic mechanism may be explained as the contracting forces within an immature ERM being stronger than its adhesion to the retina. The pathogenesis of the macular serous retinal detachment (SRD) associated with congenital optic disc pit remains controversial. The treatment is also discussed. Through this study, which includes the majority of the techniques available, we report our experiment in the treatment of this pathology. This was a retrospective single-centre study of 20 patients who presented with macular SRD associated with optic disc pit between 1983 and 2009. Various treatments were provided. At the beginning of the study, patients were treated only by juxtapapillary laser photocoagulation. After laser failure then as first-line treatment, laser photocoagulation was associated with intravitreal gas (C3F8) injection with postoperative facedown positioning for 2 weeks. During the past few years, all patients have been systematically treated with vitrectomy with or without internal limiting membrane (ILM) peeling, laser, and gas (C2F6) tamponade. This series consisted of 20 patients: nine men and 11 women. The patients' mean age at presentation was 29 years (range, 9-60 years). The mean time between the onset of the decrease in visual acuity (VA) and treatment was 6.1 months. None of these patients had a posterior vitreous detachment at the time of diagnosis. Six patients were treated by laser photocoagulation alone, which was successful only in two cases. Eleven patients (with laser treatment failure in three) were treated by laser and intravitreal gas injection, with a 72% success rate. We performed vitrectomy with posterior hyaloid dissection, laser, and gas tamponade in eight cases (with laser-gas treatment failure in two) with 87% success rate and no recurrence. Five of these patients had ILM peeling during the vitrectomy. The mean follow-up period was 60 months (range, 2 months to 17 years). This study shows that early treatment of macular SRD associated with optic disc pit by vitrectomy, ILM peeling, juxtapapillary photocoagulation, and gas tamponade is followed by good anatomical and functional results. This treatment is superior to the other less invasive procedures. Optical coherence tomography is an important exam for diagnosis and postoperative follow-up of patients. Central serous choroidopathy is a macular disease, usually with a self-limited and benign course, and predominantly affects male patients between 20 and 45 years old. A 68 year-old female patient complained of decreased visual acuity of her right eye of approximately 3 weeks of onset. Best corrected visual acuity in her right eye was 20/100. Fundus examination revealed a macular serous detachment involving its centre, as well as the presence of multiple calcified drusen. Fluorescein angiography showed late parafoveal leakage in a \"smokestack\" pattern in the right macular area. Optical coherence tomography showed a dome-shape macular detachment, also in the right eye. The patient was observed every 2 weeks and spontaneous resolution of the macular detachment was seen a month later. Based on these clinical features, a diagnosis was made of central serous choroidopathy of atypical presentation. Atypical presentation cases of serous central choroidopathy might be seen occasionally. Hence, it is an important differential diagnosis of age related macular degeneration in patients older than 60 years. To evaluate a macular buckle for exudative choroidal neovascularization secondary to age-related macular degeneration (ARMD). Forty-two eyes with choroidal neovascular membranes (CNVM) secondary to ARMD underwent surgical placement of a macular buckle. A Gore-Tex strip (2.0-2.5 mm wide) was button-holed through a 5 mm diameter silicone sponge (9 mm long) and placed behind the macula underneath the CNVM by the same surgeon (Dr Peyman) in all cases. Follow-up ranged from 7-76 months (mean, 20.9 months). Of 12 eyes with classic subfoveal CNVM: 4 (33%) gained 2 or more lines of Snellen visual acuity; 3 (25%) gained 1 line, remained the same, or lost 1 line; and 5 (42%) lost 2 or more lines (range + 6 to - 6 lines). Of 22 eyes with ill-defined subfoveal CNVM: 12 (54%) gained 1 line, remained the same, or lost 1 line; and 10 (46%) lost 2 or more lines (range + 1 to - 8 lines). Eight eyes with ill-defined juxtafoveal CNVM had the following visual acuity outcomes: 5 eyes (62%) maintained the same level of Snellen visual acuity (gained 1, 0, or lost 1 line); and 3 (38%) got worse (lost 2 or more lines of Snellen visual acuity, range + 1 to - 6 lines). Ten eyes (24%) bled subretinally during the follow-up period (average 11.5 months, range 14 days to 27 months), all outside the area of indentation of the macular buckle. The macular buckle treatment for exudative subretinal choroidal neovascular membranes in ARMD stabilized visual decline and displaced significant subfoveal hemorrhage. To report the pathogenic factors that account for cystoid macular edema and cystoid macular degeneration in chronic central serous chorioretinopathy (CSC). The clinical course and multimodal imaging findings, including fundus color photography, fundus autofluorescence, spectral-domain optical coherence tomography, and fluorescein angiography, of one eye with cystoid macular edema due to chronic CSC was documented. A 44-year old woman with a history of chronic CSC presented with progressive visual decline in the right eye. Best-corrected visual acuity was 20/40. Funduscopic examination revealed diffuse retinal pigment epithelial changes and macular edema. Fluorescein angiography demonstrated perifoveal microaneurysms and leakage in a petaloid configuration. Spectral-domain optical coherence tomography demonstrated cysts at the level of the inner nuclear layer, an epiretinal membrane, vitreomacular traction, and an attenuated retinal pigment epithelial band. Central subfield thickness was 486 μm. Three intravitreal injections of aflibercept were administered over 16 weeks following which there was resolution of leakage, release of vitreomacular traction, and resolution of microaneurysms. Central subfield thickness reduced to 379 μm, but persistent intraretinal cysts were observed. There was subjective improvement in visual symptoms, but Snellen acuity remained at 20/40. Intraretinal cystic changes in chronic CSC may be the result of multifactorial pathogenic factors and may represent the coexistence of cystoid macular edema and cystoid macular degeneration. Anti-vascular endothelial growth factor may play an important role in the treatment of cystoid macular edema caused by CSC. A patient developed choroidal neovascularization (CNV) in one eye during treatment for bilateral recurrent central serous chorioretinopathy (CSC) and was intravitreously injected with bevacizumab; she developed multiple evanescent white dots and serous retinal detachment(SRD). A 50-year-old women had a history of CSC OD at the age of 29 years. On initial examination, CSC OD was noted, and multiple detachments of the retinal pigment epithelium OU were observed. While the CSC in the right eye was successfully treated by laser photocoagulation, it spread to both eyes following this episode. Examination of the right eye by optical coherence tomography (OCT) following the recurrence of the CSC showed slight elevation of the retinal pigment epithelial layer in the central fovea, but this finding disappeared with the resolution of the CSC. However, as the CSC combined with CNV (Gass type 2) recurred within 1 year, the patient was intravitreously injected with bevacizumab. On the day following the injection, SRD OD occurred, and on the 7th day following the injection many white lesions varying in size appeared in the deep layer of the retina, but they healed 3 weeks later, leaving only the CNV. The CNV was cured later by additional photodynamic therapy. Since the lesions of the fundus observed immediately after the bevacizumab administration resolved spontaneously without sequelae, they were retrospectively diagnosed as a white dot syndrome-like disease. The white dot syndrome-like disease is suggested as a rare complication of bevacizumab. Central serous chorioretinopathy (CSCR) is an idiopathic condition characterized by serous detachment of the neurosensory retina in the macular region. It is relatively uncommon in Africans and though pregnancy is a known risk factor, there are no previous reports of CSCR in pregnant African women. We report the case of a 35-year-old pregnant woman who presented to our clinic at gestational age of 29 weeks with a 4 months history of blurring of vision in her left eye. Examination revealed visual acuity of 6/4 on the right eye and 6/9 on the left eye. She had normal anterior segments bilaterally and a normal posterior segment on the right. However, she had left macular edema with exudates. There was no significant refractive error. Her blood pressure was normal. Investigations including electrolytes and urea, urinalysis, and blood sugar profile were all normal. She was managed conservatively, and symptoms resolved 2 weeks prior to delivery. This is a case report of CSCR in a pregnant Nigerian woman with spontaneous resolution of symptoms prior to delivery. Pregnant women should be educated about the possibility of visual problems accompanying pregnancy. \nHere is the question:\nOPHTHALMOLOGY: 75-year-old woman diagnosed 3 years ago with soft drusen in the fundus. She reports presenting, since 2 weeks ago, metamorphopsia and significant visual loss in her right eye that prevents her from reading. Indicate the most probable diagnosis:\nHere are the potential choices:\n1. Macular epiretinal membrane.\n2. Macular hole.\n3. Thrombosis of the central retinal vein.\n4. Senile macular degeneration.\n5. Central serous chorioretinopathy.\nThe correct answer is: 2. Macular hole."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Classic Cushing's syndrome is a rare disease with an estimated incidence of 1 case per 100,000 persons. With routine use of imaging techniques such as ultrasound and CT, adrenal masses are being detected with increased frequency. A substantial percentage of these incidentalomas are hormonally active, with 5% to 20% of the tumors producing glucocorticoids. Autonomous glucocorticoid production without specific signs and symptoms of Cushing's syndrome is termed subclinical Cushing's syndrome. With an estimated prevalence of 79 cases per 100,000 persons, subclinical Cushing's syndrome is much more common than classic Cushing's syndrome. Depending on the amounts of glucocorticoids secreted by the tumor, the clinical spectrum ranges from slightly attenuated diurnal cortisol rhythm to complete atrophy of the contralateral adrenal gland with lasting adrenal insufficiency after unilateral adrenalectomy. Patients with subclinical Cushing's syndrome lack the classical stigmata of hypercortisolism but have a high prevalence of obesity, hypertension, and type 2 diabetes. All patients with incidentally detected adrenal masses scheduled for surgery must undergo testing for subclinical Cushing's syndrome to avoid postoperative adrenal crisis. The best screening test to uncover autonomous cortisol secretion is the short dexamethasone suppression test. Because the adrenal origin of a pathologic cortisol secretion is anticipated, the author prefers a higher dexamethasone dose (3 mg instead of 1 mg) to reduce false-positive results. A suppressed serum cortisol level of less than 3 micrograms/dL (80 nmol/L) after dexamethasone excludes significant cortisol secretion by the tumor. A serum cortisol level greater than 3 micrograms/dL requires further investigation, including confirmation by high-dose dexamethasone (8 mg) suppression testing, a CRH test, and analysis of diurnal rhythm. Determination of urinary free cortisol is less useful because increased values are a late finding usually associated with emerging clinical signs of Cushing's syndrome. Patients with suppressed plasma ACTH in response to CRH generally have adrenal insufficiency after surgery and require adequate perioperative and postoperative substitution therapy. Whether patients with subclinical Cushing's syndrome should undergo adrenalectomy is a matter of debate. The author performs surgery in young patients (&lt; 50 years), in patients with suppressed plasma ACTH, and in patients with a recent history of weight gain, substantial obesity, arterial hypertension, diabetes mellitus, and osteopenia. In completely asymptomatic patients with normal plasma ACTH concentrations and in patients older than 75 years, the author recommends a nonsurgical approach. A large prospective randomized study is necessary to evaluate the benefits of surgery versus conservative treatment in patients with subclinical Cushing's syndrome. Cushing's syndrome (CS) is a rare disease characterized by a collection of signs and symptoms, also common in the general population without elevated cortisol secretion. During the last years more patients with CS are identified earlier and with milder disease. Many of these patients are diagnosed during screening efforts performed for certain or isolated complaints like weight gain, diabetes mellitus (DM), hypertension, osteoporosis, elevated white blood cell counts and more. In this review article the most popular screening test performed in the studies cited was the 1-mg dexamethasone suppression test. Cushing is not frequent enough to support the use of routine screening in patients with morbid obesity and type 2 DM. Also only 1% of hypertensive patients have secondary hypertension due to CS. However, screening should be considered in young patients with resistant DM and/or hypertension. Among patients with osteoporosis and vertebral fractures up to 5% were diagnosed with subclinical hypercortisolism; most of these had adrenal adenoma. Screening for CS is important in subjects with adrenal incidentaloma, and many studies show a high prevalence (~10%) of Cushing or subclinical CS in these patients. A 64 year old lady, with a background history of type 2 diabetes mellitus and hypertension, presented with general deterioration of general health, poor glycemic control, difficulty in controlling blood pressure and difficulty in walking. She had past medical history of adenocarcinoma of the oesophagus, treated with surgery and subsequent chemotherapy. General examination revealed high blood glucose and blood pressure and a Cushingoid facies. Overnight dexamethasone suppression test and urinary free cortisol levels confirmed Cushing's syndrome and High dose dexamethasone suppression test showed partial suppression. CT scan of the abdomen showed bilateral hyperplasia of the adrenals with nodularity on the left side, raising the possibility of an adrenal adenoma. ACTH levels were elevated thereby ruling out autonomously functioning adrenal nodule, however increasing the possibility of ectopic ACTH secretion due to the previous medical history. MRI of the pituitary confirmed the presence of an adenoma, thereby pointing to the diagnosis of pituitary dependant Cushing's disease. The patient could not undergo further invasive investigation or surgery due to septicaemia. Medical management of Cushing's syndrome was resorted to in the interim with Ketoconazole, showing excellent response. This case depicts the need for a high index of suspicion for the diagnosis, the importance of organizing specific investigations in the appropriate order to arrive at a diagnosis and an effective management plan. Endogenous Cushing's syndrome is a rare endocrine disorder that is fatal if left untreated. It can be distinguished into adrenocorticotropic hormone (ACTH)-dependent (central and ectopic Cushing's syndrome) and ACTH-independent subtypes (unilateral or bilateral adrenal adenomas). The clinical presentation of patients includes typical stigmata of cortisol excess with physical symptoms of catabolic metabolism (myopathy, striae, parchment skin, osteoporosis) and components of metabolic syndrome (diabetes mellitus, obesity, arterial hypertension, hypercholesterolemia). Biochemical diagnosis is performed in three steps: 1. Confirmation of the diagnosis by 1‑mg dexamethasone suppression test, 24‑h urine free cortisol, and measurement of late-night salivary cortisol. 2. Differentiation of ACTH-dependent Cushing's syndrome from ACTH-independent adrenal Cushing's syndrome by measurement of plasma ACTH. 3. Further subtyping by corticotropin-releasing hormone (CRH) test, inferior petrosal sinus sampling, and imaging modalities. Therapeutic decisions are made on an interdisciplinary basis. First-line therapy for all subtypes is surgery when possible; additional options for all forms include drug therapy and bilateral adrenalectomy. Despite adequate treatment, Cushing's syndrome is associated with increased long-term morbidity and mortality. Interdisciplinary and multimodal therapy management is necessary in the long term to positively influence mortality and reduced quality of life. We report a 49-year-old woman who had minimal features of Cushing syndrome and an incidentally discovered adrenal adenoma. She was subsequently diagnosed with pituitary-dependent Cushing syndrome. Laboratory and imaging studies including serum cortisol, plasma adrenocorticotrophic hormone (ACTH), high dose dexamethasone test, corticotropin-releasing hormone test, computed tomography (CT) scan, and magnetic resonance imaging were performed. A 49-year-old woman was admitted for urosepsis. An abdominal CT scan performed during the urosepsis workup showed a 2.7-cm right adrenal adenoma. She denied any abdominal striae or other symptoms. Physical examination showed normal vital signs, minimal facial fullness without central obesity, and striae. Laboratory results were as follows: 24-hour-urine cortisol 294 μg (reference 4.0-50.0), midnight serum cortisol 23.0 μg/dL (reference &lt; 7.5), and plasma ACTH level 39 pg/mL (reference 5-27). A corticotropin-releasing hormone stimulation test showed &gt;20% rise in serum cortisol and &gt;35% rise in ACTH levels. A pituitary magnetic resonance image showed a 5 mm pituitary lesion. The patient underwent transsphenoidal pituitary surgery, which confirmed an ACTH-secreting lesion. Postoperatively, she required hydrocortisone replacement for the next 10 months. A follow-up adrenal CT performed 6 months later showed a decrease in the size of the adrenal adenoma (1.8 cm). This case highlights the importance of recognizing the coexistence of ACTH-dependent Cushing disease with an adrenal adenoma and partial ACTH dependency of the adrenal adenoma. Endogenous Cushing's syndrome is a very rare entity, with an incidence of 2-4 cases per million inhabitants per year. Cases caused by ectopic ACTH secretion are under-diagnosed. Cushing's disease is the most frequent cause of endogenous Cushing's syndrome, which is 5 or 6 times more frequent than adrenal Cushing's syndrome, with an incidence of between 1.2 and 2.4 cases per million inhabitants per year. Cushing's disease is 3-8 times higher in women than in men. The frequency of adrenal tumors is 3 times higher in women, while that of Cushing's syndrome due to adrenal tumors is 3-5 times higher. Age at diagnosis of Cushing's syndrome varies according to the etiology. Most cases of Cushing's disease are due to a pituitary adenoma, although the tumor may not be visible on the available imaging techniques. ACTH-independent Cushing's syndrome is found in 20% of cases and is most frequently due to adenomas (10%) or adrenal carcinomas (8). Bilateral micronodular hyperplasia and macronodular hyperplasia are infrequent entities, representing less than 10% of all cases of ACTH-independent Cushing's syndrome. Both familial and sporadic forms exist: the familial form, or Carney complex, and ACTH-independent bilateral macronodular hyperplasia, in which the size of the adrenal glands is considerably enlarged. The signs and symptoms of Cushing's syndrome are a direct result of long-term exposure to excessive glucocorticoids. Most signs and symptoms are highly prevalent in the general population (hypertension, central obesity, diabetes mellitus or carbohydrate intolerance, osteoporosis, and characteristic phenotypical alterations). The diagnosis of Cushing's syndrome is one of the most perplexing and controversial problems in endocrinology. However, significant advances in the diagnosis procedures have been made in the past decade. The diagnostic studies involved in the evaluation of patients with suspected Cushing's syndrome fall into two categories: confirming the presence of true hypercortisolism and establishing the precise aetiology. Diagnosis of Cushing's syndrome: ambulatory screening relies on the overnight 1 mg dexamethasone test. Negative tests are confirmed by measuring cortisol in two 24-hour urine samples. If cortisol excretion is slightly above normal, a 48-hour low-dose dexamethasone suppression test or an intravenous infusion dexamethasone suppression test are required. Diagnosis of the aetiology of Cushing's syndrome: the first step is to establish if the hypercortisolism is ACTH-dependent or not. This step is solved by measuring plasma ACTH and cortisol in the late afternoon. Computed tomography scanning of the adrenal glands is required in ACTH-independent Cushing's syndrome. A unilateral tumour will be demonstrated in most of cases. If bilateral lesions are found, dynamic testing using cortisol releasing factor and/or metyrapone must be performed to confirm the ACTH-independency of the syndrome. In ACTH-dependent Cushing's syndrome, the major difficulty is to distinguish between a pituitary source and an ectopic source of ACTH secretion. Magnetic resonance imaging of the pituitary with gadolinium enhancement must be preferred to computed tomography scanning but its sensitivity is not better than 70-80% and false positives can occur. When no macroscopic pituitary lesion can be detected, bilateral inferior petrosal sinus sampling coupled to CRH injection for ACTH measurement will indicate the source of ACTH secretion. If this test indicates the patient has Cushing's disease, pituitary trans-sphenoidal surgery can be performed. If the test indicates the patient has ectopic ACTH-secretion, a cervico-thoraco-abdominal scanning is necessary to identify the tumour. In the case of occult tumour the hypercortisolism must be controlled by pharmacological agents and the imaging investigations must be repeated at appropriate intervals. Cushing's syndrome is a rare but frequently considered disease. Its diagnosis can lead to some difficulties, including confirming the effective endogenous hypercortisolism and determining its cause. The severity of this disease, the diversity of its complications and the multiple therapeutic options make its management challenging. The aim of this review is to present the most recent data about management of Cushing's syndrome, especially diagnostic approaches and therapeutic options. Our references were obtained by screening MEDLINE database from 1996 to 2006. We also included some anterior reviews and consensus statements. We retained the following points: midnight salivary cortisol is a useful tool in the diagnosis of Cushing's syndrome; the desmopressin test can help to distinguish between Cushing's syndrome and \"pseudoCushing's\" due to alcohol consumption or psychiatric disorders; cavernous sinus and inferior petrosal sinus sampling is indicated in the evaluation of ACTH-dependent Cushing's syndromes when pituitary imaging is normal or equivocal or when dynamic tests are contradictory; multislice computed-tomography of the chest and the abdomen and somatostatin analogue scintigraphy, eventually combined, are the best imaging procedures in occult ectopic ACTH syndromes; patients with Cushing's disease should be referred to a neurosurgeon experienced in corticotroph adenomas surgery; metabolic consequences of Cushing's syndrome, such as cardiovascular risk factors and osteoporosis need an aggressive treatment. The incidence of Cushing's syndrome is only 1/100000 per year. However, hypercortisolism is diagnosed by systematic evaluation in 2 to 5% of patients with poorly controlled type 2 diabetes and adrenal incidentalomas. Endocrinological management of the disease improves metabolic disorders in these patients. If these results are confirmed, screening for Cushing's syndrome should be systematically performed in these populations. When Cushing's syndrome is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level), or a 24-hour urinary measurement for cortisol offers equal detection rates. Dexamethasone is a glucocorticoid and simulates the effects of cortisol, including negative feedback on the pituitary gland. When dexamethasone is administered and a blood sample is tested, cortisol levels >50 nmol/l (1.81 μg/dl) would be indicative of Cushing's syndrome because an ectopic source of cortisol or ACTH (such as adrenal adenoma) exists which is not inhibited by the dexamethasone. A novel approach, recently cleared by the US FDA, is sampling cortisol in saliva over 24 hours, which may be equally sensitive, as late-night levels of salivary cortisol are high in cushingoid patients. Other pituitary hormone levels may need to be ascertained. Performing a physical examination to determine any visual field defect may be necessary if a ACTH blood test Once Cushing's syndrome has been diagnosed, the first step towards finding the cause is measuring plasma adrenocorticotropic hormone (ACTH) concentration. A concentration consistently below 1.1 pmol/L is classified as corticotropin-independent and does not lead to a diagnosis of Cushing's disease. In such cases, the next step is adrenal imaging with CT. If plasma corticotropin concentrations are consistently above 3.3 pmol/L, then corticotropin-dependent Cushing's syndrome is most likely. Any intermediate values need to be cautiously interpreted and a corticotropin-releasing hormone (CRH) test is advised in order to confirm corticotropin dependency. If corticotropin-dependent Cushing's syndrome is determined then the next step is to distinguish between Cushing's disease and ectopic corticotropin syndrome. This is done via a combination of techniques including CRH, high-dose DST, BIPSS, and pituitary MRI. A 49-year-old man was referred to our hospital for the treatment of gallstones in 1993. Bilateral adrenal nodular masses were detected incidentally by abdominal computed tomography. He had no clinical signs of Cushing's syndrome such as central obesity, striae of skin and diabetes mellitus. We performed cholecystectomy and partial adrenalectomy of right adrenal gland as a biopsy, and diagnosed him as preclinical Cushing's syndrome due to adrenocorticotropin-independent bilateral adrenal macronodular hyperplasia (AIMAH) based on endocrinological and histological examinations. We followed him up for 7 years. During the observation period, the sizes of both adrenal glands increased gradually, and finally serum cortisol level increased beyond normal range, and he showed a Cushingoid appearance such as moon face and central obesity. His skin became atrophic and very fragile, and the bone mineral density of his lumbar spine was extremely low. Serum cortisol level was elevated, and plasma ACTH level was always suppressed. Urinary excretion of 17-hydroxycorticosteroid and free cortisol were increased. Diurnal rhythm of cortisol and ACTH was completely lost and high dose (8 mg/day) dexamethasone did not suppress urinary 17-hydroxycorticosteroid excretion. He became clinically overt Cushing's syndrome. We recommended total adrenalectomy, but he refused it. It is important to know the natural history of preclinical Cushing's syndrome due to AIMAH when choosing an adequate treatment. Corticosteroid overproduction Cushing's syndrome Cushing's syndrome is the manifestation of glucocorticoid excess. It can be the result of a prolonged treatment with glucocorticoids or be caused by an underlying disease which produces alterations in the HPA axis or the production of cortisol. Causes can be further classified into ACTH-dependent or ACTH-independent. The most common cause of endogenous Cushing's syndrome is a pituitary adenoma which causes an excessive production of ACTH. The disease produces a wide variety of signs and symptoms which include obesity, diabetes, increased blood pressure, excessive body hair (hirsutism), osteoporosis, depression, and most distinctively, stretch marks in the skin, caused by its progressive thinning. To review the challenges encountered in the diagnostic work-up and management of patients with subclinical Cushing's syndrome (SCS) and bilateral adrenal masses to aid in the case description of a patient with SCS and adrenocorticotropic hormone (ACTH)-independent macronodular adrenal hyperplasia (AIMAH). We describe our experience managing a patient with AIMAH and SCS. This case report is followed by an extensive review of the literature regarding differential diagnoses, work-up including adrenal venous sampling (AVS), and treatment of SCS with bilateral adrenal masses. A 51-year-old female who was diagnosed with recent onset hypertension and diabetes mellitus type 2 was evaluated for adrenal masses discovered incidentally on computed tomography (CT). She did not have any Cushingoid features. Magnetic resonance imaging (MRI) of abdomen was performed for further evaluation. Hormonal evaluation came back consistent with SCS. The AVS results were consistent with bilateral autonomous cortisol hypersecretion without lateralization. Collectively, the findings favored the diagnosis of bilateral AIMAH. A left adrenalectomy was performed, and the patient's clinical response was favorable with improvement in blood pressure (BP) accompanied by significant weight loss. Follow-up hormonal testing for autonomous cortisol hypersecretion was within the target range. AIMAH is a rare cause of SCS. AVS is a useful diagnostic tool that helps localize the source of autonomous cortisol hypersecretion in ACTH-independent SCS with bilateral adrenal masses, especially if radiological features are inconclusive. Patients undergoing unilateral adrenalectomy should be followed for monitoring of clinical response, as well as progression of AIMAH in the contralateral adrenal gland. Associated diseases Cushing's Disease Corticotropic cells can have detrimental effects on the body if they express too much or too little ACTH. One such example is Cushing's disease, which can result from overproduction of ACTH in the corticotropes due to pituitary tumors known as corticotroph adenomas; this is the cause for roughly two-thirds of those diagnosed with Cushing's disease. It is also possible that this disease can result from production of ACTH in a non-pituitary tumor, known as ectopic production, or the adrenal glands can overproduce cortisol due to an adrenal tumor. This overproduction of ACTH causes an increase in cortisol levels due to increased glucocorticoid synthesis in the adrenal cortex resulting in several associated symptoms. Symptoms of Cushing's disease include: Fatty deposits in the neck or back Stretch marks (striae) Fatigue Osteoporosis Weakened immune system Hypertension When any of these tests is positive, CT scanning of the adrenal gland and MRI of the pituitary gland are performed to detect the presence of any adrenal or pituitary adenomas or incidentalomas (the incidental discovery of harmless lesions). Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary. Occasionally, determining the ACTH levels in various veins in the body by venous catheterization, working towards the pituitary (petrosal sinus sampling) is necessary. In many cases, the tumors causing Cushing's disease are less than 2 mm in size and difficult to detect using MRI or CT imaging. In one study of 261 patients with confirmed pituitary Cushing's disease, only 48% of pituitary lesions were identified using MRI prior to surgery. Plasma CRH levels are inadequate at diagnosis (with the possible exception of tumors secreting CRH) because of peripheral dilution and binding to CRHBP. Cushing's disease, i.e., pituitary ACTH-secreting adenoma causing excess glucocorticoid secretion, is a rare disease with significant mortality and morbidity. Timely diagnosis and appropriate treatment can alter the course of the disease and are therefore mandatory. First step of the diagnostic work-up is the endogenous glucocorticoid excess by measurement of urinary free cortisol, cortisol circadian rhythmicity or suppression by low doses of dexamethasone. In patients with equivocal results, second line tests, such as the dexamethasone-suppressed CRH test and desmopressin stimulation, usually enable the diagnosis to be confirmed. Measurement of plasma ACTH then allows the distinction between ACTH-dependent (e.g., pituitary or extrapituitary neuroendocrine tumors) and ACTH-independent causes (e.g., adrenal tumors). The last step in the diagnostic algorithm is often the most fraught with problems as the distinction between Cushing's disease and ectopic ACTH secretion relies on judicious interpretation of several diagnostic procedures. Positive responses to stimulation with CRH and inhibition by high doses of dexamethasone, if concurrent, enable a pituitary origin to be established whereas conflicting results call for inferior petrosal sinus sampling, the latter to be performed in experienced centres only. Visualisation of the tumor at pituitary imaging is helpful but not required for the diagnosis, as microadenomas often remain undectected by MRI and/or CT scan and, on the other hand, visualisation of a non-secreting incidentaloma may be misleading. Surgical removal of the pituitary tumor is the optimal treatment choice and should be attempted in every patient. Surgical failures as well as relapses can be treated by radiotherapy, medical therapy or, if necessary, bilateral adrenalectomy. Finally, patients cured of Cushing's disease require long-term monitoring given the risk of relapse and clinical burden of associated ailments. Cushing's syndrome, including its mild form/state of adrenal-dependent subset (subclinical Cushing's syndrome; subCS), is known to enhance glucose intolerance, hypertension and obesity. Recently, subclinical Cushing's disease (subCD) has been identified, but its prevalence and the extent of consequent metabolic derangement are unclear. We screened 90 type 2 diabetic patients hospitalized in our department for subCD, according to the diagnostic guideline proposed by the working group of Japanese Ministry of Health, Welfare and Labor in 2006. Plasma ACTH and cortisol levels in the morning and at midnight were determined, and overnight 0.5 mg dexamethasone suppression test (DST) was performed. Those who showed poor cortisol suppression in DST underwent the desmopressin (DDAVP) test. Fifty-seven patients (63.3%) demonstrated abnormally high midnight cortisol levels (&gt;or=2.5 microg/dL), while only nine of them failed to suppress plasma cortisol levels to &lt;3 microg/dL after DST. Although none of the eight patients who underwent the DDAVP test demonstrated the anticipated paradoxical rise in plasma ACTH, these eight patients (8.9%) endocrinologically met the screening criteria of subCD. Since a considerable percentage of pituitary adenomas causing overt Cushing's disease are not identifiable in magnetic resonance imaging, many of those causing subCD may also be unidentifiable. Further follow-up studies including confirmatory testing and pituitary imaging are necessary. The most accurate test used to differentiate a pituitary adenoma from ectopic or adrenal Cushing syndrome is inferior petrosal sinus sampling. [12] [18] This invasive method measures the difference in ACTH level found in the inferior petrosal sinus (where the pituitary gland drains) compared to the periphery. [12] [18] A basal central to the peripheral ratio of over 3:1 when CRH is administered confirms the diagnosis of Cushing disease. [18] This test is considered the gold standard in diagnosing Cushing disease because it has a sensitivity and specificity of nearly 94%. Still, it is rarely used in clinical practice due to its high cost, invasiveness, rare but serious complications, and the required special expertise to perform. is diagnostic 1) Overnight DST2) 24-hour urinary free cortisol3) 11:00 pm salivary cortisol1) Plasma ACTH2) High-dose DST and urinary cortisolConfirm the diagnosisACTH gradient?Determine source of hypercortisolismDecreased ACTHLack of suppressionCT scan adrenalsIncreased ACTHPositive Increased ACTHLack of suppressionEquivocalresultsFurther testingBilateral petrosalvein samplingAdrenalsourcePituitarysourceEctopic ACTHsourceSTEPS IN DIAGNOSISDIAGNOSTIC STUDIESYesNoFigure 38-44. Diagnosis of Cushing’s syndrome. ACTH = adrenocorticotropic hormone; CT = computed tomography; DST = dexamethasone suppression test.Brunicardi_Ch38_p1625-p1704.indd 169001/03/19 11:22 AM 1691THYROID, PARATHYROID, AND ADRENALCHAPTER 38of a pituitary tumor. In patients suspected of having ectopic ACTH production, CT or MRI scans of the chest and anterior mediastinum are performed first, followed by imaging of the neck, abdomen, and pelvis if the initial studies are negative.Treatment Laparoscopic Serum ACTH levels can differentiate ACTH-dependent Cushing syndrome (elevated ACTH or inappropriately normal ACTH) from ACTH-independent (low ACTH level) Cushing syndrome. In patients with ACTH-dependent Cushing syndrome, the high-dose dexamethasone suppression test done by giving 8 mg dexamethasone by mouth at 2300 h and checking cortisol the next day at 0800 h, can differentiate pituitary ACTH from an ectopic ACTH source. A high-dose dexamethasone suppression test will decrease cortisol level by 50 % if the ACTH source is a pituitary adenoma, but not if ACTH is secreted by an ectopic tumor (e.g., oat cell lung carcinoma). Pituitary MRI, unenhanced CT scan of the adrenals, and chest X-ray and CT are also useful to localize the pathology. Cushing's syndrome is caused by either excessive cortisol-like medication, such as prednisone, or a tumor that either produces or results in the production of excessive cortisol by the adrenal glands. Cases due to a pituitary adenoma are known as Cushing's disease, which is the second most common cause of Cushing's syndrome after medication. A number of other tumors, often referred to as ectopic due to their placement outside the pituitary, may also cause Cushing's. Some of these are associated with inherited disorders such as multiple endocrine neoplasia type 1 and Carney complex. Diagnosis requires a number of steps. The first step is to check the medications a person takes. The second step is to measure levels of cortisol in the urine, saliva or in the blood after taking dexamethasone. If this test is abnormal, the cortisol may be measured late at night. If the cortisol remains high, a blood test for ACTH may be done.\nHere is the question:\nENDOCRINOLOGY: A 56-year-old female patient consulted for dorso-lumbar spine pain and progressive difficulty in performing usual tasks. In the last 5 years she gained weight, she has ecchymosis easily and arterial hypertension was detected. Physical examination: Obesity of central predominance, rounded facies, increased supraclavicular fat, decreased proximal muscle strength and some reddish striae in the abdomen. She has a blood glucose of 136 mg/dL and the radiological study showed osteoporosis and vertebral crushing. What do you think is the most coherent interpretation and attitude?\nHere are the potential choices:\n1. Postmenopausal osteoporosis, type 2 diabetes mellitus and essential hypertension, with decreased strength due to diabetic polyneuropathy.\n2. It is necessary to rule out Cushing's disease by dexamethasone suppression test and perform a cranial CT scan.\n3. Suggest Cushing's. Determine urinary free cortisol and basal ACTH, which serves to orient its etiology and select the most appropriate imaging technique.\n4. It looks like Cushing's. If basal ACTH is high, it may be due to corticosteroid use or an adrenal tumor, and an MRI should be performed.\n5. Probably has Cushing's. If the basal ACTH is low, he probably has a pituitary micro-adenoma, and a cranial CT scan should be performed.\nThe correct answer is: ",
        "gold_answer": "3 Suggest Cushing's. Determine urinary free cortisol and basal ACTH, which serves to orient its etiology and select the most appropriate imaging technique.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Classic Cushing's syndrome is a rare disease with an estimated incidence of 1 case per 100,000 persons. With routine use of imaging techniques such as ultrasound and CT, adrenal masses are being detected with increased frequency. A substantial percentage of these incidentalomas are hormonally active, with 5% to 20% of the tumors producing glucocorticoids. Autonomous glucocorticoid production without specific signs and symptoms of Cushing's syndrome is termed subclinical Cushing's syndrome. With an estimated prevalence of 79 cases per 100,000 persons, subclinical Cushing's syndrome is much more common than classic Cushing's syndrome. Depending on the amounts of glucocorticoids secreted by the tumor, the clinical spectrum ranges from slightly attenuated diurnal cortisol rhythm to complete atrophy of the contralateral adrenal gland with lasting adrenal insufficiency after unilateral adrenalectomy. Patients with subclinical Cushing's syndrome lack the classical stigmata of hypercortisolism but have a high prevalence of obesity, hypertension, and type 2 diabetes. All patients with incidentally detected adrenal masses scheduled for surgery must undergo testing for subclinical Cushing's syndrome to avoid postoperative adrenal crisis. The best screening test to uncover autonomous cortisol secretion is the short dexamethasone suppression test. Because the adrenal origin of a pathologic cortisol secretion is anticipated, the author prefers a higher dexamethasone dose (3 mg instead of 1 mg) to reduce false-positive results. A suppressed serum cortisol level of less than 3 micrograms/dL (80 nmol/L) after dexamethasone excludes significant cortisol secretion by the tumor. A serum cortisol level greater than 3 micrograms/dL requires further investigation, including confirmation by high-dose dexamethasone (8 mg) suppression testing, a CRH test, and analysis of diurnal rhythm. Determination of urinary free cortisol is less useful because increased values are a late finding usually associated with emerging clinical signs of Cushing's syndrome. Patients with suppressed plasma ACTH in response to CRH generally have adrenal insufficiency after surgery and require adequate perioperative and postoperative substitution therapy. Whether patients with subclinical Cushing's syndrome should undergo adrenalectomy is a matter of debate. The author performs surgery in young patients (&lt; 50 years), in patients with suppressed plasma ACTH, and in patients with a recent history of weight gain, substantial obesity, arterial hypertension, diabetes mellitus, and osteopenia. In completely asymptomatic patients with normal plasma ACTH concentrations and in patients older than 75 years, the author recommends a nonsurgical approach. A large prospective randomized study is necessary to evaluate the benefits of surgery versus conservative treatment in patients with subclinical Cushing's syndrome. Cushing's syndrome (CS) is a rare disease characterized by a collection of signs and symptoms, also common in the general population without elevated cortisol secretion. During the last years more patients with CS are identified earlier and with milder disease. Many of these patients are diagnosed during screening efforts performed for certain or isolated complaints like weight gain, diabetes mellitus (DM), hypertension, osteoporosis, elevated white blood cell counts and more. In this review article the most popular screening test performed in the studies cited was the 1-mg dexamethasone suppression test. Cushing is not frequent enough to support the use of routine screening in patients with morbid obesity and type 2 DM. Also only 1% of hypertensive patients have secondary hypertension due to CS. However, screening should be considered in young patients with resistant DM and/or hypertension. Among patients with osteoporosis and vertebral fractures up to 5% were diagnosed with subclinical hypercortisolism; most of these had adrenal adenoma. Screening for CS is important in subjects with adrenal incidentaloma, and many studies show a high prevalence (~10%) of Cushing or subclinical CS in these patients. A 64 year old lady, with a background history of type 2 diabetes mellitus and hypertension, presented with general deterioration of general health, poor glycemic control, difficulty in controlling blood pressure and difficulty in walking. She had past medical history of adenocarcinoma of the oesophagus, treated with surgery and subsequent chemotherapy. General examination revealed high blood glucose and blood pressure and a Cushingoid facies. Overnight dexamethasone suppression test and urinary free cortisol levels confirmed Cushing's syndrome and High dose dexamethasone suppression test showed partial suppression. CT scan of the abdomen showed bilateral hyperplasia of the adrenals with nodularity on the left side, raising the possibility of an adrenal adenoma. ACTH levels were elevated thereby ruling out autonomously functioning adrenal nodule, however increasing the possibility of ectopic ACTH secretion due to the previous medical history. MRI of the pituitary confirmed the presence of an adenoma, thereby pointing to the diagnosis of pituitary dependant Cushing's disease. The patient could not undergo further invasive investigation or surgery due to septicaemia. Medical management of Cushing's syndrome was resorted to in the interim with Ketoconazole, showing excellent response. This case depicts the need for a high index of suspicion for the diagnosis, the importance of organizing specific investigations in the appropriate order to arrive at a diagnosis and an effective management plan. Endogenous Cushing's syndrome is a rare endocrine disorder that is fatal if left untreated. It can be distinguished into adrenocorticotropic hormone (ACTH)-dependent (central and ectopic Cushing's syndrome) and ACTH-independent subtypes (unilateral or bilateral adrenal adenomas). The clinical presentation of patients includes typical stigmata of cortisol excess with physical symptoms of catabolic metabolism (myopathy, striae, parchment skin, osteoporosis) and components of metabolic syndrome (diabetes mellitus, obesity, arterial hypertension, hypercholesterolemia). Biochemical diagnosis is performed in three steps: 1. Confirmation of the diagnosis by 1‑mg dexamethasone suppression test, 24‑h urine free cortisol, and measurement of late-night salivary cortisol. 2. Differentiation of ACTH-dependent Cushing's syndrome from ACTH-independent adrenal Cushing's syndrome by measurement of plasma ACTH. 3. Further subtyping by corticotropin-releasing hormone (CRH) test, inferior petrosal sinus sampling, and imaging modalities. Therapeutic decisions are made on an interdisciplinary basis. First-line therapy for all subtypes is surgery when possible; additional options for all forms include drug therapy and bilateral adrenalectomy. Despite adequate treatment, Cushing's syndrome is associated with increased long-term morbidity and mortality. Interdisciplinary and multimodal therapy management is necessary in the long term to positively influence mortality and reduced quality of life. We report a 49-year-old woman who had minimal features of Cushing syndrome and an incidentally discovered adrenal adenoma. She was subsequently diagnosed with pituitary-dependent Cushing syndrome. Laboratory and imaging studies including serum cortisol, plasma adrenocorticotrophic hormone (ACTH), high dose dexamethasone test, corticotropin-releasing hormone test, computed tomography (CT) scan, and magnetic resonance imaging were performed. A 49-year-old woman was admitted for urosepsis. An abdominal CT scan performed during the urosepsis workup showed a 2.7-cm right adrenal adenoma. She denied any abdominal striae or other symptoms. Physical examination showed normal vital signs, minimal facial fullness without central obesity, and striae. Laboratory results were as follows: 24-hour-urine cortisol 294 μg (reference 4.0-50.0), midnight serum cortisol 23.0 μg/dL (reference &lt; 7.5), and plasma ACTH level 39 pg/mL (reference 5-27). A corticotropin-releasing hormone stimulation test showed &gt;20% rise in serum cortisol and &gt;35% rise in ACTH levels. A pituitary magnetic resonance image showed a 5 mm pituitary lesion. The patient underwent transsphenoidal pituitary surgery, which confirmed an ACTH-secreting lesion. Postoperatively, she required hydrocortisone replacement for the next 10 months. A follow-up adrenal CT performed 6 months later showed a decrease in the size of the adrenal adenoma (1.8 cm). This case highlights the importance of recognizing the coexistence of ACTH-dependent Cushing disease with an adrenal adenoma and partial ACTH dependency of the adrenal adenoma. Endogenous Cushing's syndrome is a very rare entity, with an incidence of 2-4 cases per million inhabitants per year. Cases caused by ectopic ACTH secretion are under-diagnosed. Cushing's disease is the most frequent cause of endogenous Cushing's syndrome, which is 5 or 6 times more frequent than adrenal Cushing's syndrome, with an incidence of between 1.2 and 2.4 cases per million inhabitants per year. Cushing's disease is 3-8 times higher in women than in men. The frequency of adrenal tumors is 3 times higher in women, while that of Cushing's syndrome due to adrenal tumors is 3-5 times higher. Age at diagnosis of Cushing's syndrome varies according to the etiology. Most cases of Cushing's disease are due to a pituitary adenoma, although the tumor may not be visible on the available imaging techniques. ACTH-independent Cushing's syndrome is found in 20% of cases and is most frequently due to adenomas (10%) or adrenal carcinomas (8). Bilateral micronodular hyperplasia and macronodular hyperplasia are infrequent entities, representing less than 10% of all cases of ACTH-independent Cushing's syndrome. Both familial and sporadic forms exist: the familial form, or Carney complex, and ACTH-independent bilateral macronodular hyperplasia, in which the size of the adrenal glands is considerably enlarged. The signs and symptoms of Cushing's syndrome are a direct result of long-term exposure to excessive glucocorticoids. Most signs and symptoms are highly prevalent in the general population (hypertension, central obesity, diabetes mellitus or carbohydrate intolerance, osteoporosis, and characteristic phenotypical alterations). The diagnosis of Cushing's syndrome is one of the most perplexing and controversial problems in endocrinology. However, significant advances in the diagnosis procedures have been made in the past decade. The diagnostic studies involved in the evaluation of patients with suspected Cushing's syndrome fall into two categories: confirming the presence of true hypercortisolism and establishing the precise aetiology. Diagnosis of Cushing's syndrome: ambulatory screening relies on the overnight 1 mg dexamethasone test. Negative tests are confirmed by measuring cortisol in two 24-hour urine samples. If cortisol excretion is slightly above normal, a 48-hour low-dose dexamethasone suppression test or an intravenous infusion dexamethasone suppression test are required. Diagnosis of the aetiology of Cushing's syndrome: the first step is to establish if the hypercortisolism is ACTH-dependent or not. This step is solved by measuring plasma ACTH and cortisol in the late afternoon. Computed tomography scanning of the adrenal glands is required in ACTH-independent Cushing's syndrome. A unilateral tumour will be demonstrated in most of cases. If bilateral lesions are found, dynamic testing using cortisol releasing factor and/or metyrapone must be performed to confirm the ACTH-independency of the syndrome. In ACTH-dependent Cushing's syndrome, the major difficulty is to distinguish between a pituitary source and an ectopic source of ACTH secretion. Magnetic resonance imaging of the pituitary with gadolinium enhancement must be preferred to computed tomography scanning but its sensitivity is not better than 70-80% and false positives can occur. When no macroscopic pituitary lesion can be detected, bilateral inferior petrosal sinus sampling coupled to CRH injection for ACTH measurement will indicate the source of ACTH secretion. If this test indicates the patient has Cushing's disease, pituitary trans-sphenoidal surgery can be performed. If the test indicates the patient has ectopic ACTH-secretion, a cervico-thoraco-abdominal scanning is necessary to identify the tumour. In the case of occult tumour the hypercortisolism must be controlled by pharmacological agents and the imaging investigations must be repeated at appropriate intervals. Cushing's syndrome is a rare but frequently considered disease. Its diagnosis can lead to some difficulties, including confirming the effective endogenous hypercortisolism and determining its cause. The severity of this disease, the diversity of its complications and the multiple therapeutic options make its management challenging. The aim of this review is to present the most recent data about management of Cushing's syndrome, especially diagnostic approaches and therapeutic options. Our references were obtained by screening MEDLINE database from 1996 to 2006. We also included some anterior reviews and consensus statements. We retained the following points: midnight salivary cortisol is a useful tool in the diagnosis of Cushing's syndrome; the desmopressin test can help to distinguish between Cushing's syndrome and \"pseudoCushing's\" due to alcohol consumption or psychiatric disorders; cavernous sinus and inferior petrosal sinus sampling is indicated in the evaluation of ACTH-dependent Cushing's syndromes when pituitary imaging is normal or equivocal or when dynamic tests are contradictory; multislice computed-tomography of the chest and the abdomen and somatostatin analogue scintigraphy, eventually combined, are the best imaging procedures in occult ectopic ACTH syndromes; patients with Cushing's disease should be referred to a neurosurgeon experienced in corticotroph adenomas surgery; metabolic consequences of Cushing's syndrome, such as cardiovascular risk factors and osteoporosis need an aggressive treatment. The incidence of Cushing's syndrome is only 1/100000 per year. However, hypercortisolism is diagnosed by systematic evaluation in 2 to 5% of patients with poorly controlled type 2 diabetes and adrenal incidentalomas. Endocrinological management of the disease improves metabolic disorders in these patients. If these results are confirmed, screening for Cushing's syndrome should be systematically performed in these populations. When Cushing's syndrome is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level), or a 24-hour urinary measurement for cortisol offers equal detection rates. Dexamethasone is a glucocorticoid and simulates the effects of cortisol, including negative feedback on the pituitary gland. When dexamethasone is administered and a blood sample is tested, cortisol levels >50 nmol/l (1.81 μg/dl) would be indicative of Cushing's syndrome because an ectopic source of cortisol or ACTH (such as adrenal adenoma) exists which is not inhibited by the dexamethasone. A novel approach, recently cleared by the US FDA, is sampling cortisol in saliva over 24 hours, which may be equally sensitive, as late-night levels of salivary cortisol are high in cushingoid patients. Other pituitary hormone levels may need to be ascertained. Performing a physical examination to determine any visual field defect may be necessary if a ACTH blood test Once Cushing's syndrome has been diagnosed, the first step towards finding the cause is measuring plasma adrenocorticotropic hormone (ACTH) concentration. A concentration consistently below 1.1 pmol/L is classified as corticotropin-independent and does not lead to a diagnosis of Cushing's disease. In such cases, the next step is adrenal imaging with CT. If plasma corticotropin concentrations are consistently above 3.3 pmol/L, then corticotropin-dependent Cushing's syndrome is most likely. Any intermediate values need to be cautiously interpreted and a corticotropin-releasing hormone (CRH) test is advised in order to confirm corticotropin dependency. If corticotropin-dependent Cushing's syndrome is determined then the next step is to distinguish between Cushing's disease and ectopic corticotropin syndrome. This is done via a combination of techniques including CRH, high-dose DST, BIPSS, and pituitary MRI. A 49-year-old man was referred to our hospital for the treatment of gallstones in 1993. Bilateral adrenal nodular masses were detected incidentally by abdominal computed tomography. He had no clinical signs of Cushing's syndrome such as central obesity, striae of skin and diabetes mellitus. We performed cholecystectomy and partial adrenalectomy of right adrenal gland as a biopsy, and diagnosed him as preclinical Cushing's syndrome due to adrenocorticotropin-independent bilateral adrenal macronodular hyperplasia (AIMAH) based on endocrinological and histological examinations. We followed him up for 7 years. During the observation period, the sizes of both adrenal glands increased gradually, and finally serum cortisol level increased beyond normal range, and he showed a Cushingoid appearance such as moon face and central obesity. His skin became atrophic and very fragile, and the bone mineral density of his lumbar spine was extremely low. Serum cortisol level was elevated, and plasma ACTH level was always suppressed. Urinary excretion of 17-hydroxycorticosteroid and free cortisol were increased. Diurnal rhythm of cortisol and ACTH was completely lost and high dose (8 mg/day) dexamethasone did not suppress urinary 17-hydroxycorticosteroid excretion. He became clinically overt Cushing's syndrome. We recommended total adrenalectomy, but he refused it. It is important to know the natural history of preclinical Cushing's syndrome due to AIMAH when choosing an adequate treatment. Corticosteroid overproduction Cushing's syndrome Cushing's syndrome is the manifestation of glucocorticoid excess. It can be the result of a prolonged treatment with glucocorticoids or be caused by an underlying disease which produces alterations in the HPA axis or the production of cortisol. Causes can be further classified into ACTH-dependent or ACTH-independent. The most common cause of endogenous Cushing's syndrome is a pituitary adenoma which causes an excessive production of ACTH. The disease produces a wide variety of signs and symptoms which include obesity, diabetes, increased blood pressure, excessive body hair (hirsutism), osteoporosis, depression, and most distinctively, stretch marks in the skin, caused by its progressive thinning. To review the challenges encountered in the diagnostic work-up and management of patients with subclinical Cushing's syndrome (SCS) and bilateral adrenal masses to aid in the case description of a patient with SCS and adrenocorticotropic hormone (ACTH)-independent macronodular adrenal hyperplasia (AIMAH). We describe our experience managing a patient with AIMAH and SCS. This case report is followed by an extensive review of the literature regarding differential diagnoses, work-up including adrenal venous sampling (AVS), and treatment of SCS with bilateral adrenal masses. A 51-year-old female who was diagnosed with recent onset hypertension and diabetes mellitus type 2 was evaluated for adrenal masses discovered incidentally on computed tomography (CT). She did not have any Cushingoid features. Magnetic resonance imaging (MRI) of abdomen was performed for further evaluation. Hormonal evaluation came back consistent with SCS. The AVS results were consistent with bilateral autonomous cortisol hypersecretion without lateralization. Collectively, the findings favored the diagnosis of bilateral AIMAH. A left adrenalectomy was performed, and the patient's clinical response was favorable with improvement in blood pressure (BP) accompanied by significant weight loss. Follow-up hormonal testing for autonomous cortisol hypersecretion was within the target range. AIMAH is a rare cause of SCS. AVS is a useful diagnostic tool that helps localize the source of autonomous cortisol hypersecretion in ACTH-independent SCS with bilateral adrenal masses, especially if radiological features are inconclusive. Patients undergoing unilateral adrenalectomy should be followed for monitoring of clinical response, as well as progression of AIMAH in the contralateral adrenal gland. Associated diseases Cushing's Disease Corticotropic cells can have detrimental effects on the body if they express too much or too little ACTH. One such example is Cushing's disease, which can result from overproduction of ACTH in the corticotropes due to pituitary tumors known as corticotroph adenomas; this is the cause for roughly two-thirds of those diagnosed with Cushing's disease. It is also possible that this disease can result from production of ACTH in a non-pituitary tumor, known as ectopic production, or the adrenal glands can overproduce cortisol due to an adrenal tumor. This overproduction of ACTH causes an increase in cortisol levels due to increased glucocorticoid synthesis in the adrenal cortex resulting in several associated symptoms. Symptoms of Cushing's disease include: Fatty deposits in the neck or back Stretch marks (striae) Fatigue Osteoporosis Weakened immune system Hypertension When any of these tests is positive, CT scanning of the adrenal gland and MRI of the pituitary gland are performed to detect the presence of any adrenal or pituitary adenomas or incidentalomas (the incidental discovery of harmless lesions). Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary. Occasionally, determining the ACTH levels in various veins in the body by venous catheterization, working towards the pituitary (petrosal sinus sampling) is necessary. In many cases, the tumors causing Cushing's disease are less than 2 mm in size and difficult to detect using MRI or CT imaging. In one study of 261 patients with confirmed pituitary Cushing's disease, only 48% of pituitary lesions were identified using MRI prior to surgery. Plasma CRH levels are inadequate at diagnosis (with the possible exception of tumors secreting CRH) because of peripheral dilution and binding to CRHBP. Cushing's disease, i.e., pituitary ACTH-secreting adenoma causing excess glucocorticoid secretion, is a rare disease with significant mortality and morbidity. Timely diagnosis and appropriate treatment can alter the course of the disease and are therefore mandatory. First step of the diagnostic work-up is the endogenous glucocorticoid excess by measurement of urinary free cortisol, cortisol circadian rhythmicity or suppression by low doses of dexamethasone. In patients with equivocal results, second line tests, such as the dexamethasone-suppressed CRH test and desmopressin stimulation, usually enable the diagnosis to be confirmed. Measurement of plasma ACTH then allows the distinction between ACTH-dependent (e.g., pituitary or extrapituitary neuroendocrine tumors) and ACTH-independent causes (e.g., adrenal tumors). The last step in the diagnostic algorithm is often the most fraught with problems as the distinction between Cushing's disease and ectopic ACTH secretion relies on judicious interpretation of several diagnostic procedures. Positive responses to stimulation with CRH and inhibition by high doses of dexamethasone, if concurrent, enable a pituitary origin to be established whereas conflicting results call for inferior petrosal sinus sampling, the latter to be performed in experienced centres only. Visualisation of the tumor at pituitary imaging is helpful but not required for the diagnosis, as microadenomas often remain undectected by MRI and/or CT scan and, on the other hand, visualisation of a non-secreting incidentaloma may be misleading. Surgical removal of the pituitary tumor is the optimal treatment choice and should be attempted in every patient. Surgical failures as well as relapses can be treated by radiotherapy, medical therapy or, if necessary, bilateral adrenalectomy. Finally, patients cured of Cushing's disease require long-term monitoring given the risk of relapse and clinical burden of associated ailments. Cushing's syndrome, including its mild form/state of adrenal-dependent subset (subclinical Cushing's syndrome; subCS), is known to enhance glucose intolerance, hypertension and obesity. Recently, subclinical Cushing's disease (subCD) has been identified, but its prevalence and the extent of consequent metabolic derangement are unclear. We screened 90 type 2 diabetic patients hospitalized in our department for subCD, according to the diagnostic guideline proposed by the working group of Japanese Ministry of Health, Welfare and Labor in 2006. Plasma ACTH and cortisol levels in the morning and at midnight were determined, and overnight 0.5 mg dexamethasone suppression test (DST) was performed. Those who showed poor cortisol suppression in DST underwent the desmopressin (DDAVP) test. Fifty-seven patients (63.3%) demonstrated abnormally high midnight cortisol levels (&gt;or=2.5 microg/dL), while only nine of them failed to suppress plasma cortisol levels to &lt;3 microg/dL after DST. Although none of the eight patients who underwent the DDAVP test demonstrated the anticipated paradoxical rise in plasma ACTH, these eight patients (8.9%) endocrinologically met the screening criteria of subCD. Since a considerable percentage of pituitary adenomas causing overt Cushing's disease are not identifiable in magnetic resonance imaging, many of those causing subCD may also be unidentifiable. Further follow-up studies including confirmatory testing and pituitary imaging are necessary. The most accurate test used to differentiate a pituitary adenoma from ectopic or adrenal Cushing syndrome is inferior petrosal sinus sampling. [12] [18] This invasive method measures the difference in ACTH level found in the inferior petrosal sinus (where the pituitary gland drains) compared to the periphery. [12] [18] A basal central to the peripheral ratio of over 3:1 when CRH is administered confirms the diagnosis of Cushing disease. [18] This test is considered the gold standard in diagnosing Cushing disease because it has a sensitivity and specificity of nearly 94%. Still, it is rarely used in clinical practice due to its high cost, invasiveness, rare but serious complications, and the required special expertise to perform. is diagnostic 1) Overnight DST2) 24-hour urinary free cortisol3) 11:00 pm salivary cortisol1) Plasma ACTH2) High-dose DST and urinary cortisolConfirm the diagnosisACTH gradient?Determine source of hypercortisolismDecreased ACTHLack of suppressionCT scan adrenalsIncreased ACTHPositive Increased ACTHLack of suppressionEquivocalresultsFurther testingBilateral petrosalvein samplingAdrenalsourcePituitarysourceEctopic ACTHsourceSTEPS IN DIAGNOSISDIAGNOSTIC STUDIESYesNoFigure 38-44. Diagnosis of Cushing’s syndrome. ACTH = adrenocorticotropic hormone; CT = computed tomography; DST = dexamethasone suppression test.Brunicardi_Ch38_p1625-p1704.indd 169001/03/19 11:22 AM 1691THYROID, PARATHYROID, AND ADRENALCHAPTER 38of a pituitary tumor. In patients suspected of having ectopic ACTH production, CT or MRI scans of the chest and anterior mediastinum are performed first, followed by imaging of the neck, abdomen, and pelvis if the initial studies are negative.Treatment Laparoscopic Serum ACTH levels can differentiate ACTH-dependent Cushing syndrome (elevated ACTH or inappropriately normal ACTH) from ACTH-independent (low ACTH level) Cushing syndrome. In patients with ACTH-dependent Cushing syndrome, the high-dose dexamethasone suppression test done by giving 8 mg dexamethasone by mouth at 2300 h and checking cortisol the next day at 0800 h, can differentiate pituitary ACTH from an ectopic ACTH source. A high-dose dexamethasone suppression test will decrease cortisol level by 50 % if the ACTH source is a pituitary adenoma, but not if ACTH is secreted by an ectopic tumor (e.g., oat cell lung carcinoma). Pituitary MRI, unenhanced CT scan of the adrenals, and chest X-ray and CT are also useful to localize the pathology. Cushing's syndrome is caused by either excessive cortisol-like medication, such as prednisone, or a tumor that either produces or results in the production of excessive cortisol by the adrenal glands. Cases due to a pituitary adenoma are known as Cushing's disease, which is the second most common cause of Cushing's syndrome after medication. A number of other tumors, often referred to as ectopic due to their placement outside the pituitary, may also cause Cushing's. Some of these are associated with inherited disorders such as multiple endocrine neoplasia type 1 and Carney complex. Diagnosis requires a number of steps. The first step is to check the medications a person takes. The second step is to measure levels of cortisol in the urine, saliva or in the blood after taking dexamethasone. If this test is abnormal, the cortisol may be measured late at night. If the cortisol remains high, a blood test for ACTH may be done.\nHere is the question:\nENDOCRINOLOGY: A 56-year-old female patient consulted for dorso-lumbar spine pain and progressive difficulty in performing usual tasks. In the last 5 years she gained weight, she has ecchymosis easily and arterial hypertension was detected. Physical examination: Obesity of central predominance, rounded facies, increased supraclavicular fat, decreased proximal muscle strength and some reddish striae in the abdomen. She has a blood glucose of 136 mg/dL and the radiological study showed osteoporosis and vertebral crushing. What do you think is the most coherent interpretation and attitude?\nHere are the potential choices:\n1. Postmenopausal osteoporosis, type 2 diabetes mellitus and essential hypertension, with decreased strength due to diabetic polyneuropathy.\n2. It is necessary to rule out Cushing's disease by dexamethasone suppression test and perform a cranial CT scan.\n3. Suggest Cushing's. Determine urinary free cortisol and basal ACTH, which serves to orient its etiology and select the most appropriate imaging technique.\n4. It looks like Cushing's. If basal ACTH is high, it may be due to corticosteroid use or an adrenal tumor, and an MRI should be performed.\n5. Probably has Cushing's. If the basal ACTH is low, he probably has a pituitary micro-adenoma, and a cranial CT scan should be performed.\nThe correct answer is: 3. Suggest Cushing's. Determine urinary free cortisol and basal ACTH, which serves to orient its etiology and select the most appropriate imaging technique."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Colorectal Primary signet ring cell carcinoma of the colon and rectum (PSRCCR) is rare, with a reported incidence of less than 1 percent. It has a poor prognosis because symptoms often develop late and it is usually diagnosed at an advanced stage. Five-year survival rates in previous studies ranged from nine to 30 percent. Average survival was between 20 and 45 months. It tends to affect younger adults with higher likelihood of lymphovascular invasion. It is worth noting that the overall survival rate of patients with SRCC was significantly poorer than that of patients with mucinous or poorly differentiated adenocarcinoma. In advanced gastric cancers, the prognosis for patients with the SRCCs was significantly worse than for the other histological types, which can be explained by the finding that advanced SRCC gastric cancers have a larger tumor size, more lymph node metastasis, a deeper invasive depth and more Borrmann type 4 lesions than other types. Stomach The U.S. National Comprehensive Cancer Network and American Society of Clinical Oncology provide guidelines for the follow-up of colon cancer. A medical history and physical examination are recommended every 3 to 6 months for 2 years, then every 6 months for 5 years. Carcinoembryonic antigen blood level measurements follow the same timing, but are only advised for people with T2 or greater lesions who are candidates for intervention. A CT-scan of the chest, abdomen and pelvis can be considered annually for the first 3 years for people who are at high risk of recurrence (for example, those who had poorly differentiated tumors or venous or lymphatic invasion) and are candidates for curative surgery (with the aim to cure). A colonoscopy can be done after 1 year, except if it could not be done during the initial staging because of an obstructing mass, in which case it should be performed after 3 to 6 months. If a villous polyp, a polyp >1 centimeter or high-grade dysplasia is found, it Microscopy Adenocarcinoma is a malignant epithelial tumor, originating from superficial glandular epithelial cells lining the colon and rectum. It invades the wall, infiltrating the muscularis mucosae layer, the submucosa, and then the muscularis propria. Tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, reduced stroma (\"back to back\" aspect). Sometimes, tumor cells are discohesive and secrete mucus, which invades the interstitium producing large pools of mucus. This occurs in mucinous adenocarcinoma, in which cells are poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery, this occurs in \"signet-ring cell.\" Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present three degrees of differentiation: well, moderately, and poorly differentiated. Micrographs (H&E stain) Microscopic criteria To investigate the clinicopathological features and prognosis of colorectal synchronous multiple primary cancer(SMPC). From January 2008 to June 2011, 51 patients diagnosed with colorectal SMPC underwent surgery at Department of General Surgery of Peking University First Hospital. Their clinicopathological features, diagnosis, treatment and prognosis were summarized and analyzed. SMPC was diagnosed according to the following criteria: each tumor must have a definite pathologic picture of malignancy; metastasis or recurrence from another colorectal cancer was excluded; tumors must be distinctly separated by at least 5 cm of all intact bowel wall from each other; SMPC has abnormal cells between tumor and normal mucosa and abnormal gland of transitional zone; each cancer is infiltrating carcinoma except the carcinoma in situ; all the cancers are detected at the same time or within 6 months. Multiple primary colorectal cancer originated from familial colonic polyposis or ulcerative colitis was excluded. These 51 colorectal SMPC patients accounted for 3.5% of 1 452 colorectal cancer patients in the same period at our hospital, with 32 males and 19 females, and mean age of (63±13)(29 to 82) years. Of 51 cases, 46(90.2%) had 2 original carcinoma, 3(5.9%) had 3 original carcinoma and 2(3.9%) had 4 carcinoma; 23(45.1%) complicated with colon polyps, 4(7.8%) complicated with malignancy outside the colorectum. In TNM staging, 7(13.7%), 15(29.4%), 24(47.1%) and 5(9.8%) patients were stage I(, II(, III( and IIII( respectively. Among 51 patients undergoing surgery by different procedures, 16 were subtotal colon resection, 8 were extended right colon resection, 5 were extended left hemicolon resection, 8 were right hemicolon resection plus Dixon procedure, 10 were Dixon, and 4 were right hemicolon resection plus sigmoid colon resection. Adjuvant chemotherapy and support treatment were given according to the condition after operation. A total of 105 tumors were found, including 25(23.8%) tumors in sigmoid colon, 24(22.9%) in rectum, 22(21.0%) in ascending colon and 4 in organs outside the colorectum. Tubular adenocarcinoma (86/105, 81.9%) was the main pathological type in these colorectal SMPC patients. During the follow-up of median 43.5 months, 10 cases presented local recurrence and 6 cases had liver metastasis. Multivariable analysis showed that ≤65 years old (OR=22.757, 95%CI: 1.562-331.543, P=0.002),undifferentiated carcinoma or mucous adenocarcinoma (OR=27.174, 95%CI: 2.834-260.512, P=0.004), stage III(-IIII( (OR=29.626, 95%CI: 3.216-272.884, P=0.003) were independent risk factors of postoperative 5-year recurrence and metastasis, but the number of SMPC lesions and the surgical method were not associated with postoperative 5-year recurrence and metastasis (P=0.564, P=0.513). The 3-year and 5-year survival rates of colorectal SMPC patients were 76.5% and 64.7%. Two-original carcinoma is the most common in colorectal SMPC patients, which mainly distributes in sigmoid colon and rectum. Postoperative monitoring should be strengthened for those patients with younger age, poor pathological types and advanced staging to prevent recurrence and metastasis. In Stage I colon cancer, no chemotherapy is offered, and surgery is the definitive treatment. The role of chemotherapy in Stage II colon cancer is debatable, and is usually not offered unless risk factors such as T4 tumor, undifferentiated tumor, vascular and perineural invasion or inadequate lymph node sampling is identified. It is also known that the people who carry abnormalities of the mismatch repair genes do not benefit from chemotherapy. For stage III and Stage IV colon cancer, chemotherapy is an integral part of treatment. Direct and indirect mechanisms contribute to chemotherapy resistance. Direct mechanisms include pathways that metabolize the drug, while indirect mechanisms include pathways that respond to the chemotherapy treatment. The NER DNA repair pathway plays a substantial role in reversing cell damage caused by chemotherapeutic agents such as 5-FU. Discoveries since 2010 In May 2017 the FDA approved an immunotherapeutic called Keytruda (pembrolizumab) (PD-1 inhibitor) for patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment. This indication is independent of PD-L1 expression assessment, tissue type and tumor location. Researchers have found another MSI, called elevated microsatellite alterations at selected tetranucleotide repeats (EMAST). However, EMAST is unique in that it is not derived from MMR, and it is commonly associated with TP53 mutations. It is a common opinion that the more often and the more rigorously the colon is examined, the more lesions will be discovered and diagnosed. However it has not been shown which methods of colonic examination and which regimen of surveillance should be used. Chart review was conducted on 481 patients who underwent curative resection for colorectal cancer between 1980 and 1990. Colonoscopy was performed preoperatively, after 12-15 months from surgical treatment, and then at an interval of 12-24 months, or when symptoms appeared. About ten percent of patients developed intraluminal recurrences, and more than 25% adenomatous polyps. More than one half of the metachronous lesions arise within the first 24 months. The median time to diagnosis was 25 months for intraluminal recurrences and 22 months for adenomatous polyps. Patients with left sited tumor at an advanced stage run a higher risk of developing recurrent intraluminal disease, and patients who presented associated polyps at the time of the operation for the index cancer have a higher risk of developing new polyps. About 50% of recurrences were detected when patients were asymptomatic. Colonoscopy must be performed within the first 12-15 months after operation, while an interval of 24 months between each examination seems sufficient to guarantee an early detection of metachronous lesion. Asymptomatic patients are more frequently reoperated for cure and thus have a better survival rate. Bowel cancer may be diagnosed by obtaining a sample of the colon during a sigmoidoscopy or colonoscopy. This is then followed by medical imaging to determine whether the disease has spread. Screening is effective for preventing and decreasing deaths from colorectal cancer. Screening, by one of a number of methods, is recommended starting from the age of 50 to 75. During colonoscopy, small polyps may be removed if found. If a large polyp or tumor is found, a biopsy may be performed to check if it is cancerous. Aspirin and other non-steroidal anti-inflammatory drugs decrease the risk. Their general use is not recommended for this purpose, however, due to side effects. There are two types of liquid biopsy (which is not really a biopsy as they are blood tests that do not require a biopsy of tissue): circulating tumor cell assays or cell-free circulating tumor DNA tests. These methods provide a non-invasive alternative to repeat invasive biopsies to monitor cancer treatment, test available drugs against the circulating tumor cells, evaluate the mutations in cancer and plan individualized treatments. In addition, because cancer is a heterogeneous genetic disease, and excisional biopsies provide only a snapshot in time of some of the rapid, dynamic genetic changes occurring in tumors, liquid biopsies provide some advantages over tissue biopsy-based genomic testing. In addition, excisional biopsies are invasive, can’t be used repeatedly, and are ineffective in understanding the dynamics of tumor progression and metastasis. By detecting, quantifying and characterisation of vital circulating tumor cells or genomic alterations in CTCs and cell-free DNA in Colorectal cancer is predominantly a disease of older population, but occasionally it affects younger patients, in whom very often diagnosis is overseen and treatment begins late. The aim of our study was to compare localization, clinical and pathological characteristics and survival of sporadic colorectal cancer patients aged up to 40 and over 65 years. The first group (group I) included 19 patients under 40 years and the second group (group II) 28 patients aged over 65 years, treated during 1997-2001. Patients with family history of colon cancer and inflammatory disease of the colon were not included. Arithmetic mean, standard deviation, Fisher's test, Student 's t test, x(2) test and the Kaplan-Meier method were used in the statistical analysis of the results. There was no difference among the tested groups regarding tumor localization. The most frequent localization was in the rectum and left colon. At presentation, in group I patients, besides the metastases in the liver and lymph nodes, colorectal cancer infiltrated also the duodenum, stomach, right kidney capsule in one patient, and adnexa in two patients. In group II patients we registered only liver and lymph node metastases. Pathologically, tubular and mucinous forms were present in all of the patients up to 40 years of age, while only one patient over 65 had tumor with mucinous component. In group I, Astler-Coller stage B was found in 1.5% of the patients, stage C in 72.5% and stage D in 26%; in group II, stage B was found in 1.5%, stage C in 84.5% and stage D in 14%. Grade III was 36.8% in group I and 17.8% in group II. No statistical differences were found in stage distribution (p=0.36) and grade (p=0.06) between group I and II. Five-year overall survival was 57.8% and 28.5% in younger and older patients, respectively (p=0.053). The results obtained showed no difference in clinical symptomatology and tumor localization in both groups. The incidence of more aggressive tumors was higher in younger persons. However, early detection combined with more aggressive therapeutic approach, could enable significant improvement of the 5-year survival of younger patients with colon cancer. Microsatellite instability diagnostics MSI is a good marker for determining Lynch syndrome and determining a prognosis for cancer treatments. In 1996, the National Cancer Institute (NCI) hosted an international workshop on Lynch Syndrome, which led to the development of the “Bethesda Guidelines” and loci for MSI testing. During this first workshop the NCI has agreed on five microsatellite markers necessary to determine MSI presence: two mononucleotides, BAT25 and BAT26, and three dinucleotide repeats, D2S123, D5S346, and D17S250. MSI-H tumors result from MSI of greater than 30% of unstable MSI loci (>2 or more of the 5 loci). MSI-L tumors result from less than 30% of unstable MSI biomarkers. MSI-L tumors are classified as tumors of alternative etiologies. Several studies demonstrate that MSI-H patients respond best to surgery alone, rather than chemotherapy and surgery, thus preventing patients from needlessly experiencing chemotherapy. There has been an unremitting rise in incidence of colonic cancer in this country with no recent improvement in cure rate. As a result the evolution of colorectal cancer has been the focus of considerable attention with an enlarging body of evidence pointing to the common neoplastic polyp as a precursor to malignancy. \"Neoplastic\" polyps include \"adenomatous polyps,\" \"villous adenomas\" and, lately recognized, \"villo-glandular polyps.\" Experience with endoscopic removal of over 2,000 colonic polyps (with no mortality) has introduced two questions of prime concern to the surgeon: (1) What constitutes  clinical malignancy in a polyp? AND, (2) When should laparatomy supplant or follow endoscopic removal? Eight hundred and ninety-two consecutive adenomatous (tubular), villous, villoglandular (villo-tubular) and \"polypoid cancer\" polyps are analyzed, 855 of which have been followed for 6 months to 4 years. Support is offered to the concept that villous and tubular growth patterns are merely variants of a similar base disturbance in cell renewal. Superficial cancer (carcinoma-in-situ) occurred in 6.6% of neoplastic polyps and represents no threat if the polyp is completely removed. Only when the cancer penetrates the muscularis mucosae should it be regarded as \"invasive.\" The term \"malignant polyp\" should be reserved for this form. Invasive cancer was found in 5.0% of neoplastic polyps in this series. Only in this group need the question of further surgical intervention be raised. Major considerations influencing a decision for subsequent laparotomy are polyp size and gross morphology (i.e. sessile or pedunculated), histologic type (of the polyp and of the cancer itself), adequacy of clearance between depth of invasion and plane of polyp resection, and the patient's age and general condition. These are analyzed. Twenty-five of 46 patients with \"malignant polyps\" were subjected to abdominal exploration: 17 showed no residual cancer, whereas 8 (5 with recognized incomplete endoscopic removal) had tumor in the bowel wall. Of the remaining 21 patients, for whom endoscopic polypectomy alone was deemed appropriate, none have shown residual or recurrent cancer on clinical and endoscopic followup. Colonoscopy appears to be a most promising approach in terms of the goals of cancer programs, offering both prophylaxis and opportunity for treatment at a favorable stage of disease. Treatment The specific treatment will depend on the tumor's type, location, size, and whether the cancer has spread to other organs. Surgical removal of the tumor remains the standard treatment of choice, but additional forms of therapy such as radiation therapy, chemotherapy, or immunotherapy exist. When detected early, skin cancer in cats and dogs can often be treated successfully. In many cases, a biopsy can remove the whole tumor, as long as the healthy tissues removed from just outside the tumor area do not contain any cancer cells. References External links Skin Cancer in Cats and Dogs from Pet Cancer Center Skin Cancer in Dogs from CanineCancer.com' Types of animal cancers Cancer in dogs Cancer in cats Integumentary neoplasia The authors examined the five-years postoperative survival rate of fifty patients who suffered from colorectal cancer along with the fact that the large bowel one of the neighbouring organs were resected. The subjects were divided into four groups: the colorectal resection was associated with (1) stomach resection (13 patients); (2) liver metastasectomy (14 patients); (3) small bowel resection (10 patients); (4) the resection of other organs (13 patients). In the first two years of the study they were examined once in every three months, in the next two years once in every six months and then yearly. The following tests were carried out: chest X ray, abdominal sonography, irrigography or colonoscopy and CEA. On condition that the colonoscope reached the caecum and the result was negative, the test was repeated only a year later. The patients were operated on between 1985 and 1997. The statistical analysis was made with the help of the Kaplan-Meier method. During this period fifty-six complex resections were performed. Out of fifty-six patients fifty were followed. Compliance 89%. In group 1, where the average age of patients was sixty-two years, one patient died in the forty-first and the other in the fifty-second month after the surgery. Survival rate: 11/13 (83%). The survival rates for the other groups were as follows: group 2 (average age 64) twelve patients died within five years. Survival rate 2/14 (14%). The difference between the survival rates in the first two groups in significant (P = 0.0001). Group 3 (average age 67) seven died and only three survived. Survival rate: 3/10 (30%). The difference between group 1 and group 3 is significant (P = 0.0022). Group 4 (average age 64) seven patients died. Survival rate 6/13 (46%). Comparing this rate to that of the group 1, the difference is not significant (P &gt; 0.01). Having analysed the results of the four groups it can be concluded that the patients of group 1 lived the longest (stomach resection) and those of group 2 (liver metastasectomy) died the earliest after the operation. It is surprising that the patients of group 3 lived significantly shorter than the ones of group 1 in spite of the fact that they belong by far the greatest number to stage Dukes B (group 1: 12/13 = 92%; group 3: 7/10 = 70%). The authors assume that the partial or the total absence of the stomach keeps back the growth of the tumour (gastro-colic tumour growing dependency). They think that in case of colon cancer which infiltrates the stomach surgeons experienced in gastric and colorectal surgery should be encouraged to take the risk of the double resection providing the fact that the operation is accomplishable. in understanding the dynamics of tumor progression and metastasis. By detecting, quantifying and characterisation of vital circulating tumor cells or genomic alterations in CTCs and cell-free DNA in blood, liquid biopsy can provide real-time information on the stage of tumor progression, treatment effectiveness, and cancer metastasis risk. This technological development could make it possible to diagnose and manage cancer from repeated blood tests rather than from a traditional biopsy. Colo-rectal adenoms occur more frequently in the elderly and should be considered as precancerous. The structural changes of the glandular epithelium are known as dysplasia or atypia and are classified into three grades of severity; the \"severe epithelial dysplasia\" has all the histological characteristics of a malignant tumor which however has not infiltrated the muscularis mucosa and so has not gained access to the lymphatic system. Whenever these structural changes were present the terms focal carcinoma or carcinoma in situ were used. However in 1976 the WHO accepted to change the nomenclature to \"severe epithelial dysplasia\", as Morson had proposed. Their aim was to avoid superfluous radical surgical intervention. Whenever severe dysplasia is present in an adenoma, the necessary therapy is the local excision of the adenoma together with its pedick. An exact complete histological examination is necessary. Between 1976 and 1980 we saw 201 cases of adenoma of the colon or rectum at the Surgical Clinic, University of Düsseldorf. 27 of these cases showed severe epithelial dysplasia. As described in the literature there was a correlation between the size of the adenoma, the histological picture and the risk of malignancy. The reexamination of 105 patients showed that there was a significant percentage of recurrency at the site of excision or new polyps at a different site. Therefore, regular checkups are a must for all those patients in whom polyps of the large bowel have been removed. The diagnosis of LPF depends on its clinical presentation almost exclusively in newborn and young children and, most importantly, its histopathology as determined on biopsied intact tissue or fine-needle aspiration to obtain a sampling of the tumor's cells. Intact tissue samples typical show abundant mature-appearing adipose (i.e. fat) tissue mixed with a minor component of oval-shaped or spindle-shaped fibroblast-like cells some of which have a pseudolipoblast-like morphology. Needle biopsies should show these cells. However, LPF histopathology can vary widely between cases. The cited gene abnormalities in the above section are insufficient to support a diagnosis of LPF although further study of these and discoveries of other gene abnormalities may do so. The histopathology of lipofibromatosis-like neural tumors (LPF-NT) can closely resemble LPF tumors. Unlike LPF tumors, however, LPF-NT tumors have been diagnosed in adults in more than 27% of cases with the remaining cases diagnosed Three hundred and seventy-two patients with colorectal tumours treated by curative resection between January 1982 and January 1992 were reviewed in order to determine the role of colonoscopy and the outcome of patients with multiple tumours. Thirty (8.1%) of them with a mean age of 57 (35-79) years (20 males, 10 females) had synchronous (19 cases) or metachronous (11 cases) lesions. Rectum and sigmoid colon were the most frequent site of multiple lesions, accounting for 73% of all lesions. Accurate pre-operative diagnosis was performed in 14 of the 19 patients with synchronous lesions, and in the remaining 5 cases failure to perform an intra-operative colonoscopy was the cause of missing the lesions. Three of them had over-looked lesions on the previous barium enema. Synchronous lesions has the tendency to be less invasive as compared to metachronous ones. Five-year survival rates (Kaplan-Meier method) were 45% and 58% for patients with multiple and single lesions respectively (not significant). For patients with colorectal carcinoma a thorough examination of the whole colon by intra-operative colonoscopy should be accomplished in order to rule out the possibility of associated lesions as well as to decrease the incidence of \"early\" metachronous lesions. Tumors are formed by carcinogenesis, a process in which cellular alterations lead to the formation of cancer. Multistage carcinogenesis involves the sequential genetic or epigenetic changes to a cell's DNA, where each step produces a more advanced tumor. It is often broken down into three stages; initiation, promotion and progression, and several mutations may occur at each stage. Initiation is where the first genetic mutation occurs in a cell. Promotion is the clonal expansion (repeated division) of this transformed cell into a visible tumor that is usually benign. Following promotion, progression may take place where more genetic mutations are acquired in a sub-population of tumor cells. Progression changes the benign tumor into a malignant tumor. A prominent and well studied example of this phenomenon is the tubular adenoma, a common type of colon polyp which is an important precursor to colon cancer. The cells in tubular adenomas, like most tumors that frequently progress to The emergence of drug-resistant tumors due to intra- and inter-tumoral heterogeneity an issue in treatment efficacy. A minor genetic clone within the tumor can expand after treatment if it carries a drug-resistant mutation. Initial biopsies can miss these clones due to low frequency or spatial separation of cells within the tumor. For example, since a biopsy only samples a small part of the tumor, clones that resides in a different location may go unnoticed. This can mislead research that focuses on studying the role of tumor heterogeneity in cancer progression and relapse. The use of ctDNA in research can alleviate these concerns because it could provide a more representative 'screenshot' of the genetic diversity of cancer at both primary and metastatic sites. For example, ctDNA has been shown to be useful in studying the clonal evolution of a patient’s cancer before and after treatment regimens. Early detection of cancer is still challenging but recent progress in the analysis of Flexible sigmoidoscopy is indicated for colorectal cancer screening. The decision about who needs total colonoscopy based on distal findings is still controversial because of the uncertainty of the associations between distal and proximal findings. The purpose of the study was to characterize distal findings in patients with total colonoscopy, to investigate its importance as markers of advanced proximal lesions and to evaluate the usefulness of a clinical Predictive Index, already published in the literature, in the identification of these lesions. Retrospective analysis of the patients submitted to total colonoscopy between January 2006 and February 2007, with selection of 1000 consecutive cases with reference to polyps. We analysed demographic data, indication for the exam and morphological and histological characteristics of the polyps. Advanced lesion was defined as any adenoma larger than 10 mm or any polyp with villous characteristics, high grade dysplasia or cancer. The Predictive Index was obtained through the assignment of points to 3 categories: sex, age and distal findings, which result in 3 groups: low, intermediate and high risk. The mean age of patients was 64,69 years and 65,1% were male. Distal and proximal polyps were identified in 829 (82,9%) and 369 (36,9%) patients, respectively. Advanced distal lesion was found in 342 patients (34,2%) and advanced proximal lesion in 98 (9,8%). 587 patients (58,7%) were in the high risk group. In the group of patients with advanced proximal lesion, a third presented low and intermediate risk, 52% had no distal polyps, 88,7% had less than three distal polyps and 71,4% had no advanced distal lesion. Sensitivity values for these four categories ranged between 11,2% and 66,6%. If the decision to perform total colonoscopy is based on distal colonic findings or on the Predictive Index, the ability to identify advanced proximal lesion is markedly reduced, endangering the aim of a screening program. For the esophagous Endoscopic mucosal resection has been advocated for early esophageal cancers (that is, those that are superficial and confined to the mucosa only) and has been shown to be a less invasive, safe, and effective therapy for early squamous cell carcinoma. It has also been shown to be safe and effective for early adenocarcinoma arising in Barrett’s esophagus. The prognosis after treatment with this method is comparable to surgical resection. This technique can be attempted in patients who have no evidence of nodal or distant metastases, with differentiated tumors that are slightly raised and less than 2 cm in diameter, or in differentiated tumors that are ulcerated and less than 1 cm in diameter. The most commonly employed modalities of endoscopic mucosal resection include strip biopsy, double-snare polypectomy, resection with combined use of highly concentrated saline and epinephrine, and resection using a cap. In contrast to earlier studies that suggested that colon carcinoma is unusually lethal in the young, 69 patients, ages 20 to 39 years, had a relatively good prognosis. Fifty-nine percent lived over 5 years after diagnosis, and 51% were cured. Furthermore, 67% were cured if they did not have distant spread of the carcinoma at the time of the initial operation. Neither age, sex, tumor size, location, mere presence of lymph node metastases, depth of tumor invasion, nor predisposing disease of the colon was a strong prognostic factor. Metastases to six or more lymph nodes and distant spread of the tumor at the time of initial surgery were ominous findings. Mucinous carcinoma was relatively frequent (28%) and was also an ominous feature (only 5 of 20 patients cured as opposed to 26 of 43 with classical adenocarcinoma).\nHere is the question:\nDIGESTIVE: During a colonoscopy, a 5-cm tumor located in the right colon is detected in a 48-year-old man. No other lesions were found. His maternal grandmother also suffered from colon cancer. The biopsies are superficial and show a poorly differentiated tumor with abundant inflammatory cells in the stroma that is diagnosed as a medullary type carcinoma.\nHere are the potential choices:\n1. Chemotherapy is the treatment of choice.\n2. Since the biopsy is superficial, it should be repeated before proceeding with treatment.\n3. The prognosis of the tumor depends mainly on its high degree of anaplasia.\n4. It is unlikely that this tumor has developed over a previous adenoma.\n5. Microsatellite instability and DNA error repair genes should be studied.\nThe correct answer is: ",
        "gold_answer": "5 Microsatellite instability and DNA error repair genes should be studied.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Colorectal Primary signet ring cell carcinoma of the colon and rectum (PSRCCR) is rare, with a reported incidence of less than 1 percent. It has a poor prognosis because symptoms often develop late and it is usually diagnosed at an advanced stage. Five-year survival rates in previous studies ranged from nine to 30 percent. Average survival was between 20 and 45 months. It tends to affect younger adults with higher likelihood of lymphovascular invasion. It is worth noting that the overall survival rate of patients with SRCC was significantly poorer than that of patients with mucinous or poorly differentiated adenocarcinoma. In advanced gastric cancers, the prognosis for patients with the SRCCs was significantly worse than for the other histological types, which can be explained by the finding that advanced SRCC gastric cancers have a larger tumor size, more lymph node metastasis, a deeper invasive depth and more Borrmann type 4 lesions than other types. Stomach The U.S. National Comprehensive Cancer Network and American Society of Clinical Oncology provide guidelines for the follow-up of colon cancer. A medical history and physical examination are recommended every 3 to 6 months for 2 years, then every 6 months for 5 years. Carcinoembryonic antigen blood level measurements follow the same timing, but are only advised for people with T2 or greater lesions who are candidates for intervention. A CT-scan of the chest, abdomen and pelvis can be considered annually for the first 3 years for people who are at high risk of recurrence (for example, those who had poorly differentiated tumors or venous or lymphatic invasion) and are candidates for curative surgery (with the aim to cure). A colonoscopy can be done after 1 year, except if it could not be done during the initial staging because of an obstructing mass, in which case it should be performed after 3 to 6 months. If a villous polyp, a polyp >1 centimeter or high-grade dysplasia is found, it Microscopy Adenocarcinoma is a malignant epithelial tumor, originating from superficial glandular epithelial cells lining the colon and rectum. It invades the wall, infiltrating the muscularis mucosae layer, the submucosa, and then the muscularis propria. Tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, reduced stroma (\"back to back\" aspect). Sometimes, tumor cells are discohesive and secrete mucus, which invades the interstitium producing large pools of mucus. This occurs in mucinous adenocarcinoma, in which cells are poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery, this occurs in \"signet-ring cell.\" Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present three degrees of differentiation: well, moderately, and poorly differentiated. Micrographs (H&E stain) Microscopic criteria To investigate the clinicopathological features and prognosis of colorectal synchronous multiple primary cancer(SMPC). From January 2008 to June 2011, 51 patients diagnosed with colorectal SMPC underwent surgery at Department of General Surgery of Peking University First Hospital. Their clinicopathological features, diagnosis, treatment and prognosis were summarized and analyzed. SMPC was diagnosed according to the following criteria: each tumor must have a definite pathologic picture of malignancy; metastasis or recurrence from another colorectal cancer was excluded; tumors must be distinctly separated by at least 5 cm of all intact bowel wall from each other; SMPC has abnormal cells between tumor and normal mucosa and abnormal gland of transitional zone; each cancer is infiltrating carcinoma except the carcinoma in situ; all the cancers are detected at the same time or within 6 months. Multiple primary colorectal cancer originated from familial colonic polyposis or ulcerative colitis was excluded. These 51 colorectal SMPC patients accounted for 3.5% of 1 452 colorectal cancer patients in the same period at our hospital, with 32 males and 19 females, and mean age of (63±13)(29 to 82) years. Of 51 cases, 46(90.2%) had 2 original carcinoma, 3(5.9%) had 3 original carcinoma and 2(3.9%) had 4 carcinoma; 23(45.1%) complicated with colon polyps, 4(7.8%) complicated with malignancy outside the colorectum. In TNM staging, 7(13.7%), 15(29.4%), 24(47.1%) and 5(9.8%) patients were stage I(, II(, III( and IIII( respectively. Among 51 patients undergoing surgery by different procedures, 16 were subtotal colon resection, 8 were extended right colon resection, 5 were extended left hemicolon resection, 8 were right hemicolon resection plus Dixon procedure, 10 were Dixon, and 4 were right hemicolon resection plus sigmoid colon resection. Adjuvant chemotherapy and support treatment were given according to the condition after operation. A total of 105 tumors were found, including 25(23.8%) tumors in sigmoid colon, 24(22.9%) in rectum, 22(21.0%) in ascending colon and 4 in organs outside the colorectum. Tubular adenocarcinoma (86/105, 81.9%) was the main pathological type in these colorectal SMPC patients. During the follow-up of median 43.5 months, 10 cases presented local recurrence and 6 cases had liver metastasis. Multivariable analysis showed that ≤65 years old (OR=22.757, 95%CI: 1.562-331.543, P=0.002),undifferentiated carcinoma or mucous adenocarcinoma (OR=27.174, 95%CI: 2.834-260.512, P=0.004), stage III(-IIII( (OR=29.626, 95%CI: 3.216-272.884, P=0.003) were independent risk factors of postoperative 5-year recurrence and metastasis, but the number of SMPC lesions and the surgical method were not associated with postoperative 5-year recurrence and metastasis (P=0.564, P=0.513). The 3-year and 5-year survival rates of colorectal SMPC patients were 76.5% and 64.7%. Two-original carcinoma is the most common in colorectal SMPC patients, which mainly distributes in sigmoid colon and rectum. Postoperative monitoring should be strengthened for those patients with younger age, poor pathological types and advanced staging to prevent recurrence and metastasis. In Stage I colon cancer, no chemotherapy is offered, and surgery is the definitive treatment. The role of chemotherapy in Stage II colon cancer is debatable, and is usually not offered unless risk factors such as T4 tumor, undifferentiated tumor, vascular and perineural invasion or inadequate lymph node sampling is identified. It is also known that the people who carry abnormalities of the mismatch repair genes do not benefit from chemotherapy. For stage III and Stage IV colon cancer, chemotherapy is an integral part of treatment. Direct and indirect mechanisms contribute to chemotherapy resistance. Direct mechanisms include pathways that metabolize the drug, while indirect mechanisms include pathways that respond to the chemotherapy treatment. The NER DNA repair pathway plays a substantial role in reversing cell damage caused by chemotherapeutic agents such as 5-FU. Discoveries since 2010 In May 2017 the FDA approved an immunotherapeutic called Keytruda (pembrolizumab) (PD-1 inhibitor) for patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment. This indication is independent of PD-L1 expression assessment, tissue type and tumor location. Researchers have found another MSI, called elevated microsatellite alterations at selected tetranucleotide repeats (EMAST). However, EMAST is unique in that it is not derived from MMR, and it is commonly associated with TP53 mutations. It is a common opinion that the more often and the more rigorously the colon is examined, the more lesions will be discovered and diagnosed. However it has not been shown which methods of colonic examination and which regimen of surveillance should be used. Chart review was conducted on 481 patients who underwent curative resection for colorectal cancer between 1980 and 1990. Colonoscopy was performed preoperatively, after 12-15 months from surgical treatment, and then at an interval of 12-24 months, or when symptoms appeared. About ten percent of patients developed intraluminal recurrences, and more than 25% adenomatous polyps. More than one half of the metachronous lesions arise within the first 24 months. The median time to diagnosis was 25 months for intraluminal recurrences and 22 months for adenomatous polyps. Patients with left sited tumor at an advanced stage run a higher risk of developing recurrent intraluminal disease, and patients who presented associated polyps at the time of the operation for the index cancer have a higher risk of developing new polyps. About 50% of recurrences were detected when patients were asymptomatic. Colonoscopy must be performed within the first 12-15 months after operation, while an interval of 24 months between each examination seems sufficient to guarantee an early detection of metachronous lesion. Asymptomatic patients are more frequently reoperated for cure and thus have a better survival rate. Bowel cancer may be diagnosed by obtaining a sample of the colon during a sigmoidoscopy or colonoscopy. This is then followed by medical imaging to determine whether the disease has spread. Screening is effective for preventing and decreasing deaths from colorectal cancer. Screening, by one of a number of methods, is recommended starting from the age of 50 to 75. During colonoscopy, small polyps may be removed if found. If a large polyp or tumor is found, a biopsy may be performed to check if it is cancerous. Aspirin and other non-steroidal anti-inflammatory drugs decrease the risk. Their general use is not recommended for this purpose, however, due to side effects. There are two types of liquid biopsy (which is not really a biopsy as they are blood tests that do not require a biopsy of tissue): circulating tumor cell assays or cell-free circulating tumor DNA tests. These methods provide a non-invasive alternative to repeat invasive biopsies to monitor cancer treatment, test available drugs against the circulating tumor cells, evaluate the mutations in cancer and plan individualized treatments. In addition, because cancer is a heterogeneous genetic disease, and excisional biopsies provide only a snapshot in time of some of the rapid, dynamic genetic changes occurring in tumors, liquid biopsies provide some advantages over tissue biopsy-based genomic testing. In addition, excisional biopsies are invasive, can’t be used repeatedly, and are ineffective in understanding the dynamics of tumor progression and metastasis. By detecting, quantifying and characterisation of vital circulating tumor cells or genomic alterations in CTCs and cell-free DNA in Colorectal cancer is predominantly a disease of older population, but occasionally it affects younger patients, in whom very often diagnosis is overseen and treatment begins late. The aim of our study was to compare localization, clinical and pathological characteristics and survival of sporadic colorectal cancer patients aged up to 40 and over 65 years. The first group (group I) included 19 patients under 40 years and the second group (group II) 28 patients aged over 65 years, treated during 1997-2001. Patients with family history of colon cancer and inflammatory disease of the colon were not included. Arithmetic mean, standard deviation, Fisher's test, Student 's t test, x(2) test and the Kaplan-Meier method were used in the statistical analysis of the results. There was no difference among the tested groups regarding tumor localization. The most frequent localization was in the rectum and left colon. At presentation, in group I patients, besides the metastases in the liver and lymph nodes, colorectal cancer infiltrated also the duodenum, stomach, right kidney capsule in one patient, and adnexa in two patients. In group II patients we registered only liver and lymph node metastases. Pathologically, tubular and mucinous forms were present in all of the patients up to 40 years of age, while only one patient over 65 had tumor with mucinous component. In group I, Astler-Coller stage B was found in 1.5% of the patients, stage C in 72.5% and stage D in 26%; in group II, stage B was found in 1.5%, stage C in 84.5% and stage D in 14%. Grade III was 36.8% in group I and 17.8% in group II. No statistical differences were found in stage distribution (p=0.36) and grade (p=0.06) between group I and II. Five-year overall survival was 57.8% and 28.5% in younger and older patients, respectively (p=0.053). The results obtained showed no difference in clinical symptomatology and tumor localization in both groups. The incidence of more aggressive tumors was higher in younger persons. However, early detection combined with more aggressive therapeutic approach, could enable significant improvement of the 5-year survival of younger patients with colon cancer. Microsatellite instability diagnostics MSI is a good marker for determining Lynch syndrome and determining a prognosis for cancer treatments. In 1996, the National Cancer Institute (NCI) hosted an international workshop on Lynch Syndrome, which led to the development of the “Bethesda Guidelines” and loci for MSI testing. During this first workshop the NCI has agreed on five microsatellite markers necessary to determine MSI presence: two mononucleotides, BAT25 and BAT26, and three dinucleotide repeats, D2S123, D5S346, and D17S250. MSI-H tumors result from MSI of greater than 30% of unstable MSI loci (>2 or more of the 5 loci). MSI-L tumors result from less than 30% of unstable MSI biomarkers. MSI-L tumors are classified as tumors of alternative etiologies. Several studies demonstrate that MSI-H patients respond best to surgery alone, rather than chemotherapy and surgery, thus preventing patients from needlessly experiencing chemotherapy. There has been an unremitting rise in incidence of colonic cancer in this country with no recent improvement in cure rate. As a result the evolution of colorectal cancer has been the focus of considerable attention with an enlarging body of evidence pointing to the common neoplastic polyp as a precursor to malignancy. \"Neoplastic\" polyps include \"adenomatous polyps,\" \"villous adenomas\" and, lately recognized, \"villo-glandular polyps.\" Experience with endoscopic removal of over 2,000 colonic polyps (with no mortality) has introduced two questions of prime concern to the surgeon: (1) What constitutes  clinical malignancy in a polyp? AND, (2) When should laparatomy supplant or follow endoscopic removal? Eight hundred and ninety-two consecutive adenomatous (tubular), villous, villoglandular (villo-tubular) and \"polypoid cancer\" polyps are analyzed, 855 of which have been followed for 6 months to 4 years. Support is offered to the concept that villous and tubular growth patterns are merely variants of a similar base disturbance in cell renewal. Superficial cancer (carcinoma-in-situ) occurred in 6.6% of neoplastic polyps and represents no threat if the polyp is completely removed. Only when the cancer penetrates the muscularis mucosae should it be regarded as \"invasive.\" The term \"malignant polyp\" should be reserved for this form. Invasive cancer was found in 5.0% of neoplastic polyps in this series. Only in this group need the question of further surgical intervention be raised. Major considerations influencing a decision for subsequent laparotomy are polyp size and gross morphology (i.e. sessile or pedunculated), histologic type (of the polyp and of the cancer itself), adequacy of clearance between depth of invasion and plane of polyp resection, and the patient's age and general condition. These are analyzed. Twenty-five of 46 patients with \"malignant polyps\" were subjected to abdominal exploration: 17 showed no residual cancer, whereas 8 (5 with recognized incomplete endoscopic removal) had tumor in the bowel wall. Of the remaining 21 patients, for whom endoscopic polypectomy alone was deemed appropriate, none have shown residual or recurrent cancer on clinical and endoscopic followup. Colonoscopy appears to be a most promising approach in terms of the goals of cancer programs, offering both prophylaxis and opportunity for treatment at a favorable stage of disease. Treatment The specific treatment will depend on the tumor's type, location, size, and whether the cancer has spread to other organs. Surgical removal of the tumor remains the standard treatment of choice, but additional forms of therapy such as radiation therapy, chemotherapy, or immunotherapy exist. When detected early, skin cancer in cats and dogs can often be treated successfully. In many cases, a biopsy can remove the whole tumor, as long as the healthy tissues removed from just outside the tumor area do not contain any cancer cells. References External links Skin Cancer in Cats and Dogs from Pet Cancer Center Skin Cancer in Dogs from CanineCancer.com' Types of animal cancers Cancer in dogs Cancer in cats Integumentary neoplasia The authors examined the five-years postoperative survival rate of fifty patients who suffered from colorectal cancer along with the fact that the large bowel one of the neighbouring organs were resected. The subjects were divided into four groups: the colorectal resection was associated with (1) stomach resection (13 patients); (2) liver metastasectomy (14 patients); (3) small bowel resection (10 patients); (4) the resection of other organs (13 patients). In the first two years of the study they were examined once in every three months, in the next two years once in every six months and then yearly. The following tests were carried out: chest X ray, abdominal sonography, irrigography or colonoscopy and CEA. On condition that the colonoscope reached the caecum and the result was negative, the test was repeated only a year later. The patients were operated on between 1985 and 1997. The statistical analysis was made with the help of the Kaplan-Meier method. During this period fifty-six complex resections were performed. Out of fifty-six patients fifty were followed. Compliance 89%. In group 1, where the average age of patients was sixty-two years, one patient died in the forty-first and the other in the fifty-second month after the surgery. Survival rate: 11/13 (83%). The survival rates for the other groups were as follows: group 2 (average age 64) twelve patients died within five years. Survival rate 2/14 (14%). The difference between the survival rates in the first two groups in significant (P = 0.0001). Group 3 (average age 67) seven died and only three survived. Survival rate: 3/10 (30%). The difference between group 1 and group 3 is significant (P = 0.0022). Group 4 (average age 64) seven patients died. Survival rate 6/13 (46%). Comparing this rate to that of the group 1, the difference is not significant (P &gt; 0.01). Having analysed the results of the four groups it can be concluded that the patients of group 1 lived the longest (stomach resection) and those of group 2 (liver metastasectomy) died the earliest after the operation. It is surprising that the patients of group 3 lived significantly shorter than the ones of group 1 in spite of the fact that they belong by far the greatest number to stage Dukes B (group 1: 12/13 = 92%; group 3: 7/10 = 70%). The authors assume that the partial or the total absence of the stomach keeps back the growth of the tumour (gastro-colic tumour growing dependency). They think that in case of colon cancer which infiltrates the stomach surgeons experienced in gastric and colorectal surgery should be encouraged to take the risk of the double resection providing the fact that the operation is accomplishable. in understanding the dynamics of tumor progression and metastasis. By detecting, quantifying and characterisation of vital circulating tumor cells or genomic alterations in CTCs and cell-free DNA in blood, liquid biopsy can provide real-time information on the stage of tumor progression, treatment effectiveness, and cancer metastasis risk. This technological development could make it possible to diagnose and manage cancer from repeated blood tests rather than from a traditional biopsy. Colo-rectal adenoms occur more frequently in the elderly and should be considered as precancerous. The structural changes of the glandular epithelium are known as dysplasia or atypia and are classified into three grades of severity; the \"severe epithelial dysplasia\" has all the histological characteristics of a malignant tumor which however has not infiltrated the muscularis mucosa and so has not gained access to the lymphatic system. Whenever these structural changes were present the terms focal carcinoma or carcinoma in situ were used. However in 1976 the WHO accepted to change the nomenclature to \"severe epithelial dysplasia\", as Morson had proposed. Their aim was to avoid superfluous radical surgical intervention. Whenever severe dysplasia is present in an adenoma, the necessary therapy is the local excision of the adenoma together with its pedick. An exact complete histological examination is necessary. Between 1976 and 1980 we saw 201 cases of adenoma of the colon or rectum at the Surgical Clinic, University of Düsseldorf. 27 of these cases showed severe epithelial dysplasia. As described in the literature there was a correlation between the size of the adenoma, the histological picture and the risk of malignancy. The reexamination of 105 patients showed that there was a significant percentage of recurrency at the site of excision or new polyps at a different site. Therefore, regular checkups are a must for all those patients in whom polyps of the large bowel have been removed. The diagnosis of LPF depends on its clinical presentation almost exclusively in newborn and young children and, most importantly, its histopathology as determined on biopsied intact tissue or fine-needle aspiration to obtain a sampling of the tumor's cells. Intact tissue samples typical show abundant mature-appearing adipose (i.e. fat) tissue mixed with a minor component of oval-shaped or spindle-shaped fibroblast-like cells some of which have a pseudolipoblast-like morphology. Needle biopsies should show these cells. However, LPF histopathology can vary widely between cases. The cited gene abnormalities in the above section are insufficient to support a diagnosis of LPF although further study of these and discoveries of other gene abnormalities may do so. The histopathology of lipofibromatosis-like neural tumors (LPF-NT) can closely resemble LPF tumors. Unlike LPF tumors, however, LPF-NT tumors have been diagnosed in adults in more than 27% of cases with the remaining cases diagnosed Three hundred and seventy-two patients with colorectal tumours treated by curative resection between January 1982 and January 1992 were reviewed in order to determine the role of colonoscopy and the outcome of patients with multiple tumours. Thirty (8.1%) of them with a mean age of 57 (35-79) years (20 males, 10 females) had synchronous (19 cases) or metachronous (11 cases) lesions. Rectum and sigmoid colon were the most frequent site of multiple lesions, accounting for 73% of all lesions. Accurate pre-operative diagnosis was performed in 14 of the 19 patients with synchronous lesions, and in the remaining 5 cases failure to perform an intra-operative colonoscopy was the cause of missing the lesions. Three of them had over-looked lesions on the previous barium enema. Synchronous lesions has the tendency to be less invasive as compared to metachronous ones. Five-year survival rates (Kaplan-Meier method) were 45% and 58% for patients with multiple and single lesions respectively (not significant). For patients with colorectal carcinoma a thorough examination of the whole colon by intra-operative colonoscopy should be accomplished in order to rule out the possibility of associated lesions as well as to decrease the incidence of \"early\" metachronous lesions. Tumors are formed by carcinogenesis, a process in which cellular alterations lead to the formation of cancer. Multistage carcinogenesis involves the sequential genetic or epigenetic changes to a cell's DNA, where each step produces a more advanced tumor. It is often broken down into three stages; initiation, promotion and progression, and several mutations may occur at each stage. Initiation is where the first genetic mutation occurs in a cell. Promotion is the clonal expansion (repeated division) of this transformed cell into a visible tumor that is usually benign. Following promotion, progression may take place where more genetic mutations are acquired in a sub-population of tumor cells. Progression changes the benign tumor into a malignant tumor. A prominent and well studied example of this phenomenon is the tubular adenoma, a common type of colon polyp which is an important precursor to colon cancer. The cells in tubular adenomas, like most tumors that frequently progress to The emergence of drug-resistant tumors due to intra- and inter-tumoral heterogeneity an issue in treatment efficacy. A minor genetic clone within the tumor can expand after treatment if it carries a drug-resistant mutation. Initial biopsies can miss these clones due to low frequency or spatial separation of cells within the tumor. For example, since a biopsy only samples a small part of the tumor, clones that resides in a different location may go unnoticed. This can mislead research that focuses on studying the role of tumor heterogeneity in cancer progression and relapse. The use of ctDNA in research can alleviate these concerns because it could provide a more representative 'screenshot' of the genetic diversity of cancer at both primary and metastatic sites. For example, ctDNA has been shown to be useful in studying the clonal evolution of a patient’s cancer before and after treatment regimens. Early detection of cancer is still challenging but recent progress in the analysis of Flexible sigmoidoscopy is indicated for colorectal cancer screening. The decision about who needs total colonoscopy based on distal findings is still controversial because of the uncertainty of the associations between distal and proximal findings. The purpose of the study was to characterize distal findings in patients with total colonoscopy, to investigate its importance as markers of advanced proximal lesions and to evaluate the usefulness of a clinical Predictive Index, already published in the literature, in the identification of these lesions. Retrospective analysis of the patients submitted to total colonoscopy between January 2006 and February 2007, with selection of 1000 consecutive cases with reference to polyps. We analysed demographic data, indication for the exam and morphological and histological characteristics of the polyps. Advanced lesion was defined as any adenoma larger than 10 mm or any polyp with villous characteristics, high grade dysplasia or cancer. The Predictive Index was obtained through the assignment of points to 3 categories: sex, age and distal findings, which result in 3 groups: low, intermediate and high risk. The mean age of patients was 64,69 years and 65,1% were male. Distal and proximal polyps were identified in 829 (82,9%) and 369 (36,9%) patients, respectively. Advanced distal lesion was found in 342 patients (34,2%) and advanced proximal lesion in 98 (9,8%). 587 patients (58,7%) were in the high risk group. In the group of patients with advanced proximal lesion, a third presented low and intermediate risk, 52% had no distal polyps, 88,7% had less than three distal polyps and 71,4% had no advanced distal lesion. Sensitivity values for these four categories ranged between 11,2% and 66,6%. If the decision to perform total colonoscopy is based on distal colonic findings or on the Predictive Index, the ability to identify advanced proximal lesion is markedly reduced, endangering the aim of a screening program. For the esophagous Endoscopic mucosal resection has been advocated for early esophageal cancers (that is, those that are superficial and confined to the mucosa only) and has been shown to be a less invasive, safe, and effective therapy for early squamous cell carcinoma. It has also been shown to be safe and effective for early adenocarcinoma arising in Barrett’s esophagus. The prognosis after treatment with this method is comparable to surgical resection. This technique can be attempted in patients who have no evidence of nodal or distant metastases, with differentiated tumors that are slightly raised and less than 2 cm in diameter, or in differentiated tumors that are ulcerated and less than 1 cm in diameter. The most commonly employed modalities of endoscopic mucosal resection include strip biopsy, double-snare polypectomy, resection with combined use of highly concentrated saline and epinephrine, and resection using a cap. In contrast to earlier studies that suggested that colon carcinoma is unusually lethal in the young, 69 patients, ages 20 to 39 years, had a relatively good prognosis. Fifty-nine percent lived over 5 years after diagnosis, and 51% were cured. Furthermore, 67% were cured if they did not have distant spread of the carcinoma at the time of the initial operation. Neither age, sex, tumor size, location, mere presence of lymph node metastases, depth of tumor invasion, nor predisposing disease of the colon was a strong prognostic factor. Metastases to six or more lymph nodes and distant spread of the tumor at the time of initial surgery were ominous findings. Mucinous carcinoma was relatively frequent (28%) and was also an ominous feature (only 5 of 20 patients cured as opposed to 26 of 43 with classical adenocarcinoma).\nHere is the question:\nDIGESTIVE: During a colonoscopy, a 5-cm tumor located in the right colon is detected in a 48-year-old man. No other lesions were found. His maternal grandmother also suffered from colon cancer. The biopsies are superficial and show a poorly differentiated tumor with abundant inflammatory cells in the stroma that is diagnosed as a medullary type carcinoma.\nHere are the potential choices:\n1. Chemotherapy is the treatment of choice.\n2. Since the biopsy is superficial, it should be repeated before proceeding with treatment.\n3. The prognosis of the tumor depends mainly on its high degree of anaplasia.\n4. It is unlikely that this tumor has developed over a previous adenoma.\n5. Microsatellite instability and DNA error repair genes should be studied.\nThe correct answer is: 5. Microsatellite instability and DNA error repair genes should be studied."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Traditionally, allopurinol is not initiated during an acute gout attack to avoid prolonging the painful arthritis. The 2012 American College of Rheumatology Guidelines for the Management of Gout suggest that urate-lowering therapy can be started during an acute attack, based on \"consensus opinion of experts, case studies, or standard of care.\" The aim of this study was to determine whether initiating allopurinol will adversely affect the resolution of acute, treated gout. We conducted a 28-day, placebo-controlled, double-blind study of allopurinol initiation in patients with acute gout. Patients with crystal-proven gout by arthrocentesis were enrolled if they presented to the rheumatology clinic with an acute gout attack within 72 hours from initial therapy. The patients were also required to meet at least 1 additional criterion for urate-lowering therapy including (1) the presence of gouty tophi, (2) more than 1 acute gout attack per year, (3) a history of nephrolithiasis, or (4) urate overproduction (&gt;1000 mg in 24-hour urine collection). Patients were excluded from the study if they had a glomerular filtration rate of less than 50 or liver function test of greater than 1.25 times the upper limit of normal. The treating physician determined therapy for the acute gout attack. Standard prophylaxis, with colchicine or nonsteroidal anti-inflammatory drugs, was prescribed. Allopurinol or placebo was initiated at 100 mg daily for the first 14 days and then increased to 200 mg daily for the next 14 days. The primary end point was protocol defined days to resolution of acute gout, incorporating patient-rated joint pain and physician examination. Secondary measures included Physician Global Assessment, patient-rated pain, adverse effects of therapy, and serum uric acid. Thirty-one patients (17 on placebo, 14 on allopurinol) completed the study. Both intent-to-treat and completer analyses showed only a statistically insignificant difference in days to resolution (15.4 days in the allopurinol group completers vs 13.4 days in the placebo group; P = 0.5). The secondary measures revealed that the acute phase of pain rapidly improved in both groups. We initiated allopurinol at low doses during an acute gout attack in patients who met criteria for starting urate-lowering therapy and did not have abnormal kidney or liver function. In this cohort, allopurinol did not prolong the acute, treated attack. Difficulties and errors in the treatment of patients with the gout arise, mainly, during urate-lowering therapy. The article discusses possible medical errors in acute gouty arthritis and during chronic tophaceous gout in the light of the updated international recommendations of the American College of Rheumatology (ACR) and the European Antirheumatic League (EULAR 2018). As an example of inadequate treatment, the authors describe a case of a patient with chronic tophaceous gout. Errors in the diagnosis and treatment of the patient caused various complications and unjustified surgical intervention - amputation of the right finger and removal of a large tophus in the left forearm. Based on the analysis of mistakes made in the diagnosis and treatment of gout, the authors propose an algorithm for therapeutic tactics in different periods of the disease. So, for the relief of exacerbation in acute gouty arthritis, it is recommended to take the following drugs at starting doses: colchicine at a dose of 1.8 mg/day (1.2 mg immediately followed by 0.6 mg 1 hour later during 7-10 days or until complete relief of the gout attack), non-steroidal anti-inflammatory drugs (nimesulide up to 200 mg/day) or glucocorticosteroids (prednisolone at a dose of 30 mg/day for 3-5 days with subsequent withdrawal). The first-line urate-lowering drugs for chronic tofaceous gout are xanthine oxidase inhibitors - allopurinol and febuxostat. Allopurinol is prescribed no earlier than 2 weeks after the arthritis attack has stopped at a starting dose of no more than 100 mg/day, the dose is gradually increased to the minimum effective. The starting dose of febuxostat is 40 mg/day. Also, together with allopurinol or febuxostat, it is recommended to take uricosuric drugs (probenecid 500 mg/day or benzbromarone 50-200 mg/day). At the same time, the authors draw attention to the inadmissibility of the combination of allopurinol and febuxostat. In case of gout that does not respond to the main methods of therapy, treatment with pegloticase is recommended. When prescribing urate-lowering therapy, dose titration is necessary, to avoid the development of toxic effects. Streamlining the initiation of allopurinol could result in a cost benefit for a common medical problem and obviate the perception that no treatment is required once acute attacks have resolved. Our objective was to test the hypothesis that there is no difference in patient daily pain or subsequent attacks with early versus delayed initiation of allopurinol for an acute gout attack. A total of 57 men with crystal-proven gout were randomized to allopurinol 300 mg daily or matching placebo for 10 days. All subjects received indomethacin 50 mg 3 times per day for 10 days, a prophylactic dose of colchicine 0.6 mg 2 times per day for 90 days, and open-label allopurinol starting at day 11. Primary outcome measures were pain on visual analogue scale (VAS) for the primary joint on days 1 to 10 and self-reported flares in any joint through day 30. On the basis of 51 evaluable subjects (allopurinol in 26, placebo in 25), mean daily VAS pain scores did not differ significantly between study groups at any point between days 1 and 10. Initial VAS pain scores for allopurinol and placebo arms were 6.72 versus 6.28 (P=.37), declining to 0.18 versus 0.27 (P=.54) at day 10, with neither group consistently having more daily pain. Subsequent flares occurred in 2 subjects taking allopurinol and 3 subjects taking placebo (P=.60). Although urate levels decreased rapidly in the allopurinol group (from 7.8 mg/dL at baseline to 5.9 mg/dL at day 3), sedimentation rates and C-reactive protein levels did not differ between groups at any point. Allopurinol initiation during an acute gout attack caused no significant difference in daily pain, recurrent flares, or inflammatory markers. If Dr. Sydenham could have benefited from today's therapy, he likely would not have had to endure thirty years of \"violent ... torture\" that gave birth to his most elegant and classic description of acute gout. The five key points to remember in management of the gouty spectrum are: (1) Establish the diagnosis as clearly as possible or as clearly as seems necessary under the clinical circumstances (i.e. arthrocentesis with crystal analysis to establish diagnosis is not always necessary with reliable patients when septic joint seems highly unlikely). (2) Treat acute attacks with NSAIDs alone or perhaps steroids--or rarely IV colchicine under special circumstances. (3) DO NOT START ALLOPURINOL OR PROBENECID DURING AN ACUTE FLARE OF GOUT--IT MAY MAKE THE EPISODE WORSE. (4) The pattern of disease over time (frequency and severity of attacks) determines whether or not one decides to use an agent such as allopurinol, probenecid, or prophylactic colchicine chronically once a patient is over the acute attack--the mere presence of increased uric acid and a single or rare gouty attack would not usually require any other than the appropriate acute therapy. (5) The presence of visible tophi, uric acid renal calculi and destructive gouty arthritis nearly always warrant uric acid lowering therapy. For the management of acute gouty arthritis, non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs of choice. In recent years, the use of colchicine has declined because of its frequent adverse reactions, and its reduced efficacy when administered more than 24 hours after onset of an acute attack. Intra-articular corticosteroid therapy (e.g. methylprednisolone acetate) is indicated for the treatment of acute mono or oligoarticular gouty arthritis in aged patients, and in those with co-morbid conditions contraindicating therapy with either NSAIDs or colchicine. Oral corticosteroids (e.g. prednisone), and both parenteral corticotrophin (ACTH) and corticosteroids (e.g. intramuscular triamcinolone acetonide) are valuable, relatively safe alternate treatment modalities in those with polyarticular attacks. For the treatment of hyperuricaemia and chronic gouty arthritis, allopurinol is the preferred urate-lowering drug. Its toxicity in elderly individuals, those with renal impairment, and in cyclosporine-treated transplant patients can be minimised by adjusting the initial dose according to the patient's creatinine clearance. In those experiencing cutaneous reactions to allopurinol, cautious desensitisation to the drug can be achieved using a schedule of gradually increasing doses. The therapeutic usefulness of uricosuric drugs is limited by the presence of renal impairment, occurrence of intolerable side-effects, or concomitant intake of salicylates. They are particularly indicated in patients allergic to allopurinol and in those with massive tophi requiring combined therapy with both allopurinol and a uricosuric. The treatment of gout is based on several principles. Symptom control and termination of the inflammatory process are important early goals, whereas the urate level should be lowered in the long term to prevent further gout attacks and complications. The non-pharmacological approach is based on individually informing the patient on dietary measures and changes of life style. Besides physical measures, such as cold applications on the affected joint, various medications are available for treatment of an acute gout attack. The choice of drug depends on the individual risk profile. If non-steroidal anti-inflammatory drugs (NSAID) and coxibs are chosen it should be taken into account that the use is restricted in patients with renal insufficiency. Moreover, these drugs may have gastrointestinal side effects and are associated with increased cardiovascular morbidity and mortality. Colchicine has gastrointestinal side effects at high dosages but can also be used for differential diagnostics if there is a quick response to treatment. Steroids are an effective alternative and can be given orally or parenterally in patients with dysphagia. Moreover, steroids can be used in cases of renal insufficiency. After symptoms of the acute attack have subsided, urate lowering therapy should be initiated to prevent further attacks. Low-dose urate lowering therapy can be started during an acute gout attack when acute therapy is initiated. Allopurinol is still the medication of choice but its use is restricted in patients with renal insufficiency. A rare but serious side effect is allopurinol hypersensitivity syndrome. Febuxostat can be an alternative in patients who do not tolerate allopurinol. In February 2016, lesinurad, an URAT-1 and OAT-4 inhibitor, was approved in combination with allopurinol or febuxostat. Data on the effectiveness and safety of synthetic uricases and biologicals are still sparse for elderly patients. These substances are reserved for severe cases of gout. Allopurinol, a xanthine oxidase inhibitor, is considered one of the most effective urate-lowering drugs and is frequently used in the treatment of chronic gout. To assess the efficacy and safety of allopurinol compared with placebo and other urate-lowering therapies for treating chronic gout. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE on 14 January 2014. We also handsearched the 2011 to 2012 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) abstracts, trial registers and regulatory agency drug safety databases. All randomised controlled trials (RCTs) or quasi-randomised controlled clinical trials (CCTs) that compared allopurinol with a placebo or an active therapy in adults with chronic gout. We extracted and analysed data using standard methods for Cochrane reviews. The major outcomes of interest were frequency of acute gout attacks, serum urate normalisation, pain, function, tophus regression, study participant withdrawal due to adverse events (AE) and serious adverse events (SAE). We assessed the quality of the body of evidence for these outcomes using the GRADE approach. We included 11 trials (4531 participants) that compared allopurinol (various doses) with placebo (two trials); febuxostat (four trials); benzbromarone (two trials); colchicine (one trial); probenecid (one trial); continuous versus intermittent allopurinol (one trial) and different doses of allopurinol (one trial). Only one trial was at low risk of bias in all domains. We deemed allopurinol versus placebo the main comparison, and allopurinol versus febuxostat and versus benzbromarone as the most clinically relevant active comparisons and restricted reporting to these comparisons here.Moderate-quality evidence from one trial (57 participants) indicated allopurinol 300 mg daily probably does not reduce the rate of gout attacks (2/26 with allopurinol versus 3/25 with placebo; risk ratio (RR) 0.64, 95% confidence interval (CI) 0.12 to 3.52) but increases the proportion of participants achieving a target serum urate over 30 days (25/26 with allopurinol versus 0/25 with placebo, RR 49.11, 95% CI 3.15 to 765.58; number needed to treat for an additional beneficial outcome (NNTB) 1). In two studies (453 participants), there was no significant increase in withdrawals due to AE (6% with allopurinol versus 4% with placebo, RR 1.36, 95% CI 0.61 to 3.08) or SAE (2% with allopurinol versus 1% with placebo, RR 1.93, 95% CI 0.48 to 7.80). One trial reported no difference in pain reduction or tophus regression, but did not report outcome data or measures of variance sufficiently and we could not calculate the differences between groups. Neither trial reported function.Low-quality evidence from three trials (1136 participants) indicated there may be no difference in the incidence of acute gout attacks with allopurinol up to 300 mg daily versus febuxostat 80 mg daily over eight to 24 weeks (21% with allopurinol versus 23% with febuxostat, RR 0.89, 95% CI 0.71 to 1.1); however more participants may achieve target serum urate level (four trials; 2618 participants) with febuxostat 80 mg daily versus allopurinol 300 mg daily (38% with allopurinol versus 70% with febuxostat, RR 0.56, 95% CI 0.48 to 0.65, NNTB with febuxostat 4). Two trials reported no difference in tophus regression between allopurinol and febuxostat over a 28- to 52-week period; but as the trialists did not provide variance, we could not calculate the mean difference between groups. The trials did not report pain reduction or function. Moderate-quality evidence from pooled data from three trials (2555 participants) comparing allopurinol up to 300 mg daily versus febuxostat 80 mg daily indicated no difference in the number of withdrawals due to AE (7% with allopurinol versus 8% with febuxostat, RR 0.89, 95% CI 0.62 to 1.26) or SAE (4% with allopurinol versus 4% with febuxostat, RR 1.13, 95% CI 0.71 to 1.82) over a 24- to 52-week period.Low-quality evidence from one trial (65 participants) indicated there may be no difference in the incidence of acute gout attacks with allopurinol up to 600 mg daily compared with benzbromarone up to 200 mg daily over a four-month period (0/30 with allopurinol versus 1/25 with benzbromarone, RR 0.28, 95% CI 0.01 to 6.58). Based on the pooled results of two trials (102 participants), there was moderate-quality evidence of no probable difference in the proportion of participants achieving a target serum urate level with allopurinol versus benzbromarone (58% with allopurinol versus 74% with benzbromarone, RR 0.79, 95% CI 0.56 to 1.11). Low-quality evidence from two studies indicated there may be no difference in the number of participants who withdrew due to AE with allopurinol versus benzbromarone over a four- to nine-month period (6% with allopurinol versus 7% with benzbromarone, pooled RR 0.80, 95% CI 0.18 to 3.58). There were no SAEs. They did not report tophi regression, pain and function.All other comparisons were supported by small, single studies only, limiting conclusions. Our review found low- to moderate-quality evidence indicating similar effects on withdrawals due to AEs and SAEs and incidence of acute gout attacks when allopurinol (100 to 600 mg daily) was compared with placebo, benzbromarone (100 to 200 mg daily) or febuxostat (80 mg daily). There was moderate-quality evidence of little or no difference in the proportion of participants achieving target serum urate when allopurinol was compared with benzbromarone. However, allopurinol seemed more successful than placebo and may be less successful than febuxostat (80 mg daily) in achieving a target serum urate level (6 mg/dL or less; 0.36 mmol/L or less) based on moderate- to low-quality evidence. Single studies reported no difference in pain reduction when allopurinol (300 mg daily) was compared with placebo over 10 days, and no difference in tophus regression when allopurinol (200 to 300 mg daily) was compared with febuxostat (80 mg daily). None of the trials reported on function, health-related quality of life or participant global assessment of treatment success, where further research would be useful.  This is a case report of a 36-year-old male with tophaceous gout for 16 years. He started therapy with 300 mg/day of allopurinol. He had received variable dexamethasone doses by self-prescription for 16 years. When allopurinol was initiated, he had hyperuricemia and normal renal function. Twenty days after starting allopurinol, he presented diffuse maculopapular rash, conjunctivitis, increase in serum creatinine values, leukocytosis and eosinophilia and the diagnosis of allopurinol hypersensitivity (AH) syndrome was made. He completely recovered from the AH and renal function normalized. However, the gout worsened over the following years in spite of treatment with benzobromarone, low doses of prednisone, and colchicine. Allopurinol desensitization was successful beginning with an oral low dose scheme (6.5 mug/day) until we reached 300mg/day. Today the patient receives allopurinol with no side effects. We believe that this is the first reported example of successful desensitization in full-blown AH with renal involvement. Our cautious regimen might be tried in other such patients. Medical uses Gout Colchicine is an alternative for those unable to tolerate NSAIDs when treating gout. Low doses appear to be well tolerated and may reduce gout symptoms and pain (1.2 mg in one hour, followed by 0.6 mg an hour later). This low dose may have a similar effectiveness to NSAIDS (low quality evidence). At high doses, side effects (primarily diarrhea, nausea, or vomiting) limit its use, however may be effective against pain. In addition, there is preliminary evidence that daily colchicine (0.6 mg twice daily) may be effective as a long-term prophylaxis when used with allopurinol to reduce the risk of increased uric acid levels and acute gout flares, although adverse gastrointestinal effects may occur. For treating gout symptoms, colchicine is used orally with or without food, as symptoms first appear. Subsequent doses may be needed if symptoms worsen. Treatment The initial aim of treatment is to settle the symptoms of an acute attack. Repeated attacks can be prevented by medications that reduce serum uric acid levels. Tentative evidence supports the application of ice for 20 to 30 minutes several times a day to decrease pain. Options for acute treatment include nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and Glucocorticoids. While glucocorticoids and NSAIDs work equally well, glucocorticoids may be safer. Options for prevention include allopurinol, febuxostat, and probenecid. Lowering uric acid levels can cure the disease. Treatment of associated health problems is also important. Lifestyle interventions have been poorly studied. It is unclear whether dietary supplements have an effect in people with gout. While it has been recommended that urate-lowering measures should be increased until serum uric acid levels are below 300–360 µmol/l (5.0–6.0 mg/dl), there is little evidence to support this practice over simple putting people on a standard dose of allopurinol. If these medications are in chronic use at the time of an attack, it is recommended that they be continued. Levels that cannot be brought below 6.0 mg/dl while attacks continue indicates refractory gout. While historically it is not recommended to start allopurinol during an acute attack of gout, this practice appears acceptable. Allopurinol blocks uric acid production, and is the most commonly used agent. Long term therapy is safe and well-tolerated and can be used in people with renal impairment or urate stones, although hypersensitivity occurs in a small number of individuals. This study aimed at determining whether lowering serum urate (SU) to less than 6 mg/dl in patients with gout affects ultrasonographic findings. Seven joints in five patients with monosodium urate (MSU) crystal proven gout and hyperuricemia were examined over time with serial ultrasonography. Four of the five patients were treated with urate lowering drugs (ULDs) (allopurinol, n = 3; probenecid, n = 1). One patient was treated with colchicine alone. Attention was given to changes in a hyperechoic, irregular coating of the hyaline cartilage in the examined joints (double contour sign or \"urate icing\"). This coating was considered to represent precipitate of MSU crystals. Index joints included metacarpophalangeal (MCP) joints (n = 2), knee joints (n = 3), and first metatarsophalangeal (MTP) joints (n = 2). The interval between baseline and follow-up images ranged from 7 to 18 months. Serial SU levels were obtained during the follow-up period. During the follow-up period, three patients treated with ULD (allopurinol, n = 2; probenecid, n = 1) achieved a SU level of &lt;6 mg/dl. In two patients, SU levels remained above 6 mg/dl (treated with allopurinol, n = 1; treated with colchicine, n = 1). At baseline, the double contour sign was seen in all patients. In those patients who achieved SU levels of &lt;6 ml/dl, this sign had disappeared at follow-up. Disappearance of the double contour sign was seen in two knee joints, two first MTP joints, and one MCP joint. In contrast, disappearance of the double contour sign was not seen in patients who maintained a SU level &gt; or =7 mg/dl. In one patient treated with allopurinol, SU levels improved from 13 to 7 mg/dl during the follow-up period. Decrease, but not resolution of the hyperechoic coating was seen in this patient. In the patient treated with colchicine alone, SU levels remained &gt;8 mg/dl, and no sonographic change was observed. In our patients, sonographic signs of deposition of MSU crystals on the surface of hyaline cartilage disappeared completely if sustained normouricemia was achieved. This is the first report showing that characteristic sonographic changes are influenced by ULDs once SU levels remain &lt; or =6 mg/dl for 7 months or more. Sonographic changes of gout correlate with SU levels and may be a non-invasive means to track changes in the uric acid pool. Larger prospective studies are needed to further assess these potentially important findings. Lesinurad/allopurinol (trade name Duzallo) is a fixed-dose combination drug for the treatment of gout. It contains 200 mg of lesinurad and 300 mg of allopurinol. In August 2017, the US Food and Drug Administration approved it for the treatment of hyperuricemia associated with gout in patients for whom target serum uric acid levels have not been achieved with allopurinol alone. It was approved for medical use in the European Union in August 2018. In February 2019, it was discontinued by its manufacturer for business reasons and is no longer available. References Antigout agents Combination drugs AstraZeneca brands Withdrawn drugs There are three stages in the management of gout: (i) treating the acute attack; (ii) lowering excess stores of uric acid to prevent flares of gouty arthritis and to prevent tissue deposition of urate; and (iii) providing prophylaxis to prevent acute flares. It is important to distinguish between therapy to reduce acute inflammation in acute gout and therapy to manage hyperuricaemia in patients with chronic gouty arthritis. During the acute gouty attack nonpharmacological treatments such as topical ice and rest of the inflamed joint are useful. NSAIDs are the preferred treatment in acute gout. The most important determinant of therapeutic success is not which NSAID is chosen, but rather how soon NSAID therapy is initiated. Other treatments include oral and intravenous colchicine, intra-articular and systemic corticosteroids, and intramuscular corticotropin. Optimal treatment of chronic gout requires long-standing reduction in serum uric acid. The urate-lowering drugs used to treat chronic gout are the uricosuric drugs, the uricostatic drugs, which are xanthine oxidase inhibitors, and the uricolytic drugs. Xanthine oxidase inhibitors such as allopurinol, oxipurinol and febuxastat should be used as first-line treatment in patients with renal calculi, renal insufficiency, concomitant diuretic therapy and ciclosporin (cyclosporine) therapy, and urate overproduction. Uricosuric drugs include probenecid, benzbromarone, micronised fenofibrate and losartan. They are the urate-lowering drugs of choice in allopurinol-allergic patients and underexcretors with normal renal function and no history of urolithiasis. The use of recombinant urate oxidase in patients with chronic gout is limited by the need for parenteral administration, the potential antigenicity and production of anti-urate oxidase antibodies, and declining efficacy. The effectiveness of colchicine prophylaxis as an isolated therapy is still to be confirmed by placebo-controlled trials. Another issue is prophylaxis with NSAIDs. There are no comparative studies with colchicine. To describe the current pharmacological approach to gout treatment reported by rheumatologists in Brazil. We performed a cross-sectional survey study using an online questionnaire e-mailed to 395 rheumatologists, randomly selected, from among the members of the Brazilian Society of Rheumatology. Three hundred and nine rheumatologists (78.2%) responded to the survey. For acute gout attacks, combination therapy (NSAIDs or steroid + colchicine) was often used, even in monoarticular involvement, and colchicine was commonly started as monotherapy after 36 hours or more from onset of attack. During an acute attack, urate-lowering therapy (ULT) was withdrawn by approximately a third of rheumatologists. Anti-inflammatory prophylaxis (98% colchicine) was initiated when ULT was started in most cases (92.4%), but its duration was varied. Most (70%) respondents considered the target serum uric acid level to be less than 6 mg/dl. Approximately 50% of rheumatologists reported starting allopurinol at doses of 100 mg daily or less and 42% reported the initial dose to be 300 mg daily in patients with normal renal function. ULT was maintained indefinitely in 76% of gout patients with tophi whereas in gout patients without tophi its use was kept indefinitely in 39.6%. This is the first study evaluating gout treatment in a representative, random sample of Brazilian rheumatologists describing common treatment practices among these specialists. We identified several gaps in reported gout management, mainly concerning the use of colchicine and ULT and the duration of anti-inflammatory prophylaxis and ULT. Since rheumatologists are considered as opinion leaders in this disease, a program for improving quality of care for gout patients should focus on increasing their knowledge in this common disease.\nHere is the question:\nRHEUMATOLOGY: A hyperuricemic patient who usually takes 100 mg of allopurinol daily comes to the ED with acute pain and inflammatory signs in the right knee. Arthrocentesis is performed and polarized light microscopy shows intracellular crystals with negative birefringence. Which of the following therapeutic approaches is the most appropriate in this case?\nHere are the potential choices:\n1. Discontinue allopurinol and start colchicine treatment.\n2. Discontinue allopurinol and start NSAIDs.\n3. Add an NSAID until the crisis remits.\n4. Increase the dose of allopurinol to 300 mg/day.\n5. Substitute allopurinol for uricosuric acid.\nThe correct answer is: ",
        "gold_answer": "3 Add an NSAID until the crisis remits.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Traditionally, allopurinol is not initiated during an acute gout attack to avoid prolonging the painful arthritis. The 2012 American College of Rheumatology Guidelines for the Management of Gout suggest that urate-lowering therapy can be started during an acute attack, based on \"consensus opinion of experts, case studies, or standard of care.\" The aim of this study was to determine whether initiating allopurinol will adversely affect the resolution of acute, treated gout. We conducted a 28-day, placebo-controlled, double-blind study of allopurinol initiation in patients with acute gout. Patients with crystal-proven gout by arthrocentesis were enrolled if they presented to the rheumatology clinic with an acute gout attack within 72 hours from initial therapy. The patients were also required to meet at least 1 additional criterion for urate-lowering therapy including (1) the presence of gouty tophi, (2) more than 1 acute gout attack per year, (3) a history of nephrolithiasis, or (4) urate overproduction (&gt;1000 mg in 24-hour urine collection). Patients were excluded from the study if they had a glomerular filtration rate of less than 50 or liver function test of greater than 1.25 times the upper limit of normal. The treating physician determined therapy for the acute gout attack. Standard prophylaxis, with colchicine or nonsteroidal anti-inflammatory drugs, was prescribed. Allopurinol or placebo was initiated at 100 mg daily for the first 14 days and then increased to 200 mg daily for the next 14 days. The primary end point was protocol defined days to resolution of acute gout, incorporating patient-rated joint pain and physician examination. Secondary measures included Physician Global Assessment, patient-rated pain, adverse effects of therapy, and serum uric acid. Thirty-one patients (17 on placebo, 14 on allopurinol) completed the study. Both intent-to-treat and completer analyses showed only a statistically insignificant difference in days to resolution (15.4 days in the allopurinol group completers vs 13.4 days in the placebo group; P = 0.5). The secondary measures revealed that the acute phase of pain rapidly improved in both groups. We initiated allopurinol at low doses during an acute gout attack in patients who met criteria for starting urate-lowering therapy and did not have abnormal kidney or liver function. In this cohort, allopurinol did not prolong the acute, treated attack. Difficulties and errors in the treatment of patients with the gout arise, mainly, during urate-lowering therapy. The article discusses possible medical errors in acute gouty arthritis and during chronic tophaceous gout in the light of the updated international recommendations of the American College of Rheumatology (ACR) and the European Antirheumatic League (EULAR 2018). As an example of inadequate treatment, the authors describe a case of a patient with chronic tophaceous gout. Errors in the diagnosis and treatment of the patient caused various complications and unjustified surgical intervention - amputation of the right finger and removal of a large tophus in the left forearm. Based on the analysis of mistakes made in the diagnosis and treatment of gout, the authors propose an algorithm for therapeutic tactics in different periods of the disease. So, for the relief of exacerbation in acute gouty arthritis, it is recommended to take the following drugs at starting doses: colchicine at a dose of 1.8 mg/day (1.2 mg immediately followed by 0.6 mg 1 hour later during 7-10 days or until complete relief of the gout attack), non-steroidal anti-inflammatory drugs (nimesulide up to 200 mg/day) or glucocorticosteroids (prednisolone at a dose of 30 mg/day for 3-5 days with subsequent withdrawal). The first-line urate-lowering drugs for chronic tofaceous gout are xanthine oxidase inhibitors - allopurinol and febuxostat. Allopurinol is prescribed no earlier than 2 weeks after the arthritis attack has stopped at a starting dose of no more than 100 mg/day, the dose is gradually increased to the minimum effective. The starting dose of febuxostat is 40 mg/day. Also, together with allopurinol or febuxostat, it is recommended to take uricosuric drugs (probenecid 500 mg/day or benzbromarone 50-200 mg/day). At the same time, the authors draw attention to the inadmissibility of the combination of allopurinol and febuxostat. In case of gout that does not respond to the main methods of therapy, treatment with pegloticase is recommended. When prescribing urate-lowering therapy, dose titration is necessary, to avoid the development of toxic effects. Streamlining the initiation of allopurinol could result in a cost benefit for a common medical problem and obviate the perception that no treatment is required once acute attacks have resolved. Our objective was to test the hypothesis that there is no difference in patient daily pain or subsequent attacks with early versus delayed initiation of allopurinol for an acute gout attack. A total of 57 men with crystal-proven gout were randomized to allopurinol 300 mg daily or matching placebo for 10 days. All subjects received indomethacin 50 mg 3 times per day for 10 days, a prophylactic dose of colchicine 0.6 mg 2 times per day for 90 days, and open-label allopurinol starting at day 11. Primary outcome measures were pain on visual analogue scale (VAS) for the primary joint on days 1 to 10 and self-reported flares in any joint through day 30. On the basis of 51 evaluable subjects (allopurinol in 26, placebo in 25), mean daily VAS pain scores did not differ significantly between study groups at any point between days 1 and 10. Initial VAS pain scores for allopurinol and placebo arms were 6.72 versus 6.28 (P=.37), declining to 0.18 versus 0.27 (P=.54) at day 10, with neither group consistently having more daily pain. Subsequent flares occurred in 2 subjects taking allopurinol and 3 subjects taking placebo (P=.60). Although urate levels decreased rapidly in the allopurinol group (from 7.8 mg/dL at baseline to 5.9 mg/dL at day 3), sedimentation rates and C-reactive protein levels did not differ between groups at any point. Allopurinol initiation during an acute gout attack caused no significant difference in daily pain, recurrent flares, or inflammatory markers. If Dr. Sydenham could have benefited from today's therapy, he likely would not have had to endure thirty years of \"violent ... torture\" that gave birth to his most elegant and classic description of acute gout. The five key points to remember in management of the gouty spectrum are: (1) Establish the diagnosis as clearly as possible or as clearly as seems necessary under the clinical circumstances (i.e. arthrocentesis with crystal analysis to establish diagnosis is not always necessary with reliable patients when septic joint seems highly unlikely). (2) Treat acute attacks with NSAIDs alone or perhaps steroids--or rarely IV colchicine under special circumstances. (3) DO NOT START ALLOPURINOL OR PROBENECID DURING AN ACUTE FLARE OF GOUT--IT MAY MAKE THE EPISODE WORSE. (4) The pattern of disease over time (frequency and severity of attacks) determines whether or not one decides to use an agent such as allopurinol, probenecid, or prophylactic colchicine chronically once a patient is over the acute attack--the mere presence of increased uric acid and a single or rare gouty attack would not usually require any other than the appropriate acute therapy. (5) The presence of visible tophi, uric acid renal calculi and destructive gouty arthritis nearly always warrant uric acid lowering therapy. For the management of acute gouty arthritis, non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs of choice. In recent years, the use of colchicine has declined because of its frequent adverse reactions, and its reduced efficacy when administered more than 24 hours after onset of an acute attack. Intra-articular corticosteroid therapy (e.g. methylprednisolone acetate) is indicated for the treatment of acute mono or oligoarticular gouty arthritis in aged patients, and in those with co-morbid conditions contraindicating therapy with either NSAIDs or colchicine. Oral corticosteroids (e.g. prednisone), and both parenteral corticotrophin (ACTH) and corticosteroids (e.g. intramuscular triamcinolone acetonide) are valuable, relatively safe alternate treatment modalities in those with polyarticular attacks. For the treatment of hyperuricaemia and chronic gouty arthritis, allopurinol is the preferred urate-lowering drug. Its toxicity in elderly individuals, those with renal impairment, and in cyclosporine-treated transplant patients can be minimised by adjusting the initial dose according to the patient's creatinine clearance. In those experiencing cutaneous reactions to allopurinol, cautious desensitisation to the drug can be achieved using a schedule of gradually increasing doses. The therapeutic usefulness of uricosuric drugs is limited by the presence of renal impairment, occurrence of intolerable side-effects, or concomitant intake of salicylates. They are particularly indicated in patients allergic to allopurinol and in those with massive tophi requiring combined therapy with both allopurinol and a uricosuric. The treatment of gout is based on several principles. Symptom control and termination of the inflammatory process are important early goals, whereas the urate level should be lowered in the long term to prevent further gout attacks and complications. The non-pharmacological approach is based on individually informing the patient on dietary measures and changes of life style. Besides physical measures, such as cold applications on the affected joint, various medications are available for treatment of an acute gout attack. The choice of drug depends on the individual risk profile. If non-steroidal anti-inflammatory drugs (NSAID) and coxibs are chosen it should be taken into account that the use is restricted in patients with renal insufficiency. Moreover, these drugs may have gastrointestinal side effects and are associated with increased cardiovascular morbidity and mortality. Colchicine has gastrointestinal side effects at high dosages but can also be used for differential diagnostics if there is a quick response to treatment. Steroids are an effective alternative and can be given orally or parenterally in patients with dysphagia. Moreover, steroids can be used in cases of renal insufficiency. After symptoms of the acute attack have subsided, urate lowering therapy should be initiated to prevent further attacks. Low-dose urate lowering therapy can be started during an acute gout attack when acute therapy is initiated. Allopurinol is still the medication of choice but its use is restricted in patients with renal insufficiency. A rare but serious side effect is allopurinol hypersensitivity syndrome. Febuxostat can be an alternative in patients who do not tolerate allopurinol. In February 2016, lesinurad, an URAT-1 and OAT-4 inhibitor, was approved in combination with allopurinol or febuxostat. Data on the effectiveness and safety of synthetic uricases and biologicals are still sparse for elderly patients. These substances are reserved for severe cases of gout. Allopurinol, a xanthine oxidase inhibitor, is considered one of the most effective urate-lowering drugs and is frequently used in the treatment of chronic gout. To assess the efficacy and safety of allopurinol compared with placebo and other urate-lowering therapies for treating chronic gout. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE on 14 January 2014. We also handsearched the 2011 to 2012 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) abstracts, trial registers and regulatory agency drug safety databases. All randomised controlled trials (RCTs) or quasi-randomised controlled clinical trials (CCTs) that compared allopurinol with a placebo or an active therapy in adults with chronic gout. We extracted and analysed data using standard methods for Cochrane reviews. The major outcomes of interest were frequency of acute gout attacks, serum urate normalisation, pain, function, tophus regression, study participant withdrawal due to adverse events (AE) and serious adverse events (SAE). We assessed the quality of the body of evidence for these outcomes using the GRADE approach. We included 11 trials (4531 participants) that compared allopurinol (various doses) with placebo (two trials); febuxostat (four trials); benzbromarone (two trials); colchicine (one trial); probenecid (one trial); continuous versus intermittent allopurinol (one trial) and different doses of allopurinol (one trial). Only one trial was at low risk of bias in all domains. We deemed allopurinol versus placebo the main comparison, and allopurinol versus febuxostat and versus benzbromarone as the most clinically relevant active comparisons and restricted reporting to these comparisons here.Moderate-quality evidence from one trial (57 participants) indicated allopurinol 300 mg daily probably does not reduce the rate of gout attacks (2/26 with allopurinol versus 3/25 with placebo; risk ratio (RR) 0.64, 95% confidence interval (CI) 0.12 to 3.52) but increases the proportion of participants achieving a target serum urate over 30 days (25/26 with allopurinol versus 0/25 with placebo, RR 49.11, 95% CI 3.15 to 765.58; number needed to treat for an additional beneficial outcome (NNTB) 1). In two studies (453 participants), there was no significant increase in withdrawals due to AE (6% with allopurinol versus 4% with placebo, RR 1.36, 95% CI 0.61 to 3.08) or SAE (2% with allopurinol versus 1% with placebo, RR 1.93, 95% CI 0.48 to 7.80). One trial reported no difference in pain reduction or tophus regression, but did not report outcome data or measures of variance sufficiently and we could not calculate the differences between groups. Neither trial reported function.Low-quality evidence from three trials (1136 participants) indicated there may be no difference in the incidence of acute gout attacks with allopurinol up to 300 mg daily versus febuxostat 80 mg daily over eight to 24 weeks (21% with allopurinol versus 23% with febuxostat, RR 0.89, 95% CI 0.71 to 1.1); however more participants may achieve target serum urate level (four trials; 2618 participants) with febuxostat 80 mg daily versus allopurinol 300 mg daily (38% with allopurinol versus 70% with febuxostat, RR 0.56, 95% CI 0.48 to 0.65, NNTB with febuxostat 4). Two trials reported no difference in tophus regression between allopurinol and febuxostat over a 28- to 52-week period; but as the trialists did not provide variance, we could not calculate the mean difference between groups. The trials did not report pain reduction or function. Moderate-quality evidence from pooled data from three trials (2555 participants) comparing allopurinol up to 300 mg daily versus febuxostat 80 mg daily indicated no difference in the number of withdrawals due to AE (7% with allopurinol versus 8% with febuxostat, RR 0.89, 95% CI 0.62 to 1.26) or SAE (4% with allopurinol versus 4% with febuxostat, RR 1.13, 95% CI 0.71 to 1.82) over a 24- to 52-week period.Low-quality evidence from one trial (65 participants) indicated there may be no difference in the incidence of acute gout attacks with allopurinol up to 600 mg daily compared with benzbromarone up to 200 mg daily over a four-month period (0/30 with allopurinol versus 1/25 with benzbromarone, RR 0.28, 95% CI 0.01 to 6.58). Based on the pooled results of two trials (102 participants), there was moderate-quality evidence of no probable difference in the proportion of participants achieving a target serum urate level with allopurinol versus benzbromarone (58% with allopurinol versus 74% with benzbromarone, RR 0.79, 95% CI 0.56 to 1.11). Low-quality evidence from two studies indicated there may be no difference in the number of participants who withdrew due to AE with allopurinol versus benzbromarone over a four- to nine-month period (6% with allopurinol versus 7% with benzbromarone, pooled RR 0.80, 95% CI 0.18 to 3.58). There were no SAEs. They did not report tophi regression, pain and function.All other comparisons were supported by small, single studies only, limiting conclusions. Our review found low- to moderate-quality evidence indicating similar effects on withdrawals due to AEs and SAEs and incidence of acute gout attacks when allopurinol (100 to 600 mg daily) was compared with placebo, benzbromarone (100 to 200 mg daily) or febuxostat (80 mg daily). There was moderate-quality evidence of little or no difference in the proportion of participants achieving target serum urate when allopurinol was compared with benzbromarone. However, allopurinol seemed more successful than placebo and may be less successful than febuxostat (80 mg daily) in achieving a target serum urate level (6 mg/dL or less; 0.36 mmol/L or less) based on moderate- to low-quality evidence. Single studies reported no difference in pain reduction when allopurinol (300 mg daily) was compared with placebo over 10 days, and no difference in tophus regression when allopurinol (200 to 300 mg daily) was compared with febuxostat (80 mg daily). None of the trials reported on function, health-related quality of life or participant global assessment of treatment success, where further research would be useful.  This is a case report of a 36-year-old male with tophaceous gout for 16 years. He started therapy with 300 mg/day of allopurinol. He had received variable dexamethasone doses by self-prescription for 16 years. When allopurinol was initiated, he had hyperuricemia and normal renal function. Twenty days after starting allopurinol, he presented diffuse maculopapular rash, conjunctivitis, increase in serum creatinine values, leukocytosis and eosinophilia and the diagnosis of allopurinol hypersensitivity (AH) syndrome was made. He completely recovered from the AH and renal function normalized. However, the gout worsened over the following years in spite of treatment with benzobromarone, low doses of prednisone, and colchicine. Allopurinol desensitization was successful beginning with an oral low dose scheme (6.5 mug/day) until we reached 300mg/day. Today the patient receives allopurinol with no side effects. We believe that this is the first reported example of successful desensitization in full-blown AH with renal involvement. Our cautious regimen might be tried in other such patients. Medical uses Gout Colchicine is an alternative for those unable to tolerate NSAIDs when treating gout. Low doses appear to be well tolerated and may reduce gout symptoms and pain (1.2 mg in one hour, followed by 0.6 mg an hour later). This low dose may have a similar effectiveness to NSAIDS (low quality evidence). At high doses, side effects (primarily diarrhea, nausea, or vomiting) limit its use, however may be effective against pain. In addition, there is preliminary evidence that daily colchicine (0.6 mg twice daily) may be effective as a long-term prophylaxis when used with allopurinol to reduce the risk of increased uric acid levels and acute gout flares, although adverse gastrointestinal effects may occur. For treating gout symptoms, colchicine is used orally with or without food, as symptoms first appear. Subsequent doses may be needed if symptoms worsen. Treatment The initial aim of treatment is to settle the symptoms of an acute attack. Repeated attacks can be prevented by medications that reduce serum uric acid levels. Tentative evidence supports the application of ice for 20 to 30 minutes several times a day to decrease pain. Options for acute treatment include nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and Glucocorticoids. While glucocorticoids and NSAIDs work equally well, glucocorticoids may be safer. Options for prevention include allopurinol, febuxostat, and probenecid. Lowering uric acid levels can cure the disease. Treatment of associated health problems is also important. Lifestyle interventions have been poorly studied. It is unclear whether dietary supplements have an effect in people with gout. While it has been recommended that urate-lowering measures should be increased until serum uric acid levels are below 300–360 µmol/l (5.0–6.0 mg/dl), there is little evidence to support this practice over simple putting people on a standard dose of allopurinol. If these medications are in chronic use at the time of an attack, it is recommended that they be continued. Levels that cannot be brought below 6.0 mg/dl while attacks continue indicates refractory gout. While historically it is not recommended to start allopurinol during an acute attack of gout, this practice appears acceptable. Allopurinol blocks uric acid production, and is the most commonly used agent. Long term therapy is safe and well-tolerated and can be used in people with renal impairment or urate stones, although hypersensitivity occurs in a small number of individuals. This study aimed at determining whether lowering serum urate (SU) to less than 6 mg/dl in patients with gout affects ultrasonographic findings. Seven joints in five patients with monosodium urate (MSU) crystal proven gout and hyperuricemia were examined over time with serial ultrasonography. Four of the five patients were treated with urate lowering drugs (ULDs) (allopurinol, n = 3; probenecid, n = 1). One patient was treated with colchicine alone. Attention was given to changes in a hyperechoic, irregular coating of the hyaline cartilage in the examined joints (double contour sign or \"urate icing\"). This coating was considered to represent precipitate of MSU crystals. Index joints included metacarpophalangeal (MCP) joints (n = 2), knee joints (n = 3), and first metatarsophalangeal (MTP) joints (n = 2). The interval between baseline and follow-up images ranged from 7 to 18 months. Serial SU levels were obtained during the follow-up period. During the follow-up period, three patients treated with ULD (allopurinol, n = 2; probenecid, n = 1) achieved a SU level of &lt;6 mg/dl. In two patients, SU levels remained above 6 mg/dl (treated with allopurinol, n = 1; treated with colchicine, n = 1). At baseline, the double contour sign was seen in all patients. In those patients who achieved SU levels of &lt;6 ml/dl, this sign had disappeared at follow-up. Disappearance of the double contour sign was seen in two knee joints, two first MTP joints, and one MCP joint. In contrast, disappearance of the double contour sign was not seen in patients who maintained a SU level &gt; or =7 mg/dl. In one patient treated with allopurinol, SU levels improved from 13 to 7 mg/dl during the follow-up period. Decrease, but not resolution of the hyperechoic coating was seen in this patient. In the patient treated with colchicine alone, SU levels remained &gt;8 mg/dl, and no sonographic change was observed. In our patients, sonographic signs of deposition of MSU crystals on the surface of hyaline cartilage disappeared completely if sustained normouricemia was achieved. This is the first report showing that characteristic sonographic changes are influenced by ULDs once SU levels remain &lt; or =6 mg/dl for 7 months or more. Sonographic changes of gout correlate with SU levels and may be a non-invasive means to track changes in the uric acid pool. Larger prospective studies are needed to further assess these potentially important findings. Lesinurad/allopurinol (trade name Duzallo) is a fixed-dose combination drug for the treatment of gout. It contains 200 mg of lesinurad and 300 mg of allopurinol. In August 2017, the US Food and Drug Administration approved it for the treatment of hyperuricemia associated with gout in patients for whom target serum uric acid levels have not been achieved with allopurinol alone. It was approved for medical use in the European Union in August 2018. In February 2019, it was discontinued by its manufacturer for business reasons and is no longer available. References Antigout agents Combination drugs AstraZeneca brands Withdrawn drugs There are three stages in the management of gout: (i) treating the acute attack; (ii) lowering excess stores of uric acid to prevent flares of gouty arthritis and to prevent tissue deposition of urate; and (iii) providing prophylaxis to prevent acute flares. It is important to distinguish between therapy to reduce acute inflammation in acute gout and therapy to manage hyperuricaemia in patients with chronic gouty arthritis. During the acute gouty attack nonpharmacological treatments such as topical ice and rest of the inflamed joint are useful. NSAIDs are the preferred treatment in acute gout. The most important determinant of therapeutic success is not which NSAID is chosen, but rather how soon NSAID therapy is initiated. Other treatments include oral and intravenous colchicine, intra-articular and systemic corticosteroids, and intramuscular corticotropin. Optimal treatment of chronic gout requires long-standing reduction in serum uric acid. The urate-lowering drugs used to treat chronic gout are the uricosuric drugs, the uricostatic drugs, which are xanthine oxidase inhibitors, and the uricolytic drugs. Xanthine oxidase inhibitors such as allopurinol, oxipurinol and febuxastat should be used as first-line treatment in patients with renal calculi, renal insufficiency, concomitant diuretic therapy and ciclosporin (cyclosporine) therapy, and urate overproduction. Uricosuric drugs include probenecid, benzbromarone, micronised fenofibrate and losartan. They are the urate-lowering drugs of choice in allopurinol-allergic patients and underexcretors with normal renal function and no history of urolithiasis. The use of recombinant urate oxidase in patients with chronic gout is limited by the need for parenteral administration, the potential antigenicity and production of anti-urate oxidase antibodies, and declining efficacy. The effectiveness of colchicine prophylaxis as an isolated therapy is still to be confirmed by placebo-controlled trials. Another issue is prophylaxis with NSAIDs. There are no comparative studies with colchicine. To describe the current pharmacological approach to gout treatment reported by rheumatologists in Brazil. We performed a cross-sectional survey study using an online questionnaire e-mailed to 395 rheumatologists, randomly selected, from among the members of the Brazilian Society of Rheumatology. Three hundred and nine rheumatologists (78.2%) responded to the survey. For acute gout attacks, combination therapy (NSAIDs or steroid + colchicine) was often used, even in monoarticular involvement, and colchicine was commonly started as monotherapy after 36 hours or more from onset of attack. During an acute attack, urate-lowering therapy (ULT) was withdrawn by approximately a third of rheumatologists. Anti-inflammatory prophylaxis (98% colchicine) was initiated when ULT was started in most cases (92.4%), but its duration was varied. Most (70%) respondents considered the target serum uric acid level to be less than 6 mg/dl. Approximately 50% of rheumatologists reported starting allopurinol at doses of 100 mg daily or less and 42% reported the initial dose to be 300 mg daily in patients with normal renal function. ULT was maintained indefinitely in 76% of gout patients with tophi whereas in gout patients without tophi its use was kept indefinitely in 39.6%. This is the first study evaluating gout treatment in a representative, random sample of Brazilian rheumatologists describing common treatment practices among these specialists. We identified several gaps in reported gout management, mainly concerning the use of colchicine and ULT and the duration of anti-inflammatory prophylaxis and ULT. Since rheumatologists are considered as opinion leaders in this disease, a program for improving quality of care for gout patients should focus on increasing their knowledge in this common disease.\nHere is the question:\nRHEUMATOLOGY: A hyperuricemic patient who usually takes 100 mg of allopurinol daily comes to the ED with acute pain and inflammatory signs in the right knee. Arthrocentesis is performed and polarized light microscopy shows intracellular crystals with negative birefringence. Which of the following therapeutic approaches is the most appropriate in this case?\nHere are the potential choices:\n1. Discontinue allopurinol and start colchicine treatment.\n2. Discontinue allopurinol and start NSAIDs.\n3. Add an NSAID until the crisis remits.\n4. Increase the dose of allopurinol to 300 mg/day.\n5. Substitute allopurinol for uricosuric acid.\nThe correct answer is: 1. Discontinue allopurinol and start colchicine treatment."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The ELISA antibody tests were developed to provide a high level of confidence that donated blood was not infected with HIV. It is therefore not possible to conclude that blood rejected for transfusion because of a positive ELISA antibody test is in fact infected with HIV. Sometimes, retesting the donor in several months will produce a negative ELISA antibody test. This is why a confirmatory western blot is always used before reporting a \"positive\" HIV test result. If no antibodies to HIV are detected, this does not mean the person has not been infected with HIV. It may take several months after HIV infection for the antibody response to reach detectable levels, during which time rapid testing for antibodies to HIV will not be indicative of true infection status. For most people, HIV antibodies reach a detectable level after two to six weeks. Although these tests have high specificity, false positives do occur. Any positive test result should be confirmed by a lab using the western blot. Interpreting antibody tests ELISA testing alone cannot be used to diagnose HIV, even if the test suggests a high probability that antibody to HIV-1 is present. In the United States, such ELISA results are not reported as \"positive\" unless confirmed by a western blot. HIV antibody testing is unreliable Diagnosis of infection using antibody testing is a well-established technique in medicine. HIV antibody tests exceed the performance of most other infectious disease tests in both sensitivity (the ability of the screening test to give a positive finding when the person tested truly has the disease) and specificity (the ability of the test to give a negative finding when the subjects tested are free of the disease under study). Many current HIV antibody tests have sensitivity and specificity in excess of 96% and are therefore extremely reliable. While most patients with HIV show an antibody response after six weeks, window periods vary and may occasionally be as long as three months. The specificity rate given here for the inexpensive enzyme immunoassay screening tests indicates that, in 1,000 HIV test results of healthy individuals, about 15 of these results will be a false positive. Confirming the test result (i.e., by repeating the test, if this option is available) could reduce the ultimate likelihood of a false positive to about 1 result in 250,000 tests given. The sensitivity rating, likewise, indicates that, in 1,000 test results of HIV infected people, 3 will actually be a false negative result. However, based upon the HIV prevalence rates at most testing centers within the United States, the negative predictive value of these tests is extremely high, meaning that a negative test result will be correct more than 9,997 times in 10,000 (99.97% of the time). The very high negative predictive value of these tests is why the CDC recommends that a negative test result be considered conclusive evidence that an individual does not have HIV. Antibody tests may give false negative (no antibodies were detected despite the presence of HIV) results during the window period, an interval of three weeks to six months between the time of HIV infection and the production of measurable antibodies to HIV seroconversion. Most people develop detectable antibodies approximately 30 days after infection, although some seroconvert later. The vast majority of people (97%) have detectable antibodies by three months after HIV infection; a six-month window is extremely rare with modern antibody testing. During the window period, an infected person can transmit HIV to others although their HIV infection may not be detectable with an antibody test. Antiretroviral therapy during the window period can delay the formation of antibodies and extend the window period beyond 12 months. This was not the case with patients that underwent treatment with post-exposure prophylaxis (PEP). Those patients must take ELISA tests at various intervals after the According the WHO there are about 14,000 new HIV infections a day. However, in a few cases the diagnosis will be made in the acute phase of the disease. Acute HIV infection is the period between infection with the virus and complete seroconversion, defined by a positive Western blot test. This period lasts approximately 30 days and most patients (40-90%) have mild clinical manifestations (fever, rash, pharyngitis, mucosal ulcers, among others) for 2 weeks which, because they are nonspecific, can be confused with other community-acquired infections. Microbiological diagnosis is based on the absence of serum antibodies (negative ELISA test) together with a positive HIV viral load in plasma (&gt; 10,000 copies/ml). Diagnosis of acute HIV infection is important for several reasons: firstly, from the epidemiological point of view, this is the period with the highest rates of HIV transmission and identification of new HIV infections reveals the growth of the epidemic and the transmission rates of resistant HIV strains, which in Spain is about 10%; secondly, from the immunopathological point of view, this period provides a unique opportunity to study the virological, immunological and genetic mechanisms that play a role in the transmission and pathogenesis of this disease; and thirdly, therapeutically, starting antiretroviral therapy during this phase could alter the natural history of the disease. However, this is a controversial issue and currently most guidelines recommend treatment only if these patients can be included in clinical trials or if they show lasting or severe clinical manifestations. Three instances of delayed HIV seroconversion occurring in health-care workers have been reported; in these instances, the health-care workers tested negative for HIV antibodies greater than 6 months postexposure but were seropositive within 12 months after the exposure. DNA sequencing confirmed the source of infection in one instance. Two of the delayed seroconversions were associated with simultaneous exposure to hepatitis C virus (HCV). In one case, co-infection was associated with a rapidly fatal HCV disease course; however, it is not known whether HCV directly influences the risk for or course of HIV infection or is a marker for other exposure-related factors. ELISA The enzyme-linked immunosorbent assay (ELISA), or enzyme immunoassay (EIA), was the first screening test commonly employed for HIV. It has a high sensitivity. Viral load tests can also be used to diagnose HIV infection, especially in children under 18 months born to mothers with HIV, where the presence of maternal antibodies prevents the use of antibody-based (ELISA) diagnostic tests. Pooled viral RNA testing shortens the window period to a median of 17 days (95% CI, 13-28 Days). Although it is not the standard of care to use this test for diagnosis, in communities with high HIV prevalence, this test has a significantly improved negative predictive value over 3rd and 4th generation tests for detecting acute HIV infections. HIV-1 testing is initially done using an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV-1. Specimens with a non-reactive result from the initial ELISA are considered HIV-negative, unless new exposure to an infected partner or partner of unknown HIV status has occurred. Specimens with a reactive ELISA result are retested in duplicate. If the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., a polymerase chain reaction (PCR), western blot or, less commonly, an immunofluorescence assay (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or PCR or reactive by western blot are considered HIV-positive and indicative of HIV infection. Specimens that are repeatedly ELISA-reactive occasionally provide an indeterminate western blot result, which may be either an incomplete antibody response to HIV in an infected person or Diagnosis HIV-2 diagnosis can be made when a patient has no symptoms but positive blood work indicating the individual has HIV. The Multispot HIV-1/HIV-2 Rapid Test is currently the only FDA approved method for such differentiation between the two viruses. Recommendations for the screening and diagnosis of HIV has always been to use enzyme immunoassays that detect HIV-1, HIV-1 group O, and HIV-2. When screening the combination, if the test is positive followed by an indeterminate HIV-1 western blot, a follow up test, such as amino acid testing, must be performed to distinguish which infection is present. According to the NIH, a differential diagnosis of HIV-2 should be considered when a person is of West African descent or has had sexual contact or shared needles with such a person. West Africa is at the highest risk as it is the origin of the virus. The HIV set point is the viral load or number of virions in the blood of a person infected with HIV. HIV infections are broken down into three stages: acute infection, asymptomatic infection, and AIDS. The acute infection stage refers to the first weeks after infection, where the majority of infected individuals display severe flu-like symptoms such as fever, myalgia, sore throat, swollen lymph nodes, arthralgia, fatigue, headache, and sometimes rash. At this stage, viral loads reach high levels and the number of CD4 helper T cells in the blood begins to drop. At this point, seroconversion, the development of antibodies, occurs and the CD4 T cell counts begin to recover as the immune system attempts to fight the virus, marking the HIV set point. The higher the viral load at the set point, the faster the virus will progress to AIDS; the lower the viral load at the set point, the longer the patient will remain in clinical latency, the next stage of the infection. To diagnose an individual with HIV, a test must be taken to determine if the virus is present in their system. There are several test options including ELISA, at-home, saliva, viral load, and western blot. To establish the presence of the HIV virus, some tests measure the level of HIV antibodies in the blood and/or saliva or the level of both HIV antigens and antibodies in the blood. Other tests can detect the presence of the HIV virus by calculating the amount of actual virus present in the blood. None of the tests available can determine if a person is positive immediately after they believe they have been exposed to the virus. Each test has a window of time after the initial exposure occurred until the test can accurately tell if an individual has been infected or not. One reason for this is because the focus of some of the tests are antibodies. After the initial exposure to the virus, it usually takes 3–4 weeks but it can take up to six months for antibodies to be produced by the The most updated HIV testing protocols recommend using the HIV-1 and HIV-2 antigen/antibody combination immunoassay as the initial screening test for an HIV infection. This blood test assesses whether or not the mother has created antibodies, which are disease-fighting proteins of the immune system, against the HIV-1 and HIV-2 viruses. These antibodies will only be present if the patient has been exposed to HIV, therefore, they act as a marker of infection. This test also detects a protein called p24 in maternal blood, which is a specific component of the HIV virus itself and also acts as an early marker of an HIV infection. If this test is positive, the CDC recommends performing follow-up testing using a test called the HIV-1/HIV-2 antibody differentiation immunoassay that both confirms the diagnosis and determines the specific type of HIV infection the patient has to specifically tailor further management of the patient. HIV antibody tests are highly sensitive, meaning they react preferentially with HIV antibodies, but not all positive or inconclusive HIV ELISA tests mean the person is infected by HIV. Risk history, and clinical judgement should be included in the assessment, and a confirmation test (western blot) should be administered. An individual with an inconclusive test should be re-tested at a later date. HIV tests are used to detect the presence of the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS), in serum, saliva, or urine. Such tests may detect antibodies, antigens, or RNA. AIDS diagnosis AIDS is diagnosed separately from HIV. Terminology The window period is the time from infection until a test can detect any change. The average window period with HIV-1 antibody tests is 25 days for subtype B. Antigen testing cuts the window period to approximately 16 days and nucleic acid testing (NAT) further reduces this period to 12 days. Performance of medical tests is often described in terms of: Sensitivity: The percentage of the results that will be positive when HIV is present Specificity: The percentage of the results that will be negative when HIV is not present. Diagnosis of HIV infection Tests used for the diagnosis of HIV infection in a particular person require a high degree of both sensitivity and specificity. In the United States, this is achieved using an algorithm combining two tests for HIV antibodies. If antibodies are detected by an initial test based on the ELISA method, then a second test using the western blot procedure determines the size of the antigens in the test kit binding to the antibodies. The combination of these two methods is highly accurate Human rights The UNAIDS/WHO policy statement on HIV Testing states that conditions under which people undergo HIV testing must be anchored in a human rights approach that pays due respect to ethical principles. According to these principles, the conduct of HIV testing of individuals must be Confidential; Accompanied by counseling (for those who test positive); Conducted with the informed consent of the person being tested. Confidentiality Serology is the primary means for identifying patients with HIV infection and Acquired Immunodeficiency Syndrome (AIDS). Testing of serum by serologic methods has been extensively used since 1985, not only for clinical diagnosis but also for epidemiological surveillance and donor screening in blood banks. Fast serological diagnostic techniques are now being developed, using urine and oral fluid, as an alternative for anti-HIV antibody screening, and many parallel studies are proving its accuracy. The purpose of this study was to evaluate the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of the ImmunoComb II HIV 1&amp;2 Saliva((R)) test from Orgenics (Dot-ELISA) compared to the routine exams (ELISA and Western Blot) of HIV positive/AIDS patients, undergoing antiretroviral treatment or not, in different stages of the disease's evolution, and compared to serologic testing of known HIV negative patients by the use of serum ELISA (blood donors). To accomplish this, patients of the Immunogenic Deficiencies Control Center (CCDI) and voluntary blood donors of the Blood Bank Center of the Medical School of S&amp;atilde:o Paulo/Federal University of São Paulo (EPM-UN I FESP) were evaluated. Sensitivity of Dot-ELISA in oral fluid was 100%, specificity 97.08%, PPV 96.66% and NPV 100%. The method used in this case study was shown to be highly sensitive and specific, being useful particularly in epidemiological surveillance and screening. In the non-clinical setting, oral swab tests are still primarily enzyme-linked immunosorbent assay (ELISA) antibody tests performed as rapid tests but need to be confirmed with a serum western blot. An advantage of rapid tests is that they can be offered in a non-clinical setting such as community health fairs, places of worship, HIV service centers, and other locations outside healthcare facilities. Results are presented within 20 minutes, which decreases the number of patients who do not know the outcome of their test because they do not follow up for a return appointment, as can occur in the clinical setting. ELISA tests are Ab-only tests and detect HIV as early as 3 weeks after transmission. [5] In 1985, early tests using the ELISA method looked for antibodies, which are the immune system's response to the virus. However, there is a window period when using this method in which a person who has been infected with HIV is able to spread the disease but may test negative for the virus. This window period can be as long as three to six months, with an average of 22 days. Tests using the ELISA methods are often still used in developed countries because of their ease-of-use, as well as their fairly high sensitivity, which boasts 100% sensitivity. To cover the window period resultant from the use of these tests, donors are also screened for high risk behaviors, one of which is a history of same-sex sexual activity among male potential donors. Newer tests look for the virus itself, such as the p24 antigen test, which looks for a part of the virus on the surface of infected cells, and Nucleic acid tests (NAT), which look for the genetic material of the virus in HIV-infected cells. Diagnosis HIV/AIDS is diagnosed via laboratory testing and then staged based on the presence of certain signs or symptoms. HIV screening is recommended by the United States Preventive Services Task Force for all people 15 years to 65 years of age, including all pregnant women. Additionally, testing is recommended for those at high risk, which includes anyone diagnosed with a sexually transmitted illness. In many areas of the world, a third of HIV carriers only discover they are infected at an advanced stage of the disease when AIDS or severe immunodeficiency has become apparent. HIV testing Most people infected with HIV develop specific antibodies (i.e. seroconvert) within three to twelve weeks after the initial infection. Diagnosis of primary HIV before seroconversion is done by measuring HIV-RNA or p24 antigen. Positive results obtained by antibody or PCR testing are confirmed either by a different antibody or by PCR. On June 15, 2010, the FDA approved the first diagnostic test capable of detecting HIV antigens and HIV antibodies. The Abbott ARCHITECT HIV Ag/Ab combo test, a fourth-generation test, has an increased sensitivity for detecting infections during the acute phase (when compared to 1st and 3rd generation tests), when the immune system is still developing antibodies and the virus is replicating unchecked, and in one study, was able to detect 83% of such infections. Society and culture A person, who may be unaware of the infection, is highly infectious during this time yet may test negative for HIV using tests that detect anti-HIV antibodies only. Although Nucleic Acid Amplification Testing NAAT is more expensive and can take a week for processing, some have argued that it may still be a preferred way to screen for HIV. There are no universal criteria for interpreting the western blot test: The number of viral bands that must be present may vary. If no viral bands are detected, the result is negative. If at least one viral band for each of the GAG, POL, and ENV gene-product groups are present, the result is positive. The three-gene-product approach to western blot interpretation has not been adopted for public health or clinical practice. Tests in which less than the required number of viral bands are detected are reported as indeterminate: a person who has an indeterminate result should be retested, as later tests may be more conclusive. Almost all HIV-infected persons with indeterminate western blot results will develop a positive result when tested in one month; persistently indeterminate results over a period of six months suggests the results are not due to HIV infection. In a generally healthy low-risk population, indeterminate results on western blot occur on the order of 1 in 5,000 patients. Since the advent of HIV testing of donor blood in the mid/later 1980s, ex. 1985's ELISA, the transmission of HIV during transfusion has dropped dramatically. Prior testing of donor blood only included testing for antibodies to HIV. However, because of latent infection (the \"window period\" in which an individual is infectious, but has not had time to develop antibodies) many cases of HIV seropositive blood were missed. The development of a nucleic acid test for the HIV-1 RNA has dramatically lowered the rate of donor blood seropositivity to about 1 in 3 million units. As transmittance of HIV does not necessarily mean HIV infection, the latter could still occur at an even lower rate. The transmission of hepatitis C via transfusion currently stands at a rate of about 1 in 2 million units. As with HIV, this low rate has been attributed to the ability to screen for both antibodies as well as viral RNA nucleic acid testing in donor blood. To evaluate a WHO testing strategy based on the use of two consecutive enzyme-linked immunosorbent assays (ELISA) as an alternative to ELISA followed by Western blotting (WB) for the serologic diagnosis of HIV infection. The study was of 2069 consecutive serum specimens from patients suspected of HIV infection received for HIV diagnostic testing at the HIV laboratory, Muhimbili Medical Centre, Dar es Salaam. The strategy involved testing all sera with Behring indirect anti-HIV 1 + 2 peptide ELISA, followed by Wellcozyme anti-HIV-1 recombinant competitive ELISA on those sera reactive by the first ELISA. WB was done on a sample of the sera reactive on both ELISAs and on all those giving discordant results on the two ELISAs. Of the 2069 sera tested, 837 (40.5%) were negative on the first ELISA, 1172 (56.6%) were reactive on both ELISAs and 60 (2.9%) were initially reactive on the first test but not on the second assay. Of the 1172 sera reactive on both ELISAs, 329 (28.1%) were tested by WB. The diagnostic accuracy of the WHO alternative testing strategy using WB confirmation as the 'gold' standard was as follows: sensitivity 99.4% (326/328), specificity 99.7%, (893/896), positive predictive value 99.1% (328/331) and negative predictive value 99.8% (893/895). Repeated testing by ELISA of the sera which initially gave discordant results on the two ELISAs increased the sensitivity to 100%. Three sera giving false positive reactions on both ELISAs became negative on both ELISAs after retesting. In order to achieve a specificity and a positive predictive value of 100%, it would have been necessary to subject all sera reacting on both ELISAs to retesting on one ELISA. A second ELISA based on different antigens and a different test principle compared with the first ELISA could be used as an alternative to the WB assay for confirmation of HIV antibodies. However, some modifications of the WHO strategy for diagnostic HIV antibody testing were required in order to maximize the diagnostic accuracy. Contagiousness The higher the viral load value, the more viral elements there are in blood and other body fluids. For example, individuals with HIV are most contagious during the earliest (acute) stages of the infection, sometimes with millions of copies of HIV per centiliter of blood. According to one estimate, the majority of transmissions among gay men in the UK occur during primary infection. This is because, at this phase, the immune response is still developing. Antibody levels against the virus during acute infection are often too low to be detected, meaning that an antibody test for a highly infectious individual can come back negative. The latest recommendations of the US Centers for Disease Control and Prevention (CDC) show that HIV testing must start with an immunoassay combination test for HIV-1 and HIV-2 antibodies and p24 antigen. A negative result rules out HIV exposure, while a positive one must be followed by an HIV-1/2 antibody differentiation immunoassay to detect which antibodies are present. This gives rise to four possible scenarios: 1. HIV-1 (+) & HIV-2 (−): HIV-1 antibodies detected 2. HIV-1 (−) & HIV-2 (+): HIV-2 antibodies detected 3. HIV-1 (+) & HIV-2 (+): both HIV-1 and HIV-2 antibodies detected 4. HIV-1 (−) or indeterminate & HIV-2 (−): Nucleic acid test must be carried out to detect the acute infection of HIV-1 or its absence. Research HIV/AIDS research includes all medical research that attempts to prevent, treat, or cure HIV/AIDS, as well as fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV. antibodies to HIV, an series of assay, HIV-1 RNA assay, or HIV-1 DNA PCR and specific serologic point-of-care tests can provide results in 1–60 min. Among the most testing for HIV-2. If the p24 and HIV RNA assays are negative and popular of these is the OraQuick Rapid HIV-1 antibody test that can be run on blood, plasma, or saliva. The sensitivity and specificity of this test is ~99% when run on whole blood. Specificity remains the SEROLOGIC TESTS IN THE DIAGNOSIS OF HIV-1 OR same but sensitivity drops to 98% when the test is run on saliva. While The standard blood screening tests for HIV infection are based on the detection of antibodies to HIV. A common platform is the ELISA, also referred to as an enzyme immunoassay (EIA). This solid-phase assay is an extremely good screening test with a sensitivity of >99.5%. Most diagnostic laboratories use commercial kits that contain antigens from both HIV-1 and HIV-2 and thus are able to detect antibodies to either. These kits use both natural and recombinant antigens and are continuously updated to increase their sensitivity to newly discovered species, such as group O viruses (Fig. 226-1). The fourth-generation EIA tests combine detection of antibodies to HIV with detection of the p24 antigen of HIV. EIA tests are generally scored as positive (highly reactive), negative (nonreactive), or indeterminate (partially reactive). While the EIA is an extremely sensitive test, it is not optimal with regard to specificity. This is particularly true in studies of low-risk individuals, such as The aim of the study was to detect HIV RNA in seropositive patients using RT-PCR method and thus, to establish PCR methodology in the routine laboratory works. The total of 33 examined persons were divided in two groups: 1) 13 persons seropositive for HIV; and 2) 20 healthy persons - randomly selected blood donors that made the case control group. The subjects age was between 25 and 52 years (average 38,5). ELFA test for combined detection of HIV p24 antigen and anti HIV-1+2 IgG and ELISA test for detection of antibodies against HIV-1 and HIV-2, were performed for each examined person. RNA from the whole blood was extracted using a commercial kit based on salt precipitation. Detection of HIV RNA was performed using RT-PCR kit. Following nested PCR, the product was separated by electrophoresis in 1,5 % agarose gel. The result was scored positive if the band of 210bp was visible regardless of intensity. Measures of precaution were taken during all the steps of the work and HIV infected materials were disposed of accordingly. In the group of blood donors ELFA, ELISA and RT-PCR were negative. Assuming that prevalence of HIV infection is zero, the clinical specificity of RT-PCR is 100 %. The analytical specificity of RT-PCR method was tested against Hepatitis C and B, Human Papiloma Virus, Cytomegalovirus, Herpes Simplex Virus, Rubella Virus, Mycobacterium tuberculosis, Chlamydia trachomatis. None of these templates yielded amplicon. In the group of 13 seropositive persons, 33 samples were analyzed. HIV RNA was detected in 15 samples. ELISA and ELFA test were positive in all samples. Different aliquots of the samples were tested independently and showed the same results. After different periods of storing the RNA samples at -70 masculineC, RT-PCR reaction was identical to the one performed initially. The obtained amplicons were maintained frozen at -20 masculineC for a week and the subsequently performed electrophoresis was identical to the previous one. The reaction is fast, simple for manipulation; with low detection level of 60 IU/ml. RT-PCR needs a small amount of RNA, as well as a small volume of sample. HIV RNA was detected in different periods of time with different clinical presentations in patients, with or without antiretroviral therapy. RT-PCR method gives the opportunity for reliable determination of HIV-1 RNA with border of detection of 60 IU/ml. The test is reproducible and has high analytical and clinical specificity. a period of six months suggests the results are not due to HIV infection. In a generally healthy low-risk population, indeterminate results on western blot occur on the order of 1 in 5,000 patients. However, for those individuals who have had high-risk exposures to individuals where HIV-2 is most prevalent, Western Africa, an inconclusive western blot test may prove infection with HIV-2. AIDS denialism HIV tests have been criticized by AIDS denialists (a fringe group whose members believe that HIV either does not exist or is harmless). The accuracy of serologic testing has been verified by isolation and culture of HIV and by detection of HIV RNA by PCR, which are widely accepted \"gold standards\" in microbiology. While AIDS denialists focus on individual components of HIV testing, the combination of ELISA and western blot used for the diagnosis of HIV is remarkably accurate, with very low false-positive and -negative rates as described above. The views of AIDS denialists are based on highly selective analysis of mostly outdated scientific papers; there is broad scientific consensus that HIV is the cause of AIDS. The study aims to evaluate the HIV-1/2 rapid diagnostic test kit is routinely used to screen HIV infection for safe blood transfusion and VCT services in many parts of Ethiopia. A total of 324 sera were collected from consecutive blood donors from February to May 2006. All samples were screened for HIV infection using Determine HIV-1/2 (Abbott Japan) at hospital blood bank laboratory. Blindly, all serums were retested at Regional Health Research Laboratory using 4th generation ELISA (Vironostika HIV Uni-Form II AG/Ab) and Determine HIV-1/2 (Abbott lab). Discordant samples were repeatedly retested using the same ELISA and Determine HIV-1/2 to avoid technical errors. Finally, discordant results were resolved using Western Blot at the National HIV/AIDS Laboratory. Determine HIV-1/2 and ELISA showed 94.4% concordance in HIV antibody testing with fair Cohen's Kappa statistic value (0.68) among blood donors. The sensitivity, specificity, positive and negative predictive values of Determine HIV-1/2 were 60.5%, 98.9%, 88.5% and 94.9% respectively. As a rapid HIV screening test for blood donors, Determine HIV-1/2 showed poor sensitivity. Further evaluation at multiple centres is recommended to test its validity as a routine HIV screening test in blood donors. Use of a combination of rapid assays is also recommended for screening of HIV infection among the donor population.\nHere is the question:\nINFECTIOUS DISEASES: A 20-year-old girl comes to the clinic with an acute fever, cervical lymphadenopathy and skin rash. According to the patient, 3 weeks ago she had a sexual relationship that could be a risk for contracting the HIV virus. Indicate which of the following answers is true:\nHere are the potential choices:\n1. A negative HIV-1/HIV-2 serology performed by ELISA technique rules out the possibility that the patient has been infected with the HIV virus.\n2. The clinical process that the patient suffers from is not consistent with acute HIV infection.\n3. If the patient's ELISA test was positive, nothing further would be necessary for the diagnosis of HIV infection.\n4. The ELISA technique has a high sensitivity for the diagnosis of HIV infection, but its specificity is even higher.\n5. If the ELISA test to diagnose HIV in the patient was negative, we could determine by PCR technique the viral load in blood.\nThe correct answer is: ",
        "gold_answer": "5 If the ELISA test to diagnose HIV in the patient was negative, we could determine by PCR technique the viral load in blood.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The ELISA antibody tests were developed to provide a high level of confidence that donated blood was not infected with HIV. It is therefore not possible to conclude that blood rejected for transfusion because of a positive ELISA antibody test is in fact infected with HIV. Sometimes, retesting the donor in several months will produce a negative ELISA antibody test. This is why a confirmatory western blot is always used before reporting a \"positive\" HIV test result. If no antibodies to HIV are detected, this does not mean the person has not been infected with HIV. It may take several months after HIV infection for the antibody response to reach detectable levels, during which time rapid testing for antibodies to HIV will not be indicative of true infection status. For most people, HIV antibodies reach a detectable level after two to six weeks. Although these tests have high specificity, false positives do occur. Any positive test result should be confirmed by a lab using the western blot. Interpreting antibody tests ELISA testing alone cannot be used to diagnose HIV, even if the test suggests a high probability that antibody to HIV-1 is present. In the United States, such ELISA results are not reported as \"positive\" unless confirmed by a western blot. HIV antibody testing is unreliable Diagnosis of infection using antibody testing is a well-established technique in medicine. HIV antibody tests exceed the performance of most other infectious disease tests in both sensitivity (the ability of the screening test to give a positive finding when the person tested truly has the disease) and specificity (the ability of the test to give a negative finding when the subjects tested are free of the disease under study). Many current HIV antibody tests have sensitivity and specificity in excess of 96% and are therefore extremely reliable. While most patients with HIV show an antibody response after six weeks, window periods vary and may occasionally be as long as three months. The specificity rate given here for the inexpensive enzyme immunoassay screening tests indicates that, in 1,000 HIV test results of healthy individuals, about 15 of these results will be a false positive. Confirming the test result (i.e., by repeating the test, if this option is available) could reduce the ultimate likelihood of a false positive to about 1 result in 250,000 tests given. The sensitivity rating, likewise, indicates that, in 1,000 test results of HIV infected people, 3 will actually be a false negative result. However, based upon the HIV prevalence rates at most testing centers within the United States, the negative predictive value of these tests is extremely high, meaning that a negative test result will be correct more than 9,997 times in 10,000 (99.97% of the time). The very high negative predictive value of these tests is why the CDC recommends that a negative test result be considered conclusive evidence that an individual does not have HIV. Antibody tests may give false negative (no antibodies were detected despite the presence of HIV) results during the window period, an interval of three weeks to six months between the time of HIV infection and the production of measurable antibodies to HIV seroconversion. Most people develop detectable antibodies approximately 30 days after infection, although some seroconvert later. The vast majority of people (97%) have detectable antibodies by three months after HIV infection; a six-month window is extremely rare with modern antibody testing. During the window period, an infected person can transmit HIV to others although their HIV infection may not be detectable with an antibody test. Antiretroviral therapy during the window period can delay the formation of antibodies and extend the window period beyond 12 months. This was not the case with patients that underwent treatment with post-exposure prophylaxis (PEP). Those patients must take ELISA tests at various intervals after the According the WHO there are about 14,000 new HIV infections a day. However, in a few cases the diagnosis will be made in the acute phase of the disease. Acute HIV infection is the period between infection with the virus and complete seroconversion, defined by a positive Western blot test. This period lasts approximately 30 days and most patients (40-90%) have mild clinical manifestations (fever, rash, pharyngitis, mucosal ulcers, among others) for 2 weeks which, because they are nonspecific, can be confused with other community-acquired infections. Microbiological diagnosis is based on the absence of serum antibodies (negative ELISA test) together with a positive HIV viral load in plasma (&gt; 10,000 copies/ml). Diagnosis of acute HIV infection is important for several reasons: firstly, from the epidemiological point of view, this is the period with the highest rates of HIV transmission and identification of new HIV infections reveals the growth of the epidemic and the transmission rates of resistant HIV strains, which in Spain is about 10%; secondly, from the immunopathological point of view, this period provides a unique opportunity to study the virological, immunological and genetic mechanisms that play a role in the transmission and pathogenesis of this disease; and thirdly, therapeutically, starting antiretroviral therapy during this phase could alter the natural history of the disease. However, this is a controversial issue and currently most guidelines recommend treatment only if these patients can be included in clinical trials or if they show lasting or severe clinical manifestations. Three instances of delayed HIV seroconversion occurring in health-care workers have been reported; in these instances, the health-care workers tested negative for HIV antibodies greater than 6 months postexposure but were seropositive within 12 months after the exposure. DNA sequencing confirmed the source of infection in one instance. Two of the delayed seroconversions were associated with simultaneous exposure to hepatitis C virus (HCV). In one case, co-infection was associated with a rapidly fatal HCV disease course; however, it is not known whether HCV directly influences the risk for or course of HIV infection or is a marker for other exposure-related factors. ELISA The enzyme-linked immunosorbent assay (ELISA), or enzyme immunoassay (EIA), was the first screening test commonly employed for HIV. It has a high sensitivity. Viral load tests can also be used to diagnose HIV infection, especially in children under 18 months born to mothers with HIV, where the presence of maternal antibodies prevents the use of antibody-based (ELISA) diagnostic tests. Pooled viral RNA testing shortens the window period to a median of 17 days (95% CI, 13-28 Days). Although it is not the standard of care to use this test for diagnosis, in communities with high HIV prevalence, this test has a significantly improved negative predictive value over 3rd and 4th generation tests for detecting acute HIV infections. HIV-1 testing is initially done using an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV-1. Specimens with a non-reactive result from the initial ELISA are considered HIV-negative, unless new exposure to an infected partner or partner of unknown HIV status has occurred. Specimens with a reactive ELISA result are retested in duplicate. If the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., a polymerase chain reaction (PCR), western blot or, less commonly, an immunofluorescence assay (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or PCR or reactive by western blot are considered HIV-positive and indicative of HIV infection. Specimens that are repeatedly ELISA-reactive occasionally provide an indeterminate western blot result, which may be either an incomplete antibody response to HIV in an infected person or Diagnosis HIV-2 diagnosis can be made when a patient has no symptoms but positive blood work indicating the individual has HIV. The Multispot HIV-1/HIV-2 Rapid Test is currently the only FDA approved method for such differentiation between the two viruses. Recommendations for the screening and diagnosis of HIV has always been to use enzyme immunoassays that detect HIV-1, HIV-1 group O, and HIV-2. When screening the combination, if the test is positive followed by an indeterminate HIV-1 western blot, a follow up test, such as amino acid testing, must be performed to distinguish which infection is present. According to the NIH, a differential diagnosis of HIV-2 should be considered when a person is of West African descent or has had sexual contact or shared needles with such a person. West Africa is at the highest risk as it is the origin of the virus. The HIV set point is the viral load or number of virions in the blood of a person infected with HIV. HIV infections are broken down into three stages: acute infection, asymptomatic infection, and AIDS. The acute infection stage refers to the first weeks after infection, where the majority of infected individuals display severe flu-like symptoms such as fever, myalgia, sore throat, swollen lymph nodes, arthralgia, fatigue, headache, and sometimes rash. At this stage, viral loads reach high levels and the number of CD4 helper T cells in the blood begins to drop. At this point, seroconversion, the development of antibodies, occurs and the CD4 T cell counts begin to recover as the immune system attempts to fight the virus, marking the HIV set point. The higher the viral load at the set point, the faster the virus will progress to AIDS; the lower the viral load at the set point, the longer the patient will remain in clinical latency, the next stage of the infection. To diagnose an individual with HIV, a test must be taken to determine if the virus is present in their system. There are several test options including ELISA, at-home, saliva, viral load, and western blot. To establish the presence of the HIV virus, some tests measure the level of HIV antibodies in the blood and/or saliva or the level of both HIV antigens and antibodies in the blood. Other tests can detect the presence of the HIV virus by calculating the amount of actual virus present in the blood. None of the tests available can determine if a person is positive immediately after they believe they have been exposed to the virus. Each test has a window of time after the initial exposure occurred until the test can accurately tell if an individual has been infected or not. One reason for this is because the focus of some of the tests are antibodies. After the initial exposure to the virus, it usually takes 3–4 weeks but it can take up to six months for antibodies to be produced by the The most updated HIV testing protocols recommend using the HIV-1 and HIV-2 antigen/antibody combination immunoassay as the initial screening test for an HIV infection. This blood test assesses whether or not the mother has created antibodies, which are disease-fighting proteins of the immune system, against the HIV-1 and HIV-2 viruses. These antibodies will only be present if the patient has been exposed to HIV, therefore, they act as a marker of infection. This test also detects a protein called p24 in maternal blood, which is a specific component of the HIV virus itself and also acts as an early marker of an HIV infection. If this test is positive, the CDC recommends performing follow-up testing using a test called the HIV-1/HIV-2 antibody differentiation immunoassay that both confirms the diagnosis and determines the specific type of HIV infection the patient has to specifically tailor further management of the patient. HIV antibody tests are highly sensitive, meaning they react preferentially with HIV antibodies, but not all positive or inconclusive HIV ELISA tests mean the person is infected by HIV. Risk history, and clinical judgement should be included in the assessment, and a confirmation test (western blot) should be administered. An individual with an inconclusive test should be re-tested at a later date. HIV tests are used to detect the presence of the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS), in serum, saliva, or urine. Such tests may detect antibodies, antigens, or RNA. AIDS diagnosis AIDS is diagnosed separately from HIV. Terminology The window period is the time from infection until a test can detect any change. The average window period with HIV-1 antibody tests is 25 days for subtype B. Antigen testing cuts the window period to approximately 16 days and nucleic acid testing (NAT) further reduces this period to 12 days. Performance of medical tests is often described in terms of: Sensitivity: The percentage of the results that will be positive when HIV is present Specificity: The percentage of the results that will be negative when HIV is not present. Diagnosis of HIV infection Tests used for the diagnosis of HIV infection in a particular person require a high degree of both sensitivity and specificity. In the United States, this is achieved using an algorithm combining two tests for HIV antibodies. If antibodies are detected by an initial test based on the ELISA method, then a second test using the western blot procedure determines the size of the antigens in the test kit binding to the antibodies. The combination of these two methods is highly accurate Human rights The UNAIDS/WHO policy statement on HIV Testing states that conditions under which people undergo HIV testing must be anchored in a human rights approach that pays due respect to ethical principles. According to these principles, the conduct of HIV testing of individuals must be Confidential; Accompanied by counseling (for those who test positive); Conducted with the informed consent of the person being tested. Confidentiality Serology is the primary means for identifying patients with HIV infection and Acquired Immunodeficiency Syndrome (AIDS). Testing of serum by serologic methods has been extensively used since 1985, not only for clinical diagnosis but also for epidemiological surveillance and donor screening in blood banks. Fast serological diagnostic techniques are now being developed, using urine and oral fluid, as an alternative for anti-HIV antibody screening, and many parallel studies are proving its accuracy. The purpose of this study was to evaluate the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of the ImmunoComb II HIV 1&amp;2 Saliva((R)) test from Orgenics (Dot-ELISA) compared to the routine exams (ELISA and Western Blot) of HIV positive/AIDS patients, undergoing antiretroviral treatment or not, in different stages of the disease's evolution, and compared to serologic testing of known HIV negative patients by the use of serum ELISA (blood donors). To accomplish this, patients of the Immunogenic Deficiencies Control Center (CCDI) and voluntary blood donors of the Blood Bank Center of the Medical School of S&amp;atilde:o Paulo/Federal University of São Paulo (EPM-UN I FESP) were evaluated. Sensitivity of Dot-ELISA in oral fluid was 100%, specificity 97.08%, PPV 96.66% and NPV 100%. The method used in this case study was shown to be highly sensitive and specific, being useful particularly in epidemiological surveillance and screening. In the non-clinical setting, oral swab tests are still primarily enzyme-linked immunosorbent assay (ELISA) antibody tests performed as rapid tests but need to be confirmed with a serum western blot. An advantage of rapid tests is that they can be offered in a non-clinical setting such as community health fairs, places of worship, HIV service centers, and other locations outside healthcare facilities. Results are presented within 20 minutes, which decreases the number of patients who do not know the outcome of their test because they do not follow up for a return appointment, as can occur in the clinical setting. ELISA tests are Ab-only tests and detect HIV as early as 3 weeks after transmission. [5] In 1985, early tests using the ELISA method looked for antibodies, which are the immune system's response to the virus. However, there is a window period when using this method in which a person who has been infected with HIV is able to spread the disease but may test negative for the virus. This window period can be as long as three to six months, with an average of 22 days. Tests using the ELISA methods are often still used in developed countries because of their ease-of-use, as well as their fairly high sensitivity, which boasts 100% sensitivity. To cover the window period resultant from the use of these tests, donors are also screened for high risk behaviors, one of which is a history of same-sex sexual activity among male potential donors. Newer tests look for the virus itself, such as the p24 antigen test, which looks for a part of the virus on the surface of infected cells, and Nucleic acid tests (NAT), which look for the genetic material of the virus in HIV-infected cells. Diagnosis HIV/AIDS is diagnosed via laboratory testing and then staged based on the presence of certain signs or symptoms. HIV screening is recommended by the United States Preventive Services Task Force for all people 15 years to 65 years of age, including all pregnant women. Additionally, testing is recommended for those at high risk, which includes anyone diagnosed with a sexually transmitted illness. In many areas of the world, a third of HIV carriers only discover they are infected at an advanced stage of the disease when AIDS or severe immunodeficiency has become apparent. HIV testing Most people infected with HIV develop specific antibodies (i.e. seroconvert) within three to twelve weeks after the initial infection. Diagnosis of primary HIV before seroconversion is done by measuring HIV-RNA or p24 antigen. Positive results obtained by antibody or PCR testing are confirmed either by a different antibody or by PCR. On June 15, 2010, the FDA approved the first diagnostic test capable of detecting HIV antigens and HIV antibodies. The Abbott ARCHITECT HIV Ag/Ab combo test, a fourth-generation test, has an increased sensitivity for detecting infections during the acute phase (when compared to 1st and 3rd generation tests), when the immune system is still developing antibodies and the virus is replicating unchecked, and in one study, was able to detect 83% of such infections. Society and culture A person, who may be unaware of the infection, is highly infectious during this time yet may test negative for HIV using tests that detect anti-HIV antibodies only. Although Nucleic Acid Amplification Testing NAAT is more expensive and can take a week for processing, some have argued that it may still be a preferred way to screen for HIV. There are no universal criteria for interpreting the western blot test: The number of viral bands that must be present may vary. If no viral bands are detected, the result is negative. If at least one viral band for each of the GAG, POL, and ENV gene-product groups are present, the result is positive. The three-gene-product approach to western blot interpretation has not been adopted for public health or clinical practice. Tests in which less than the required number of viral bands are detected are reported as indeterminate: a person who has an indeterminate result should be retested, as later tests may be more conclusive. Almost all HIV-infected persons with indeterminate western blot results will develop a positive result when tested in one month; persistently indeterminate results over a period of six months suggests the results are not due to HIV infection. In a generally healthy low-risk population, indeterminate results on western blot occur on the order of 1 in 5,000 patients. Since the advent of HIV testing of donor blood in the mid/later 1980s, ex. 1985's ELISA, the transmission of HIV during transfusion has dropped dramatically. Prior testing of donor blood only included testing for antibodies to HIV. However, because of latent infection (the \"window period\" in which an individual is infectious, but has not had time to develop antibodies) many cases of HIV seropositive blood were missed. The development of a nucleic acid test for the HIV-1 RNA has dramatically lowered the rate of donor blood seropositivity to about 1 in 3 million units. As transmittance of HIV does not necessarily mean HIV infection, the latter could still occur at an even lower rate. The transmission of hepatitis C via transfusion currently stands at a rate of about 1 in 2 million units. As with HIV, this low rate has been attributed to the ability to screen for both antibodies as well as viral RNA nucleic acid testing in donor blood. To evaluate a WHO testing strategy based on the use of two consecutive enzyme-linked immunosorbent assays (ELISA) as an alternative to ELISA followed by Western blotting (WB) for the serologic diagnosis of HIV infection. The study was of 2069 consecutive serum specimens from patients suspected of HIV infection received for HIV diagnostic testing at the HIV laboratory, Muhimbili Medical Centre, Dar es Salaam. The strategy involved testing all sera with Behring indirect anti-HIV 1 + 2 peptide ELISA, followed by Wellcozyme anti-HIV-1 recombinant competitive ELISA on those sera reactive by the first ELISA. WB was done on a sample of the sera reactive on both ELISAs and on all those giving discordant results on the two ELISAs. Of the 2069 sera tested, 837 (40.5%) were negative on the first ELISA, 1172 (56.6%) were reactive on both ELISAs and 60 (2.9%) were initially reactive on the first test but not on the second assay. Of the 1172 sera reactive on both ELISAs, 329 (28.1%) were tested by WB. The diagnostic accuracy of the WHO alternative testing strategy using WB confirmation as the 'gold' standard was as follows: sensitivity 99.4% (326/328), specificity 99.7%, (893/896), positive predictive value 99.1% (328/331) and negative predictive value 99.8% (893/895). Repeated testing by ELISA of the sera which initially gave discordant results on the two ELISAs increased the sensitivity to 100%. Three sera giving false positive reactions on both ELISAs became negative on both ELISAs after retesting. In order to achieve a specificity and a positive predictive value of 100%, it would have been necessary to subject all sera reacting on both ELISAs to retesting on one ELISA. A second ELISA based on different antigens and a different test principle compared with the first ELISA could be used as an alternative to the WB assay for confirmation of HIV antibodies. However, some modifications of the WHO strategy for diagnostic HIV antibody testing were required in order to maximize the diagnostic accuracy. Contagiousness The higher the viral load value, the more viral elements there are in blood and other body fluids. For example, individuals with HIV are most contagious during the earliest (acute) stages of the infection, sometimes with millions of copies of HIV per centiliter of blood. According to one estimate, the majority of transmissions among gay men in the UK occur during primary infection. This is because, at this phase, the immune response is still developing. Antibody levels against the virus during acute infection are often too low to be detected, meaning that an antibody test for a highly infectious individual can come back negative. The latest recommendations of the US Centers for Disease Control and Prevention (CDC) show that HIV testing must start with an immunoassay combination test for HIV-1 and HIV-2 antibodies and p24 antigen. A negative result rules out HIV exposure, while a positive one must be followed by an HIV-1/2 antibody differentiation immunoassay to detect which antibodies are present. This gives rise to four possible scenarios: 1. HIV-1 (+) & HIV-2 (−): HIV-1 antibodies detected 2. HIV-1 (−) & HIV-2 (+): HIV-2 antibodies detected 3. HIV-1 (+) & HIV-2 (+): both HIV-1 and HIV-2 antibodies detected 4. HIV-1 (−) or indeterminate & HIV-2 (−): Nucleic acid test must be carried out to detect the acute infection of HIV-1 or its absence. Research HIV/AIDS research includes all medical research that attempts to prevent, treat, or cure HIV/AIDS, as well as fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV. antibodies to HIV, an series of assay, HIV-1 RNA assay, or HIV-1 DNA PCR and specific serologic point-of-care tests can provide results in 1–60 min. Among the most testing for HIV-2. If the p24 and HIV RNA assays are negative and popular of these is the OraQuick Rapid HIV-1 antibody test that can be run on blood, plasma, or saliva. The sensitivity and specificity of this test is ~99% when run on whole blood. Specificity remains the SEROLOGIC TESTS IN THE DIAGNOSIS OF HIV-1 OR same but sensitivity drops to 98% when the test is run on saliva. While The standard blood screening tests for HIV infection are based on the detection of antibodies to HIV. A common platform is the ELISA, also referred to as an enzyme immunoassay (EIA). This solid-phase assay is an extremely good screening test with a sensitivity of >99.5%. Most diagnostic laboratories use commercial kits that contain antigens from both HIV-1 and HIV-2 and thus are able to detect antibodies to either. These kits use both natural and recombinant antigens and are continuously updated to increase their sensitivity to newly discovered species, such as group O viruses (Fig. 226-1). The fourth-generation EIA tests combine detection of antibodies to HIV with detection of the p24 antigen of HIV. EIA tests are generally scored as positive (highly reactive), negative (nonreactive), or indeterminate (partially reactive). While the EIA is an extremely sensitive test, it is not optimal with regard to specificity. This is particularly true in studies of low-risk individuals, such as The aim of the study was to detect HIV RNA in seropositive patients using RT-PCR method and thus, to establish PCR methodology in the routine laboratory works. The total of 33 examined persons were divided in two groups: 1) 13 persons seropositive for HIV; and 2) 20 healthy persons - randomly selected blood donors that made the case control group. The subjects age was between 25 and 52 years (average 38,5). ELFA test for combined detection of HIV p24 antigen and anti HIV-1+2 IgG and ELISA test for detection of antibodies against HIV-1 and HIV-2, were performed for each examined person. RNA from the whole blood was extracted using a commercial kit based on salt precipitation. Detection of HIV RNA was performed using RT-PCR kit. Following nested PCR, the product was separated by electrophoresis in 1,5 % agarose gel. The result was scored positive if the band of 210bp was visible regardless of intensity. Measures of precaution were taken during all the steps of the work and HIV infected materials were disposed of accordingly. In the group of blood donors ELFA, ELISA and RT-PCR were negative. Assuming that prevalence of HIV infection is zero, the clinical specificity of RT-PCR is 100 %. The analytical specificity of RT-PCR method was tested against Hepatitis C and B, Human Papiloma Virus, Cytomegalovirus, Herpes Simplex Virus, Rubella Virus, Mycobacterium tuberculosis, Chlamydia trachomatis. None of these templates yielded amplicon. In the group of 13 seropositive persons, 33 samples were analyzed. HIV RNA was detected in 15 samples. ELISA and ELFA test were positive in all samples. Different aliquots of the samples were tested independently and showed the same results. After different periods of storing the RNA samples at -70 masculineC, RT-PCR reaction was identical to the one performed initially. The obtained amplicons were maintained frozen at -20 masculineC for a week and the subsequently performed electrophoresis was identical to the previous one. The reaction is fast, simple for manipulation; with low detection level of 60 IU/ml. RT-PCR needs a small amount of RNA, as well as a small volume of sample. HIV RNA was detected in different periods of time with different clinical presentations in patients, with or without antiretroviral therapy. RT-PCR method gives the opportunity for reliable determination of HIV-1 RNA with border of detection of 60 IU/ml. The test is reproducible and has high analytical and clinical specificity. a period of six months suggests the results are not due to HIV infection. In a generally healthy low-risk population, indeterminate results on western blot occur on the order of 1 in 5,000 patients. However, for those individuals who have had high-risk exposures to individuals where HIV-2 is most prevalent, Western Africa, an inconclusive western blot test may prove infection with HIV-2. AIDS denialism HIV tests have been criticized by AIDS denialists (a fringe group whose members believe that HIV either does not exist or is harmless). The accuracy of serologic testing has been verified by isolation and culture of HIV and by detection of HIV RNA by PCR, which are widely accepted \"gold standards\" in microbiology. While AIDS denialists focus on individual components of HIV testing, the combination of ELISA and western blot used for the diagnosis of HIV is remarkably accurate, with very low false-positive and -negative rates as described above. The views of AIDS denialists are based on highly selective analysis of mostly outdated scientific papers; there is broad scientific consensus that HIV is the cause of AIDS. The study aims to evaluate the HIV-1/2 rapid diagnostic test kit is routinely used to screen HIV infection for safe blood transfusion and VCT services in many parts of Ethiopia. A total of 324 sera were collected from consecutive blood donors from February to May 2006. All samples were screened for HIV infection using Determine HIV-1/2 (Abbott Japan) at hospital blood bank laboratory. Blindly, all serums were retested at Regional Health Research Laboratory using 4th generation ELISA (Vironostika HIV Uni-Form II AG/Ab) and Determine HIV-1/2 (Abbott lab). Discordant samples were repeatedly retested using the same ELISA and Determine HIV-1/2 to avoid technical errors. Finally, discordant results were resolved using Western Blot at the National HIV/AIDS Laboratory. Determine HIV-1/2 and ELISA showed 94.4% concordance in HIV antibody testing with fair Cohen's Kappa statistic value (0.68) among blood donors. The sensitivity, specificity, positive and negative predictive values of Determine HIV-1/2 were 60.5%, 98.9%, 88.5% and 94.9% respectively. As a rapid HIV screening test for blood donors, Determine HIV-1/2 showed poor sensitivity. Further evaluation at multiple centres is recommended to test its validity as a routine HIV screening test in blood donors. Use of a combination of rapid assays is also recommended for screening of HIV infection among the donor population.\nHere is the question:\nINFECTIOUS DISEASES: A 20-year-old girl comes to the clinic with an acute fever, cervical lymphadenopathy and skin rash. According to the patient, 3 weeks ago she had a sexual relationship that could be a risk for contracting the HIV virus. Indicate which of the following answers is true:\nHere are the potential choices:\n1. A negative HIV-1/HIV-2 serology performed by ELISA technique rules out the possibility that the patient has been infected with the HIV virus.\n2. The clinical process that the patient suffers from is not consistent with acute HIV infection.\n3. If the patient's ELISA test was positive, nothing further would be necessary for the diagnosis of HIV infection.\n4. The ELISA technique has a high sensitivity for the diagnosis of HIV infection, but its specificity is even higher.\n5. If the ELISA test to diagnose HIV in the patient was negative, we could determine by PCR technique the viral load in blood.\nThe correct answer is: 2. The clinical process that the patient suffers from is not consistent with acute HIV infection."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Most authors agree that surgery is the treatment of choice for benign tumours of the parotid gland. However, the best surgical technique and the extent of surgery remain controversial. This study attempts to establish whether the implementation of a partial superficial parotidectomy (PSP) is appropriate for the treatment of benign parotid gland tumours. We selected 63 patients with benign parotid gland surgery, of whom 43 had a pleomorphic adenoma and 20, a Warthin tumour. Of this group of 63 patients, 6 could not be included. We consequently studied 57 patients, 41 of them diagnosed as pleomorphic adenoma and 16, as Warthin tumours. In all of them, a PSP was performed without intraoperative monitoring of the facial nerve. Transient facial nerve paralysis, 14 patients (24.5%). Ten cases were resolved within the first month after surgery and 4 before the third month, after indicating facial physiotherapy. One patient (1.7%) had a permanent difficulty in keeping one side of the lower lip aligned under pressure-mobility, without altering commissure mobility. None of the patients studied had a recurrence (control, 3-13 years). Although PSP is a technique with a few complications, it has a recurrence rate comparable to or lower than other techniques used for the treatment of pleomorphic adenomas or Warthin parotid tumours. Intraoperative facial nerve monitoring can be helpful during surgery. The lack of monitoring would not be considered a contraindication for surgery. Botulinum toxin has been successfully used to treat Frey's syndrome occurring in a 31-year-old patient following superficial parotidectomy for pleomorphic adenoma. An initial injection of 7.5 U (0.3 ml over 6 cm2 of cheek) resulted in 3 months' resolution of gustatory sweating and flushing and a second injection 12 months' symptomatic improvement. The symptoms recurred after further facial surgery. A case of Frey syndrome (FS) secondary to submaxillar gland exeresis is presented and the results of the treatment with botulinum toxin (BTX) type A. FS is a condition of sweating cheek and preauricular area during realtime as a sequel detected in about 20-60% of patients after parotidectomy. The clinical symptoms include swelling, flushing and hyperhidrosis. The treatment choice for this condition is intracutaneous injection of BTX type A which blocks acetylcholine release at the sweat glands. A 30-year-old man, with thyroid medullar carcinoma diagnosed in 2002 received 6 cicles of cisplatin plus doxorubicin previous to the thyroidectomy with anterolateral neck dissection. During surgery the left ramus marginalis mandibulae was damaged. Two years later the patient referred sweating in submaxillar region during meals. CT scan demonstrated the absence of left submaxillar gland. Minor's test disclosed the affected area and BTX type A was injected (2.5 U/cm2/17 points). A twenty-one-day control showed a 95% reduction of the affected skin area. Persistent efficacy was observed up to one year follow-up time when he was reinjected. The FS, also known as \"gustatory hyperhidrosis\", was probably first reported by M. Duphenix in 1757. Lucja Frey considered its physiopathology as a disorder of both sympathetic and parasympathetic innervation. In our case the FS was caused by a misdirected regeneration of postganglionic parasympathetic nerve fibers that arrised from the nervus lingualis rami ganglionares of the nervus trigeminus. After nerve injury the colinergic parasympathetic fibers seek out colinergic receptors--sympathetic receptors of the skin--innervating sweat glands and small skin vessels. All previous cases were located at masseter region post-parotidectomy. We have not found any description of FS in the submaxillary region. The self-assessed efficacy of the treatment with a hyperhidrosis disease severity scale revealed a very satisfied patient at 20 months follow-up after being injected twice with BTX type A. This is a retrospective study of 10 patients who underwent surgery for a first or multiple recurrence of pleomorphic adenoma (P.A.). Recurrence may come more than 10 years after an initial episode. During initial surgery, the risk of recurrence is related to pre-operative dissemination and to failure to identify tumoral prolongations in the parotid gland. Recurrence is generally multifocal. In 2 cases, carcinoma developed in association with P.A. Treatment of benign recurrence is surgical: it consists of totalizing the previous parotidectomy. If the previous parotidectomy has been total, tumorectomy is carried out. In all cases, surgery preserves the facial nerve trunk. Gustatory sweating is a common complication of parotid surgery. In order to evaluate the incidence of Frey's syndrome following superficial parotidectomy, 69 patients who underwent surgery due to adenoma were studied. Forty-three patients (62%) suffered from gustatory sweating following superficial parotidectomy, and 33 of them requested treatment. Nineteen patients felt that their quality of life had been decreased by the symptoms. Minor's starch iodine test proved that 85% of the patients who did not notice Frey's syndrome after surgery actually had a subclinical manifestation. Eight patients were successfully treated with intracutaneous injections of botulinum toxin A. Within 1 week gustatory sweating disappeared. Frey's syndrome is present in almost all patients following superficial parotidectomy and there is a strong need for treatment. Intracutaneous injection of botulinum toxin A is an effective treatment in severe cases of the syndrome. Complications Complications that may occur due to parotidectomy involve nerve dysfunction, Frey’s syndrome (uncharacteristic sweating near glands), salivation from wound, numbness, facial asymmetry, necrosis (death of skin) near incision, and tumor reappearance. Prognosis There is a 25-50% risk of facial weakness directly after parotidectomy and a 1-2% risk of permanent weakness. Frey’s syndrome may occur in up to 90% of patients. Risk of mortality is very low in reference to the surgery. In a case of benign tumor, such as pleomorphic adenoma, a significant outcome is also the rate of tumor recurrence. Pleomorphic adenomas may recur after a very long time from primary surgery, on average over 7–10 years and up to 24 years. Survival rates due to malignancy depends on the patient and extent of disease. A 10-year survival ranges from 32-83%. Of all cancers, salivary gland tumors account for only 1%. Parotid tumors account for 7% of all head and neck cancers. Etymology To describe the results of parotidectomy for pleomorphic adenoma of the parotid gland in 245 patients, 1974-1994. Descriptive. Academic Medical Hospital, Free University, Amsterdam, the Netherlands. Of all patients follow-up data were obtained by yearly physical diagnostic examination during 10 years, and by a questionnaire (1995) from the general practitioners involved. In the period 1974-1994, 246 primary surgical parotid procedures were performed on 245 patients for pleomorphic adenoma. The surgical procedures included: 131 'partial' and 61 'complete' superficial parotidectomies, 30 partial superficial/ deep lobe parotidectomies, 8 total parotidectomies, and 16 'selective' deep lobe parotidectomies. Eleven patients received postoperative radiotherapy for different reasons. The median follow-up was 95 months. Fourteen patients died without recurrent tumour. Two patients (0.8%) developed a local recurrence, both after total parotidectomy for a deep lobe tumour. None of the patients experienced permanent facial nerve paresis or paralysis. The incidence of auriculotemporal sweating for partial superficial parotidectomy proved to be 6.9% (9/I31) as compared with 13.1% (8/61) for complete superficial parotidectomy. In the later years, in the majority of patients, the posterior branch of the greater auricular nerve was preserved. In the hands of the experienced head and neck surgeon partial parotidectomy is an effective treatment for the great majority of pleomorphic adenomas: local recurrence is rare, while in general morbidity is minimal. Rarely there is a need for prolonged follow-up. Between 1967 and 1994, 344 patients were treated with total conservative parotidectomy for benign pleomorphic adenoma of the parotid gland. Our retrospective study focuses on a sixty-two patients group treated for recurrence after biopsy, enucleation or total parotidectomy. Twenty-two patients underwent a systematic total parotidectomy after biopsy (n = 7) or enucleation (n = 15). Twenty-nine patients were treated with total parotidectomy for local recurrence after enucleation. The mean time before this treatment was 8 years-9 months. In the third group, 11 patients, (7 patients from our institution), were surgically treated for recurrence after total parotidectomy. After enucleation, the recurrence rate was high and insufficient margins were found in 27% of the cases. In this group, a multicentric recurrence was found in 45% of the cases. In our own experience, recurrence after total parotidectomy was noted in 2.4%. The surgical salvage was performed with enucleation after identification of the branches of the facial nerve. The operative microscope was usefull. In 1 case, a second recurrence occured, and in 1 case iterative recurrence was noted. The local control rate after total parotidectomy was 99.6% (292/293). Total conservative parotidectomy is, for us, the treatment of choice for pleomorphic adenoma of the parotid gland. A twenty-year-old woman underwent right superficial parotidectomy for pleomorphic adenoma. On the 10th postoperative day she presented with a salivary fistula, for which repeated aspirations with pressure dressings were applied for a month. Despite decreases in the salivary fluid volume, reaccumulation persisted. Following aspiration of the salivary fluid, 40 units of botulinum toxin was injected into the pouch. On the second day of injection, the discharge ceased and the pouch disappeared. No side effects were observed and the patient remained symptom-free during four-month follow-up. Frey s syndrome or Gustatory sweating was first described by Baillarger in 1853. Lucie Frey had described a patient as \"auriculotemporal syndrome\" in 1923. The explanation for this symptom has been an aberrant regeneration of postganglionic parasympathetic fibers feeding the parotid gland that are severed during parotidectomy. After parotidectomy, these cholinergic parasympathetic fibers regenerate and anastomosis with postganglionic sympathetic fibers that supply vessel and sweat gland of the skin. According to a recent study, the treatment of Frey's syndrome has no treatment of choice. The authors investigated the effectiveness of botulinum toxin type A in the treatment of Frey's syndrome for the first time in Thai patients. The present study was a prospective non-randomized, exploratory study. Nine patients with a median involvement skin area of 4.2 cm2 (1-16.3) were injected intradermal with botulinum toxin type A 2 unit in every 1 cm2 of involved skin. The mean total dose was 10.6 units (range 2-32 unit). All of the patients showed improvement after 4-7 days. Five patients have no Gustatory sweating. In the same way, four patients present with a dramatic decrease in Gustatory sweating. When comparing the skin involvement area, indicated by Minor's iodine starch test and calculated by program ImageJ 1.34s, between before and after injection of botulinum toxin type A using sign test, the result is statistically significant with p = 0.0039. The result lasted for 9.2 months (7-10 months). Intradermal injection of botulinum toxin type A for patients with Frey's syndrome is not only effective with no side effect but also minimally invasive. The present report supports that intradermal injection of botulinum toxin type A should be the treatment of choice for Frey's syndrome. The Frey's syndrome, manifest after parotid trauma, is characterized by head and neck hyperemia and abundant sweating of the hyperemic skin in response to gustatory stimuli. The use of the botulin toxin to treat the symptoms in patients with Frey's syndrome has been described in numerous studies. For some time up until now our Center has achieved excellent results using the group A botulin toxin to overcome the hypertonus of the cricopharyngeal muscle in patients who had undergone laryngectomy and were rehabilitated with voice button. We have sought to extend the use of this toxin to Frey's syndrome, a relatively frequent complication of parotidectomy. A total of 86 patients participated in the study: 41 males (47.6%) and 45 females (52.4%) ranging in age from 25 to 77 years (average age 51 years). Of these patients 7 (8.1%) had undergone post-operative radiotherapy. Of the 86 patients studied, 18 referred significant symptoms in terms of abundance and frequency. The syndrome was considered severe if the symptoms were present at each meal and if the patient indicated a significant worsening of his quality of life. Intermittent episodes were indicated by 22 patients. The remaining 46 (43.5%) did not complain of any symptoms. The exact extension of the cervicofacial gustatory sweating was evaluated using the Minor test and the involved region was divided into 1 square centimeters sections. The amount of skin surface involved ranged from 10 to 80 square centimeters. The type A neurotoxin was frozen and was reconstituted with a sterile saline solution at a final concentration of 2.5 UI/0.1 ml. The intracutaneous infiltration was performed without anesthesia, infiltrating 0.1 ml of solution, containing 2.5 UI of toxin into the center of each 1 square centimeters section. Statistical analysis was performed to evaluate the potential relationship between how long the treatment was effective, incidence of recurrence, seriousness of the crises and the following variables: age, sex, histology, cutaneous surface involved, injected dose of botulin toxin and post-operative radiotherapy. In the group of 18 patients with severe symptoms (20.9%) the benefit was immediate in all cases although the recurrence rate was 50%. The Frey's syndrome symptoms disappeared within 7 days of infiltration. In the group of 22 patients with less severe involvement (25.5%), the treatment gave positive, definitive results in 16 patients (72.7%). Those patients whose symptoms persisted were treated a second time with an infiltration of 2.5 UI per square centimeters. We feel that the use of the type A botulin toxin is the most appropriate treatment for the Frey's syndrome. In fact, such treatment offers the following advantages: it is effective within 7 days, has limited side effects, can be applied on an outpatient basis, is inexpensive and is positively considered by the patients. There have been several approaches for surgery of parotid pleomorphic adenoma in the course of time. Enucleation of the tumor (i.e. intracapsular dissection), a procedure that was common in the early 20th century, is nowadays obsolete due to very high incidence of recurrence. After the time of enucleations, pleomorphic adenomas of parotid gland were recommended to be routinely treated with superficial or total parotidectomy. These procedures combine complete tumor removal and identification of the main trunk of facial nerve during surgery to avoid any lesions to the nerve. However, extensive surgery may cause significant morbidity, such as Frey´s syndrome (excessive sweat while eating) and salivary fistula. Also, aesthetic outcome may be compromised. Therefore, less invasive procedures have been preferred in selected cases during the recent years, and introduction of perioperative neuromonitoring enabled the evolution of several different surgical techniques some twenty years ago. Frey's syndrome, gustatory sweating in the preauricular area, is an unpleasant phenomenon occurring during meals after surgery on the parotid gland. Recently, botulinum toxin A (BTX) has been shown to reduce the symptoms, but the variation in the reported doses is large. To quantify the effect of treatment with low-dose BTX in a case of Frey's syndrome over a period of 6 months. A 56-year-old woman was treated with 10 U Botox given as 20 single, intracutaneous injections of 0.5 U, one for each cm(2), 3 years after resection of the parotid gland. Before treatment and repeatedly during the 6-month period, the sweating was rated subjectively on a 100-mm visual analog scale (VAS) and by a severity index, and objectively by assessment of the extent of the involved skin area using Minor's iodine-starch test, staining the area of sweating dark. The treatment decreased the involved area from 20 to 5 cm(2) and the VAS ratings from 98 to 8 mm. The index showed that treatment affected the sweating intensity, not the frequency. After the 6-month period the patient was still satisfied, but the involved skin area had increased; however, not entirely to pretreatment values. The effect of BTX injections for gustatory sweating obtained in this case was comparable to results reported using higher doses. Low doses of BTX can therefore be used in the treatment of Frey's syndrome, but studies to clarify the dose-response relationship, in terms of both time-course and obtained effect, are needed. Almost all patients who undergo parotidectomy will to some extent develop Frey syndrome (auriculotemporal syndrome or gustatory sweating) after surgery, because of aberrant regeneration of cut parasympathetic fibers between otic ganglion and subcutaneous vessels. However, only the minority of these patients needs treatment. The syndrome consists of gustatory sweating, flushing, and warming over the preauricular and temporal areas. Thick skin flap and partial superficial parotidectomy are the most important techniques to minimize the risk of developing symptomatic Frey syndrome. Intracutaneous injection of botulinum toxin A is an effective, long-lasting, and well-tolerated treatment of Frey syndrome. If recurrence occurs, the treatment can be repeated. Frey’s syndrome: more accurately referred to as gustatory sweating. Patients report facial swelling and sweating at the site of the parotidectomy in occurrence with meals. Etiology is believed to be aberrant innervation of the sweat glands with branches emerging from the auriculotemporal nerve after their division during surgery. This provides parasympathetic innervation to the normally sympathetic-innervated sweat glands [38] . Diagnosis is usually based on patient history, however if there is any doubt an iodine-starch test (Minor test) will confirm the diagnosis, where iodine starch placed on the affected area turns blue signaling sweat secretion. The incidence historically has been reported as high as 50 to 100%, though, with modern techniques and the use of SMAS flaps and thicker skin flaps at the time of initial elevation, this is greatly reduced and is now quite rare. Should this develop, surgical treatment options can be disappointing, with the best results obtained using SMAS and superficial temporal artery flaps as a barrier between the surgical site and the skin. Gold standard treatment now is botulinum toxin injection. Relief of symptoms is obtained for 6 to 36 months. It works at the pre-synaptic level of the neuromuscular and neuroglandular junction by blocking the release of acetylcholine. [37] [39] Currently, the choice of surgical approach for parotid pleomorphic adenoma is mainly based on the size, location, and mobility of the tumor. The recommended main techniques include extracapsular dissection, partial superficial parotidectomy, and lateral or total parotidectomy. Nevertheless, the experience of surgeon plays a key role in the results of these distinct procedures. An important point of view is that recurrent pleomorphic adenomas may occur after a very long time from primary surgery, on average over 7–10 years but up to 24 years afterwards. Thus, it is of utmost importance to evaluate the ultimate results of these different surgical techniques in the future. The benign tumors of the submandibular gland is treated by simple excision with preservation of mandibular branch of the facial nerve, the hypoglossal nerve, and the lingual nerve. Other benign tumors of minor salivary glands are treated similarly. Several authors demand emphatically that the minimal operative procedure in benign parotid gland tumors has to be a superficial parotidectomy. Of a consecutive series of 372 patients with benign parotid tumors treated in our department between 1973-1996 81% of the patients could be followed up 1-24 years. in 10.9% a total parotidectomy was performed, in 16% a lateral parotidectomy and in 73.1% a simple extirpation of the tumor (often taking away a small margin of surrounding parotid parenchyma). The operating microscope and microsurgical techniques were used in all of these operations. Of all the followed-up patients 2.3% developed a recurrence. There were no recurrences of cystadenolymphomas or of rare types of adenomas. Recurrences of primary treated pleomorphic adenomas occurred in 3.0%. In recurrent pleomorphic adenomas a further recurrence could be seen in 7.4% of the cases. The over-all incidence of permanent facial nerve weakness was 2.1%: 0.7% after extirpation, 3.3% after lateral parotidectomy and 9.7% after total parotidectomy. we observed in 6.3% a gustatory sweating. Our data prove that with simple extirpation similar results compared to lateral parotidectomy can be achieved concerning recurrence, function of the facial nerve and the Frey's syndrome. We suggest a surgical management adapted to the extent, the size and the location of the parotid gland tumors. In our opinion lateral or total parotidectomy should be reserved for tumors of larger amount or deep located tumors. Post-Operation After completion of a parotidectomy, patients can expect postoperative hospitalization ranging from one-to-three days, to help ensure the safest and most effective postoperative management. At this time, patients will be administered antibiotics to minimize risk of infection as well as an assessment of pain management throughout their stay. Duration of hospitalization is subject to change from patient to patient, with most patients being discharged within 24 hours after surgery. If a tumor was malignant, many patients are referred to radiation therapy. For benign tumors and slow growing cancers, surgery typically provides a complete cure or remission (no evidence for disease). Patient Care after Discharge Throughout history, many different types and techniques have been developed in order to complete a parotidectomy and consequently, many different names have been associated with each type. However, there are really only two main distinctions to be made in parotidectomies: The specific nerve(s) to be dissected or not dissected The amount of gland excised It is important to note that the specific surgery chosen is based on preservation of the facial nerve in order to avoid significant morbidities (diseases). Furthermore, there are still many controversies regarding the choice of surgery and incidence of cancer recurrence. Below indicates the various and main techniques typically associated with a parotidectomy: Extracapsular dissection - excision of the parotid tumor surrounded by some millimetres of healthy tissue, without searching and exposing the main truck of the facial nerve. This study compared extracapsular dissection (ED) vs superficial parotidectomy (SP) in the treatment of pleomorphic adenoma and benign parotid tumors. The research covered the years 1950-2011 in PubMed, Ovid MEDLINE, the Cochrane Database of Systematic Reviews, and Scopus. Of 1152 articles screened, 123 studies met the inclusion criteria. A review of the nomenclature of the different parotid surgery techniques was done. Recurrence rate, permanent facial nerve paralysis, and Frey syndrome of patients who underwent ED vs those who underwent SP were compared by meta-analysis. Our meta-analysis data comparing ED and SP found that: (1) the recurrence rate is higher in patients treated with SP; (2) SP has a higher incidence of cranial nerve VII paralysis; and (3) Frey syndrome is more common after SP. ED may be a viable option in the treatment of unilateral benign parotid tumors of the superficial lobe, sized less than 4 cm, without involvement of the facial nerve. Treatments Injection of botulinum toxin A Surgical transection of the nerve fibers (a temporary treatment) Application of an ointment containing an anticholinergic drug such as scopolamine Cochrane reviews of interventions to either prevent or treat Frey’s syndrome have found little or no evidence to support their effectiveness or safety, and conclude that further clinical trials are needed. Epidemiology The condition is rare, although the exact incidence is unknown. The disorder most often occurs as a complication of the surgical removal of a parotid gland (parotidectomy). The percentage of individuals who develop Frey syndrome after a parotidectomy is controversial and reported estimates range from 30–50 percent. In follow-up examinations, approximately 15 percent of affected individuals rated their symptoms as severe. Frey syndrome affects males and females in equal numbers. Twenty years experience of lateral parotidectomy as suspical treatment for pleomorphic adenoma are reviewed. All cases were managed at the ORL Clinic of the University of Zürich. 167 patients were followed for the frequency of possible recurrent tumors. Three patients (3/123) operated primarily developed a recurrences. Recurrences appeared after an average of 10 years, ranging from 1-30 years. The follow-up time varied from 1 to 21 years (average, 8 years). 39% (13 of 33) of the patients, who were re-operated for a recurrent tumor, developed another recurrence. The second recurrence appeared after an average of 10 years, ranging from 1-22 years. A persistent partial paresis of the facial nerve was found in 1% of the patients operated primarily and in 9% of the patients operated more than once. No paralysis was seen. We now choose \"en-bloc\" resections of pleomorphic adenomas without intra-operative opening of the tumor capsule as the treatment of choice. This treatment was possible in 83% of all cases, using a lateral parotidectomy. If tumor extends into the medial parotid lobe, total parotidectomy is required. The tumors of the salivary glands are infrequent in children, and parotid gland is involved in 80% of them. When a salivary gland tumor is present, the chance of malignancy is greater in the child than in the adult. We reviewed 8 cases identified in patients aged 14 years and younger in our hospital, analyzing its antecedents, signs and symptoms, histological features, diagnosis, treatment and evolution. All the patients displayed preauricular painless, non-inflammatory and slow-growing masses to an age between 10 months and 14 years. Four or them were pleomorphic adenomas, two haemangiomas, one epidermal cysts and one myoepithelial carcinoma. We emphasize the exceptional nature of the carcinoma for its rareness and for the high degree of malignancy expressed. We made a fine needle aspiration biopsy in four cases but they were conclusive only in three. All were treated by surgical resection of the tumour except for the myoepithelial carcinoma and the recurrent pleomorphic adenoma that were treated by total parotidectomy. The malignant tumours of the parotid gland are clinically indistinguishable of the benign ones, thus when any palpable mass appears in the zone of the parotid gland, an accurate diagnosis should be made without delay. The treatment of choice is the surgical excision with wide margins, being other adjuvant treatments less useful to this age than in the adult age. To evaluate salivary gland chemodenervation with botulinum toxin in chronic parotid sialadenitis. Patients who underwent parotid gland chemodenervation for chronic sialadenitis due to duct stenosis refractory to siaendoscopy were reviewed (case series). Additionally, a systematic review of the literature on botulinum toxin injection for chronic parotid sialadenitis was performed. Inclusion criteria included studies containing original data on botulinum toxin injections in patients with chronic sialadenitis symptoms. Sialadenitis symptoms from 10 patients with 13 affected parotid glands were examined. All had duct stenosis diagnosed on sialendoscopy, refractory sialadenitis symptoms, and received parotid onabotulinum toxin injection(s) (median dose 65U). Of patients with 3-month follow-up, 78% reported significant improvement in symptoms. Mean Chronic Obstructive Sialadenitis Symptoms (COSS) Score improved at 3 months post-injection (47-25.9, <iP</i = .039) with significant reduction in gland pain frequency and gland swelling severity. No patients had a facial nerve paralysis or increased xerostomia. With the systematic review, 518 abstracts were reviewed and 11 studies met inclusion criteria and included case series or case reports with a total of 40 patients treated with botulinum toxin for chronic parotitis. Thirty-four out of a total of 35 patients in the studies (97%) reported complete (9, 26%) or partial (25, 71%) improvement in sialadenitis symptoms with minimal complications. Parotid gland chemodenervation with botulinum toxin is a minimally invasive treatment option for symptomatic chronic sialadenitis refractory to medical treatment or sialendoscopy. Botulinum toxin injections alleviate gland pain and swelling associated with salivary obstruction and provide an alternative to parotidectomy for recurrent sialadenitis.Level of evidence: 4.\nHere is the question:\nOTOLARYNGOLOGY AND MAXILLOFACIAL SURGERY: A 47-year-old man, with a history of a right parotid pleomorphic adenoma, treated with surgery (extrafacial parotidectomy) 6 months ago, who comes to our office for presenting pain with sweating and reddening of the skin in the preauricular region during mastication. What treatment would be the treatment of choice?\nHere are the potential choices:\n1. Extended total parotidectomy on suspicion of tumor recurrence.\n2. Pregabalin.\n3. Intradermal botulinum toxin injection.\n4. Broad-spectrum antibiotherapy.\nThe correct answer is: ",
        "gold_answer": "3 Intradermal botulinum toxin injection.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Most authors agree that surgery is the treatment of choice for benign tumours of the parotid gland. However, the best surgical technique and the extent of surgery remain controversial. This study attempts to establish whether the implementation of a partial superficial parotidectomy (PSP) is appropriate for the treatment of benign parotid gland tumours. We selected 63 patients with benign parotid gland surgery, of whom 43 had a pleomorphic adenoma and 20, a Warthin tumour. Of this group of 63 patients, 6 could not be included. We consequently studied 57 patients, 41 of them diagnosed as pleomorphic adenoma and 16, as Warthin tumours. In all of them, a PSP was performed without intraoperative monitoring of the facial nerve. Transient facial nerve paralysis, 14 patients (24.5%). Ten cases were resolved within the first month after surgery and 4 before the third month, after indicating facial physiotherapy. One patient (1.7%) had a permanent difficulty in keeping one side of the lower lip aligned under pressure-mobility, without altering commissure mobility. None of the patients studied had a recurrence (control, 3-13 years). Although PSP is a technique with a few complications, it has a recurrence rate comparable to or lower than other techniques used for the treatment of pleomorphic adenomas or Warthin parotid tumours. Intraoperative facial nerve monitoring can be helpful during surgery. The lack of monitoring would not be considered a contraindication for surgery. Botulinum toxin has been successfully used to treat Frey's syndrome occurring in a 31-year-old patient following superficial parotidectomy for pleomorphic adenoma. An initial injection of 7.5 U (0.3 ml over 6 cm2 of cheek) resulted in 3 months' resolution of gustatory sweating and flushing and a second injection 12 months' symptomatic improvement. The symptoms recurred after further facial surgery. A case of Frey syndrome (FS) secondary to submaxillar gland exeresis is presented and the results of the treatment with botulinum toxin (BTX) type A. FS is a condition of sweating cheek and preauricular area during realtime as a sequel detected in about 20-60% of patients after parotidectomy. The clinical symptoms include swelling, flushing and hyperhidrosis. The treatment choice for this condition is intracutaneous injection of BTX type A which blocks acetylcholine release at the sweat glands. A 30-year-old man, with thyroid medullar carcinoma diagnosed in 2002 received 6 cicles of cisplatin plus doxorubicin previous to the thyroidectomy with anterolateral neck dissection. During surgery the left ramus marginalis mandibulae was damaged. Two years later the patient referred sweating in submaxillar region during meals. CT scan demonstrated the absence of left submaxillar gland. Minor's test disclosed the affected area and BTX type A was injected (2.5 U/cm2/17 points). A twenty-one-day control showed a 95% reduction of the affected skin area. Persistent efficacy was observed up to one year follow-up time when he was reinjected. The FS, also known as \"gustatory hyperhidrosis\", was probably first reported by M. Duphenix in 1757. Lucja Frey considered its physiopathology as a disorder of both sympathetic and parasympathetic innervation. In our case the FS was caused by a misdirected regeneration of postganglionic parasympathetic nerve fibers that arrised from the nervus lingualis rami ganglionares of the nervus trigeminus. After nerve injury the colinergic parasympathetic fibers seek out colinergic receptors--sympathetic receptors of the skin--innervating sweat glands and small skin vessels. All previous cases were located at masseter region post-parotidectomy. We have not found any description of FS in the submaxillary region. The self-assessed efficacy of the treatment with a hyperhidrosis disease severity scale revealed a very satisfied patient at 20 months follow-up after being injected twice with BTX type A. This is a retrospective study of 10 patients who underwent surgery for a first or multiple recurrence of pleomorphic adenoma (P.A.). Recurrence may come more than 10 years after an initial episode. During initial surgery, the risk of recurrence is related to pre-operative dissemination and to failure to identify tumoral prolongations in the parotid gland. Recurrence is generally multifocal. In 2 cases, carcinoma developed in association with P.A. Treatment of benign recurrence is surgical: it consists of totalizing the previous parotidectomy. If the previous parotidectomy has been total, tumorectomy is carried out. In all cases, surgery preserves the facial nerve trunk. Gustatory sweating is a common complication of parotid surgery. In order to evaluate the incidence of Frey's syndrome following superficial parotidectomy, 69 patients who underwent surgery due to adenoma were studied. Forty-three patients (62%) suffered from gustatory sweating following superficial parotidectomy, and 33 of them requested treatment. Nineteen patients felt that their quality of life had been decreased by the symptoms. Minor's starch iodine test proved that 85% of the patients who did not notice Frey's syndrome after surgery actually had a subclinical manifestation. Eight patients were successfully treated with intracutaneous injections of botulinum toxin A. Within 1 week gustatory sweating disappeared. Frey's syndrome is present in almost all patients following superficial parotidectomy and there is a strong need for treatment. Intracutaneous injection of botulinum toxin A is an effective treatment in severe cases of the syndrome. Complications Complications that may occur due to parotidectomy involve nerve dysfunction, Frey’s syndrome (uncharacteristic sweating near glands), salivation from wound, numbness, facial asymmetry, necrosis (death of skin) near incision, and tumor reappearance. Prognosis There is a 25-50% risk of facial weakness directly after parotidectomy and a 1-2% risk of permanent weakness. Frey’s syndrome may occur in up to 90% of patients. Risk of mortality is very low in reference to the surgery. In a case of benign tumor, such as pleomorphic adenoma, a significant outcome is also the rate of tumor recurrence. Pleomorphic adenomas may recur after a very long time from primary surgery, on average over 7–10 years and up to 24 years. Survival rates due to malignancy depends on the patient and extent of disease. A 10-year survival ranges from 32-83%. Of all cancers, salivary gland tumors account for only 1%. Parotid tumors account for 7% of all head and neck cancers. Etymology To describe the results of parotidectomy for pleomorphic adenoma of the parotid gland in 245 patients, 1974-1994. Descriptive. Academic Medical Hospital, Free University, Amsterdam, the Netherlands. Of all patients follow-up data were obtained by yearly physical diagnostic examination during 10 years, and by a questionnaire (1995) from the general practitioners involved. In the period 1974-1994, 246 primary surgical parotid procedures were performed on 245 patients for pleomorphic adenoma. The surgical procedures included: 131 'partial' and 61 'complete' superficial parotidectomies, 30 partial superficial/ deep lobe parotidectomies, 8 total parotidectomies, and 16 'selective' deep lobe parotidectomies. Eleven patients received postoperative radiotherapy for different reasons. The median follow-up was 95 months. Fourteen patients died without recurrent tumour. Two patients (0.8%) developed a local recurrence, both after total parotidectomy for a deep lobe tumour. None of the patients experienced permanent facial nerve paresis or paralysis. The incidence of auriculotemporal sweating for partial superficial parotidectomy proved to be 6.9% (9/I31) as compared with 13.1% (8/61) for complete superficial parotidectomy. In the later years, in the majority of patients, the posterior branch of the greater auricular nerve was preserved. In the hands of the experienced head and neck surgeon partial parotidectomy is an effective treatment for the great majority of pleomorphic adenomas: local recurrence is rare, while in general morbidity is minimal. Rarely there is a need for prolonged follow-up. Between 1967 and 1994, 344 patients were treated with total conservative parotidectomy for benign pleomorphic adenoma of the parotid gland. Our retrospective study focuses on a sixty-two patients group treated for recurrence after biopsy, enucleation or total parotidectomy. Twenty-two patients underwent a systematic total parotidectomy after biopsy (n = 7) or enucleation (n = 15). Twenty-nine patients were treated with total parotidectomy for local recurrence after enucleation. The mean time before this treatment was 8 years-9 months. In the third group, 11 patients, (7 patients from our institution), were surgically treated for recurrence after total parotidectomy. After enucleation, the recurrence rate was high and insufficient margins were found in 27% of the cases. In this group, a multicentric recurrence was found in 45% of the cases. In our own experience, recurrence after total parotidectomy was noted in 2.4%. The surgical salvage was performed with enucleation after identification of the branches of the facial nerve. The operative microscope was usefull. In 1 case, a second recurrence occured, and in 1 case iterative recurrence was noted. The local control rate after total parotidectomy was 99.6% (292/293). Total conservative parotidectomy is, for us, the treatment of choice for pleomorphic adenoma of the parotid gland. A twenty-year-old woman underwent right superficial parotidectomy for pleomorphic adenoma. On the 10th postoperative day she presented with a salivary fistula, for which repeated aspirations with pressure dressings were applied for a month. Despite decreases in the salivary fluid volume, reaccumulation persisted. Following aspiration of the salivary fluid, 40 units of botulinum toxin was injected into the pouch. On the second day of injection, the discharge ceased and the pouch disappeared. No side effects were observed and the patient remained symptom-free during four-month follow-up. Frey s syndrome or Gustatory sweating was first described by Baillarger in 1853. Lucie Frey had described a patient as \"auriculotemporal syndrome\" in 1923. The explanation for this symptom has been an aberrant regeneration of postganglionic parasympathetic fibers feeding the parotid gland that are severed during parotidectomy. After parotidectomy, these cholinergic parasympathetic fibers regenerate and anastomosis with postganglionic sympathetic fibers that supply vessel and sweat gland of the skin. According to a recent study, the treatment of Frey's syndrome has no treatment of choice. The authors investigated the effectiveness of botulinum toxin type A in the treatment of Frey's syndrome for the first time in Thai patients. The present study was a prospective non-randomized, exploratory study. Nine patients with a median involvement skin area of 4.2 cm2 (1-16.3) were injected intradermal with botulinum toxin type A 2 unit in every 1 cm2 of involved skin. The mean total dose was 10.6 units (range 2-32 unit). All of the patients showed improvement after 4-7 days. Five patients have no Gustatory sweating. In the same way, four patients present with a dramatic decrease in Gustatory sweating. When comparing the skin involvement area, indicated by Minor's iodine starch test and calculated by program ImageJ 1.34s, between before and after injection of botulinum toxin type A using sign test, the result is statistically significant with p = 0.0039. The result lasted for 9.2 months (7-10 months). Intradermal injection of botulinum toxin type A for patients with Frey's syndrome is not only effective with no side effect but also minimally invasive. The present report supports that intradermal injection of botulinum toxin type A should be the treatment of choice for Frey's syndrome. The Frey's syndrome, manifest after parotid trauma, is characterized by head and neck hyperemia and abundant sweating of the hyperemic skin in response to gustatory stimuli. The use of the botulin toxin to treat the symptoms in patients with Frey's syndrome has been described in numerous studies. For some time up until now our Center has achieved excellent results using the group A botulin toxin to overcome the hypertonus of the cricopharyngeal muscle in patients who had undergone laryngectomy and were rehabilitated with voice button. We have sought to extend the use of this toxin to Frey's syndrome, a relatively frequent complication of parotidectomy. A total of 86 patients participated in the study: 41 males (47.6%) and 45 females (52.4%) ranging in age from 25 to 77 years (average age 51 years). Of these patients 7 (8.1%) had undergone post-operative radiotherapy. Of the 86 patients studied, 18 referred significant symptoms in terms of abundance and frequency. The syndrome was considered severe if the symptoms were present at each meal and if the patient indicated a significant worsening of his quality of life. Intermittent episodes were indicated by 22 patients. The remaining 46 (43.5%) did not complain of any symptoms. The exact extension of the cervicofacial gustatory sweating was evaluated using the Minor test and the involved region was divided into 1 square centimeters sections. The amount of skin surface involved ranged from 10 to 80 square centimeters. The type A neurotoxin was frozen and was reconstituted with a sterile saline solution at a final concentration of 2.5 UI/0.1 ml. The intracutaneous infiltration was performed without anesthesia, infiltrating 0.1 ml of solution, containing 2.5 UI of toxin into the center of each 1 square centimeters section. Statistical analysis was performed to evaluate the potential relationship between how long the treatment was effective, incidence of recurrence, seriousness of the crises and the following variables: age, sex, histology, cutaneous surface involved, injected dose of botulin toxin and post-operative radiotherapy. In the group of 18 patients with severe symptoms (20.9%) the benefit was immediate in all cases although the recurrence rate was 50%. The Frey's syndrome symptoms disappeared within 7 days of infiltration. In the group of 22 patients with less severe involvement (25.5%), the treatment gave positive, definitive results in 16 patients (72.7%). Those patients whose symptoms persisted were treated a second time with an infiltration of 2.5 UI per square centimeters. We feel that the use of the type A botulin toxin is the most appropriate treatment for the Frey's syndrome. In fact, such treatment offers the following advantages: it is effective within 7 days, has limited side effects, can be applied on an outpatient basis, is inexpensive and is positively considered by the patients. There have been several approaches for surgery of parotid pleomorphic adenoma in the course of time. Enucleation of the tumor (i.e. intracapsular dissection), a procedure that was common in the early 20th century, is nowadays obsolete due to very high incidence of recurrence. After the time of enucleations, pleomorphic adenomas of parotid gland were recommended to be routinely treated with superficial or total parotidectomy. These procedures combine complete tumor removal and identification of the main trunk of facial nerve during surgery to avoid any lesions to the nerve. However, extensive surgery may cause significant morbidity, such as Frey´s syndrome (excessive sweat while eating) and salivary fistula. Also, aesthetic outcome may be compromised. Therefore, less invasive procedures have been preferred in selected cases during the recent years, and introduction of perioperative neuromonitoring enabled the evolution of several different surgical techniques some twenty years ago. Frey's syndrome, gustatory sweating in the preauricular area, is an unpleasant phenomenon occurring during meals after surgery on the parotid gland. Recently, botulinum toxin A (BTX) has been shown to reduce the symptoms, but the variation in the reported doses is large. To quantify the effect of treatment with low-dose BTX in a case of Frey's syndrome over a period of 6 months. A 56-year-old woman was treated with 10 U Botox given as 20 single, intracutaneous injections of 0.5 U, one for each cm(2), 3 years after resection of the parotid gland. Before treatment and repeatedly during the 6-month period, the sweating was rated subjectively on a 100-mm visual analog scale (VAS) and by a severity index, and objectively by assessment of the extent of the involved skin area using Minor's iodine-starch test, staining the area of sweating dark. The treatment decreased the involved area from 20 to 5 cm(2) and the VAS ratings from 98 to 8 mm. The index showed that treatment affected the sweating intensity, not the frequency. After the 6-month period the patient was still satisfied, but the involved skin area had increased; however, not entirely to pretreatment values. The effect of BTX injections for gustatory sweating obtained in this case was comparable to results reported using higher doses. Low doses of BTX can therefore be used in the treatment of Frey's syndrome, but studies to clarify the dose-response relationship, in terms of both time-course and obtained effect, are needed. Almost all patients who undergo parotidectomy will to some extent develop Frey syndrome (auriculotemporal syndrome or gustatory sweating) after surgery, because of aberrant regeneration of cut parasympathetic fibers between otic ganglion and subcutaneous vessels. However, only the minority of these patients needs treatment. The syndrome consists of gustatory sweating, flushing, and warming over the preauricular and temporal areas. Thick skin flap and partial superficial parotidectomy are the most important techniques to minimize the risk of developing symptomatic Frey syndrome. Intracutaneous injection of botulinum toxin A is an effective, long-lasting, and well-tolerated treatment of Frey syndrome. If recurrence occurs, the treatment can be repeated. Frey’s syndrome: more accurately referred to as gustatory sweating. Patients report facial swelling and sweating at the site of the parotidectomy in occurrence with meals. Etiology is believed to be aberrant innervation of the sweat glands with branches emerging from the auriculotemporal nerve after their division during surgery. This provides parasympathetic innervation to the normally sympathetic-innervated sweat glands [38] . Diagnosis is usually based on patient history, however if there is any doubt an iodine-starch test (Minor test) will confirm the diagnosis, where iodine starch placed on the affected area turns blue signaling sweat secretion. The incidence historically has been reported as high as 50 to 100%, though, with modern techniques and the use of SMAS flaps and thicker skin flaps at the time of initial elevation, this is greatly reduced and is now quite rare. Should this develop, surgical treatment options can be disappointing, with the best results obtained using SMAS and superficial temporal artery flaps as a barrier between the surgical site and the skin. Gold standard treatment now is botulinum toxin injection. Relief of symptoms is obtained for 6 to 36 months. It works at the pre-synaptic level of the neuromuscular and neuroglandular junction by blocking the release of acetylcholine. [37] [39] Currently, the choice of surgical approach for parotid pleomorphic adenoma is mainly based on the size, location, and mobility of the tumor. The recommended main techniques include extracapsular dissection, partial superficial parotidectomy, and lateral or total parotidectomy. Nevertheless, the experience of surgeon plays a key role in the results of these distinct procedures. An important point of view is that recurrent pleomorphic adenomas may occur after a very long time from primary surgery, on average over 7–10 years but up to 24 years afterwards. Thus, it is of utmost importance to evaluate the ultimate results of these different surgical techniques in the future. The benign tumors of the submandibular gland is treated by simple excision with preservation of mandibular branch of the facial nerve, the hypoglossal nerve, and the lingual nerve. Other benign tumors of minor salivary glands are treated similarly. Several authors demand emphatically that the minimal operative procedure in benign parotid gland tumors has to be a superficial parotidectomy. Of a consecutive series of 372 patients with benign parotid tumors treated in our department between 1973-1996 81% of the patients could be followed up 1-24 years. in 10.9% a total parotidectomy was performed, in 16% a lateral parotidectomy and in 73.1% a simple extirpation of the tumor (often taking away a small margin of surrounding parotid parenchyma). The operating microscope and microsurgical techniques were used in all of these operations. Of all the followed-up patients 2.3% developed a recurrence. There were no recurrences of cystadenolymphomas or of rare types of adenomas. Recurrences of primary treated pleomorphic adenomas occurred in 3.0%. In recurrent pleomorphic adenomas a further recurrence could be seen in 7.4% of the cases. The over-all incidence of permanent facial nerve weakness was 2.1%: 0.7% after extirpation, 3.3% after lateral parotidectomy and 9.7% after total parotidectomy. we observed in 6.3% a gustatory sweating. Our data prove that with simple extirpation similar results compared to lateral parotidectomy can be achieved concerning recurrence, function of the facial nerve and the Frey's syndrome. We suggest a surgical management adapted to the extent, the size and the location of the parotid gland tumors. In our opinion lateral or total parotidectomy should be reserved for tumors of larger amount or deep located tumors. Post-Operation After completion of a parotidectomy, patients can expect postoperative hospitalization ranging from one-to-three days, to help ensure the safest and most effective postoperative management. At this time, patients will be administered antibiotics to minimize risk of infection as well as an assessment of pain management throughout their stay. Duration of hospitalization is subject to change from patient to patient, with most patients being discharged within 24 hours after surgery. If a tumor was malignant, many patients are referred to radiation therapy. For benign tumors and slow growing cancers, surgery typically provides a complete cure or remission (no evidence for disease). Patient Care after Discharge Throughout history, many different types and techniques have been developed in order to complete a parotidectomy and consequently, many different names have been associated with each type. However, there are really only two main distinctions to be made in parotidectomies: The specific nerve(s) to be dissected or not dissected The amount of gland excised It is important to note that the specific surgery chosen is based on preservation of the facial nerve in order to avoid significant morbidities (diseases). Furthermore, there are still many controversies regarding the choice of surgery and incidence of cancer recurrence. Below indicates the various and main techniques typically associated with a parotidectomy: Extracapsular dissection - excision of the parotid tumor surrounded by some millimetres of healthy tissue, without searching and exposing the main truck of the facial nerve. This study compared extracapsular dissection (ED) vs superficial parotidectomy (SP) in the treatment of pleomorphic adenoma and benign parotid tumors. The research covered the years 1950-2011 in PubMed, Ovid MEDLINE, the Cochrane Database of Systematic Reviews, and Scopus. Of 1152 articles screened, 123 studies met the inclusion criteria. A review of the nomenclature of the different parotid surgery techniques was done. Recurrence rate, permanent facial nerve paralysis, and Frey syndrome of patients who underwent ED vs those who underwent SP were compared by meta-analysis. Our meta-analysis data comparing ED and SP found that: (1) the recurrence rate is higher in patients treated with SP; (2) SP has a higher incidence of cranial nerve VII paralysis; and (3) Frey syndrome is more common after SP. ED may be a viable option in the treatment of unilateral benign parotid tumors of the superficial lobe, sized less than 4 cm, without involvement of the facial nerve. Treatments Injection of botulinum toxin A Surgical transection of the nerve fibers (a temporary treatment) Application of an ointment containing an anticholinergic drug such as scopolamine Cochrane reviews of interventions to either prevent or treat Frey’s syndrome have found little or no evidence to support their effectiveness or safety, and conclude that further clinical trials are needed. Epidemiology The condition is rare, although the exact incidence is unknown. The disorder most often occurs as a complication of the surgical removal of a parotid gland (parotidectomy). The percentage of individuals who develop Frey syndrome after a parotidectomy is controversial and reported estimates range from 30–50 percent. In follow-up examinations, approximately 15 percent of affected individuals rated their symptoms as severe. Frey syndrome affects males and females in equal numbers. Twenty years experience of lateral parotidectomy as suspical treatment for pleomorphic adenoma are reviewed. All cases were managed at the ORL Clinic of the University of Zürich. 167 patients were followed for the frequency of possible recurrent tumors. Three patients (3/123) operated primarily developed a recurrences. Recurrences appeared after an average of 10 years, ranging from 1-30 years. The follow-up time varied from 1 to 21 years (average, 8 years). 39% (13 of 33) of the patients, who were re-operated for a recurrent tumor, developed another recurrence. The second recurrence appeared after an average of 10 years, ranging from 1-22 years. A persistent partial paresis of the facial nerve was found in 1% of the patients operated primarily and in 9% of the patients operated more than once. No paralysis was seen. We now choose \"en-bloc\" resections of pleomorphic adenomas without intra-operative opening of the tumor capsule as the treatment of choice. This treatment was possible in 83% of all cases, using a lateral parotidectomy. If tumor extends into the medial parotid lobe, total parotidectomy is required. The tumors of the salivary glands are infrequent in children, and parotid gland is involved in 80% of them. When a salivary gland tumor is present, the chance of malignancy is greater in the child than in the adult. We reviewed 8 cases identified in patients aged 14 years and younger in our hospital, analyzing its antecedents, signs and symptoms, histological features, diagnosis, treatment and evolution. All the patients displayed preauricular painless, non-inflammatory and slow-growing masses to an age between 10 months and 14 years. Four or them were pleomorphic adenomas, two haemangiomas, one epidermal cysts and one myoepithelial carcinoma. We emphasize the exceptional nature of the carcinoma for its rareness and for the high degree of malignancy expressed. We made a fine needle aspiration biopsy in four cases but they were conclusive only in three. All were treated by surgical resection of the tumour except for the myoepithelial carcinoma and the recurrent pleomorphic adenoma that were treated by total parotidectomy. The malignant tumours of the parotid gland are clinically indistinguishable of the benign ones, thus when any palpable mass appears in the zone of the parotid gland, an accurate diagnosis should be made without delay. The treatment of choice is the surgical excision with wide margins, being other adjuvant treatments less useful to this age than in the adult age. To evaluate salivary gland chemodenervation with botulinum toxin in chronic parotid sialadenitis. Patients who underwent parotid gland chemodenervation for chronic sialadenitis due to duct stenosis refractory to siaendoscopy were reviewed (case series). Additionally, a systematic review of the literature on botulinum toxin injection for chronic parotid sialadenitis was performed. Inclusion criteria included studies containing original data on botulinum toxin injections in patients with chronic sialadenitis symptoms. Sialadenitis symptoms from 10 patients with 13 affected parotid glands were examined. All had duct stenosis diagnosed on sialendoscopy, refractory sialadenitis symptoms, and received parotid onabotulinum toxin injection(s) (median dose 65U). Of patients with 3-month follow-up, 78% reported significant improvement in symptoms. Mean Chronic Obstructive Sialadenitis Symptoms (COSS) Score improved at 3 months post-injection (47-25.9, <iP</i = .039) with significant reduction in gland pain frequency and gland swelling severity. No patients had a facial nerve paralysis or increased xerostomia. With the systematic review, 518 abstracts were reviewed and 11 studies met inclusion criteria and included case series or case reports with a total of 40 patients treated with botulinum toxin for chronic parotitis. Thirty-four out of a total of 35 patients in the studies (97%) reported complete (9, 26%) or partial (25, 71%) improvement in sialadenitis symptoms with minimal complications. Parotid gland chemodenervation with botulinum toxin is a minimally invasive treatment option for symptomatic chronic sialadenitis refractory to medical treatment or sialendoscopy. Botulinum toxin injections alleviate gland pain and swelling associated with salivary obstruction and provide an alternative to parotidectomy for recurrent sialadenitis.Level of evidence: 4.\nHere is the question:\nOTOLARYNGOLOGY AND MAXILLOFACIAL SURGERY: A 47-year-old man, with a history of a right parotid pleomorphic adenoma, treated with surgery (extrafacial parotidectomy) 6 months ago, who comes to our office for presenting pain with sweating and reddening of the skin in the preauricular region during mastication. What treatment would be the treatment of choice?\nHere are the potential choices:\n1. Extended total parotidectomy on suspicion of tumor recurrence.\n2. Pregabalin.\n3. Intradermal botulinum toxin injection.\n4. Broad-spectrum antibiotherapy.\nThe correct answer is: 3. Intradermal botulinum toxin injection."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Pregnant women are usually at risk of urinary tract infections (UTIs) such as asymptomatic bacteriuria. In the current multidrug-resistance era, appropriate diagnosis and treatment should be provided to avoid complications in pregnant women in developing countries, which have limited facilities, such as Indonesia. The aim of this study was to evaluate in vitro susceptibility tests. Urinary isolates were collected from 715 pregnant women who visited eight Community Health Centers in Jakarta, Indonesia, between 2015 and 2017. We identified bacterial uropathogens from samples that were positive for nitrite/leukocyte esterase (LE), using two types of VITEK cards. Since noncompliance among patients is a major problem, fosfomycin-trometamol 3 g single-dose sachets were given to the patients, and the side effects of the medication and neonatal outcomes were reported. Asymptomatic bacteriuria was found in 10.5% of the 715 pregnant women. <iEscherichia coli</i was the most common etiological factor (26.7%), followed by <iKlebsiella pneumoniae</i (20%), <iStreptococcus agalactiae</i (9.3%), <iEnterobacter cloacae</i (5.3%), <iEnterococcus faecalis</i (5.3%), <iStaphylococcus saprophyticus</i (4%), <iAcinetobacter baumannii</i (4%), and others. Out of 76 pregnant women who took fosfomycin-trometamol, two complained of diarrhea that subsided without medication and fever that responded to paracetamol. Neonatal outcomes showed 100% full-term and normal-weight babies. <iE. coli</i, including extended-spectrum beta-lactamase- (ESBL-) producing <iE. coli</i, was 100% susceptible to fosfomycin. Nitrite/LE test results are often used as evidence for empiric antibiotic administration for treating asymptomatic bacteriuria in pregnancy, but the diagnosis should be confirmed using culture tests. Based on in vitro susceptibility patterns and medication outcomes, fosfomycin-trometamol single dose could be administered to noncompliant UTI patients, including pregnant women. II. CYSTITIS A. Infection of the bladder B. Presents as dysuria, urinary frequency, urgency, and suprapubic pain; systemic signs (e.g., fever) are usually absent. C. Laboratory findings 1. Urinalysis-cloudy urine with > 10 WBCs/high power field (hpf) 2. Dipstick-Positive leukocyte esterase (due to pyuria) and nitrites (bacteria convert nitrates to nitrites) 3. Culture-greater than 100,000 colony forming units (gold standard) D. Etiology 1. E coli (80%) 2. Staphylococcus saprophyticus-increased incidence in young, sexually active women (but E coli is still more common in this population) 3. Klebsiella pneumoniae 4. Proteus mirabilis-alkaline urine with ammonia scent Fig. 12.15 Linear IF, Goodpasture syndrome. Fig. 12.16 lgA nephropathy. (Courtesy ofTony (Courtesy ofTony Chang, MD) Chang, MD) 5. Enterococcus faecalis E. Sterile pyuria is the presence of pyuria (> 10 WBCs/hpf and leukocyte esterase) with a negative urine culture. Urinary tract infection (UTI) is a common bacterial infection during pregnancy and a significant cause of perinatal and maternal morbidity and mortality. The causative bacteria have remained virtually the same although with variations in individual prevalence. There has been an increasing resistance by these bacteria to the commonly available antibiotics. To determine the prevalence of UTI, the common causative bacteria, and their antibiotic sensitivity pattern among pregnant women with UTI. This is a descriptive study that was carried out at the Obstetrics Department of two tertiary institutions in Abakaliki, Ebonyi State, Nigeria (Federal Medical Center and Ebonyi State University Teaching Hospital) over a period of 12 months. Midstream urine specimens from selected pregnant women with clinical features of UTI were collected for microscopy, culture, and sensitivity. The results were analyzed with the 2008 Epi Info™ software. A total of 542 pregnant women presented with symptoms of UTI and were recruited for the study over the study period. Of the 542 pregnant women, 252 (46.5%) had significant bacteriuria with positive urine culture and varying antibiotic sensitivity pattern. The prevalence of symptomatic UTI was 3%. Escherichia coli was the most common bacteria isolated with a percentage of 50.8%. Other isolated micro organisms included Stapylococcus aereus (52 cultures, 20.6%), Proteus mirabilis (24 cultures, 9.5%), S. saprophyticus (18 cultures, 7.1%), Streptococcus spp. (14 cultures, 5.6%), Citrobacter spp. (5 cultures, 2.0%), Klebsiella spp. (4 cultures, 1.6%), Enterobacter spp. (4 cultures, 1.6%), and Pseudomonas spp. (3 cultures, 1.2%). Levofloxacin had the highest overall antibiotic sensitivity of 92.5%. Others with overall antibiotic sensitivity pattern greater than 50% included cefpodoxime (87.3%), ofloxacin (77.4%), ciprofloxacin (66.7%), ceftriaxone (66.7%), and gentamicin (50.8%). E. coli was the most common etiological agent of UTI in pregnancy with Enterococcus (Staphylococcus) gaining prominence. Cephalosporin and quinolones were shown to be very effective against the organisms causing UTI in these pregnant women. Uncomplicated urinary tract infections (uUTIs) are common in adult women across the entire age spectrum, with mean annual incidences of approximately 15% and 10% in those aged 15-39 and 40-79 years, respectively. By definition, UTIs in males or pregnant females and those associated with risk factors known to increase the risk of infection or treatment failure (e.g. acquisition in a hospital setting, presence of an indwelling urinary catheter, urinary tract instrumentation/interventions, diabetes mellitus or immunosuppression) are not considered herein. The majority of uUTIs are caused by Escherichia coli (70-95%), with Proteus mirabilis, Klebsiella spp. and Staphylococcus saprophyticus accounting for 1-2%, 1-2% and 5-10% of infections, respectively. If clinical signs and symptoms consistent with uUTI are present (e.g. dysuria, frequency, back pain or costovertebral angle tenderness) and there is no vaginal discharge or irritation present, the likelihood of uUTI is &gt;90-95%. Laboratory testing (i.e. urinary nitrites, leukocyte esterase, culture) is not necessary in this circumstance and empirical treatment can be initiated. The ever-increasing incidence of antimicrobial resistance of the common uropathogens in uUTI has been and is a continuing focus of intensive study. Resistance to cotrimoxazole (trimethoprim/sulfamethoxazole) has made the empirical use of this drug problematic in many geographical areas. If local uropathogen resistance rates to cotrimoxazole exceed 10-25%, empirical cotrimoxazole therapy should not be utilized (fluoroquinolones become the new first-line agents). In a few countries, uropathogen resistance rates to the fluoroquinolones now exceed 10-25%, rendering empirical use of fluoroquinolones problematic. With the exception of fosfomycin (a second-line therapy), single-dose therapy is not recommended because of suboptimal cure rates and high relapse rates. Cotrimoxazole and the fluoroquinolones can be administered in 3-day regimens. Nitrofurantoin, a second-line therapy, should be given for 7 days. beta-Lactams are not recommended because of suboptimal clinical and bacteriological results compared with those of non-beta-lactams. If a beta-lactam is chosen, it should be given for 7 days. Management of uUTIs can frequently be triaged to non-physician healthcare personnel without adverse clinical consequences, resulting in substantial cost savings. It can be anticipated that the optimal approach to the management of uUTIs will change substantially in the future as a consequence of antimicrobial resistance. This report describes a case of urinary tract infection (UTI) due to Shigella sonnei during pregnancy. A 31-year-old pregnant woman was admitted complaining of left-flank tenderness, dysuria, and fever. Following examination, significant laboratory data were collected including increased leukocyte count (10,800/ul with 86% neutrophils) and C-reactive protein (9.6 mg/dl). Urinalysis revealed 30 to 50 leukocytes per high power field while from the quantitative urine culture Shigella sonnei was recovered after 24 h incubation at 37 degrees C. After a two-week course with 750 mg cefuroxime every 8 h, the patient experienced gradual resolution of all symptoms and urinary cultures were negative two weeks and one month, respectively, after completing the therapy. The gestational course was uneventful and the patient delivered a healthy baby girl at term. Shigella sonnei can be responsible for UTI during pregnancy even when no predisposing factors or an apparent source of infection can be identified. To determine the prevalence of outpatient-diagnosed urinary tract infection (UTI) in consecutive febrile neonates ≤ 30 days of age and correlate demographic, laboratory and radiographic imaging results with infectious etiology. Review of medical records of consecutive febrile infants ≤ 30 days of age presenting to an urban pediatric emergency department during a 10-year period, whose policy is to perform a sepsis evaluation (urine culture obtained by bladder catheterization) and hospitalize for parenteral antibiotic therapy pending culture results. Of 670 febrile neonates ≤ 30 days of age evaluated for sepsis, urine culture was obtained in 651 cases (97%). Of 100 patients with UTI (15.4%), 73% were male; the most common uropathogens were Escherichia coli (71%), Enterococcus (10%) and Klebsiella sp. (10%). In all, 39% had a maximum documented fever ≥ 102 °F, and 40% had CBC total white blood cells count ≥ 15,000/mm(3). Urine dipstick test was positive for leukocyte esterase or nitrite in 79%. Renal ultrasound performed in 95 patients (95%) showed anatomic abnormalities in 47%; 5/26 (24%) with hydronephrosis had vesicoureteral reflux on voiding cystourethrogram. Four patients had urosepsis; none had bacterial meningitis and no patients died. UTI affects approximately 1 in 6 febrile neonates ≤ 30 days of age. Males are affected 2.5-times greater than females. E. coli continues to be the predominant uropathogen. Clinical parameters like height of fever, CBC total white blood cell count and urine dipstick test lack sensitivity in identifying UTI risk in the outpatient setting. Only 4 infants had urosepsis (4%). Nearly half of neonates with UTI have a radiographically identified anatomic abnormality. All febrile young infants should receive performance of a urine culture; those with UTI require imaging. If this infection is suspected, a urine sample obtained by catheterization may be preferred to avoid obscuring contamination from the lower genital tract. he urinary sediment contains many leukocytes, frequently in clumps, and numerous bacteria. Bacteremia is demonstrated in 15 to 20 percent of these women. E coli is isolated from urine or blood in 70 to 80 percent of infections, Klebsiela pneumoniae in 3 to 5 percent, Enterobacter or Proteus species in 3 to 5 percent, and gram-positive organisms, including group B Streptococcus and Staphylococcus aureus, in up to 10 percent of cases (Hill, 2005; Wing, 2000). The objective of this study was (1) to determine the reliability of urinalysis (UA) for predicting urinary tract infection (UTI) in febrile children, (2) to determine whether UA findings can predict Escherichia coli versus non-E. coli urinary tract infection, and (3) to determine if empiric antibiotics should be selected based on E. coli versus non-E. coli infection predictions. This was a retrospective chart review of children from 2 months to 2 years of age who presented to the emergency department with fever (rectal temperature &gt;100.4°F) and had a positive urine culture. This study was conducted between January 2004 and December 2007. Negative UA was defined as urine white blood cell count less than 5 per high-power field, negative leukocyte esterase, and negative nitrites. Urine cultures were classified into E. coli and non-E. coli groups. These groups were compared for sex, race, and UA findings. Multivariate forward logistic regression, using the Wald test, was performed to calculate the likelihood ratio (LR) of each variable (eg, sex, race, UA parameters) in predicting UTI. In addition, antibiotic sensitivities between both groups were compared. Of 749 medical records reviewed, 608 were included; negative UA(-) was present in 183 cases, and positive UA(+) was observed in 425 cases. Furthermore, 424 cases were caused by E. coli, and 184 were due to non-E. coli organisms. Among 425 UA(+) cases, E. coli was identified in 349 (82.1%), whereas non-E. coli organisms were present in 76 (17.9%); in contrast, in 183 UA(-) cases, 108 (59%) were due to non-E. coli organisms versus 75 (41%), which were caused by E. coli. Urinalysis results were shown to be associated with organism group (P &lt; 0.001). Positive leukocytes esterase had an LR of 2.5 (95% confidence interval [CI], 1.5-4.2), positive nitrites had an LR of 2.8 (95% CI, 1.4-5.5), and urine white blood cell count had an LR of 1.8 (95% CI, 1.3-2.4) in predicting E. coli versus non-E. coli infections. Antibiotic sensitivity compared between UA groups demonstrated equivalent superiority of cefazolin (94.7% sensitive in UA(+) vs 84.0% in UA(-) group; P &lt; 0.0001), cefuroxime (98.2% vs 91.7%; P &lt; 0.001), and nitrofurantoin (96.1% vs 82.2%; P &lt; 0.0001) in the UA(+) group. In contrast, the UA(-) group showed significant sensitivity to trimethoprim-sulfamethoxazole (82.2% vs 71.3% in UA(+); P = 0.008). Urinalysis is not an accurate predictor of UTI. A positive urine culture in the presence of negative UA most likely grew non-E. coli organisms, whereas most UA(+) results were associated with E. coli. This study also highlighted local patterns of antibiotic resistance between E. coli and non-E. coli groups. Negative UA results in the presence of strong suspicion of a UTI suggest a non-E. coli organism, which may be best treated with trimethoprim-sulfamethoxazole. Conversely, UA(+) results suggest E. coli, which calls for treatment with cefazolin or cefuroxime. Urinary tract infection (UTI) is the most common serious bacterial infection in young infants. Signs and symptoms are often nonspecific. To describe clinical, demographic and laboratory features of UTI in infants ≤ 3 months old. Cross-sectional study of infants ≤ 3 months old with UTI diagnosed in a pediatric emergency department, for the period 2010-2012. UTI was defined as ≥ 50,000 colony-forming units per milliliter of a single uropathogen isolated from bladder catheterization. Paired urinalysis and urine culture from group culture-positive and group culture-negative were used to determine the sensitivity and specificity of pyuria and nitrite tests in detecting UTI. Of 519 urine cultures collected, UTI was diagnosed in 65 cases (prevalence: 12.5%); with male predominance (77%). The most common etiologies were Escherichia coli (56.9%), Klebsiella pneumoniae (18.5%) and Enterococcus faecalis (7.7%). Frequent clinical manifestations were fever (77.8%), irritability (41.4%) and vomiting (25.4%). The median temperature was 38.7°C. The sensitivity of the nitrite test was 30.8% (95%CI:19.9-43.4%), specificity of 100% (95%CI:99.2-100%). Pyuria ≥ 10,000/mL had a sensitivity of 87.7% (95%CI:77.2-94.5%), specificity of 74.9% (95%CI:70.6 -78.8%). The median peripheral white blood cell count was 13,150/mm3; C-reactive protein levels were normal in 30.5% of cases. The male: female ratio for urinary tract infection was 3.3:1. Non-Escherichia coli etiologies should be considered in empirical treatment. Fever was the main symptom. Positive nitrite is highly suggestive of UTI but has low sensitivity; whereas pyuria ≥ 10,000/mL revealed good sensitivity, but low specificity. Peripheral white blood cell count and C-reactive protein concentration have limited usefulness to suggest UTI. Diagnosis In straightforward cases, a diagnosis may be made and treatment given based on symptoms alone without further laboratory confirmation. In complicated or questionable cases, it may be useful to confirm the diagnosis via urinalysis, looking for the presence of urinary nitrites, white blood cells (leukocytes), or leukocyte esterase. Another test, urine microscopy, looks for the presence of red blood cells, white blood cells, or bacteria. Urine culture is deemed positive if it shows a bacterial colony count of greater than or equal to 103 colony-forming units per mL of a typical urinary tract organism. Antibiotic sensitivity can also be tested with these cultures, making them useful in the selection of antibiotic treatment. However, women with negative cultures may still improve with antibiotic treatment. As symptoms can be vague and without reliable tests for urinary tract infections, diagnosis can be difficult in the elderly. Septic arthritis of a lumbar facet joint is a rare condition. We report the case of a 77-year-old diabetic woman who developed fever and back pain 15 days after she had been diagnosed with a genitourinary infection for which she had received ciprofloxacin. Physical examination showed fever (38°C) and pain on pressure over the lower lumbar spinous vertebral apophyses and over the lower left paraspinal musculature. Investigations showed a white cell count of 8.4×10⁹/l, neutrophils 85.3%, erythrocyte sedimentation rate of 125 mm/h, and C-reactive protein of ≥9 mg/dl. Two blood cultures were both positive for Escherichia coli resistant to ciprofloxacin. There was no growth of pathogens from the urine cultures. Scintigraphy with gallium citrate Ga⁶⁷ showed vertical lower lumbar (L4-L5) radionuclide uptake lateralized to the left. Magnetic resonance imaging of the lumbar spine demonstrated signal changes and alteration of the structure at the left interapophyseal L4-L5 joint, an adjacent small collection of 1cm in diameter, and infiltration of the surrounding soft tissues, which extended to the epidural area, left conjunction hole, and paraspinal muscles. The patient was treated with intravenous cefotaxime and gentamicin and bed rest for 21 days, and recovered. This is the first report of interapophyseal arthritis caused by E. coli. Urinary nitrite test A nitrite test is a standard component of a urinary test strip. A positive test for nitrites in the urine is called nitrituria. This test is commonly used in diagnosing urinary tract infections (UTIs). A positive nitrite test indicates that the cause of the UTI is a gram negative organism, most commonly Escherichia coli. The reason for nitrites' existence in the presence of a UTI is due to a bacterial conversion of endogenous nitrates to nitrites. This may be a sign of infection. However, other parameters, such as leukocyte esterase, urine white blood cell count, and symptoms such as dysuria, urinary urgency, fevers, and chills must be correlated to diagnose an infection. Organisms causing UTI in pregnancy are the same uropathogens which commonly cause UTI in non-pregnant patients. Escherichia coli is the most common organism isolated. An 18-year retrospective analysis found E. coli to be the causative agent in 82.5% of cases of pyelonephritis in pregnant patients. [3] Other bacteria which may be seen include Klebsiella pneumoniae, Staphylococcus, Streptococcus, Proteus, and Enterococcus species. It is normal to find up to 3 (occasionally 5) leukocytes per high power field (40X) in a urine sample, with women having slightly higher results owing to vaginal contamination. Higher numbers indicate urinary infection. The urine test strip test for white blood cells detects leukocyte esterase, which is present in azurophilic granules of monocytes and granulocytes (neutrophilic, eosinophilic and basophilic). Bacteria, lymphocytes and epithelial cells from the genitourinary tract do not contain esterases. Neutrophil granulocytes are the leukocytes most commonly associated with urinary infections. A positive test for leukocyte esterase normally indicates the presence of bacteria and a positive nitrite test (although it is not always the case). Infections caused by Trichomonas, Chlamydia and yeasts produce leukocyturia without bacteriuria. The inflammation of the renal tissues (interstitial nephritis) can produce leukocyturia, in particular toxic interstitial nephritis with predominant Pathogenesis The bacteria that cause urinary tract infections typically enter the bladder via the urethra. However, infection may also occur via the blood or lymph. It is believed that the bacteria are usually transmitted to the urethra from the bowel, with females at greater risk due to their anatomy. After gaining entry to the bladder, E. Coli are able to attach to the bladder wall and form a biofilm that resists the body's immune response. Escherichia coli is the single most common microorganism, followed by Klebsiella and Proteus spp., to cause urinary tract infection. Klebsiella and Proteus spp., are frequently associated with stone disease. The presence of Gram positive bacteria such as Enterococcus and Staphylococcus increased. The increased resistance of urinary pathogens to quinolone antibiotics has been reported worldwide and might be the consequence of overuse and misuse of quinolones. Diagnosis We compare the test characteristics of urine dipstick and urinalysis at various test cutoff points in women presenting to emergency departments and an intermediate care center with symptoms of urinary tract infection. This was a prospective, observational study of adult women presenting to 1 of 2 community hospital EDs or an intermediate care center with dysuria, urgency, or urinary frequency on history, or suprapubic or costovertebral angle tenderness on examination. Patients who had taken antibiotics in the past 72 hours, had indwelling Foley catheters, symptomatic vaginal discharge, diabetes mellitus, immunodeficiency disorders, or were unable to provide a reliable history were excluded. The patient's clean-catch or catheterized urine specimen was tested immediately by a nurse using a Multistix 9 SG reagent strip. A second aliquot was sent within 1 hour of collection to the hospital laboratory, where a semiautomated microscopic urinalysis and a urine culture were performed. A positive urine culture was defined as more than 100,000 colonies of 1 or 2 uropathogenic bacteria per mL of urine at 48 hours. Dipstick and urinalysis data were compared with urine culture results. Sensitivity, specificity, and predictive values were calculated at various definitions of a positive test, or \"test cutoff points,\" for combinations of leukocyte esterase, nitrite, and blood on dipstick and for RBCs and WBCs on urinalyses. The probability of an erroneous decision to withhold treatment on the basis of a negative test result was defined as \"undertreatment,\" or 1 minus the negative predictive value. \"Overtreatment\" was defined as 1 minus the positive predictive value. Three hundred forty-three patients were enrolled in this study. Twelve patients were withdrawn because of missing laboratory results. Forty-six percent (152/331) of patients had positive urine cultures. If urine dipstick results are defined as positive when leukocyte esterase or nitrite is positive or blood is more than trace, the overtreatment rate is 47% (156/331) and the undertreatment rate is 13% (43/331). If urinalysis results are defined as positive when WBCs are more than 3 per high-power field or RBCs are more than 5 per high-power field, the overtreatment rate is 44% (146/331) and the undertreatment rate is 11% (36/331). Matched pairs of test characteristics were identified when the analysis was repeated using more than 10,000 colonies per mL as a positive culture. In this patient population, similar overtreatment and undertreatment rates were identified for various test cutoff points for urine dipstick tests and urinalysis. Although a urine dipstick may be equivalent to a urinalysis for the diagnosis of urinary tract infection, the limitations in the diagnostic accuracy of both tests should be incorporated into medical decisionmaking. Urinary tract infection (UTI) is one of the most common infections during pregnancy, which can lead to significant maternal and perinatal morbidity and mortality if left untreated. Challenges when treating UTIs in pregnancy include fetal protection and resistance development of uropathogens. Currently, the Essential Medicines List recommends nitrofurantoin to treat cystitis and ceftriaxone to treat pyelonephritis in pregnant women. To determine common pathogens causing UTI in pregnancy and their antibiotic susceptibility patterns. A retrospective analysis was performed of laboratory data for positive urine specimens from obstetric departments of 6 KwaZulu- Natal Province hospitals during 2011 - 2016. Identification and susceptibility testing were performed using the VITEK 2 system. Results were interpreted according to the breakpoints of the Clinical and Laboratory Standards Institute, USA. From 5 971 positive urine specimens, the most common isolate was Escherichia coli (n=3 236; 54.2%), followed by Klebsiella pneumoniae (n=770; 12.9%). Group B streptococcus (GBS) (n=239; 4.0%) and Enterococcus faecalis (n=251; 4.2%) were the most common Gram-positive pathogens. E. coli displayed significant resistance to trimethoprim-sulfamethoxazole (65.1%), cephalothin (38.3%), cefuroxime (27.3%), ciprofloxacin (16.9%) and amoxicillin-clavulanic acid (17.1%). Resistance to ceftriaxone and nitrofurantoin remained low ‒ 9.1% and 7.7%, respectively. Among Gram-positive pathogens, GBS displayed 100% penicillin susceptibility and E. faecalis showed 92.9% susceptibility to ampicillin. E. coli is unsurprisingly the most common cause of UTI in pregnancy in KwaZulu-Natal. Susceptibility to ceftriaxone and nitrofurantoin remains good. Among Gram positives, GBS is prevalent and susceptible to penicillin, while E. faecalis is susceptible to ampicillin. As antimicrobial resistance evolves, routine surveillance is necessary to modify recommended empirical antibiotic use.\nHere is the question:\nMICROBIOLOGY: Pregnant woman, 27 years old, 30 weeks of gestation. She comes to the emergency room because she noticed pain in the left lumbar region and dysuria since yesterday. She has no febrile sensation. She refers repeated urinary tract infections (UTI). Urinalysis shows Hb 3+, leukocytes 3+, nitrites 2+, sediment: 15-20 leukocytes per field and 5-10 red blood cells per field. Which of the following microorganisms is the most frequent culprit in pregnant women?\nHere are the potential choices:\n1. Escherichia coli.\n2. Enterococcus faecalis.\n3. Streptococcus agalactiae.\n4. Proteus mirabilis.\n5. Satphylococcus saprophyticus.\nThe correct answer is: ",
        "gold_answer": "1 Escherichia coli.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Pregnant women are usually at risk of urinary tract infections (UTIs) such as asymptomatic bacteriuria. In the current multidrug-resistance era, appropriate diagnosis and treatment should be provided to avoid complications in pregnant women in developing countries, which have limited facilities, such as Indonesia. The aim of this study was to evaluate in vitro susceptibility tests. Urinary isolates were collected from 715 pregnant women who visited eight Community Health Centers in Jakarta, Indonesia, between 2015 and 2017. We identified bacterial uropathogens from samples that were positive for nitrite/leukocyte esterase (LE), using two types of VITEK cards. Since noncompliance among patients is a major problem, fosfomycin-trometamol 3 g single-dose sachets were given to the patients, and the side effects of the medication and neonatal outcomes were reported. Asymptomatic bacteriuria was found in 10.5% of the 715 pregnant women. <iEscherichia coli</i was the most common etiological factor (26.7%), followed by <iKlebsiella pneumoniae</i (20%), <iStreptococcus agalactiae</i (9.3%), <iEnterobacter cloacae</i (5.3%), <iEnterococcus faecalis</i (5.3%), <iStaphylococcus saprophyticus</i (4%), <iAcinetobacter baumannii</i (4%), and others. Out of 76 pregnant women who took fosfomycin-trometamol, two complained of diarrhea that subsided without medication and fever that responded to paracetamol. Neonatal outcomes showed 100% full-term and normal-weight babies. <iE. coli</i, including extended-spectrum beta-lactamase- (ESBL-) producing <iE. coli</i, was 100% susceptible to fosfomycin. Nitrite/LE test results are often used as evidence for empiric antibiotic administration for treating asymptomatic bacteriuria in pregnancy, but the diagnosis should be confirmed using culture tests. Based on in vitro susceptibility patterns and medication outcomes, fosfomycin-trometamol single dose could be administered to noncompliant UTI patients, including pregnant women. II. CYSTITIS A. Infection of the bladder B. Presents as dysuria, urinary frequency, urgency, and suprapubic pain; systemic signs (e.g., fever) are usually absent. C. Laboratory findings 1. Urinalysis-cloudy urine with > 10 WBCs/high power field (hpf) 2. Dipstick-Positive leukocyte esterase (due to pyuria) and nitrites (bacteria convert nitrates to nitrites) 3. Culture-greater than 100,000 colony forming units (gold standard) D. Etiology 1. E coli (80%) 2. Staphylococcus saprophyticus-increased incidence in young, sexually active women (but E coli is still more common in this population) 3. Klebsiella pneumoniae 4. Proteus mirabilis-alkaline urine with ammonia scent Fig. 12.15 Linear IF, Goodpasture syndrome. Fig. 12.16 lgA nephropathy. (Courtesy ofTony (Courtesy ofTony Chang, MD) Chang, MD) 5. Enterococcus faecalis E. Sterile pyuria is the presence of pyuria (> 10 WBCs/hpf and leukocyte esterase) with a negative urine culture. Urinary tract infection (UTI) is a common bacterial infection during pregnancy and a significant cause of perinatal and maternal morbidity and mortality. The causative bacteria have remained virtually the same although with variations in individual prevalence. There has been an increasing resistance by these bacteria to the commonly available antibiotics. To determine the prevalence of UTI, the common causative bacteria, and their antibiotic sensitivity pattern among pregnant women with UTI. This is a descriptive study that was carried out at the Obstetrics Department of two tertiary institutions in Abakaliki, Ebonyi State, Nigeria (Federal Medical Center and Ebonyi State University Teaching Hospital) over a period of 12 months. Midstream urine specimens from selected pregnant women with clinical features of UTI were collected for microscopy, culture, and sensitivity. The results were analyzed with the 2008 Epi Info™ software. A total of 542 pregnant women presented with symptoms of UTI and were recruited for the study over the study period. Of the 542 pregnant women, 252 (46.5%) had significant bacteriuria with positive urine culture and varying antibiotic sensitivity pattern. The prevalence of symptomatic UTI was 3%. Escherichia coli was the most common bacteria isolated with a percentage of 50.8%. Other isolated micro organisms included Stapylococcus aereus (52 cultures, 20.6%), Proteus mirabilis (24 cultures, 9.5%), S. saprophyticus (18 cultures, 7.1%), Streptococcus spp. (14 cultures, 5.6%), Citrobacter spp. (5 cultures, 2.0%), Klebsiella spp. (4 cultures, 1.6%), Enterobacter spp. (4 cultures, 1.6%), and Pseudomonas spp. (3 cultures, 1.2%). Levofloxacin had the highest overall antibiotic sensitivity of 92.5%. Others with overall antibiotic sensitivity pattern greater than 50% included cefpodoxime (87.3%), ofloxacin (77.4%), ciprofloxacin (66.7%), ceftriaxone (66.7%), and gentamicin (50.8%). E. coli was the most common etiological agent of UTI in pregnancy with Enterococcus (Staphylococcus) gaining prominence. Cephalosporin and quinolones were shown to be very effective against the organisms causing UTI in these pregnant women. Uncomplicated urinary tract infections (uUTIs) are common in adult women across the entire age spectrum, with mean annual incidences of approximately 15% and 10% in those aged 15-39 and 40-79 years, respectively. By definition, UTIs in males or pregnant females and those associated with risk factors known to increase the risk of infection or treatment failure (e.g. acquisition in a hospital setting, presence of an indwelling urinary catheter, urinary tract instrumentation/interventions, diabetes mellitus or immunosuppression) are not considered herein. The majority of uUTIs are caused by Escherichia coli (70-95%), with Proteus mirabilis, Klebsiella spp. and Staphylococcus saprophyticus accounting for 1-2%, 1-2% and 5-10% of infections, respectively. If clinical signs and symptoms consistent with uUTI are present (e.g. dysuria, frequency, back pain or costovertebral angle tenderness) and there is no vaginal discharge or irritation present, the likelihood of uUTI is &gt;90-95%. Laboratory testing (i.e. urinary nitrites, leukocyte esterase, culture) is not necessary in this circumstance and empirical treatment can be initiated. The ever-increasing incidence of antimicrobial resistance of the common uropathogens in uUTI has been and is a continuing focus of intensive study. Resistance to cotrimoxazole (trimethoprim/sulfamethoxazole) has made the empirical use of this drug problematic in many geographical areas. If local uropathogen resistance rates to cotrimoxazole exceed 10-25%, empirical cotrimoxazole therapy should not be utilized (fluoroquinolones become the new first-line agents). In a few countries, uropathogen resistance rates to the fluoroquinolones now exceed 10-25%, rendering empirical use of fluoroquinolones problematic. With the exception of fosfomycin (a second-line therapy), single-dose therapy is not recommended because of suboptimal cure rates and high relapse rates. Cotrimoxazole and the fluoroquinolones can be administered in 3-day regimens. Nitrofurantoin, a second-line therapy, should be given for 7 days. beta-Lactams are not recommended because of suboptimal clinical and bacteriological results compared with those of non-beta-lactams. If a beta-lactam is chosen, it should be given for 7 days. Management of uUTIs can frequently be triaged to non-physician healthcare personnel without adverse clinical consequences, resulting in substantial cost savings. It can be anticipated that the optimal approach to the management of uUTIs will change substantially in the future as a consequence of antimicrobial resistance. This report describes a case of urinary tract infection (UTI) due to Shigella sonnei during pregnancy. A 31-year-old pregnant woman was admitted complaining of left-flank tenderness, dysuria, and fever. Following examination, significant laboratory data were collected including increased leukocyte count (10,800/ul with 86% neutrophils) and C-reactive protein (9.6 mg/dl). Urinalysis revealed 30 to 50 leukocytes per high power field while from the quantitative urine culture Shigella sonnei was recovered after 24 h incubation at 37 degrees C. After a two-week course with 750 mg cefuroxime every 8 h, the patient experienced gradual resolution of all symptoms and urinary cultures were negative two weeks and one month, respectively, after completing the therapy. The gestational course was uneventful and the patient delivered a healthy baby girl at term. Shigella sonnei can be responsible for UTI during pregnancy even when no predisposing factors or an apparent source of infection can be identified. To determine the prevalence of outpatient-diagnosed urinary tract infection (UTI) in consecutive febrile neonates ≤ 30 days of age and correlate demographic, laboratory and radiographic imaging results with infectious etiology. Review of medical records of consecutive febrile infants ≤ 30 days of age presenting to an urban pediatric emergency department during a 10-year period, whose policy is to perform a sepsis evaluation (urine culture obtained by bladder catheterization) and hospitalize for parenteral antibiotic therapy pending culture results. Of 670 febrile neonates ≤ 30 days of age evaluated for sepsis, urine culture was obtained in 651 cases (97%). Of 100 patients with UTI (15.4%), 73% were male; the most common uropathogens were Escherichia coli (71%), Enterococcus (10%) and Klebsiella sp. (10%). In all, 39% had a maximum documented fever ≥ 102 °F, and 40% had CBC total white blood cells count ≥ 15,000/mm(3). Urine dipstick test was positive for leukocyte esterase or nitrite in 79%. Renal ultrasound performed in 95 patients (95%) showed anatomic abnormalities in 47%; 5/26 (24%) with hydronephrosis had vesicoureteral reflux on voiding cystourethrogram. Four patients had urosepsis; none had bacterial meningitis and no patients died. UTI affects approximately 1 in 6 febrile neonates ≤ 30 days of age. Males are affected 2.5-times greater than females. E. coli continues to be the predominant uropathogen. Clinical parameters like height of fever, CBC total white blood cell count and urine dipstick test lack sensitivity in identifying UTI risk in the outpatient setting. Only 4 infants had urosepsis (4%). Nearly half of neonates with UTI have a radiographically identified anatomic abnormality. All febrile young infants should receive performance of a urine culture; those with UTI require imaging. If this infection is suspected, a urine sample obtained by catheterization may be preferred to avoid obscuring contamination from the lower genital tract. he urinary sediment contains many leukocytes, frequently in clumps, and numerous bacteria. Bacteremia is demonstrated in 15 to 20 percent of these women. E coli is isolated from urine or blood in 70 to 80 percent of infections, Klebsiela pneumoniae in 3 to 5 percent, Enterobacter or Proteus species in 3 to 5 percent, and gram-positive organisms, including group B Streptococcus and Staphylococcus aureus, in up to 10 percent of cases (Hill, 2005; Wing, 2000). The objective of this study was (1) to determine the reliability of urinalysis (UA) for predicting urinary tract infection (UTI) in febrile children, (2) to determine whether UA findings can predict Escherichia coli versus non-E. coli urinary tract infection, and (3) to determine if empiric antibiotics should be selected based on E. coli versus non-E. coli infection predictions. This was a retrospective chart review of children from 2 months to 2 years of age who presented to the emergency department with fever (rectal temperature &gt;100.4°F) and had a positive urine culture. This study was conducted between January 2004 and December 2007. Negative UA was defined as urine white blood cell count less than 5 per high-power field, negative leukocyte esterase, and negative nitrites. Urine cultures were classified into E. coli and non-E. coli groups. These groups were compared for sex, race, and UA findings. Multivariate forward logistic regression, using the Wald test, was performed to calculate the likelihood ratio (LR) of each variable (eg, sex, race, UA parameters) in predicting UTI. In addition, antibiotic sensitivities between both groups were compared. Of 749 medical records reviewed, 608 were included; negative UA(-) was present in 183 cases, and positive UA(+) was observed in 425 cases. Furthermore, 424 cases were caused by E. coli, and 184 were due to non-E. coli organisms. Among 425 UA(+) cases, E. coli was identified in 349 (82.1%), whereas non-E. coli organisms were present in 76 (17.9%); in contrast, in 183 UA(-) cases, 108 (59%) were due to non-E. coli organisms versus 75 (41%), which were caused by E. coli. Urinalysis results were shown to be associated with organism group (P &lt; 0.001). Positive leukocytes esterase had an LR of 2.5 (95% confidence interval [CI], 1.5-4.2), positive nitrites had an LR of 2.8 (95% CI, 1.4-5.5), and urine white blood cell count had an LR of 1.8 (95% CI, 1.3-2.4) in predicting E. coli versus non-E. coli infections. Antibiotic sensitivity compared between UA groups demonstrated equivalent superiority of cefazolin (94.7% sensitive in UA(+) vs 84.0% in UA(-) group; P &lt; 0.0001), cefuroxime (98.2% vs 91.7%; P &lt; 0.001), and nitrofurantoin (96.1% vs 82.2%; P &lt; 0.0001) in the UA(+) group. In contrast, the UA(-) group showed significant sensitivity to trimethoprim-sulfamethoxazole (82.2% vs 71.3% in UA(+); P = 0.008). Urinalysis is not an accurate predictor of UTI. A positive urine culture in the presence of negative UA most likely grew non-E. coli organisms, whereas most UA(+) results were associated with E. coli. This study also highlighted local patterns of antibiotic resistance between E. coli and non-E. coli groups. Negative UA results in the presence of strong suspicion of a UTI suggest a non-E. coli organism, which may be best treated with trimethoprim-sulfamethoxazole. Conversely, UA(+) results suggest E. coli, which calls for treatment with cefazolin or cefuroxime. Urinary tract infection (UTI) is the most common serious bacterial infection in young infants. Signs and symptoms are often nonspecific. To describe clinical, demographic and laboratory features of UTI in infants ≤ 3 months old. Cross-sectional study of infants ≤ 3 months old with UTI diagnosed in a pediatric emergency department, for the period 2010-2012. UTI was defined as ≥ 50,000 colony-forming units per milliliter of a single uropathogen isolated from bladder catheterization. Paired urinalysis and urine culture from group culture-positive and group culture-negative were used to determine the sensitivity and specificity of pyuria and nitrite tests in detecting UTI. Of 519 urine cultures collected, UTI was diagnosed in 65 cases (prevalence: 12.5%); with male predominance (77%). The most common etiologies were Escherichia coli (56.9%), Klebsiella pneumoniae (18.5%) and Enterococcus faecalis (7.7%). Frequent clinical manifestations were fever (77.8%), irritability (41.4%) and vomiting (25.4%). The median temperature was 38.7°C. The sensitivity of the nitrite test was 30.8% (95%CI:19.9-43.4%), specificity of 100% (95%CI:99.2-100%). Pyuria ≥ 10,000/mL had a sensitivity of 87.7% (95%CI:77.2-94.5%), specificity of 74.9% (95%CI:70.6 -78.8%). The median peripheral white blood cell count was 13,150/mm3; C-reactive protein levels were normal in 30.5% of cases. The male: female ratio for urinary tract infection was 3.3:1. Non-Escherichia coli etiologies should be considered in empirical treatment. Fever was the main symptom. Positive nitrite is highly suggestive of UTI but has low sensitivity; whereas pyuria ≥ 10,000/mL revealed good sensitivity, but low specificity. Peripheral white blood cell count and C-reactive protein concentration have limited usefulness to suggest UTI. Diagnosis In straightforward cases, a diagnosis may be made and treatment given based on symptoms alone without further laboratory confirmation. In complicated or questionable cases, it may be useful to confirm the diagnosis via urinalysis, looking for the presence of urinary nitrites, white blood cells (leukocytes), or leukocyte esterase. Another test, urine microscopy, looks for the presence of red blood cells, white blood cells, or bacteria. Urine culture is deemed positive if it shows a bacterial colony count of greater than or equal to 103 colony-forming units per mL of a typical urinary tract organism. Antibiotic sensitivity can also be tested with these cultures, making them useful in the selection of antibiotic treatment. However, women with negative cultures may still improve with antibiotic treatment. As symptoms can be vague and without reliable tests for urinary tract infections, diagnosis can be difficult in the elderly. Septic arthritis of a lumbar facet joint is a rare condition. We report the case of a 77-year-old diabetic woman who developed fever and back pain 15 days after she had been diagnosed with a genitourinary infection for which she had received ciprofloxacin. Physical examination showed fever (38°C) and pain on pressure over the lower lumbar spinous vertebral apophyses and over the lower left paraspinal musculature. Investigations showed a white cell count of 8.4×10⁹/l, neutrophils 85.3%, erythrocyte sedimentation rate of 125 mm/h, and C-reactive protein of ≥9 mg/dl. Two blood cultures were both positive for Escherichia coli resistant to ciprofloxacin. There was no growth of pathogens from the urine cultures. Scintigraphy with gallium citrate Ga⁶⁷ showed vertical lower lumbar (L4-L5) radionuclide uptake lateralized to the left. Magnetic resonance imaging of the lumbar spine demonstrated signal changes and alteration of the structure at the left interapophyseal L4-L5 joint, an adjacent small collection of 1cm in diameter, and infiltration of the surrounding soft tissues, which extended to the epidural area, left conjunction hole, and paraspinal muscles. The patient was treated with intravenous cefotaxime and gentamicin and bed rest for 21 days, and recovered. This is the first report of interapophyseal arthritis caused by E. coli. Urinary nitrite test A nitrite test is a standard component of a urinary test strip. A positive test for nitrites in the urine is called nitrituria. This test is commonly used in diagnosing urinary tract infections (UTIs). A positive nitrite test indicates that the cause of the UTI is a gram negative organism, most commonly Escherichia coli. The reason for nitrites' existence in the presence of a UTI is due to a bacterial conversion of endogenous nitrates to nitrites. This may be a sign of infection. However, other parameters, such as leukocyte esterase, urine white blood cell count, and symptoms such as dysuria, urinary urgency, fevers, and chills must be correlated to diagnose an infection. Organisms causing UTI in pregnancy are the same uropathogens which commonly cause UTI in non-pregnant patients. Escherichia coli is the most common organism isolated. An 18-year retrospective analysis found E. coli to be the causative agent in 82.5% of cases of pyelonephritis in pregnant patients. [3] Other bacteria which may be seen include Klebsiella pneumoniae, Staphylococcus, Streptococcus, Proteus, and Enterococcus species. It is normal to find up to 3 (occasionally 5) leukocytes per high power field (40X) in a urine sample, with women having slightly higher results owing to vaginal contamination. Higher numbers indicate urinary infection. The urine test strip test for white blood cells detects leukocyte esterase, which is present in azurophilic granules of monocytes and granulocytes (neutrophilic, eosinophilic and basophilic). Bacteria, lymphocytes and epithelial cells from the genitourinary tract do not contain esterases. Neutrophil granulocytes are the leukocytes most commonly associated with urinary infections. A positive test for leukocyte esterase normally indicates the presence of bacteria and a positive nitrite test (although it is not always the case). Infections caused by Trichomonas, Chlamydia and yeasts produce leukocyturia without bacteriuria. The inflammation of the renal tissues (interstitial nephritis) can produce leukocyturia, in particular toxic interstitial nephritis with predominant Pathogenesis The bacteria that cause urinary tract infections typically enter the bladder via the urethra. However, infection may also occur via the blood or lymph. It is believed that the bacteria are usually transmitted to the urethra from the bowel, with females at greater risk due to their anatomy. After gaining entry to the bladder, E. Coli are able to attach to the bladder wall and form a biofilm that resists the body's immune response. Escherichia coli is the single most common microorganism, followed by Klebsiella and Proteus spp., to cause urinary tract infection. Klebsiella and Proteus spp., are frequently associated with stone disease. The presence of Gram positive bacteria such as Enterococcus and Staphylococcus increased. The increased resistance of urinary pathogens to quinolone antibiotics has been reported worldwide and might be the consequence of overuse and misuse of quinolones. Diagnosis We compare the test characteristics of urine dipstick and urinalysis at various test cutoff points in women presenting to emergency departments and an intermediate care center with symptoms of urinary tract infection. This was a prospective, observational study of adult women presenting to 1 of 2 community hospital EDs or an intermediate care center with dysuria, urgency, or urinary frequency on history, or suprapubic or costovertebral angle tenderness on examination. Patients who had taken antibiotics in the past 72 hours, had indwelling Foley catheters, symptomatic vaginal discharge, diabetes mellitus, immunodeficiency disorders, or were unable to provide a reliable history were excluded. The patient's clean-catch or catheterized urine specimen was tested immediately by a nurse using a Multistix 9 SG reagent strip. A second aliquot was sent within 1 hour of collection to the hospital laboratory, where a semiautomated microscopic urinalysis and a urine culture were performed. A positive urine culture was defined as more than 100,000 colonies of 1 or 2 uropathogenic bacteria per mL of urine at 48 hours. Dipstick and urinalysis data were compared with urine culture results. Sensitivity, specificity, and predictive values were calculated at various definitions of a positive test, or \"test cutoff points,\" for combinations of leukocyte esterase, nitrite, and blood on dipstick and for RBCs and WBCs on urinalyses. The probability of an erroneous decision to withhold treatment on the basis of a negative test result was defined as \"undertreatment,\" or 1 minus the negative predictive value. \"Overtreatment\" was defined as 1 minus the positive predictive value. Three hundred forty-three patients were enrolled in this study. Twelve patients were withdrawn because of missing laboratory results. Forty-six percent (152/331) of patients had positive urine cultures. If urine dipstick results are defined as positive when leukocyte esterase or nitrite is positive or blood is more than trace, the overtreatment rate is 47% (156/331) and the undertreatment rate is 13% (43/331). If urinalysis results are defined as positive when WBCs are more than 3 per high-power field or RBCs are more than 5 per high-power field, the overtreatment rate is 44% (146/331) and the undertreatment rate is 11% (36/331). Matched pairs of test characteristics were identified when the analysis was repeated using more than 10,000 colonies per mL as a positive culture. In this patient population, similar overtreatment and undertreatment rates were identified for various test cutoff points for urine dipstick tests and urinalysis. Although a urine dipstick may be equivalent to a urinalysis for the diagnosis of urinary tract infection, the limitations in the diagnostic accuracy of both tests should be incorporated into medical decisionmaking. Urinary tract infection (UTI) is one of the most common infections during pregnancy, which can lead to significant maternal and perinatal morbidity and mortality if left untreated. Challenges when treating UTIs in pregnancy include fetal protection and resistance development of uropathogens. Currently, the Essential Medicines List recommends nitrofurantoin to treat cystitis and ceftriaxone to treat pyelonephritis in pregnant women. To determine common pathogens causing UTI in pregnancy and their antibiotic susceptibility patterns. A retrospective analysis was performed of laboratory data for positive urine specimens from obstetric departments of 6 KwaZulu- Natal Province hospitals during 2011 - 2016. Identification and susceptibility testing were performed using the VITEK 2 system. Results were interpreted according to the breakpoints of the Clinical and Laboratory Standards Institute, USA. From 5 971 positive urine specimens, the most common isolate was Escherichia coli (n=3 236; 54.2%), followed by Klebsiella pneumoniae (n=770; 12.9%). Group B streptococcus (GBS) (n=239; 4.0%) and Enterococcus faecalis (n=251; 4.2%) were the most common Gram-positive pathogens. E. coli displayed significant resistance to trimethoprim-sulfamethoxazole (65.1%), cephalothin (38.3%), cefuroxime (27.3%), ciprofloxacin (16.9%) and amoxicillin-clavulanic acid (17.1%). Resistance to ceftriaxone and nitrofurantoin remained low ‒ 9.1% and 7.7%, respectively. Among Gram-positive pathogens, GBS displayed 100% penicillin susceptibility and E. faecalis showed 92.9% susceptibility to ampicillin. E. coli is unsurprisingly the most common cause of UTI in pregnancy in KwaZulu-Natal. Susceptibility to ceftriaxone and nitrofurantoin remains good. Among Gram positives, GBS is prevalent and susceptible to penicillin, while E. faecalis is susceptible to ampicillin. As antimicrobial resistance evolves, routine surveillance is necessary to modify recommended empirical antibiotic use.\nHere is the question:\nMICROBIOLOGY: Pregnant woman, 27 years old, 30 weeks of gestation. She comes to the emergency room because she noticed pain in the left lumbar region and dysuria since yesterday. She has no febrile sensation. She refers repeated urinary tract infections (UTI). Urinalysis shows Hb 3+, leukocytes 3+, nitrites 2+, sediment: 15-20 leukocytes per field and 5-10 red blood cells per field. Which of the following microorganisms is the most frequent culprit in pregnant women?\nHere are the potential choices:\n1. Escherichia coli.\n2. Enterococcus faecalis.\n3. Streptococcus agalactiae.\n4. Proteus mirabilis.\n5. Satphylococcus saprophyticus.\nThe correct answer is: 1. Escherichia coli."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n This study evaluated the real-world weight loss and glycemic outcomes of multidrug therapy (MDT) according to various combinations of metformin, sodium-glucose cotransporter -2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor analogs (GLP1a), and orlistat in diabesity. Data retrospectively captured from medical records of 2 different centers in New Delhi for patients &gt;35 years-age having prediabetes/diabetes and on at least any one of the 4 above medications with &gt;6-months follow-up was analyzed. In total, 5,336 patient records were screened; 2,442 with prediabetes/diabetes were considered; 1,509 patients who fulfilled all criteria were analyzed. Use of metformin, SGLT2i, sulfonylureas, DPP4i, pioglitazone, orlistat, and GLP1a was 85.35%, 74.95%, 68.32%, 60%, 39.16%, 9.08%, and 4.17%, respectively. However, 365, 970, and 104 patients were on one of 4 concerned medications (Group-1; 24.18%), dual MDT (Group-2; 64.28%), and triple/quadruple MDT (Group-3; 6.89%). Metformin with SGLT2i was most commonly used dual MDT (94.12%). Analysis according to weight-loss quartiles from 558 patients showed 6.9 kg weight-loss in the highest quartile. People losing maximum weight were significantly younger; had higher use of metformin, SGLT2i, GLP1, orlistat, and lower pioglitazone use; greatest HbA1c reduction (-1.3 vs. -0.3; quartile-1 vs. quartile -4; <iP</i &lt; 0.001); and significantly higher occurrence of HbA1c&lt;5.7% (16.8% vs. 6.29%; quartile-1 vs. 4; <iP</i &lt; 0.001). Patients in Group-3 had the highest baseline BMI and maximum weight loss with highest number of patients with HbA1c&lt;5.7% (19.44% vs. 10.34%; Group-3 vs. Group-1; <iP</i &lt; 0.001). Greater weight loss with HbA1c reduction along with a greater number of patients attaining HbA1c &lt;5.7% highlights that MDT is the way forward to tackle diabesity in India. A detailed description is given of a case we encountered in which unexpectedly marked weight gain occurred following a treatment switch from a GLP-1 receptor agonist to an SGLT-2 inhibitor The patient, a 44-year-old man with type 2 diabetes mellitus, had gained about 10 kg in weight in the previous year. Therefore, metformin was replaced with liraglutide to obtain reduction of body weight. Although the patient lost about 8 kg (7%), during the 18-month period on the medication, the weight loss stabilized; therefore, the treatment was again switched to tofogliflozin to obtain further reduction of body weight. However, the patient reported increasing hunger and an exaggerated appetite from week 3 onward after the start of tofogliflozin, and gained about 9 kg in weight within 2 weeks, associated with a tendency towards increased HbA1c; therefore, tofogliflozin was discontinued. Immediate reinstitution of liraglutide resulted in reduction of the increased appetite, weight, and HbA1c level. Caution should be exercised against hyperphagia and weight gain due to hunger that may occur following discontinuation of a GLP-1 receptor agonist and/or initiation of an SGLT-2 inhibitor. Treatment of diabetes mellitus type2 (DM2) includes healthy eating and exercise (150minutes/week) as basic pillars. For pharmacological treatment, metformin is the initial drug except contraindication or intolerance; in case of poor control, 8 therapeutic families are available (6 oral and 2 injectable) as possible combinations. An algorithm and some recommendations for the treatment of DM2 are presented. In secondary cardiovascular prevention, it is recommended to associate an inhibitor of the sodium-glucose cotransporter type 2 (iSGLT2) or a glucagon-like peptide-1 receptor agonist (arGLP1) in patients with obesity. In primary prevention if the patient is obese or overweight metformin should be combined with iSGLT2, arGLP1, or inhibitors of type4 dipeptidylpeptidase (iDPP4). If the patient does not present obesity, iDPP4, iSGLT2 or gliclazide, sulfonylurea, recommended due to its lower tendency to hypoglycaemia, may be used. The algorithms and guidelines of the American Association of Clinical Endocrinologists and the American Diabetes Association recommend that insulin administration be strongly considered for people with type 2 diabetes (T2D) with HbA1c levels exceeding 9.0% and 10%, respectively. Although the caveat is given in both sets of recommendations that this is particularly appropriate when patients are \"symptomatic,\" referring to urinary frequency with increased thirst and appetite, weight loss, and ketosis, the clinical definition of such presentations may be ill-defined, and it is noteworthy that both documents consider insulin to offer particular benefit under such circumstances. However, with multiple options for glycemic treatment, it is of interest to reconsider this argument for insulin use. It should be recalled that in the UK Prospective Diabetes Study, diet alone was associated with a reduction in HbA1c from 9% to 7%. Drug-naïve people with T2D do often show surprisingly strong reductions in HbA1c with metformin-based dual-agent oral treatment approaches; a recent report showed that even with baseline HbA1c &gt;11%, the combination of metformin with a sulfonylurea, pioglitazone, or sitagliptin was associated with reduction in HbA1c from 11.6% to 6.0%. A 32-week study of the combination of rosiglitazone with metformin in patients with mean baseline HbA1c 8.9% showed a mean HbA1c reduction of 2.3%, and an open-label cohort with baseline HbA1c 11.8% had a reduction in HbA1c to 7.8%. With metformin plus sitagliptin, a mean placebo-adjusted HbA1c reduction of 2.1% from a baseline of 8.8% was reported, with those patients with baseline HbA1c &gt;9% having a 2.6% reduction in HbA1c, and an open-label cohort with baseline HbA1c 11.2% having a 2.9% reduction in HbA1c. Similar 2% HbA1c reductions from baseline levels of 9.1% were seen with metformin in initial combination with the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin. Although such dual oral agent approaches are more effective than monotherapy, with a combination regimen the HbA1c reduction will not be directly additive, because the expected reduction decreases at lower baseline HbA1c levels. As an example of this, administration of canagliflozin 300 mg daily to patients with baseline HbA1c &gt;9% reduced levels from 9.6% by 1.8%, whereas at a baseline HbA1c of 10% either canagliflozin 300 mg or metformin 2 g/day reduced HbA1c by 2%; the addition of both agents led to an HbA1c reduction by somewhat less than 3%, which appears concordant with a reduction by the second agent from approximately 8% (10% to 2%). Similar less-than-additive effects of the addition of exenatide QW to dapagliflozin have been reported, with HbA1c reduction from a baseline of 10.0%-10.1% of 1.9% and 1.6% with the individual agents, respectively, and a reduction of 2.2% with their combination. However, one may consider these approaches inferior to the expected HbA1c reduction with insulin, suggesting that insulin should, indeed, be the preferred treatment for people with T2D and HbA1c &gt;9%. Rather, studies comparing basal insulin directly with glucagon-like peptide-1 (GLP-1) receptor agonists (RA) suggest that the latter agents may offer superior benefit. The Diabetes Therapy Utilization: Researching Changes in HBA1C, Weight, and Other Factors Through Intervention with Exenatide Once Weekly (DURATION)-3 and Liraglutide Effect and Action in Diabetes (LEAD)-5 studies compared exenatide QW and liraglutide, respectively, with insulin glargine. Those study participants in the highest quartile of baseline HbA1c had levels ≥9.0% and ≥8.9%, with the GLP-1RA leading to 0.3% and 0.2% greater reductions in HbA1c, respectively, than insulin glargine. Another study comparing T2D patients receiving oral agents given liraglutide with those given insulin glargine showed that those in the highest baseline HbA1c quartile (mean 10.6%) had an HbA1c reduction of 3.1% with either agent. In the exenatide QW study, the reduction in HbA1c with this agent exceeded that with insulin glargine for those groups of study participants with HbA1c 9.0%-9.4%, 9.5%-9.9%, 10.0%-10.4%, 10.5%-10.9%, and even ≥11.0%. Similar superiority of the HbA1c-lowering effect of exenatide QW compared with that of insulin glargine was reported in a study with baseline HbA1c 8.5%. An individual-patient meta-analysis of six studies of another weekly GLP-1RA, namely dulaglutide, showed that at a baseline HbA1c of 10% the expected HbA1c reduction would be nearly 2.5%, and a study directly comparing dulaglutide with insulin glargine also showed a superior HbA1c-lowering effect of the former. Another advantage of the GLP-1RAs is their association with weight loss, rather than the weight gain associated with insulin treatment. An interesting potential combination is that of a GLP-1RA with a thiazolidinedione. In a study comparing the addition of exenatide QW and pioglitazone with the addition of basal-bolus insulin in 101 people receiving sulfonylureas and metformin with baseline HbA1c &gt;10%, HbA1c fell from &gt;11% by &gt;4% compared with &lt;4%, respectively, and the GLP-1RA plus thiazolidinedione treatment was associated with less weight gain and hypoglycemia. What can we conclude? Should HbA1c 11% be the new \"use insulin\" point? Insulin is an important part of our armamentarium for T2D, and is certainly needed for many patients, but with current therapeutic approaches including metformin, incretin-based treatments, SGLT2 inhibitors, and, possibly, thiazolidinediones, we can reconsider its use in many instances. Although there is no doubt that insulin is necessary for truly uncontrolled diabetes, we may wish to better define its correct indications. To evaluate the efficacy of SGLT2 inhibitors as an add-on therapy along with stricter lifestyle modification in Asian Indian type 2 diabetes mellitus (T2DM) patients with inadequate glycemic control despite receiving an optimum dose of at least 4 oral antidiabetic drugs (OADs). A retrospective analysis of data of 808 T2DM patients being treated with an SGLT2 inhibitor (Dapagliflozin, Empagliflozin or Canagliflozin) as an add-on drug in patients with inadequate glycemic control despite receiving optimum doses of at least any four OADs(metformin, sulphonylureas, pioglitazone, DPP4 Inhibitors, alpha-Glucosidase Inhibitors) and who preferred not to initiate insulin. The average age of the patients included was 51.63 years (SD ± 9.88). 57.7% were males. Average weight was 81.95±16.08 kg. Mean duration of diabetes was 34.08±39.04 months. The mean baseline fasting plasma glucose was 198.21 ± 38.21 mg/dl and mean post prandial plasma glucose was 264.22 ± 45.22 mg/ dl. The baseline HbA1c was 8.92 ± 1.47 %. Total 87.4 % of the cases responded to addition of SGLT2 inhibitors during a mean follow-up period of 6 months. The fasting plasma glucose (FBS) was reduced by -63.65 ± 19.93 mg/dl to a mean FBS of 134.57 ± 33.65 mg/dl (P=0.001). The post prandial plasma glucose (PPBS) was reduced by -79.28 ± 23.57 mg/dl to a mean PPBS of 184.94 ± 38.34 mg/dl (P=0.001). The mean HbA1c reduced significantly by -1.63 ± 0.99 % (P= 0.001). The mean weight reduction at 6 months of therapy was -3.03± 01.84 kg that is 3.8 % decrease from baseline (p=0.001).The response in age group &lt; 55 years was 90.9 %, whereas in ≥55 years, it was 82.2% (p=0.001). The males responded more (91.0%) compared to females (82.5%) (p=0.001). Those with BMI &lt; 23.5 kg/ m2 had marginally higher but insignificant response of 93.0% as compared to 87.1% in patients with high a BMI (≥23.5 kg/m2) (p=0.253). Patients with &lt; 5years duration of diabetes responded better (91.8%) as compared to patients with a ≥ 5 years of diabetes (85.4%). SGLT2 inhibitors are effective in achieving desired glycemic goals even when used as a fifth add-on drug along with strict lifestyle modification in patients with inadequate glycemic control despite receiving an optimum dose of at least 4 oral antidiabetic drugs (OADs). SGLT2 inhibitors can be effectively used at any stage of diabetes. Case 1 was a 41-year-old man with type 1 diabetes. He presented with poor glycemic control [hemoglobin A1c (HbA1c) of 8-9%] despite treatment with more than 20 units/day of insulin and 150 mg of miglitol. Before administration of sodium glucose cotransporter 2 (SGLT2) inhibitor, hyperglycemia was noted mainly at night by Flash Glucose Monitoring (FGM). Administration of ipragliflozin at 50 mg improved the hyperglycemia mainly at night (mean blood glucose, before administration: 205 mg/dl, day 6 of treatment: 119 mg/dl). Two months later, the HbA1c improved to 7.2% without hypoglycemia or ketosis. Case 2 was a 46-year-old woman with type 1 diabetes. She was morbidly obese and presented with poor glycemic control (HbA1c: 9-11%) although she was being treated with more than 50 units/day of insulin and 2,250 mg of metformin. Before administration of SGLT2 inhibitor, hyperglycemia was noted to be mainly nocturnal by FGM. Administration of dapagliflozin at 5 mg improved the hyperglycemia mainly at night on day 2 with improvement in the mean blood glucose level from 188 mg/dl before administration to 128 mg/dl on day 5. Four months later, the HbA1c improved to 8.0% without hypoglycemia and ketosis, and her body weight decreased from 92.1 to 89.8 kg. The hypoglycemic effect of SGLT2 inhibitors is independent of insulin. These agents also have various other effects, including weight loss, improvement of blood pressure and lipid metabolism. Here we report the short-term glucose lowering effects of two SGLT2 inhibitors, as confirmed by FGM, in two outpatients with type 1 diabetes. The overall goal in the treatment of type 2 diabetes mellitus (T2DM) is remission. However, the effects of a sodium-glucose cotransporter 2 inhibitor (SGLT2i) on remission of T2DM are unknown. We herein report a case involving an overweight 43-year-old man who completely recovered from T2DM after SGLT2i therapy (dapagliflozin at 5 mg/day). In the pretreatment period, he had a body mass index (BMI) of 26.0 kg/m<sup2</sup, hemoglobin A1c (HbA1c) concentration of 10.3%, advanced insulin resistance, pancreatic β-cell dysfunction, and fatty liver. Eighteen months after comprehensive therapy, including the administration of an SGLT2i and metformin, his BMI had decreased to 21.3 kg/m<sup2</sup and his glycemic control was almost normal (HbA1c of 5.3%) despite discontinuation of all hypoglycemic medications. This report is the first to propose the usefulness of the combination therapy of SGLT2i and metformin for achieving normal body weight and remission of newly diagnosed T2DM in a real-world clinical situation. Insulin resistance is a critical aspect of the pathophysiology of type 2 diabetes mellitus and is also associated with other risk factors for cardiovascular disease (eg, dyslipidemia and hypertension). Accordingly, insulin resistance is a possible target for lowering plasma glucose concentration and preventing diabetic macroangiopathy. Biguanides, such as metformin, and thiazolidinediones (TZDs), such as pioglitazone, improve insulin resistance. The aims of this study were to assess the effects of replacing a biguanide with a TZD on glycemic control in patients with poorly controlled type 2 diabetes mellitus, and also to identify the factors affecting interpatient variation in the effects of treatment change. This was a 12-week, open-label, prospective study in which previously prescribed metformin (500 or 750 mg/d) was replaced with pioglitazone (15 or 30 mg/d) in patients with poorly controlled type 2 diabetes mellitus. Patients with a glycosylated hemoglobin (HbA1c) concentration &gt;7% despite treatment with diet, exercise, and hypoglycemic agents other than TZDs were eligible for the study. Patients who never received TZDs were also eligible for inclusion. Vital signs, metabolic parameters, and arterial stiffness were assessed at baseline and after 12 weeks of treatment with pioglitazone. The primary end point was change in HbA1c concentration after replacing metformin with pioglitazone. Tolerability was assessed by medical history, physical examination, and laboratory tests (aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase). Twenty-one Japanese patients (15 women, 6 men; mean [SD] age, 61.8 [8.4] years; body mass index, 25.5 [3.0] kg/m(2)) were included in the study. HbA1c concentration was not significantly changed from baseline after 12 weeks of pioglitazone treatment (8.0% [0.7%] vs 8.2% [0.7%]). Fasting plasma glucose (FPG) concentration also was not significantly changed after the replacement of treatment (156 [27] vs 144 [30] mg/dL). In addition, the resistin concentration did not change significantly from baseline after 12 weeks of pioglitazone treatment (6.6 [3.8] vs 6.4 [3.6] ng/mL). In contrast, significant improvement from baseline was observed in triglyceride (TG) concentrations (157 [109] vs 117 [68] mg/dL; P = 0.003), high-density lipoprotein cholesterol (HDL-C) (55 [12] vs 61 [16] mg/dL; P = 0.016), remnant-like particle cholesterol (6.6 [6.0] vs 5.3 [3.5] mg/dL; P = 0.048), and serum adiponectin (8.8 [4.3] vs 23.3 [11.7] μg/mL; P &lt; 0.001). Pulse wave velocity was also significantly improved (1730 [361] vs 1622 [339] m/sec; P = 0.009). Changes in HbA1c were significantly correlated with serum fasting insulin concentration at baseline in the patients not receiving insulin preparations (r = -0.635, P = 0.013). The percentage change in serum adiponectin concentration was correlated with the percentage changes in HbA1c and FPG concentrations (HbA1c, r = -0.518, P = 0.019; FPG, r = -0.594, P = 0.006). Body weight was significantly increased after treatment (62.6 [11.9] vs 65.5 [12.2] kg; P &lt; 0.001). Mild edema was reported in 5 patients. One patient discontinued treatment due to an increase in serum creatine kinase activity to ~6.6 times the upper limit of normal. Replacement of metformin with pioglitazone did not produce significant differences in HbA1c and FPG concentrations from baseline after 12 weeks of treatment in these patients with poorly controlled type 2 diabetes mellitus. However, the replacement was effective in a subset of patients whose serum insulin concentrations were high or whose serum adiponectin concentrations were sensitive to TZDs. In addition, the replacement was associated with significant improvements in TG, HDL-C, serum adiponectin concentration, pulse wave velocity, and body weight increase from baseline. lost 5–7% of their body weight during the 3 years of the study. Studies in Finnish and Chinese populations noted similar efficacy of diet and exercise in preventing or delaying type 2 DM. A number of agents, including α-glucosidase inhibitors, metformin, thiazolidinediones, GLP-1 receptor pathway modifiers, and orlistat, prevent or delay type 2 DM but are not approved for this purpose. Individuals with a strong family history of type 2 DM and individuals with IFG or IGT should be strongly encouraged to maintain a normal BMI and engage in regular physical activity. Pharmacologic therapy for individuals with prediabetes is currently controversial because its cost-effectiveness and safety profile are not known. The ADA has suggested that metformin be considered in individuals with both IFG and IGT who are at very high risk for progression to diabetes (age <60 years, BMI ≥35 kg/m2, family history of diabetes in first-degree relative, and women with a history of GDM). Individuals with IFG, To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes. This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7-11% (previous oral antidiabetes drug [OAD] monotherapy &gt;or=3 months) or 7-10% (previous OAD combination therapy &gt;or=3 months), and BMI &lt;or=45 kg/m(2). Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean +/- SE -1.5 +/- 0.1% for both 1.2 and 1.8 mg liraglutide and -0.5 +/- 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P &lt; 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 +/- 0.3 and 2.0 +/- 0.3 kg, respectively) (P &lt; 0.0001) compared with weight gain with placebo (0.6 +/- 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of beta-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient. Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control. Medical uses In the United States dapagliflozin/saxagliptin/metformin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. In the European Union it is indicated in adults aged 18 years and older with type 2 diabetes mellitus: to improve glycemic control when metformin with or without sulphonylurea (SU) and either saxagliptin or dapagliflozin does not provide adequate glycemic control. when already being treated with metformin and saxagliptin and dapagliflozin. References External links Anti-diabetic drugs AstraZeneca brands Biguanides Chloroarenes Combination drugs Glucosides Guanidines Phenol ethers SGLT2 inhibitors Medical uses Canagliflozin/metformin is indicated in adults aged 18 years of age and older with type 2 diabetes as an adjunct to diet and exercise to improve glycemic control. Adverse effects To lessen the risk of developing ketoacidosis (a serious condition in which the body produces high levels of blood acids called ketones) after surgery, the FDA approved changes to the prescribing information for SGLT2 inhibitor diabetes medicines to recommend they be stopped temporarily before scheduled surgery. Canagliflozin, dapagliflozin, and empagliflozin should each be stopped at least three days before, and ertugliflozin should be stopped at least four days before scheduled surgery. Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing. References Further reading External links Anti-diabetic drugs Biguanides Combination drugs Fluoroarenes Glucosides Guanidines SGLT2 inhibitors Thiophenes Medical uses In the United States pioglitazone/glimepiride is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a thiazolidinedione and sulfonylurea or who have inadequate glycemic control on a thiazolidinedione alone or a sulfonylurea alone. In the European Union pioglitazone/glimepiride is indicated for the treatment of people with type 2 diabetes mellitus who show intolerance to metformin or for whom metformin is contraindicated and who are already treated with a combination of pioglitazone and glimepiride. References External links Anti-diabetic drugs\nHere is the question:\nENDOCRINOLOGY: A 66-year-old woman diagnosed with type 2 diabetes mellitus since three months ago. She has a BMI of 31 kg/m2 and presents poor glycemic control despite a program of non-pharmacological measures (healthy diet, exercise). Which of the following hypoglycemic drugs is associated with weight gain and should we avoid in this patient?:\nHere are the potential choices:\n1. Metformin (biguanide).\n2. Pioglitazone (thiazolidinedione).\n3. Canagliflozin (sodium-glucose cotransporter 2 inhibitor- iSGLT2).\n4. Liraglutide (GLP-1 receptor agonist).\nThe correct answer is: ",
        "gold_answer": "2 Pioglitazone (thiazolidinedione).",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n This study evaluated the real-world weight loss and glycemic outcomes of multidrug therapy (MDT) according to various combinations of metformin, sodium-glucose cotransporter -2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor analogs (GLP1a), and orlistat in diabesity. Data retrospectively captured from medical records of 2 different centers in New Delhi for patients &gt;35 years-age having prediabetes/diabetes and on at least any one of the 4 above medications with &gt;6-months follow-up was analyzed. In total, 5,336 patient records were screened; 2,442 with prediabetes/diabetes were considered; 1,509 patients who fulfilled all criteria were analyzed. Use of metformin, SGLT2i, sulfonylureas, DPP4i, pioglitazone, orlistat, and GLP1a was 85.35%, 74.95%, 68.32%, 60%, 39.16%, 9.08%, and 4.17%, respectively. However, 365, 970, and 104 patients were on one of 4 concerned medications (Group-1; 24.18%), dual MDT (Group-2; 64.28%), and triple/quadruple MDT (Group-3; 6.89%). Metformin with SGLT2i was most commonly used dual MDT (94.12%). Analysis according to weight-loss quartiles from 558 patients showed 6.9 kg weight-loss in the highest quartile. People losing maximum weight were significantly younger; had higher use of metformin, SGLT2i, GLP1, orlistat, and lower pioglitazone use; greatest HbA1c reduction (-1.3 vs. -0.3; quartile-1 vs. quartile -4; <iP</i &lt; 0.001); and significantly higher occurrence of HbA1c&lt;5.7% (16.8% vs. 6.29%; quartile-1 vs. 4; <iP</i &lt; 0.001). Patients in Group-3 had the highest baseline BMI and maximum weight loss with highest number of patients with HbA1c&lt;5.7% (19.44% vs. 10.34%; Group-3 vs. Group-1; <iP</i &lt; 0.001). Greater weight loss with HbA1c reduction along with a greater number of patients attaining HbA1c &lt;5.7% highlights that MDT is the way forward to tackle diabesity in India. A detailed description is given of a case we encountered in which unexpectedly marked weight gain occurred following a treatment switch from a GLP-1 receptor agonist to an SGLT-2 inhibitor The patient, a 44-year-old man with type 2 diabetes mellitus, had gained about 10 kg in weight in the previous year. Therefore, metformin was replaced with liraglutide to obtain reduction of body weight. Although the patient lost about 8 kg (7%), during the 18-month period on the medication, the weight loss stabilized; therefore, the treatment was again switched to tofogliflozin to obtain further reduction of body weight. However, the patient reported increasing hunger and an exaggerated appetite from week 3 onward after the start of tofogliflozin, and gained about 9 kg in weight within 2 weeks, associated with a tendency towards increased HbA1c; therefore, tofogliflozin was discontinued. Immediate reinstitution of liraglutide resulted in reduction of the increased appetite, weight, and HbA1c level. Caution should be exercised against hyperphagia and weight gain due to hunger that may occur following discontinuation of a GLP-1 receptor agonist and/or initiation of an SGLT-2 inhibitor. Treatment of diabetes mellitus type2 (DM2) includes healthy eating and exercise (150minutes/week) as basic pillars. For pharmacological treatment, metformin is the initial drug except contraindication or intolerance; in case of poor control, 8 therapeutic families are available (6 oral and 2 injectable) as possible combinations. An algorithm and some recommendations for the treatment of DM2 are presented. In secondary cardiovascular prevention, it is recommended to associate an inhibitor of the sodium-glucose cotransporter type 2 (iSGLT2) or a glucagon-like peptide-1 receptor agonist (arGLP1) in patients with obesity. In primary prevention if the patient is obese or overweight metformin should be combined with iSGLT2, arGLP1, or inhibitors of type4 dipeptidylpeptidase (iDPP4). If the patient does not present obesity, iDPP4, iSGLT2 or gliclazide, sulfonylurea, recommended due to its lower tendency to hypoglycaemia, may be used. The algorithms and guidelines of the American Association of Clinical Endocrinologists and the American Diabetes Association recommend that insulin administration be strongly considered for people with type 2 diabetes (T2D) with HbA1c levels exceeding 9.0% and 10%, respectively. Although the caveat is given in both sets of recommendations that this is particularly appropriate when patients are \"symptomatic,\" referring to urinary frequency with increased thirst and appetite, weight loss, and ketosis, the clinical definition of such presentations may be ill-defined, and it is noteworthy that both documents consider insulin to offer particular benefit under such circumstances. However, with multiple options for glycemic treatment, it is of interest to reconsider this argument for insulin use. It should be recalled that in the UK Prospective Diabetes Study, diet alone was associated with a reduction in HbA1c from 9% to 7%. Drug-naïve people with T2D do often show surprisingly strong reductions in HbA1c with metformin-based dual-agent oral treatment approaches; a recent report showed that even with baseline HbA1c &gt;11%, the combination of metformin with a sulfonylurea, pioglitazone, or sitagliptin was associated with reduction in HbA1c from 11.6% to 6.0%. A 32-week study of the combination of rosiglitazone with metformin in patients with mean baseline HbA1c 8.9% showed a mean HbA1c reduction of 2.3%, and an open-label cohort with baseline HbA1c 11.8% had a reduction in HbA1c to 7.8%. With metformin plus sitagliptin, a mean placebo-adjusted HbA1c reduction of 2.1% from a baseline of 8.8% was reported, with those patients with baseline HbA1c &gt;9% having a 2.6% reduction in HbA1c, and an open-label cohort with baseline HbA1c 11.2% having a 2.9% reduction in HbA1c. Similar 2% HbA1c reductions from baseline levels of 9.1% were seen with metformin in initial combination with the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin. Although such dual oral agent approaches are more effective than monotherapy, with a combination regimen the HbA1c reduction will not be directly additive, because the expected reduction decreases at lower baseline HbA1c levels. As an example of this, administration of canagliflozin 300 mg daily to patients with baseline HbA1c &gt;9% reduced levels from 9.6% by 1.8%, whereas at a baseline HbA1c of 10% either canagliflozin 300 mg or metformin 2 g/day reduced HbA1c by 2%; the addition of both agents led to an HbA1c reduction by somewhat less than 3%, which appears concordant with a reduction by the second agent from approximately 8% (10% to 2%). Similar less-than-additive effects of the addition of exenatide QW to dapagliflozin have been reported, with HbA1c reduction from a baseline of 10.0%-10.1% of 1.9% and 1.6% with the individual agents, respectively, and a reduction of 2.2% with their combination. However, one may consider these approaches inferior to the expected HbA1c reduction with insulin, suggesting that insulin should, indeed, be the preferred treatment for people with T2D and HbA1c &gt;9%. Rather, studies comparing basal insulin directly with glucagon-like peptide-1 (GLP-1) receptor agonists (RA) suggest that the latter agents may offer superior benefit. The Diabetes Therapy Utilization: Researching Changes in HBA1C, Weight, and Other Factors Through Intervention with Exenatide Once Weekly (DURATION)-3 and Liraglutide Effect and Action in Diabetes (LEAD)-5 studies compared exenatide QW and liraglutide, respectively, with insulin glargine. Those study participants in the highest quartile of baseline HbA1c had levels ≥9.0% and ≥8.9%, with the GLP-1RA leading to 0.3% and 0.2% greater reductions in HbA1c, respectively, than insulin glargine. Another study comparing T2D patients receiving oral agents given liraglutide with those given insulin glargine showed that those in the highest baseline HbA1c quartile (mean 10.6%) had an HbA1c reduction of 3.1% with either agent. In the exenatide QW study, the reduction in HbA1c with this agent exceeded that with insulin glargine for those groups of study participants with HbA1c 9.0%-9.4%, 9.5%-9.9%, 10.0%-10.4%, 10.5%-10.9%, and even ≥11.0%. Similar superiority of the HbA1c-lowering effect of exenatide QW compared with that of insulin glargine was reported in a study with baseline HbA1c 8.5%. An individual-patient meta-analysis of six studies of another weekly GLP-1RA, namely dulaglutide, showed that at a baseline HbA1c of 10% the expected HbA1c reduction would be nearly 2.5%, and a study directly comparing dulaglutide with insulin glargine also showed a superior HbA1c-lowering effect of the former. Another advantage of the GLP-1RAs is their association with weight loss, rather than the weight gain associated with insulin treatment. An interesting potential combination is that of a GLP-1RA with a thiazolidinedione. In a study comparing the addition of exenatide QW and pioglitazone with the addition of basal-bolus insulin in 101 people receiving sulfonylureas and metformin with baseline HbA1c &gt;10%, HbA1c fell from &gt;11% by &gt;4% compared with &lt;4%, respectively, and the GLP-1RA plus thiazolidinedione treatment was associated with less weight gain and hypoglycemia. What can we conclude? Should HbA1c 11% be the new \"use insulin\" point? Insulin is an important part of our armamentarium for T2D, and is certainly needed for many patients, but with current therapeutic approaches including metformin, incretin-based treatments, SGLT2 inhibitors, and, possibly, thiazolidinediones, we can reconsider its use in many instances. Although there is no doubt that insulin is necessary for truly uncontrolled diabetes, we may wish to better define its correct indications. To evaluate the efficacy of SGLT2 inhibitors as an add-on therapy along with stricter lifestyle modification in Asian Indian type 2 diabetes mellitus (T2DM) patients with inadequate glycemic control despite receiving an optimum dose of at least 4 oral antidiabetic drugs (OADs). A retrospective analysis of data of 808 T2DM patients being treated with an SGLT2 inhibitor (Dapagliflozin, Empagliflozin or Canagliflozin) as an add-on drug in patients with inadequate glycemic control despite receiving optimum doses of at least any four OADs(metformin, sulphonylureas, pioglitazone, DPP4 Inhibitors, alpha-Glucosidase Inhibitors) and who preferred not to initiate insulin. The average age of the patients included was 51.63 years (SD ± 9.88). 57.7% were males. Average weight was 81.95±16.08 kg. Mean duration of diabetes was 34.08±39.04 months. The mean baseline fasting plasma glucose was 198.21 ± 38.21 mg/dl and mean post prandial plasma glucose was 264.22 ± 45.22 mg/ dl. The baseline HbA1c was 8.92 ± 1.47 %. Total 87.4 % of the cases responded to addition of SGLT2 inhibitors during a mean follow-up period of 6 months. The fasting plasma glucose (FBS) was reduced by -63.65 ± 19.93 mg/dl to a mean FBS of 134.57 ± 33.65 mg/dl (P=0.001). The post prandial plasma glucose (PPBS) was reduced by -79.28 ± 23.57 mg/dl to a mean PPBS of 184.94 ± 38.34 mg/dl (P=0.001). The mean HbA1c reduced significantly by -1.63 ± 0.99 % (P= 0.001). The mean weight reduction at 6 months of therapy was -3.03± 01.84 kg that is 3.8 % decrease from baseline (p=0.001).The response in age group &lt; 55 years was 90.9 %, whereas in ≥55 years, it was 82.2% (p=0.001). The males responded more (91.0%) compared to females (82.5%) (p=0.001). Those with BMI &lt; 23.5 kg/ m2 had marginally higher but insignificant response of 93.0% as compared to 87.1% in patients with high a BMI (≥23.5 kg/m2) (p=0.253). Patients with &lt; 5years duration of diabetes responded better (91.8%) as compared to patients with a ≥ 5 years of diabetes (85.4%). SGLT2 inhibitors are effective in achieving desired glycemic goals even when used as a fifth add-on drug along with strict lifestyle modification in patients with inadequate glycemic control despite receiving an optimum dose of at least 4 oral antidiabetic drugs (OADs). SGLT2 inhibitors can be effectively used at any stage of diabetes. Case 1 was a 41-year-old man with type 1 diabetes. He presented with poor glycemic control [hemoglobin A1c (HbA1c) of 8-9%] despite treatment with more than 20 units/day of insulin and 150 mg of miglitol. Before administration of sodium glucose cotransporter 2 (SGLT2) inhibitor, hyperglycemia was noted mainly at night by Flash Glucose Monitoring (FGM). Administration of ipragliflozin at 50 mg improved the hyperglycemia mainly at night (mean blood glucose, before administration: 205 mg/dl, day 6 of treatment: 119 mg/dl). Two months later, the HbA1c improved to 7.2% without hypoglycemia or ketosis. Case 2 was a 46-year-old woman with type 1 diabetes. She was morbidly obese and presented with poor glycemic control (HbA1c: 9-11%) although she was being treated with more than 50 units/day of insulin and 2,250 mg of metformin. Before administration of SGLT2 inhibitor, hyperglycemia was noted to be mainly nocturnal by FGM. Administration of dapagliflozin at 5 mg improved the hyperglycemia mainly at night on day 2 with improvement in the mean blood glucose level from 188 mg/dl before administration to 128 mg/dl on day 5. Four months later, the HbA1c improved to 8.0% without hypoglycemia and ketosis, and her body weight decreased from 92.1 to 89.8 kg. The hypoglycemic effect of SGLT2 inhibitors is independent of insulin. These agents also have various other effects, including weight loss, improvement of blood pressure and lipid metabolism. Here we report the short-term glucose lowering effects of two SGLT2 inhibitors, as confirmed by FGM, in two outpatients with type 1 diabetes. The overall goal in the treatment of type 2 diabetes mellitus (T2DM) is remission. However, the effects of a sodium-glucose cotransporter 2 inhibitor (SGLT2i) on remission of T2DM are unknown. We herein report a case involving an overweight 43-year-old man who completely recovered from T2DM after SGLT2i therapy (dapagliflozin at 5 mg/day). In the pretreatment period, he had a body mass index (BMI) of 26.0 kg/m<sup2</sup, hemoglobin A1c (HbA1c) concentration of 10.3%, advanced insulin resistance, pancreatic β-cell dysfunction, and fatty liver. Eighteen months after comprehensive therapy, including the administration of an SGLT2i and metformin, his BMI had decreased to 21.3 kg/m<sup2</sup and his glycemic control was almost normal (HbA1c of 5.3%) despite discontinuation of all hypoglycemic medications. This report is the first to propose the usefulness of the combination therapy of SGLT2i and metformin for achieving normal body weight and remission of newly diagnosed T2DM in a real-world clinical situation. Insulin resistance is a critical aspect of the pathophysiology of type 2 diabetes mellitus and is also associated with other risk factors for cardiovascular disease (eg, dyslipidemia and hypertension). Accordingly, insulin resistance is a possible target for lowering plasma glucose concentration and preventing diabetic macroangiopathy. Biguanides, such as metformin, and thiazolidinediones (TZDs), such as pioglitazone, improve insulin resistance. The aims of this study were to assess the effects of replacing a biguanide with a TZD on glycemic control in patients with poorly controlled type 2 diabetes mellitus, and also to identify the factors affecting interpatient variation in the effects of treatment change. This was a 12-week, open-label, prospective study in which previously prescribed metformin (500 or 750 mg/d) was replaced with pioglitazone (15 or 30 mg/d) in patients with poorly controlled type 2 diabetes mellitus. Patients with a glycosylated hemoglobin (HbA1c) concentration &gt;7% despite treatment with diet, exercise, and hypoglycemic agents other than TZDs were eligible for the study. Patients who never received TZDs were also eligible for inclusion. Vital signs, metabolic parameters, and arterial stiffness were assessed at baseline and after 12 weeks of treatment with pioglitazone. The primary end point was change in HbA1c concentration after replacing metformin with pioglitazone. Tolerability was assessed by medical history, physical examination, and laboratory tests (aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase). Twenty-one Japanese patients (15 women, 6 men; mean [SD] age, 61.8 [8.4] years; body mass index, 25.5 [3.0] kg/m(2)) were included in the study. HbA1c concentration was not significantly changed from baseline after 12 weeks of pioglitazone treatment (8.0% [0.7%] vs 8.2% [0.7%]). Fasting plasma glucose (FPG) concentration also was not significantly changed after the replacement of treatment (156 [27] vs 144 [30] mg/dL). In addition, the resistin concentration did not change significantly from baseline after 12 weeks of pioglitazone treatment (6.6 [3.8] vs 6.4 [3.6] ng/mL). In contrast, significant improvement from baseline was observed in triglyceride (TG) concentrations (157 [109] vs 117 [68] mg/dL; P = 0.003), high-density lipoprotein cholesterol (HDL-C) (55 [12] vs 61 [16] mg/dL; P = 0.016), remnant-like particle cholesterol (6.6 [6.0] vs 5.3 [3.5] mg/dL; P = 0.048), and serum adiponectin (8.8 [4.3] vs 23.3 [11.7] μg/mL; P &lt; 0.001). Pulse wave velocity was also significantly improved (1730 [361] vs 1622 [339] m/sec; P = 0.009). Changes in HbA1c were significantly correlated with serum fasting insulin concentration at baseline in the patients not receiving insulin preparations (r = -0.635, P = 0.013). The percentage change in serum adiponectin concentration was correlated with the percentage changes in HbA1c and FPG concentrations (HbA1c, r = -0.518, P = 0.019; FPG, r = -0.594, P = 0.006). Body weight was significantly increased after treatment (62.6 [11.9] vs 65.5 [12.2] kg; P &lt; 0.001). Mild edema was reported in 5 patients. One patient discontinued treatment due to an increase in serum creatine kinase activity to ~6.6 times the upper limit of normal. Replacement of metformin with pioglitazone did not produce significant differences in HbA1c and FPG concentrations from baseline after 12 weeks of treatment in these patients with poorly controlled type 2 diabetes mellitus. However, the replacement was effective in a subset of patients whose serum insulin concentrations were high or whose serum adiponectin concentrations were sensitive to TZDs. In addition, the replacement was associated with significant improvements in TG, HDL-C, serum adiponectin concentration, pulse wave velocity, and body weight increase from baseline. lost 5–7% of their body weight during the 3 years of the study. Studies in Finnish and Chinese populations noted similar efficacy of diet and exercise in preventing or delaying type 2 DM. A number of agents, including α-glucosidase inhibitors, metformin, thiazolidinediones, GLP-1 receptor pathway modifiers, and orlistat, prevent or delay type 2 DM but are not approved for this purpose. Individuals with a strong family history of type 2 DM and individuals with IFG or IGT should be strongly encouraged to maintain a normal BMI and engage in regular physical activity. Pharmacologic therapy for individuals with prediabetes is currently controversial because its cost-effectiveness and safety profile are not known. The ADA has suggested that metformin be considered in individuals with both IFG and IGT who are at very high risk for progression to diabetes (age <60 years, BMI ≥35 kg/m2, family history of diabetes in first-degree relative, and women with a history of GDM). Individuals with IFG, To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes. This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7-11% (previous oral antidiabetes drug [OAD] monotherapy &gt;or=3 months) or 7-10% (previous OAD combination therapy &gt;or=3 months), and BMI &lt;or=45 kg/m(2). Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean +/- SE -1.5 +/- 0.1% for both 1.2 and 1.8 mg liraglutide and -0.5 +/- 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P &lt; 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 +/- 0.3 and 2.0 +/- 0.3 kg, respectively) (P &lt; 0.0001) compared with weight gain with placebo (0.6 +/- 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of beta-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient. Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control. Medical uses In the United States dapagliflozin/saxagliptin/metformin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. In the European Union it is indicated in adults aged 18 years and older with type 2 diabetes mellitus: to improve glycemic control when metformin with or without sulphonylurea (SU) and either saxagliptin or dapagliflozin does not provide adequate glycemic control. when already being treated with metformin and saxagliptin and dapagliflozin. References External links Anti-diabetic drugs AstraZeneca brands Biguanides Chloroarenes Combination drugs Glucosides Guanidines Phenol ethers SGLT2 inhibitors Medical uses Canagliflozin/metformin is indicated in adults aged 18 years of age and older with type 2 diabetes as an adjunct to diet and exercise to improve glycemic control. Adverse effects To lessen the risk of developing ketoacidosis (a serious condition in which the body produces high levels of blood acids called ketones) after surgery, the FDA approved changes to the prescribing information for SGLT2 inhibitor diabetes medicines to recommend they be stopped temporarily before scheduled surgery. Canagliflozin, dapagliflozin, and empagliflozin should each be stopped at least three days before, and ertugliflozin should be stopped at least four days before scheduled surgery. Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing. References Further reading External links Anti-diabetic drugs Biguanides Combination drugs Fluoroarenes Glucosides Guanidines SGLT2 inhibitors Thiophenes Medical uses In the United States pioglitazone/glimepiride is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a thiazolidinedione and sulfonylurea or who have inadequate glycemic control on a thiazolidinedione alone or a sulfonylurea alone. In the European Union pioglitazone/glimepiride is indicated for the treatment of people with type 2 diabetes mellitus who show intolerance to metformin or for whom metformin is contraindicated and who are already treated with a combination of pioglitazone and glimepiride. References External links Anti-diabetic drugs\nHere is the question:\nENDOCRINOLOGY: A 66-year-old woman diagnosed with type 2 diabetes mellitus since three months ago. She has a BMI of 31 kg/m2 and presents poor glycemic control despite a program of non-pharmacological measures (healthy diet, exercise). Which of the following hypoglycemic drugs is associated with weight gain and should we avoid in this patient?:\nHere are the potential choices:\n1. Metformin (biguanide).\n2. Pioglitazone (thiazolidinedione).\n3. Canagliflozin (sodium-glucose cotransporter 2 inhibitor- iSGLT2).\n4. Liraglutide (GLP-1 receptor agonist).\nThe correct answer is: 2. Pioglitazone (thiazolidinedione)."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n In France, 60,000 neonates are born preterm every year (7.4%), half of them after the spontaneous onset of labor. Among preventable risk factors of spontaneous prematurity, only cessation of smoking is associated with decreased prematurity (level of evidence [LE]1). It is therefore recommended (Grade A). Routine screening and treatment of vaginal bacteriosis is not recommended in the general population (Grade A). The only population for which vaginal progesterone is recommended is that comprising asymptomatic women with singleton pregnancies, no history of preterm delivery, and a short cervix at 16-24 weeks of gestation (Grade B). A history-indicated cerclage is not recommended for women with only a history of conization (Grade C), uterine malformation (professional consensus), isolated history of preterm delivery (Grade B), or twin pregnancies for primary (Grade B) or secondary (Grade C) prevention of preterm birth. A history-indicated cerclage is recommended for a singleton pregnancy with a history of at least 3 late miscarriages or preterm deliveries (Grade A). Ultrasound cervical length screening is recommended between 16 and 22 weeks for women with a singleton previously delivered before 34 weeks gestation, so that cerclage can be offered if cervical length &lt;25mm before 24 weeks (Grade C). A cervical pessary is not recommended for the prevention of preterm birth in a general population of asymptomatic women with twin pregnancies (Grade A) or in populations of asymptomatic women with a short cervix (professional consensus). Although the implementation of universal screening by transvaginal ultrasound for cervical length at 18-24 weeks of gestation in women with a singleton gestation and no history of preterm birth can be considered by individual practitioners, this screening cannot be universally recommended. In cases of preterm labor, (i) it is not possible to recommend any one of the several methods (ultrasound of the cervical length, vaginal examination, or fetal fibronectin assay) over any other to predict preterm birth (Grade B); (ii) routine antibiotic therapy is not recommended (Grade A); (iii) prolonged hospitalization (Grade B) and bed rest (Grade C) are not recommended. Compared with placebo, tocolytics are not associated with a reduction in neonatal mortality or morbidity (LE2) and maternal severe adverse effects may occur with all tocolytics (LE4). Atosiban and nifedipine (Grade B), unlike beta-agonists (Grade C), can be used for tocolysis in spontaneous preterm labor without preterm premature rupture of membranes. Maintenance tocolysis is not recommended (Grade B). Antenatal corticosteroid administration is recommended for all women at risk of preterm delivery before 34 weeks of gestation (Grade A). After 34 weeks, the evidence is insufficiently consistent to justify recommending systematic antenatal corticosteroid treatment (Grade B), but a course of this treatment might be indicated in clinical situations associated with high risk of severe respiratory distress syndrome, mainly in case of planned cesarean delivery (Grade C). Repeated courses of antenatal corticosteroids are not recommended (Grade A). Rescue courses are not recommended (Professional consensus). Magnesium sulfate administration is recommended for women at high risk of imminent preterm birth before 32 weeks (Grade A). Cesareans are not recommended for fetuses in vertex presentation (professional consensus). Both planned vaginal and elective cesarean delivery are possible for breech presentations (professional consensus). Delayed cord clamping may be considered if the neonatal or maternal state allows (professional consensus). To determine the measures to prevent spontaneous preterm birth (excluding preterm premature rupture of membranes)and its consequences. The PubMed database, the Cochrane Library and the recommendations from the French and foreign obstetrical societies or colleges have been consulted. In France, premature birth concerns 60,000 neonates every year (7.4 %), half of them are delivered after spontaneous onset of labor. Among preventable risk factors of spontaneous prematurity, only cessation of smoking is associated to a decrease of prematurity (level of evidence [LE] 1). This is therefore recommended (grade A). Routine screening and treatment of vaginal bacteriosis in general population is not recommended (grade A). Asymptomatic women with single pregnancy without history of preterm delivery and a short cervix between 16 and 24 weeks is the only population in which vaginal progesterone is recommended (grade B). A history-indicated cerclage is not recommended in case of only past history of conisation (grade C), uterine malformation (Professional consensus), isolated history of pretem delivery (grade B) or twin pregnancies in primary (grade B) or secondary (grade C) prevention of preterm birth. A history-indicated cerclage is recommended for single pregnancy with a history of at least 3 late miscarriages or preterm deliveries (grade A).). In case of past history of a single pregnancy delivery before 34 weeks gestation (WG), ultrasound cervical length screening is recommended between 16 and 22 WG in order to propose a cerclage in case of length&lt;25mm before 24 WG (grade C). Cervical pessary is not recommended for the prevention of preterm birth in a general population of asymptomatic women with a twin pregnancy (grade A) and in populations of asymptomatic women with a short cervix (Professional consensus). Although the implementation of a universal transvaginal cervical length screening at 18-24 weeks of gestation in women with a singleton gestation and no history of preterm birth can be considered by individual practitioners, this screening cannot be universally recommended. In case of preterm labor, (i) it is not possible to recommend one of the methods over another (ultrasound of the cervical length, vaginal examination, fetal fibronectin) to predict preterm birth (grade B); (ii) routine antibiotic therapy is not recommended (grade A); (iii) prolonged hospitalization (grade B) and bed rest (grade C) is not recommended. Compared with placebo, tocolytics are not associated with a reduction in neonatal mortality or morbidity (LE2) and maternal severe adverse effects may occur with all tocolytics (LE4). Atosiban and nifedipine (grade B), contrary to betamimetics (grade C), can be used for tocolysis in spontaneous preterm labour without preterm premature rupture of membranes. Maintenance tocolysis is not recomended (grade B). Antenatal corticosteroid administration is recommended to every woman at risk of preterm delivery before 34 weeks of gestation (grade A). After 34 weeks, evidences are not consistent enough to recommend systematic antenatal corticosteroid treatment (grade B), however, a course might be indicated in the clinical situations associated with the higher risk of severe respiratory distress syndrome, mainly in case of planned cesarean delivery (grade C). Repeated courses of antenatal corticosteroids are not recommended (grade A). Rescue courses are not recommended (Professional consensus). Magnesium sulfate administration is recommended to women at high risk of imminent preterm birth before 32WG (grade A). Cesarean is not recommended in case of vertex presentation (Professional consensus). Both planned vaginal or elective cesarean delivery is possible in case of breech presentation (Professional consensus). A delayed cord clamping may be considered if the neonatal or maternal state so permits (Professional consensus). Except for antenatal corticosteroid and magnesium sulfate administration, diagnostic tools or prenatal pharmacological treatments implemented since 30 years to prevent preterm birth and its consequences have not matched expectations of caregivers and families. Afecting approximately 1 percent of fertile couples, recurrent pregnancy loss (RPL) is classically deined as three or more consecutive pregnancy losses <20 weeks' gestation or with a fetal weight < 500 g. Mindful of this threshold, data from two large studies showed the risk for a subsequent miscarriage to be similar whether following two or three prior pregnancy losses (Bhattacharya, 2010; Brigham, 1999). And, the American Society for Reproductive Medicine (2013) now deines RPL as two or more failed pregnancies conirmed by sonographic or histopathological examination. Primary PL refers to multiple losses in a woman who has never delivered a liveborn, and secondary PL refers to multiple pregnancy losses in a patient with a prior live birth. Remarkably, the chances for a successful pregnancy arei> 50 percent even after five losses (Table 18-4). TABLE 18-4. Predicted Success Rate of Subsequent Pregnancy According to Age and Number of Previous Miscarriages The differential diagnosis of third trimester bleeding can range from placenta abruptia to placenta previa to uterine rupture and the placenta accreta spectrum (PAS). However, patients with risk factors such as multiple cesarean sections (c-sections), advanced maternal age (AMA), grand multiparity, and single-layer uterine closure are at greater risk of developing these complications earlier than we would traditionally expect. This case recounts a 38-year-old gravida 6 preterm 3 term 1 abortus 1 live 4 (G6P3114) at 23 weeks and five days gestational age (GA) with a past medical history of preterm pregnancy, pre-eclampsia, chronic abruptia, three previous c-sections, and low-lying placenta who presented to the emergency department (ED) with vaginal bleeding. Initial workup revealed placenta accreta and possible percreta. The patient was placed on intramuscular (IM) corticosteroids in anticipation of preterm delivery. As soon as the patient was stable, she was discharged home. She presented to a different hospital the next day with the same complaints. Imaging was consistent with accreta and her presentation with abruption. During the hospital stay, the patient went into threatened preterm labor (PTL). At first, we suspected preterm premature rupture of membranes (PPROM) due to apparent pooling of amniotic fluid in the vaginal canal. Upon further work up, the diagnosis was consistent with chronic abruption oligohydramnios sequence (CAOS). Before this could be investigated, her hospital course was complicated by acute abruption and Category III/nonreassuring fetal heart rate (FHR) tracing. The patient underwent an emergency c-section at 26 weeks GA as well as a planned supracervical hysterectomy for desired permanent sterilization. During the operation, the patient suffered a postpartum hemorrhage (PPH) of 4500 mL. She was later discharged home on postoperative day (POD) eight. What is it? This question arose early this year during a discussion with my doula partner, who lived in Great Britain for 20 years, and one of the midwives I work with, who attends only homebirths, which is very rare in France. The mom whose case we were discussing was late going into labor but not postdated according to the official pregnancy term here in France (37-42 WA--\"weeks of amenorrhea\"). The midwife expressed her discomfort with waiting. My doula partner and I felt differently, but we knew we were influenced by American and British midwives' practices. I had been shocked the previous December by the position of the chief of the maternity department in a private hospital (a small unit with no residents, in which nurse-midwives attend \"normal\" births and obstetricians are called in case of complications only). This OB explained to my client and me that if she didn't go into labor naturally, she would be called at 41 + 1 for a vaginal exam to check her cervix and would be induced at 41 + 2. Waiting until 42 weeks requires daily checks, for which he has neither the room nor personnel. He clearly stated that it was a matter of management of time and finances. A month later one of our clients reported the story of her brother and sister-in-law's planned homebirth in London. Their doctors had put a lot of pressure on the mother during her pregnancy with gestational diabetes regarding her length of term. They started to talk about induction. The parents didn't feel comfortable with this, and at that point our client had asked me to refer them to someone who could help them there. We referred them to the National Childbirth Trust and to the sweetest doula we know there. This doula (Liliana Lammers) and her famous doctor partner (Dr. Michel Odent) were a good match. The doctor advised waiting, on the condition that the health of the baby and the amount of fluid be checked daily at the local hospital. The mother had already been waiting several weeks past what was supposed to be her term. Finally, she went naturally into labor at home. The doctor and the doula came and, after some hours of observation, decided it would be wiser for the mother to deliver in the hospital. The doctor and doula were not comfortable with the prolonged prelabor, when, at nearly 44 weeks, the health of the baby and the amount of fluid had not been checked for five days. The mother finally had a vaginal birth without drugs at the hospital. After hearing this story, I suggested it would be interesting to collect the official lengths of term and the different routines in other countries as a learning tool and in order to give us something other than French protocol on which to base our practice. So I sent the question to every midwife for whom I had an e-mail address from the last Midwifery Today conference in Paris. Beyond this motivation was my own curiosity regarding the relationship between the official term in each country and its uses and routines. The most significant (because the most unique) answer, in my opinion, is from The Netherlands, where physiology is a priority. Data is now more than ever available to inform couples at risk of second trimester miscarriage or preterm delivery. We are able to give customized information according to the obstetrical history and to the evolution of the cervix during the second trimester although the level of scientific evidence is limited or poor. Elective cerclage can be proposed to patients with a history of at least 3 second trimester miscarriages or preterm deliveries. There is no clear consensus on which patients could benefit from therapeutic cerclage. Indications would have to be motivated by a short cervix on ultrasound measurements and the cerclage performed before 24 weeks of gestation. A diagnosis of cervical cancer during pregnancy poses difficult management and ethical problems. Survival of the patient is the foremost concern, but fetal viability and well-being must also be addressed. Radical trachelectomy (RT) has recently begun to be performed as a possible treatment modality for early stage invasive uterine cervical cancer in pregnant patients who would like to continue their pregnancy. A 32-year-old Japanese woman visited a local hospital for prenatal care, and was diagnosed with a FIGO I B1 adenocarcinoma of the uterine cervix. She had a strong desire to avoid pregnancy termination, so she was admitted to our hospital for fertility-preserving surgery. After extensive counseling, vaginal radical trachelectomy with abdominal pelvic lymphadenectomy was performed in the 16th gestational week. The excised uterine cervix and lymph nodes were pathologically negative for cancer. To maintain her pregnancy, daily vaginal disinfection with povidone iodine, bed rest, and administration of ritodrine and an ulinastatin vaginal suppository were continued until the delivery. At 34 weeks' gestation, an emergency cesarean section was performed because of sudden premature rupture of the membranes. A baby girl was born weighing 2112 g, with Apgar score of 8/9. The mother remains without evidence of recurrence at the time of this report. This is the first case of successful pregnancy and delivery in Japan after vaginal RT. Prevention of preterm birth remains an elusive goal. Still, may be achievable. Of options, cerclage placement may be used to prevent pre term birth in at least three circumstances. First, the procedure may beneit women who have a history of recurrent midtrimester losses and who are diagnosed with cervical insuiciency. A second instance is the woman identiied during sonographic examination to have a short cervix. The third indication is a \"rescue\" cerclage, done emergently when cervical incompetence is recognized in women with threatened preterm labor. A 26-year-old primigravid woman presented with a dichorionic diamniotic twin pregnancy after 7 years of infertility. No formal ultrasound was performed until a morphology check at 19 weeks and 4 days of gestation, at which time a shortened cervix was identified. The patient was already on vaginal progesterone pessaries from conception, as per her infertility specialist, and was advised to change to a rectal route of administration. At 20 weeks and 5 days, progesterone pessaries were increased to twice daily. A repeat scan at 21 weeks and 4 days showed a funnelled cervix 29 mm in length, a closed portion of 4-6 mm and bulging membranes. A speculum examination at this time showed a shortened cervix, 5 mm open, with visible membranes. A cervical cerclage was placed at 21 weeks and 5 days. The patient was given oral antibiotics for 1 week and was continued on progesterone pessaries. The patient was managed through the twins clinic and had serial ultrasound scans throughout the pregnancy. She went on to develop gestational diabetes and pre-eclampsia. She had a caesarean section at 33 weeks and 4 days due to pre-eclampsia, with abnormal doppler scans. Cervical cerclage was removed at the time of the caesarean section. Both twins were admitted to the nursery for prematurity and progressed well. This case report illustrates how a cervical cerclage can be utilised successfully in a primigravid dichorionic diamniotic twin pregnancy. Case Study  Sarah is a 58-year-old breast cancer survivor, social worker, and health-care administrator at a long-term care facility. She lives with her husband and enjoys gardening and reading. She has two grown children and three grandchildren who live approximately 180 miles away. SECOND CANCER DIAGNOSIS  One morning while showering, Sarah detected a painless quarter-sized lump on her inner thigh. While she thought it was unusual, she felt it would probably go away. One month later, she felt the lump again; she thought that it had grown, so she scheduled a visit with her primary care physician. A CT scan revealed a 6.2-cm soft-tissue mass in the left groin. She was referred to an oncologic surgeon and underwent an excision of the groin mass. Pathology revealed a grade 3 malignant melanoma. She was later tested and found to have BRAF-negative status. Following her recovery from surgery, Sarah was further evaluated with an MRI scan of the brain, which was negative, and a PET scan, which revealed two nodules in the left lung. As Sarah had attended a cancer support group during her breast cancer treatment in the past, she decided to go back to the group when she learned of her melanoma diagnosis. While the treatment options for her lung lesions included interleukin-2, ipilimumab (Yervoy), temozolomide, dacarbazine, a clinical trial, or radiosurgery, Sarah's oncologist felt that ipilimumab or radiosurgery would be the best course of action. She shared with her support group that she was ambivalent about this decision, as she had experienced profound fatigue and nausea with chemotherapy during her past treatment for breast cancer. She eventually opted to undergo stereotactic radiosurgery. DISEASE RECURRENCE  After the radiosurgery, Sarah was followed every 2 months. She complained of shortness of breath about 2 weeks prior to each follow-up visit. Each time her chest x-ray was normal, and she eventually believed that her breathlessness was anxiety-related. Unfortunately, Sarah's 1-year follow-up exam revealed a 2 cm × 3 cm mass in her left lung, for which she had a surgical wedge resection. Her complaints of shortness of breath increased following the surgery and occurred most often with anxiety, heat, and gardening activities, especially when she needed to bend over. Sarah also complained of a burning \"pins and needles\" sensation at the surgical chest wall site that was bothersome and would wake her up at night. Sarah met with the nurse practitioner in the symptom management clinic to discuss her concerns. Upon physical examination, observable signs of breathlessness were lacking, and oxygen saturation remained stable at 94%, but Sarah rated her breathlessness as 7 on the 0 to 10 Borg scale. The nurse practitioner prescribed duloxetine to help manage the surgical site neuropathic pain and to assist with anxiety, which in turn could possibly improve Sarah's breathlessness. Several nonpharmacologic modalities for breathlessness were also recommended: using a fan directed toward her face, working in the garden in the early morning when the weather is cooler, gardening in containers that are at eye level to avoid the need to bend down, and performing relaxation exercises with pursed lip breathing to relieve anxiety-provoked breathlessness. One month later, Sarah reported relief of her anxiety; she stated that the fan directed toward her face helped most when she started to feel \"air hungry.\" She rated her breathlessness at 4/10 on the Borg scale. SECOND RECURRENCE: MULTIPLE PULMONARY NODULES  Sarah's chest x-rays remained clear for 6 months, but she developed a chronic cough shortly before the 9-month exam. An x-ray revealed several bilateral lung lesions and growth in the area of the previously resected lung nodule. Systemic therapy was recommended, and she underwent two cycles of ipilimumab. Sarah's cough and breathlessness worsened, she developed colitis, and she decided to stop therapy after the third cycle. In addition, her coughing spells triggered bronchospasms that resulted in severe anxiety, panic attacks, and air hunger. She rated her breathlessness at 10/10 on the Borg scale during these episodes. She found communication difficult due to the cough and began to isolate herself. She continued to attend the support group weekly but had difficulty participating in conversation due to her cough. Sarah was seen in the symptom management clinic every 2 weeks or more often as needed. No acute distress was present at the beginning of each visit, but when Sarah began to talk about her symptoms and fear of dying, her shortness of breath and anxiety increased. The symptom management nurse practitioner treated the suspected underlying cause of the breathlessness and prescribed oral lorazepam (0.5 to 1 mg every 6 hours) for anxiety and codeine cough syrup for the cough. Opioids were initiated for chest wall pain and to control the breathlessness. Controlled-release oxycodone was started at 10 mg every 12 hours with a breakthrough pain (BTP) dose of 5 mg every 2 hours as needed for breathlessness or pain. Sarah noted improvement in her symptoms and reported a Borg scale rating of 5/10. Oxygen therapy was attempted, but subjective improvement in Sarah's breathlessness was lacking. END OF LIFE  Sarah's disease progressed to the liver, and she began experiencing more notable signs of breathlessness: nasal flaring, tachycardia, and restlessness. Opioid doses were titrated over the course of 3 months to oxycodone (40 mg every 12 hours) with a BTP dose of 10 to 15 mg every 2 hours as needed, but her breathlessness caused significant distress, which she rated 8/10. The oxycodone was rotated to IV morphine continuous infusion with patient-controlled analgesia (PCA) that was delivered through her implantable port. This combination allowed Sarah to depress the PCA as needed and achieve immediate control of her dyspneic episodes. Oral lorazepam was also continued as needed. Sarah's daughter moved home to take care of her mother, and hospice became involved for end-of-life care. As Sarah became less responsive, nurses maintained doses of morphine for control of pain and breathlessness and used a respiratory distress observation scale to assess for breathlessness since Sarah could no longer self-report. A bolus PCA dose of morphine was administered by Sarah's daughter if her mother appeared to be in distress. Sarah died peacefully in her home without signs of distress.  Cervical cerclage has always been the main treatment option in cases of so-called cervical insufficiency, a condition that is notoriously associated with a high risk of second trimester abortion and/or preterm delivery. We can distinguish between a prophylactic cerclage, to be performed electively, usually at 13-16 weeks gestation, only when the woman has a history extremely suggestive for cervical incompetence (3 or more mid-trimester abortions or preterm deliveries) and a therapeutic cerclage. This last cerclage is recommended either for women who have ultrasonographic changes consistent with a short cervix or the presence of funneling after the 16-20 weeks gestation (urgent cerclage) and for women who present the asymptomatic dilation of the uterine cervix of at least 2 cm and/or a prolapse of the amniochorial membranes (emergent cerclage). So far there is still a lack of controlled and randomized trials that can unquestionably demonstrate the advantages of the cervical cerclage in comparison with a ''wait and see'' aptitude. The cerclage can be performed either transvaginally, usually according to the McDonald technique, or transabdominally. This last approach is recommended when a transvaginal cerclage has to be avoided because of technical difficulties depending on the conditions of the cervix or when the pregnant woman has a history of one or more failed transvaginal cerclages. Interesting perspectives are currently offered by the laparoscopic cerclage, a method that has been effective and unexpectedly safe till now. Healthcare workers (HCWs) are at an increased risk for exposure to infections. <iSerratia marcescens</i (<iS</i. <imarcescens</i) is a gram-negative, opportunistic and nosocomial pathogen belonging to the Enterobacterieae family. A few case reports have been published of chorioamnionitis caused by <iS. marcescens</i infection. Immunological changes during pregnancy can also affect the risk of infection. However, few studies have examined hospital-acquired bacterial infection in pregnant HCWs. A 33-year-old woman, a resident in anesthesiology, was admitted at 14 wk gestation for fever with chills. She had no medical history other than contact dermatitis of both hands that started from the beginning of the trainee. There was no obvious infection focus and no bacterial growth in blood cultures. She was discharged after 1 wk of empirical antibiotic treatment. At three weeks before the fever started, she had a blister on the site of contact dermatitis on both hands, she applied antibiotic ointment for three days and the blisters had healed. At 19 wk gestation, she had a high fever and was readmitted. Physical examination and image studies were nonspecific and the patient had no other symptoms. <iS. marcescens</i grew in blood cultures at 19 wk gestation. Treatment with intravenous antibiotics was started. However, she suffered a miscarriage at 22<sup4/7</sup wk gestation. Pathologically, the amniotic membrane showed chorioamnionitis with a focal infarct. Subsequently, a placenta tissue culture grew <iS. marcescens</i. HCWs can be exposed to pathogens that can cause opportunistic infections such as <iS. marcescens</i. Pregnancy affects the immune system, making it susceptible to opportunistic infections. Therefore, pregnant HCWs may require more preventive measures, including hand hygiene and avoid risk factors (ex. wrapping the skin).\nHere is the question:\nGYNECOLOGY AND OBSTETRICS: A 32-year-old woman requests preconception counseling. The patient reports that she underwent cervical conization for a high-grade intraepithelial lesion (H-SIL) and subsequently had three miscarriages between 20 and 22 weeks gestation. She has no living children. On all three occasions she came to the emergency department with a feeling of weight in the hypogastrium, where she was found to be 8 cm dilated and with prominent amniotic membranes. She had never felt contractions before, what advice would you give her for the next pregnancy?\nHere are the potential choices:\n1. I would prescribe oral atosiban prophylaxis throughout the pregnancy.\n2. I would offer lung maturation with corticosteroids from 19-20 weeks of gestation.\n3. I would recommend a cervical cerclage at 14 weeks gestation.\n4. I would advise her not to attempt any more pregnancies because of the high risk of recurrence.\n5. I would recommend resorting to assisted reproductive techniques.\nThe correct answer is: ",
        "gold_answer": "3 I would recommend a cervical cerclage at 14 weeks gestation.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n In France, 60,000 neonates are born preterm every year (7.4%), half of them after the spontaneous onset of labor. Among preventable risk factors of spontaneous prematurity, only cessation of smoking is associated with decreased prematurity (level of evidence [LE]1). It is therefore recommended (Grade A). Routine screening and treatment of vaginal bacteriosis is not recommended in the general population (Grade A). The only population for which vaginal progesterone is recommended is that comprising asymptomatic women with singleton pregnancies, no history of preterm delivery, and a short cervix at 16-24 weeks of gestation (Grade B). A history-indicated cerclage is not recommended for women with only a history of conization (Grade C), uterine malformation (professional consensus), isolated history of preterm delivery (Grade B), or twin pregnancies for primary (Grade B) or secondary (Grade C) prevention of preterm birth. A history-indicated cerclage is recommended for a singleton pregnancy with a history of at least 3 late miscarriages or preterm deliveries (Grade A). Ultrasound cervical length screening is recommended between 16 and 22 weeks for women with a singleton previously delivered before 34 weeks gestation, so that cerclage can be offered if cervical length &lt;25mm before 24 weeks (Grade C). A cervical pessary is not recommended for the prevention of preterm birth in a general population of asymptomatic women with twin pregnancies (Grade A) or in populations of asymptomatic women with a short cervix (professional consensus). Although the implementation of universal screening by transvaginal ultrasound for cervical length at 18-24 weeks of gestation in women with a singleton gestation and no history of preterm birth can be considered by individual practitioners, this screening cannot be universally recommended. In cases of preterm labor, (i) it is not possible to recommend any one of the several methods (ultrasound of the cervical length, vaginal examination, or fetal fibronectin assay) over any other to predict preterm birth (Grade B); (ii) routine antibiotic therapy is not recommended (Grade A); (iii) prolonged hospitalization (Grade B) and bed rest (Grade C) are not recommended. Compared with placebo, tocolytics are not associated with a reduction in neonatal mortality or morbidity (LE2) and maternal severe adverse effects may occur with all tocolytics (LE4). Atosiban and nifedipine (Grade B), unlike beta-agonists (Grade C), can be used for tocolysis in spontaneous preterm labor without preterm premature rupture of membranes. Maintenance tocolysis is not recommended (Grade B). Antenatal corticosteroid administration is recommended for all women at risk of preterm delivery before 34 weeks of gestation (Grade A). After 34 weeks, the evidence is insufficiently consistent to justify recommending systematic antenatal corticosteroid treatment (Grade B), but a course of this treatment might be indicated in clinical situations associated with high risk of severe respiratory distress syndrome, mainly in case of planned cesarean delivery (Grade C). Repeated courses of antenatal corticosteroids are not recommended (Grade A). Rescue courses are not recommended (Professional consensus). Magnesium sulfate administration is recommended for women at high risk of imminent preterm birth before 32 weeks (Grade A). Cesareans are not recommended for fetuses in vertex presentation (professional consensus). Both planned vaginal and elective cesarean delivery are possible for breech presentations (professional consensus). Delayed cord clamping may be considered if the neonatal or maternal state allows (professional consensus). To determine the measures to prevent spontaneous preterm birth (excluding preterm premature rupture of membranes)and its consequences. The PubMed database, the Cochrane Library and the recommendations from the French and foreign obstetrical societies or colleges have been consulted. In France, premature birth concerns 60,000 neonates every year (7.4 %), half of them are delivered after spontaneous onset of labor. Among preventable risk factors of spontaneous prematurity, only cessation of smoking is associated to a decrease of prematurity (level of evidence [LE] 1). This is therefore recommended (grade A). Routine screening and treatment of vaginal bacteriosis in general population is not recommended (grade A). Asymptomatic women with single pregnancy without history of preterm delivery and a short cervix between 16 and 24 weeks is the only population in which vaginal progesterone is recommended (grade B). A history-indicated cerclage is not recommended in case of only past history of conisation (grade C), uterine malformation (Professional consensus), isolated history of pretem delivery (grade B) or twin pregnancies in primary (grade B) or secondary (grade C) prevention of preterm birth. A history-indicated cerclage is recommended for single pregnancy with a history of at least 3 late miscarriages or preterm deliveries (grade A).). In case of past history of a single pregnancy delivery before 34 weeks gestation (WG), ultrasound cervical length screening is recommended between 16 and 22 WG in order to propose a cerclage in case of length&lt;25mm before 24 WG (grade C). Cervical pessary is not recommended for the prevention of preterm birth in a general population of asymptomatic women with a twin pregnancy (grade A) and in populations of asymptomatic women with a short cervix (Professional consensus). Although the implementation of a universal transvaginal cervical length screening at 18-24 weeks of gestation in women with a singleton gestation and no history of preterm birth can be considered by individual practitioners, this screening cannot be universally recommended. In case of preterm labor, (i) it is not possible to recommend one of the methods over another (ultrasound of the cervical length, vaginal examination, fetal fibronectin) to predict preterm birth (grade B); (ii) routine antibiotic therapy is not recommended (grade A); (iii) prolonged hospitalization (grade B) and bed rest (grade C) is not recommended. Compared with placebo, tocolytics are not associated with a reduction in neonatal mortality or morbidity (LE2) and maternal severe adverse effects may occur with all tocolytics (LE4). Atosiban and nifedipine (grade B), contrary to betamimetics (grade C), can be used for tocolysis in spontaneous preterm labour without preterm premature rupture of membranes. Maintenance tocolysis is not recomended (grade B). Antenatal corticosteroid administration is recommended to every woman at risk of preterm delivery before 34 weeks of gestation (grade A). After 34 weeks, evidences are not consistent enough to recommend systematic antenatal corticosteroid treatment (grade B), however, a course might be indicated in the clinical situations associated with the higher risk of severe respiratory distress syndrome, mainly in case of planned cesarean delivery (grade C). Repeated courses of antenatal corticosteroids are not recommended (grade A). Rescue courses are not recommended (Professional consensus). Magnesium sulfate administration is recommended to women at high risk of imminent preterm birth before 32WG (grade A). Cesarean is not recommended in case of vertex presentation (Professional consensus). Both planned vaginal or elective cesarean delivery is possible in case of breech presentation (Professional consensus). A delayed cord clamping may be considered if the neonatal or maternal state so permits (Professional consensus). Except for antenatal corticosteroid and magnesium sulfate administration, diagnostic tools or prenatal pharmacological treatments implemented since 30 years to prevent preterm birth and its consequences have not matched expectations of caregivers and families. Afecting approximately 1 percent of fertile couples, recurrent pregnancy loss (RPL) is classically deined as three or more consecutive pregnancy losses <20 weeks' gestation or with a fetal weight < 500 g. Mindful of this threshold, data from two large studies showed the risk for a subsequent miscarriage to be similar whether following two or three prior pregnancy losses (Bhattacharya, 2010; Brigham, 1999). And, the American Society for Reproductive Medicine (2013) now deines RPL as two or more failed pregnancies conirmed by sonographic or histopathological examination. Primary PL refers to multiple losses in a woman who has never delivered a liveborn, and secondary PL refers to multiple pregnancy losses in a patient with a prior live birth. Remarkably, the chances for a successful pregnancy arei> 50 percent even after five losses (Table 18-4). TABLE 18-4. Predicted Success Rate of Subsequent Pregnancy According to Age and Number of Previous Miscarriages The differential diagnosis of third trimester bleeding can range from placenta abruptia to placenta previa to uterine rupture and the placenta accreta spectrum (PAS). However, patients with risk factors such as multiple cesarean sections (c-sections), advanced maternal age (AMA), grand multiparity, and single-layer uterine closure are at greater risk of developing these complications earlier than we would traditionally expect. This case recounts a 38-year-old gravida 6 preterm 3 term 1 abortus 1 live 4 (G6P3114) at 23 weeks and five days gestational age (GA) with a past medical history of preterm pregnancy, pre-eclampsia, chronic abruptia, three previous c-sections, and low-lying placenta who presented to the emergency department (ED) with vaginal bleeding. Initial workup revealed placenta accreta and possible percreta. The patient was placed on intramuscular (IM) corticosteroids in anticipation of preterm delivery. As soon as the patient was stable, she was discharged home. She presented to a different hospital the next day with the same complaints. Imaging was consistent with accreta and her presentation with abruption. During the hospital stay, the patient went into threatened preterm labor (PTL). At first, we suspected preterm premature rupture of membranes (PPROM) due to apparent pooling of amniotic fluid in the vaginal canal. Upon further work up, the diagnosis was consistent with chronic abruption oligohydramnios sequence (CAOS). Before this could be investigated, her hospital course was complicated by acute abruption and Category III/nonreassuring fetal heart rate (FHR) tracing. The patient underwent an emergency c-section at 26 weeks GA as well as a planned supracervical hysterectomy for desired permanent sterilization. During the operation, the patient suffered a postpartum hemorrhage (PPH) of 4500 mL. She was later discharged home on postoperative day (POD) eight. What is it? This question arose early this year during a discussion with my doula partner, who lived in Great Britain for 20 years, and one of the midwives I work with, who attends only homebirths, which is very rare in France. The mom whose case we were discussing was late going into labor but not postdated according to the official pregnancy term here in France (37-42 WA--\"weeks of amenorrhea\"). The midwife expressed her discomfort with waiting. My doula partner and I felt differently, but we knew we were influenced by American and British midwives' practices. I had been shocked the previous December by the position of the chief of the maternity department in a private hospital (a small unit with no residents, in which nurse-midwives attend \"normal\" births and obstetricians are called in case of complications only). This OB explained to my client and me that if she didn't go into labor naturally, she would be called at 41 + 1 for a vaginal exam to check her cervix and would be induced at 41 + 2. Waiting until 42 weeks requires daily checks, for which he has neither the room nor personnel. He clearly stated that it was a matter of management of time and finances. A month later one of our clients reported the story of her brother and sister-in-law's planned homebirth in London. Their doctors had put a lot of pressure on the mother during her pregnancy with gestational diabetes regarding her length of term. They started to talk about induction. The parents didn't feel comfortable with this, and at that point our client had asked me to refer them to someone who could help them there. We referred them to the National Childbirth Trust and to the sweetest doula we know there. This doula (Liliana Lammers) and her famous doctor partner (Dr. Michel Odent) were a good match. The doctor advised waiting, on the condition that the health of the baby and the amount of fluid be checked daily at the local hospital. The mother had already been waiting several weeks past what was supposed to be her term. Finally, she went naturally into labor at home. The doctor and the doula came and, after some hours of observation, decided it would be wiser for the mother to deliver in the hospital. The doctor and doula were not comfortable with the prolonged prelabor, when, at nearly 44 weeks, the health of the baby and the amount of fluid had not been checked for five days. The mother finally had a vaginal birth without drugs at the hospital. After hearing this story, I suggested it would be interesting to collect the official lengths of term and the different routines in other countries as a learning tool and in order to give us something other than French protocol on which to base our practice. So I sent the question to every midwife for whom I had an e-mail address from the last Midwifery Today conference in Paris. Beyond this motivation was my own curiosity regarding the relationship between the official term in each country and its uses and routines. The most significant (because the most unique) answer, in my opinion, is from The Netherlands, where physiology is a priority. Data is now more than ever available to inform couples at risk of second trimester miscarriage or preterm delivery. We are able to give customized information according to the obstetrical history and to the evolution of the cervix during the second trimester although the level of scientific evidence is limited or poor. Elective cerclage can be proposed to patients with a history of at least 3 second trimester miscarriages or preterm deliveries. There is no clear consensus on which patients could benefit from therapeutic cerclage. Indications would have to be motivated by a short cervix on ultrasound measurements and the cerclage performed before 24 weeks of gestation. A diagnosis of cervical cancer during pregnancy poses difficult management and ethical problems. Survival of the patient is the foremost concern, but fetal viability and well-being must also be addressed. Radical trachelectomy (RT) has recently begun to be performed as a possible treatment modality for early stage invasive uterine cervical cancer in pregnant patients who would like to continue their pregnancy. A 32-year-old Japanese woman visited a local hospital for prenatal care, and was diagnosed with a FIGO I B1 adenocarcinoma of the uterine cervix. She had a strong desire to avoid pregnancy termination, so she was admitted to our hospital for fertility-preserving surgery. After extensive counseling, vaginal radical trachelectomy with abdominal pelvic lymphadenectomy was performed in the 16th gestational week. The excised uterine cervix and lymph nodes were pathologically negative for cancer. To maintain her pregnancy, daily vaginal disinfection with povidone iodine, bed rest, and administration of ritodrine and an ulinastatin vaginal suppository were continued until the delivery. At 34 weeks' gestation, an emergency cesarean section was performed because of sudden premature rupture of the membranes. A baby girl was born weighing 2112 g, with Apgar score of 8/9. The mother remains without evidence of recurrence at the time of this report. This is the first case of successful pregnancy and delivery in Japan after vaginal RT. Prevention of preterm birth remains an elusive goal. Still, may be achievable. Of options, cerclage placement may be used to prevent pre term birth in at least three circumstances. First, the procedure may beneit women who have a history of recurrent midtrimester losses and who are diagnosed with cervical insuiciency. A second instance is the woman identiied during sonographic examination to have a short cervix. The third indication is a \"rescue\" cerclage, done emergently when cervical incompetence is recognized in women with threatened preterm labor. A 26-year-old primigravid woman presented with a dichorionic diamniotic twin pregnancy after 7 years of infertility. No formal ultrasound was performed until a morphology check at 19 weeks and 4 days of gestation, at which time a shortened cervix was identified. The patient was already on vaginal progesterone pessaries from conception, as per her infertility specialist, and was advised to change to a rectal route of administration. At 20 weeks and 5 days, progesterone pessaries were increased to twice daily. A repeat scan at 21 weeks and 4 days showed a funnelled cervix 29 mm in length, a closed portion of 4-6 mm and bulging membranes. A speculum examination at this time showed a shortened cervix, 5 mm open, with visible membranes. A cervical cerclage was placed at 21 weeks and 5 days. The patient was given oral antibiotics for 1 week and was continued on progesterone pessaries. The patient was managed through the twins clinic and had serial ultrasound scans throughout the pregnancy. She went on to develop gestational diabetes and pre-eclampsia. She had a caesarean section at 33 weeks and 4 days due to pre-eclampsia, with abnormal doppler scans. Cervical cerclage was removed at the time of the caesarean section. Both twins were admitted to the nursery for prematurity and progressed well. This case report illustrates how a cervical cerclage can be utilised successfully in a primigravid dichorionic diamniotic twin pregnancy. Case Study  Sarah is a 58-year-old breast cancer survivor, social worker, and health-care administrator at a long-term care facility. She lives with her husband and enjoys gardening and reading. She has two grown children and three grandchildren who live approximately 180 miles away. SECOND CANCER DIAGNOSIS  One morning while showering, Sarah detected a painless quarter-sized lump on her inner thigh. While she thought it was unusual, she felt it would probably go away. One month later, she felt the lump again; she thought that it had grown, so she scheduled a visit with her primary care physician. A CT scan revealed a 6.2-cm soft-tissue mass in the left groin. She was referred to an oncologic surgeon and underwent an excision of the groin mass. Pathology revealed a grade 3 malignant melanoma. She was later tested and found to have BRAF-negative status. Following her recovery from surgery, Sarah was further evaluated with an MRI scan of the brain, which was negative, and a PET scan, which revealed two nodules in the left lung. As Sarah had attended a cancer support group during her breast cancer treatment in the past, she decided to go back to the group when she learned of her melanoma diagnosis. While the treatment options for her lung lesions included interleukin-2, ipilimumab (Yervoy), temozolomide, dacarbazine, a clinical trial, or radiosurgery, Sarah's oncologist felt that ipilimumab or radiosurgery would be the best course of action. She shared with her support group that she was ambivalent about this decision, as she had experienced profound fatigue and nausea with chemotherapy during her past treatment for breast cancer. She eventually opted to undergo stereotactic radiosurgery. DISEASE RECURRENCE  After the radiosurgery, Sarah was followed every 2 months. She complained of shortness of breath about 2 weeks prior to each follow-up visit. Each time her chest x-ray was normal, and she eventually believed that her breathlessness was anxiety-related. Unfortunately, Sarah's 1-year follow-up exam revealed a 2 cm × 3 cm mass in her left lung, for which she had a surgical wedge resection. Her complaints of shortness of breath increased following the surgery and occurred most often with anxiety, heat, and gardening activities, especially when she needed to bend over. Sarah also complained of a burning \"pins and needles\" sensation at the surgical chest wall site that was bothersome and would wake her up at night. Sarah met with the nurse practitioner in the symptom management clinic to discuss her concerns. Upon physical examination, observable signs of breathlessness were lacking, and oxygen saturation remained stable at 94%, but Sarah rated her breathlessness as 7 on the 0 to 10 Borg scale. The nurse practitioner prescribed duloxetine to help manage the surgical site neuropathic pain and to assist with anxiety, which in turn could possibly improve Sarah's breathlessness. Several nonpharmacologic modalities for breathlessness were also recommended: using a fan directed toward her face, working in the garden in the early morning when the weather is cooler, gardening in containers that are at eye level to avoid the need to bend down, and performing relaxation exercises with pursed lip breathing to relieve anxiety-provoked breathlessness. One month later, Sarah reported relief of her anxiety; she stated that the fan directed toward her face helped most when she started to feel \"air hungry.\" She rated her breathlessness at 4/10 on the Borg scale. SECOND RECURRENCE: MULTIPLE PULMONARY NODULES  Sarah's chest x-rays remained clear for 6 months, but she developed a chronic cough shortly before the 9-month exam. An x-ray revealed several bilateral lung lesions and growth in the area of the previously resected lung nodule. Systemic therapy was recommended, and she underwent two cycles of ipilimumab. Sarah's cough and breathlessness worsened, she developed colitis, and she decided to stop therapy after the third cycle. In addition, her coughing spells triggered bronchospasms that resulted in severe anxiety, panic attacks, and air hunger. She rated her breathlessness at 10/10 on the Borg scale during these episodes. She found communication difficult due to the cough and began to isolate herself. She continued to attend the support group weekly but had difficulty participating in conversation due to her cough. Sarah was seen in the symptom management clinic every 2 weeks or more often as needed. No acute distress was present at the beginning of each visit, but when Sarah began to talk about her symptoms and fear of dying, her shortness of breath and anxiety increased. The symptom management nurse practitioner treated the suspected underlying cause of the breathlessness and prescribed oral lorazepam (0.5 to 1 mg every 6 hours) for anxiety and codeine cough syrup for the cough. Opioids were initiated for chest wall pain and to control the breathlessness. Controlled-release oxycodone was started at 10 mg every 12 hours with a breakthrough pain (BTP) dose of 5 mg every 2 hours as needed for breathlessness or pain. Sarah noted improvement in her symptoms and reported a Borg scale rating of 5/10. Oxygen therapy was attempted, but subjective improvement in Sarah's breathlessness was lacking. END OF LIFE  Sarah's disease progressed to the liver, and she began experiencing more notable signs of breathlessness: nasal flaring, tachycardia, and restlessness. Opioid doses were titrated over the course of 3 months to oxycodone (40 mg every 12 hours) with a BTP dose of 10 to 15 mg every 2 hours as needed, but her breathlessness caused significant distress, which she rated 8/10. The oxycodone was rotated to IV morphine continuous infusion with patient-controlled analgesia (PCA) that was delivered through her implantable port. This combination allowed Sarah to depress the PCA as needed and achieve immediate control of her dyspneic episodes. Oral lorazepam was also continued as needed. Sarah's daughter moved home to take care of her mother, and hospice became involved for end-of-life care. As Sarah became less responsive, nurses maintained doses of morphine for control of pain and breathlessness and used a respiratory distress observation scale to assess for breathlessness since Sarah could no longer self-report. A bolus PCA dose of morphine was administered by Sarah's daughter if her mother appeared to be in distress. Sarah died peacefully in her home without signs of distress.  Cervical cerclage has always been the main treatment option in cases of so-called cervical insufficiency, a condition that is notoriously associated with a high risk of second trimester abortion and/or preterm delivery. We can distinguish between a prophylactic cerclage, to be performed electively, usually at 13-16 weeks gestation, only when the woman has a history extremely suggestive for cervical incompetence (3 or more mid-trimester abortions or preterm deliveries) and a therapeutic cerclage. This last cerclage is recommended either for women who have ultrasonographic changes consistent with a short cervix or the presence of funneling after the 16-20 weeks gestation (urgent cerclage) and for women who present the asymptomatic dilation of the uterine cervix of at least 2 cm and/or a prolapse of the amniochorial membranes (emergent cerclage). So far there is still a lack of controlled and randomized trials that can unquestionably demonstrate the advantages of the cervical cerclage in comparison with a ''wait and see'' aptitude. The cerclage can be performed either transvaginally, usually according to the McDonald technique, or transabdominally. This last approach is recommended when a transvaginal cerclage has to be avoided because of technical difficulties depending on the conditions of the cervix or when the pregnant woman has a history of one or more failed transvaginal cerclages. Interesting perspectives are currently offered by the laparoscopic cerclage, a method that has been effective and unexpectedly safe till now. Healthcare workers (HCWs) are at an increased risk for exposure to infections. <iSerratia marcescens</i (<iS</i. <imarcescens</i) is a gram-negative, opportunistic and nosocomial pathogen belonging to the Enterobacterieae family. A few case reports have been published of chorioamnionitis caused by <iS. marcescens</i infection. Immunological changes during pregnancy can also affect the risk of infection. However, few studies have examined hospital-acquired bacterial infection in pregnant HCWs. A 33-year-old woman, a resident in anesthesiology, was admitted at 14 wk gestation for fever with chills. She had no medical history other than contact dermatitis of both hands that started from the beginning of the trainee. There was no obvious infection focus and no bacterial growth in blood cultures. She was discharged after 1 wk of empirical antibiotic treatment. At three weeks before the fever started, she had a blister on the site of contact dermatitis on both hands, she applied antibiotic ointment for three days and the blisters had healed. At 19 wk gestation, she had a high fever and was readmitted. Physical examination and image studies were nonspecific and the patient had no other symptoms. <iS. marcescens</i grew in blood cultures at 19 wk gestation. Treatment with intravenous antibiotics was started. However, she suffered a miscarriage at 22<sup4/7</sup wk gestation. Pathologically, the amniotic membrane showed chorioamnionitis with a focal infarct. Subsequently, a placenta tissue culture grew <iS. marcescens</i. HCWs can be exposed to pathogens that can cause opportunistic infections such as <iS. marcescens</i. Pregnancy affects the immune system, making it susceptible to opportunistic infections. Therefore, pregnant HCWs may require more preventive measures, including hand hygiene and avoid risk factors (ex. wrapping the skin).\nHere is the question:\nGYNECOLOGY AND OBSTETRICS: A 32-year-old woman requests preconception counseling. The patient reports that she underwent cervical conization for a high-grade intraepithelial lesion (H-SIL) and subsequently had three miscarriages between 20 and 22 weeks gestation. She has no living children. On all three occasions she came to the emergency department with a feeling of weight in the hypogastrium, where she was found to be 8 cm dilated and with prominent amniotic membranes. She had never felt contractions before, what advice would you give her for the next pregnancy?\nHere are the potential choices:\n1. I would prescribe oral atosiban prophylaxis throughout the pregnancy.\n2. I would offer lung maturation with corticosteroids from 19-20 weeks of gestation.\n3. I would recommend a cervical cerclage at 14 weeks gestation.\n4. I would advise her not to attempt any more pregnancies because of the high risk of recurrence.\n5. I would recommend resorting to assisted reproductive techniques.\nThe correct answer is: 3. I would recommend a cervical cerclage at 14 weeks gestation."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Ten patients, eight males and two females, suffered myocardial rupture following acute myocardial infarction and required surgery. There were five ventricular septal ruptures, four papillary muscle ruptures and one free wall rupture. Ventricular septal rupture was suspected clinically by the appearance of a new systolic murmur, usually associated with a thrill at the left sternal border. A left to right shunt was confirmed by bedside oximetry using a Swan-Ganz catheter. The mean pulmonary to systemic flow ratio was 3.04:1. Following cardiac catheterization all patients underwent corrective surgery with or without aortocoronary bypass grafting. Three patients with inferior wall myocardial infarction died. Papillary muscle rupture was suspected clinically following the abrupt onset of hypotension with severe acute pulmonary edema accompanied by a new systolic murmur. The diagnosis was confirmed by cardiac catheterization. All underwent surgery for mitral valve replacement with or without aortocoronary bypass grafting. One patient died postoperatively of multiorgan failure. Free wall rupture was suspected clinically by the sudden onset of loss of consciousness, apnea, junctional bradycardia and severe hypotension leading to electromechanical dissociation. The diagnosis was confirmed by demonstrating a significant pericardial effusion by two dimensional echocardiography. Immediate surgery was performed. This patient is totally asymptomatic on no drug treatment six months following discharge. Ten patients underwent emergency surgery for myocardial rupture. Operative mortality was 40%. Patients with ventricular septal rupture associated with an inferior myocardial infarction had a poor prognosis. Right ventricular rupture is a rare complication of cardiopulmonary resuscitation and could be fatal. We report a survival case of right ventricular rupture induced by cardiopulmonary resuscitation in a patient with acute myocardial infarction. A 57-year-old man was admitted to our hospital with ventricular fibrillation. Although chest compression and defibrillation were performed, ventricular fibrillation continued. We inserted a percutaneous cardiopulmonary system and performed coronary angiography, which revealed occlusion of the left anterior descending artery. After coronary stenting and intra-aortic balloon pumping, we succeeded in defibrillation and vital signs became stable. Twenty hours after the intervention, systolic blood pressure dropped to 60 mmHg. Ultrasonic cardiogram at that time revealed massive pericardial effusion. We diagnosed cardiac tamponade, and 8Fr drainage tube was placed in the pericardial space. We determined that emergent operation was necessary because we suspected left ventricular rupture due to acute myocardial infarction or coronary rupture induced by percutaneous coronary intervention. However, operative findings revealed right ventricular free wall rupture, which could have been induced by chest compression. In these cases, we should consider the possibility of not only the rupture of left ventricle and coronary artery but also the rupture of right ventricle induced by cardiopulmonary resuscitation. A 58-year-old man who suffered from acute myocardial infarction complicated with left ventricular rupture and subacute pericardial tamponade was reported. On admission, echocardiography strongly suspected presence of intrapericardial fluid. And immediate pericardiocentesis proved left ventricular free wall rupture (LVFWR). Coronary angiography with the support of IABP revealed occlusion of LAD (# 8). Percutaneous transluminal coronary angioplasty was performed with partial success. After pericardiotomy, the hemodynamic state was improved, however, 2 hours later, his blood pressure fell down to 40 mmHg suddenly. Emergent operation (re-mediastinumotomy+ ) was performed under the suspicion of left ventricular blowout rupture with the direct closure of the perforated site with 4 woven Dacron pledgets at bedside in ICU. The patient ran an uneventful postoperative course and is now doing well. Clinical and therapeutic features of LVFWR were discussed. Ventricular septal (VS) rupture after acute myocardial infarction (AMI) is an uncommon complication in the reperfusion era. Bedside echocardiography (BECH) continues to be a strong diagnostic tool for emergency physicians treating dyspneic patients, especially for decision-making on the management strategies to use with these unstable patients. In the case we present here, a patient is diagnosed with a delayed mechanical complication after AMI, and a swift management plan is made with the aid of point-of-care BECH. The patient is a 72-year-old man with dyspnea who was admitted to the ED 5 days after receiving a primary percutaneous coronary intervention with stent implantation for AMI; in the ED, the patient was diagnosed, via BECH, with a VS rupture. On arrival, his vital signs and the results of his physical examination depicted shock and low perfusion with wet lung. A cardiac examination revealed a new 2/6 harsh holosystolic murmur along the left sternal border without pretibial oedema. Emergency physicians performed BECH, and subcostal views of the heart revealed a wide interventricular septal rupture and left-to-right shunting with minimal pericardial effusion. The patient underwent surgery immediately to repair the defect. The post-operative course was uneventful, and he was discharged in stable condition on the seventh day after the surgery. The use of BECH to recognize a VS rupture is critical because such a defect may be the most important determinant of mortality in AMI patients who are in shock. BECH thus can influence clinicians' acute management and disposition decisions. Three distinct forms of rupture of the heart may be identified after myocardial infarction: sudden rupture with massive intrapericardial haemorrhage, and sudden death with clinical signs of electromechanical dissociation; rupture into the pericardium resulting in a false aneurysm, the treatment of which is surgical; subacute rupture which accounts for 30% of cases in which bleeding into the pericardium is slow and/or repeated. Over an 8 year period and in a series of 2,400 consecutive infarcts admitted to the intensive care unit, 10 cases of subacute rupture of the heart were diagnosed. They were 6 men and 4 women, with a mean age of 73.6 years. The clinical presentation was isolated chest pain in 5 cases, syncope alone in 2 cases and the association of pain and syncope in 3 cases. Six patients were in shock on admission. In two cases, shock developed after admission. The infarction was confirmed biologically by a significant elevation of creatinine kinase in 9 out of 10 cases. Transmural infarction was observed in 9 cases: the infarct was electrocardiographically non-transmural in 1 case. Emergency echocardiography showed pericardial effusion in all cases, usually moderate, but sometimes compressive with an intrapericardial echogenic mass suggesting a thrombus. Haemodynamic improvement was obtained by medication allowing cardiac catheterisation which showed adiastole in 3 cases. Coronary angiography was performed in 7 cases. In 5 of the 7 cases, apart from occlusion of the artery presumed to be responsible for the infarct, the coronary vessels were diffusely infiltrated without significant stenosis. Left ventriculography was performed in 7 cases. In 6 of the 7 cases regional akinesis was demonstrated: the 7th case showed dyskinesia of the anterior wall. In two cases, contrast medium was observed to fill the pericardium during ventriculography, indicating myocardial rupture. The diagnosis of subacute rupture, suggested by clinical and paraclinical (particularly echocardiography), was confirmed in 9 cases at surgery and in the 10th case at autopsy. Surgery consisted of repairing the rupture. In the last two cases, biological glue was used to reinforce the surgical repair. The clinical outcome was good after surgery in 6 cases with a follow-up of 5 months to 8 years. The diagnosis of subacute rupture should therefore be made on clinical and echocardiographic criteria, as these results suggest that surgery is often possible, with a good prognosis. A 70-year-old man was transferred to our hospital with severe congestive heart failure and ventricular arrhythmia due to acute myocardial infarction. He had experienced chest pain 3 weeks previously and was admitted to another hospital for dyspnea, where he required assist ventilation, 1 week prior to the transfer. An echocardiogram revealed a broad anteroseptal infarction and very poor left ventricular function with an ejection fraction (EF) of 22%. He remained in a severe congestive heart failure condition despite a full administration of catecholamines. Coronary angiogram findings revealed an occlusion of the proximal left anterior descending coronary artery and 1 week later severe hypotension was suddenly presented. An echocardiogram showed pericardial effusion with signs of cardiac tamponade. A pericardiocentesis was performed and hemodynamic improvement was obtained for a short time, after which the patient underwent urgent open heart surgery. During the operation, exclusion of the anteroseptal akinetic area using an oval patch was performed under a cardiopulmonary bypass and ventricular fibrillation. Severe cardiac failure remained postoperatively and the patient could not be weaned from cardiopulmonary bypass, therefore, we implanted a percutaneous cardiopulmonary support (PCPS) and started intraaortic balloon pumping (IABP). The patient was weaned from PCPS at 26 days after surgery and from IABP at 30 days. Following hospital release, he has continued to do well without heart failure for 39 months after the operation. A 76-year-old man suffering from chest pain was admitted to our hospital with a suspected acute myocardial infarction (AMI). Emergent coronary angiography revealed a totally occluded proximal left circumflex artery (LCX). During primary percutaneous coronary intervention, his blood pressure suddenly fell within seconds, and he developed pulseless electrical activity (PEA). Surprisingly, the 12-lead electrocardiogram (ECG) findings including the heart rate remained unchanged before and after the PEA, but a heart rate reduction and asystole occurred a few minutes after developing PEA. After tracheal intubation and mechanical assistance by venoarterial extracorporeal membrane oxygenation (VA-ECMO), the sudden onset of PEA appeared to be caused by cardiac tamponade due to a blowout-type left ventricular free wall rupture (BO-LVFWR) diagnosed by transthoracic echocardiography. While pericardiocentesis was performed and the drained blood was directly continuously perfused intravenously to keep the VA-ECMO flow, the patient was moved to the operation room. The surgical findings revealed a solitary BO-LVFWR due to a lateral AMI, and a direct closure was performed. Successful perioperative management, oral medication administration, and rehabilitation lead to the patient being transferred to a rehabilitation hospital without any serious cerebral damage. This case report suggested the detailed onset pattern of a BO-LVFWR followed by a rapid diagnosis by echocardiography and lifesaving treatment. To evaluate the ability of bedside emergency Doppler/Echocardiographic (ECOCG/DP) studies in the diagnosis of mechanic complications during acute myocardial infarction (AMI). Retrospective analysis of 44 fatal AMI cases, studied by ECOCG/DP and with diagnostic confirmation by surgery and/or necropsy. Patients (pts) with AMI admitted to an Intensive Care Unit of a tertiary Hospital (UCIM), Hospital de Santa Maria. 44 fatal AMI cases were analysed (24 men and 20 women; mean age +/- SD: 72 +/- 9 years) and were divided in two groups according to Killip classification in Group 1 (III/IV): 35 pts and Group 2 (I/II): 9 pts. ECOCG/DP was performed in a routine basis at admission, using all standard views and by subcostal view when in an emergency scenario. In 20 pts with bad left ventricular function (LVF) (Group 1) at admission, ECOCG/DP monitoring showed that death was due to worsening of LVF, which was confirmed by necropsy. In the other 15 pts of this group, ECOCG/DP documented the clinical diagnosis of cardiac rupture (free wall: 4 pts; papillary muscle: 4 pts; interventricular septum: 7 pts) which was confirmed by surgery and/or necropsy. In the 9 pts of Group 2, ECOCG/DP disclosed, at admission, good LVF in all. In 5 pts there was a sudden worsening clinical status, and ECOCG/DP showed a severe pericardial effusion with right chambers collapse, highly suggestive of free wall rupture also confirmed at necropsy. In the other 4 pts, ECOCG/DP showed aggravation of wall motion abnormalities and of LVF without rupture, once again in agreement with necropsy. Five clinical cases are presented for illustration of this issue. In the 44 fatal AMI cases of our study there was complete agreement between the ECOCG/DP and necropsy studies. In AMI patients, ECOCG/DP monitoring can in a routine basis, evaluate wall motion abnormalities and LVF. In an emergency setting ECOCG/DP can diagnose all the mechanic complications with a great certainty. Risk factors for rupture after an acute myocardial infarction include female gender, advanced age of the individual, first ischemic event, and a low body mass index. Other presenting signs associated with myocardial rupture include a pericardial friction rub, sluggish flow in the coronary artery after it is opened i.e. revascularized with an angioplasty, the left anterior descending artery being often the cause of the acute MI, and delay of revascularization greater than 2 hours. Diagnosis Due to the acute hemodynamic deterioration associated with myocardial rupture, the diagnosis is generally made based on physical examination, changes in the vital signs, and clinical suspicion. The diagnosis can be confirmed with echocardiography. The diagnosis is ultimately made at autopsy. Although a rare complication of acute myocardial infarction (AMI), ventricular rupture is a serious event associated with significant mortality and morbidity. Patients normally present with hemodynamic instability, often in cardiogenic shock. Despite improvements in surgical techniques and diagnostic tools, post-myocardial infarction ventricular rupture remains a difficult therapeutic challenge. There are three categories of ventricular rupture: free wall rupture (FWR), ventricular septal rupture (VSR), and papillary muscle rupture (PWR). The incidence of FWR occurs following up to 10% of myocardial infarctions. VSR and PWR have a lower incidence of 1-2% and 0.5-5%, respectively. Patients often present with single-vessel coronary artery disease and usually do not have a positive history for a previous myocardial infarction. The incidence of post infarction angina in these patients is significantly greater than in patients without ventricular rupture. Delay in treatment and continued physical activity post infarction increases the risk of ventricular rupture. Diagnostic tools such as two-dimensional echocardiography and cardiac catheterization confirm the diagnosis of ventricular rupture in only 45-88% of cases. Knowledge of the disease progression is necessary to insure accurate and timely diagnosis. Due to the rapid deterioration of these patients, there is a 50-80% mortality rate within the first week if untreated. With surgical correction, patients can extend their 5-year survival rates to 65%. A good example of the complex course of ventricular rupture is the case of a 71-year-old patient at our institution. The patient presented in cardiogenic shock following an AMI. Preoperative diagnosis was unsuccessful in determining the extent of the ventricular rupture. The correct diagnosis was determined in the operating room, and both a mitral valve replacement and closure of a ventricular septal defect were completed. The patient was successfully treated with this difficult pathology. Acute myocardial infarction (AMI) may culminate in sudden death by ventricular fibrillation, cardiogenic shock, and cardiac rupture. We present a case of postinfarction rupture treated by direct closure and coronary artery bypass grafting after thrombolytic therapy. A 67-year-old woman with cardiac risk factors of hypertension, diabetes mellitus, and being post-menopausal was admitted complaining of chest pain and sweating. Thrombolytic therapy with streptokinase was started due to acute myocardial infarction. But, reperfusion criteria were not achieved. Echocardiography revealed a moderate pericardial effusion with mild right chamber collapse and pericardial thrombus. Cardiac catheterization revealed totally occluded left anterior descending (LAD) and circumflex coronary arteries. She was taken to the operating-room immediately. The pericardium was opened and a large amount of blood with thrombus was removed. Her hemodynamic indices improved immediately. There was active bleeding from multiple sites with a 4 mm rupture. Cardiopulmonary bypass was established. Direct closure of rupture was carried out. Reversed autogenous saphenous vein bypass grafts were placed to the LAD and second obtuse margin coronary arteries. Postoperative recovery was uneventful and she was discharged from hospital in good condition. She remained asymptomatic during first year following the surgery. This case demonstrates that left ventricular free wall rupture is not always fatal and that early diagnosis and emergency surgical therapy may be successful. The combination of surgical repair with revascularization should be considered, because 80% of patients who experience LVFWR have multivessel coronary artery disease. Right ventricular assistance (RVA) using centrifugal pump in combination with IABP was used to treat a patient who was difficult to wean from a cardiopulmonary bypass following emergency coronary revascularization and resection of a ventricular aneurysm performed to treat acute right ventricular infarction due to a PTCA complication. After 131 hours of RVA at 3.2 to 4.8 l/min, it was possible to remove the pump. No heparin was administered during this time, changing the pump head twice, was used for 64 and 50 hour period, no thrombi were detected either time. After being weaned from RVA, the patient developed severe respiratory dysfunction, but on the 10th postoperative day (POD) IABP was weaned, and on the 13th POD the artificial respirator was withdrawn. The results of the postoperative cardiac catheterization were favorable, the patient was discharged on the 57th POD, and has returned to society at the present time. The indications for RVA include a central venous pressure &gt; 20 mmHg and a cardiac index &lt; 1.8 l/min/m2, and tissue perfusion pressure and general preoperative condition should severe as guides. The higher the assisted flow volume the more efficacious in relieving ventricular load, but, since there is a limit to how much the left ventricle and lungs can withstand, it should not exceed levels which ensure the maintainance of cardiac output and tissue perfusion pressure. Left ventricular wall rupture remains a major lethal complication of acute myocardial infarction and hypertension is a well-known predisposing factor of cardiac rupture after myocardial infarction. An 87-year-old man was admitted to our hospital, diagnosed as acute myocardial infarction (AMI). The echocardiogram showed 0.67-cm(2) aortic valve, consistent with severe aortic stenosis (AS). A coronary angiography showed a chronic occlusion of the proximal left circumflex artery and a 99 % stenosis and thrombus in the mid right coronary artery. During percutaneous angioplasty of the latter, transient hypotension and bradycardia developed at the time of balloon inflation, and low doses of noradrenaline and etilefrine were intravenously administered as needed. The patient suddenly lost consciousness and developed electro-mechanical dissociation. Cardio-pulmonary resuscitation followed by insertion of an intra-aortic balloon pump (IABP) and percutaneous cardiopulmonary support were initiated. The echocardiogram revealed moderate pericardial effusion, though the site of free wall rupture was not distinctly visible. A left ventriculogram clearly showed an infero-posterior apical wall rupture. Surgical treatment was withheld because of the interim development of brain death. In this patient, who presented with severe AS, the administration of catecholamine to stabilize the blood pressure probably increased the intraventricular pressures considerably despite apparently normal measurements of the central aortic pressure. IABP, temporary pacemaker, or both are recommended instead of intravenous catecholamines for patients with AMI complicated with significant AS to stabilize hemodynamic function during angioplasty. In the era before reperfusion therapy, ventricular septal rupture complicated 1approximate3% of acute myocardial infarctions (AMI) usually 3-5 days after onset. Studies have reported a positive correlation between the incidence of septal perforation and total occlusion of the coronary arteries. A 70-year old female patient was referred to the emergency room with the diagnosis of acute anterior myocardial infarction (MI) and recent cerebral infarction. The coronary angiogram showed a 90% stenosis at the mid-portion of the left anterior descending artery (LAD), and the lesion was successfully treated by percutaneous coronary intervention (PCI) with stent implantation. After PCI, the anterior wall motion improved on the follow-up echocardiogram. However, on the 20th hospital day, the patient condition deteriorated suddenly with pulmonary congestion. The echocardiography revealed a 1.3 cm ventricular septal defect at the apical septum with a left-to-right shunt. We report this rare case of delayed septal rupture in a patient with patent LAD after PCI and recovery of wall motion. We reported a case of a 70 year-old woman who suffered from right ventricular infarction with cardiogenic shock, detected clearly by transesophageal echocardiography. On admission, her pulse rate was 31 bpm and her blood pressure was unobtainable. Conscious level was III-1-2 and she was cold and clammy. The ECG showed complete AV block with junctional escape rhythm at a rate of 31 bpm which required temporary pacing and ST elevation in leads II, III, a VF, V4R, V3R, V1. An echocardiogram showed akinesis of RV free wall and paradoxical septal motion. Transesophageal echocardiography was performed safely on the 5th hospital day and detected RV wall motion abnormality clearly. A Swan-Ganz catheter was inserted. Mean PCW was 12 mmHg. PA pressure was 19/11 mmHg. Mean RA pressure was 13 mmHg. Cardiac index was 1.33 l/min/m2. SvO2 was 54%. Volume loading, administration of dopamine, dobutamine and nitroprusside were started. Cardiac index increased to 1.88 l/min/m2, and SvO2 increased to 59%. On the 4th hospital day, mean RA pressure increased to 29 mmHg and PA pressure increased to 47/31 mmHg acutely. Endotracheal intubation was done and PEEP 6 cmH2O was used and mean RA pressure and PA pressure decreased. On the 6th hospital day, cardiac index increased 4.08 l/min/m2. Cardiac catheterization done two months after acute myocardial infarction showed 75% stenosis of the proximal right coronary artery. Incomplete rupture of the ventricle free wall can occur after myocardial infarction. This occurs when an organized thrombus and the pericardium seal the ventricular perforation. This can progress to the formation of a left ventricle pseudoaneurysm (LVPA). A 70-year-old male with an antero-septal ST-elevation myocardial infarction (STEMI) underwent an emergent left heart catheterization which revealed severe three-vessel disease with occluded grafts, non-amenable to re-vascularization, and an apical thrombus. As he was high-risk for repeat coronary artery bypass graft, he was medically managed. Transthoracic echocardiogram (TTE) showed a normal left ventricle ejection fraction (LVEF), apical anterior and inferior wall akinesis, moderate sized apical thrombus, and pericardial thickening. On hospital day 7, examination revealed a new 3/6 to-and-fro murmur that was loudest at the apex. The patient was asymptomatic with normal vital signs. A repeat TTE revealed an apical wall rupture with flow into the pericardial cavity and absence of the apical thrombus. A LVPA was diagnosed and the patient was immediately referred for surgical repair. This case illustrates the potential for developing LVPA in STEMI patients and the importance of physical examination. If identified early a potential emergent situation in a previously asymptomatic patient can be averted, thereby preventing fatal consequences. &lt;<bLearning objective:</b With the growing use of diagnostic testing the importance of physical examination is being lost. However, with an astute cardiac examination, potential complications such as a left ventricular pseudoaneurysm can be identified and promptly managed. In addition, a ventricular pseudoaneurysm must be considered in the differential as a rare complication in post ST-elevation myocardial infarction patients with a new murmur.&gt;. An 80 years old man suffered a cardiac arrest shortly after arrival to his local health department. Basic Life Support was started promptly and nine minutes later, on evaluation by an Advanced Life Support team, the victim was defibrillated with a 200J shock. When orotracheal intubation was attempted, masseter muscle contraction was noticed: on reevaluation, the victim had pulse and spontaneous breathing.Thirty minutes later, the patient had been transferred to an emergency department. As he complained of chest pain, the ECG showed a ST segment depression in leads V4 to V6 and laboratory tests showed cardiac troponine I slightly elevated. A coronary angiography was performed urgently: significant left main plus three vessel coronary artery disease was disclosed.Eighteen hours after the cardiac arrest, a quadruple coronary artery bypass grafting operation was undertaken. During surgery, a fresh thrombus was removed from the middle left anterior descendent artery. Post-operative course was uneventful and the patient was discharged seven days after the procedure. Twenty four months later, he remains asymptomatic.In this case, the immediate call for the Advanced Life Support team, prompt basic life support and the successful defibrillation, altogether, contributed for the full recovery. Furthermore, the swiftness in the detection and treatment of the acute reversible cause (myocardial ischemia in this case) was crucial for long-term prognosis. Ventricular septal defect (VSD) is a severe complication of acute myocardial infarction and has a high mortality rate. This complication appears to have declined in the reperfusion era. It has mostly been reported in elderly or female patients who suffer from anterior wall infarction, patients with multivessel coronary artery disease (CAD) or occluded infarct-related artery (IRA) without collateral circulation, or patients who have had delayed reperfusion therapy. Here, we report the case of a 60-year-old male patient who presented with persistent chest pain and Killip I ST-segment-elevation myocardial infarction. Thrombolytic therapy was started 3 hours after the onset of chest pain. Based on the subsidence of chest pain, resolution of the elevated ST segment, and early peak of cardiac enzymes, reperfusion was thought to be successful. However, on the third day of admission, the patient complained of dyspnea after defecation and was found to have new-onset grade 3 pansystolic murmur over the left sternal border. Cardiac echography showed an apical VSD. A Swan-Ganz catheter was inserted into the right side of the heart; analysis of blood oxygen saturation revealed a 6% step-up of oxygen in the right ventricle. Coronary angiography showed only one-vessel CAD and TIMI 3 flow in the IRA. The patient received intensive medical management and underwent VSD repair and internal mammary artery bypass grafting to the left anterior descending artery. His recovery was uneventful. This case illustrates that VSD can be found in patients receiving early successful reperfusion therapy, with one-vessel CAD, and TIMI 3 flow in the IRA. Ventricular septal rupture is a potentially fatal complication of acute myocardial infarction. Its incidence has declined with modern reperfusion therapy. In the era of percutaneous coronary interventions, it occurs a median of 18-24 hours after myocardial infarction and is most commonly associated with anterior myocardial infarction. We present a case of delayed ventricular septal rupture complicating acute inferior wall myocardial infarction. A 53-year-old Caucasian male presented with epigastric pain for three days and electrocardiographic evidence for an acute inferior wall myocardial infarction. Coronary angiography revealed a total occlusion of the proximal right coronary artery. Reperfusion was achieved by balloon angioplasty followed by placement of a bare metal stent. On hospital day six, the patient developed acute respiratory distress, a new loud pansystolic murmur, and hemodynamic instability. Echocardiography revealed the presence of a large defect in the inferobasal interventricular septum with significant left-to-right shunt consistent with ventricular septal rupture. The patient underwent emergent surgical repair with a bovine pericardial patch. Ventricular septal rupture after myocardial infarction should be suspected in the presence of new physical findings and hemodynamic compromise regardless of revascularization therapy.\nHere is the question:\nCARDIOLOGY AND VASCULAR SURGERY: A 70-year-old female patient is admitted to the ICU after suffering anterior AMI treated by coronary angioplasty and stent placement in the anterior descending artery. Four days later she suddenly presented hypotension that required vigorous volume support, initiation of vasoactive drugs, orotracheal intubation and connection to mechanical ventilation. Physical examination revealed a murmur not previously present. Suspicion of a mechanical complication of the infarction led to transthoracic echocardiography showing pericardial effusion. Mark the CORRECT answer:\nHere are the potential choices:\n1. Mortality with medical treatment is 20%.\n2. In case of free wall rupture there is an oximetric jump in the right ventricle in the Swan-Ganz catheterization.\n3. In case of free wall rupture, there is no palpable frémito.\n4. Mechanical complications usually appear on the first post-infarction day.\nThe correct answer is: ",
        "gold_answer": "3 In case of free wall rupture, there is no palpable frémito.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Ten patients, eight males and two females, suffered myocardial rupture following acute myocardial infarction and required surgery. There were five ventricular septal ruptures, four papillary muscle ruptures and one free wall rupture. Ventricular septal rupture was suspected clinically by the appearance of a new systolic murmur, usually associated with a thrill at the left sternal border. A left to right shunt was confirmed by bedside oximetry using a Swan-Ganz catheter. The mean pulmonary to systemic flow ratio was 3.04:1. Following cardiac catheterization all patients underwent corrective surgery with or without aortocoronary bypass grafting. Three patients with inferior wall myocardial infarction died. Papillary muscle rupture was suspected clinically following the abrupt onset of hypotension with severe acute pulmonary edema accompanied by a new systolic murmur. The diagnosis was confirmed by cardiac catheterization. All underwent surgery for mitral valve replacement with or without aortocoronary bypass grafting. One patient died postoperatively of multiorgan failure. Free wall rupture was suspected clinically by the sudden onset of loss of consciousness, apnea, junctional bradycardia and severe hypotension leading to electromechanical dissociation. The diagnosis was confirmed by demonstrating a significant pericardial effusion by two dimensional echocardiography. Immediate surgery was performed. This patient is totally asymptomatic on no drug treatment six months following discharge. Ten patients underwent emergency surgery for myocardial rupture. Operative mortality was 40%. Patients with ventricular septal rupture associated with an inferior myocardial infarction had a poor prognosis. Right ventricular rupture is a rare complication of cardiopulmonary resuscitation and could be fatal. We report a survival case of right ventricular rupture induced by cardiopulmonary resuscitation in a patient with acute myocardial infarction. A 57-year-old man was admitted to our hospital with ventricular fibrillation. Although chest compression and defibrillation were performed, ventricular fibrillation continued. We inserted a percutaneous cardiopulmonary system and performed coronary angiography, which revealed occlusion of the left anterior descending artery. After coronary stenting and intra-aortic balloon pumping, we succeeded in defibrillation and vital signs became stable. Twenty hours after the intervention, systolic blood pressure dropped to 60 mmHg. Ultrasonic cardiogram at that time revealed massive pericardial effusion. We diagnosed cardiac tamponade, and 8Fr drainage tube was placed in the pericardial space. We determined that emergent operation was necessary because we suspected left ventricular rupture due to acute myocardial infarction or coronary rupture induced by percutaneous coronary intervention. However, operative findings revealed right ventricular free wall rupture, which could have been induced by chest compression. In these cases, we should consider the possibility of not only the rupture of left ventricle and coronary artery but also the rupture of right ventricle induced by cardiopulmonary resuscitation. A 58-year-old man who suffered from acute myocardial infarction complicated with left ventricular rupture and subacute pericardial tamponade was reported. On admission, echocardiography strongly suspected presence of intrapericardial fluid. And immediate pericardiocentesis proved left ventricular free wall rupture (LVFWR). Coronary angiography with the support of IABP revealed occlusion of LAD (# 8). Percutaneous transluminal coronary angioplasty was performed with partial success. After pericardiotomy, the hemodynamic state was improved, however, 2 hours later, his blood pressure fell down to 40 mmHg suddenly. Emergent operation (re-mediastinumotomy+ ) was performed under the suspicion of left ventricular blowout rupture with the direct closure of the perforated site with 4 woven Dacron pledgets at bedside in ICU. The patient ran an uneventful postoperative course and is now doing well. Clinical and therapeutic features of LVFWR were discussed. Ventricular septal (VS) rupture after acute myocardial infarction (AMI) is an uncommon complication in the reperfusion era. Bedside echocardiography (BECH) continues to be a strong diagnostic tool for emergency physicians treating dyspneic patients, especially for decision-making on the management strategies to use with these unstable patients. In the case we present here, a patient is diagnosed with a delayed mechanical complication after AMI, and a swift management plan is made with the aid of point-of-care BECH. The patient is a 72-year-old man with dyspnea who was admitted to the ED 5 days after receiving a primary percutaneous coronary intervention with stent implantation for AMI; in the ED, the patient was diagnosed, via BECH, with a VS rupture. On arrival, his vital signs and the results of his physical examination depicted shock and low perfusion with wet lung. A cardiac examination revealed a new 2/6 harsh holosystolic murmur along the left sternal border without pretibial oedema. Emergency physicians performed BECH, and subcostal views of the heart revealed a wide interventricular septal rupture and left-to-right shunting with minimal pericardial effusion. The patient underwent surgery immediately to repair the defect. The post-operative course was uneventful, and he was discharged in stable condition on the seventh day after the surgery. The use of BECH to recognize a VS rupture is critical because such a defect may be the most important determinant of mortality in AMI patients who are in shock. BECH thus can influence clinicians' acute management and disposition decisions. Three distinct forms of rupture of the heart may be identified after myocardial infarction: sudden rupture with massive intrapericardial haemorrhage, and sudden death with clinical signs of electromechanical dissociation; rupture into the pericardium resulting in a false aneurysm, the treatment of which is surgical; subacute rupture which accounts for 30% of cases in which bleeding into the pericardium is slow and/or repeated. Over an 8 year period and in a series of 2,400 consecutive infarcts admitted to the intensive care unit, 10 cases of subacute rupture of the heart were diagnosed. They were 6 men and 4 women, with a mean age of 73.6 years. The clinical presentation was isolated chest pain in 5 cases, syncope alone in 2 cases and the association of pain and syncope in 3 cases. Six patients were in shock on admission. In two cases, shock developed after admission. The infarction was confirmed biologically by a significant elevation of creatinine kinase in 9 out of 10 cases. Transmural infarction was observed in 9 cases: the infarct was electrocardiographically non-transmural in 1 case. Emergency echocardiography showed pericardial effusion in all cases, usually moderate, but sometimes compressive with an intrapericardial echogenic mass suggesting a thrombus. Haemodynamic improvement was obtained by medication allowing cardiac catheterisation which showed adiastole in 3 cases. Coronary angiography was performed in 7 cases. In 5 of the 7 cases, apart from occlusion of the artery presumed to be responsible for the infarct, the coronary vessels were diffusely infiltrated without significant stenosis. Left ventriculography was performed in 7 cases. In 6 of the 7 cases regional akinesis was demonstrated: the 7th case showed dyskinesia of the anterior wall. In two cases, contrast medium was observed to fill the pericardium during ventriculography, indicating myocardial rupture. The diagnosis of subacute rupture, suggested by clinical and paraclinical (particularly echocardiography), was confirmed in 9 cases at surgery and in the 10th case at autopsy. Surgery consisted of repairing the rupture. In the last two cases, biological glue was used to reinforce the surgical repair. The clinical outcome was good after surgery in 6 cases with a follow-up of 5 months to 8 years. The diagnosis of subacute rupture should therefore be made on clinical and echocardiographic criteria, as these results suggest that surgery is often possible, with a good prognosis. A 70-year-old man was transferred to our hospital with severe congestive heart failure and ventricular arrhythmia due to acute myocardial infarction. He had experienced chest pain 3 weeks previously and was admitted to another hospital for dyspnea, where he required assist ventilation, 1 week prior to the transfer. An echocardiogram revealed a broad anteroseptal infarction and very poor left ventricular function with an ejection fraction (EF) of 22%. He remained in a severe congestive heart failure condition despite a full administration of catecholamines. Coronary angiogram findings revealed an occlusion of the proximal left anterior descending coronary artery and 1 week later severe hypotension was suddenly presented. An echocardiogram showed pericardial effusion with signs of cardiac tamponade. A pericardiocentesis was performed and hemodynamic improvement was obtained for a short time, after which the patient underwent urgent open heart surgery. During the operation, exclusion of the anteroseptal akinetic area using an oval patch was performed under a cardiopulmonary bypass and ventricular fibrillation. Severe cardiac failure remained postoperatively and the patient could not be weaned from cardiopulmonary bypass, therefore, we implanted a percutaneous cardiopulmonary support (PCPS) and started intraaortic balloon pumping (IABP). The patient was weaned from PCPS at 26 days after surgery and from IABP at 30 days. Following hospital release, he has continued to do well without heart failure for 39 months after the operation. A 76-year-old man suffering from chest pain was admitted to our hospital with a suspected acute myocardial infarction (AMI). Emergent coronary angiography revealed a totally occluded proximal left circumflex artery (LCX). During primary percutaneous coronary intervention, his blood pressure suddenly fell within seconds, and he developed pulseless electrical activity (PEA). Surprisingly, the 12-lead electrocardiogram (ECG) findings including the heart rate remained unchanged before and after the PEA, but a heart rate reduction and asystole occurred a few minutes after developing PEA. After tracheal intubation and mechanical assistance by venoarterial extracorporeal membrane oxygenation (VA-ECMO), the sudden onset of PEA appeared to be caused by cardiac tamponade due to a blowout-type left ventricular free wall rupture (BO-LVFWR) diagnosed by transthoracic echocardiography. While pericardiocentesis was performed and the drained blood was directly continuously perfused intravenously to keep the VA-ECMO flow, the patient was moved to the operation room. The surgical findings revealed a solitary BO-LVFWR due to a lateral AMI, and a direct closure was performed. Successful perioperative management, oral medication administration, and rehabilitation lead to the patient being transferred to a rehabilitation hospital without any serious cerebral damage. This case report suggested the detailed onset pattern of a BO-LVFWR followed by a rapid diagnosis by echocardiography and lifesaving treatment. To evaluate the ability of bedside emergency Doppler/Echocardiographic (ECOCG/DP) studies in the diagnosis of mechanic complications during acute myocardial infarction (AMI). Retrospective analysis of 44 fatal AMI cases, studied by ECOCG/DP and with diagnostic confirmation by surgery and/or necropsy. Patients (pts) with AMI admitted to an Intensive Care Unit of a tertiary Hospital (UCIM), Hospital de Santa Maria. 44 fatal AMI cases were analysed (24 men and 20 women; mean age +/- SD: 72 +/- 9 years) and were divided in two groups according to Killip classification in Group 1 (III/IV): 35 pts and Group 2 (I/II): 9 pts. ECOCG/DP was performed in a routine basis at admission, using all standard views and by subcostal view when in an emergency scenario. In 20 pts with bad left ventricular function (LVF) (Group 1) at admission, ECOCG/DP monitoring showed that death was due to worsening of LVF, which was confirmed by necropsy. In the other 15 pts of this group, ECOCG/DP documented the clinical diagnosis of cardiac rupture (free wall: 4 pts; papillary muscle: 4 pts; interventricular septum: 7 pts) which was confirmed by surgery and/or necropsy. In the 9 pts of Group 2, ECOCG/DP disclosed, at admission, good LVF in all. In 5 pts there was a sudden worsening clinical status, and ECOCG/DP showed a severe pericardial effusion with right chambers collapse, highly suggestive of free wall rupture also confirmed at necropsy. In the other 4 pts, ECOCG/DP showed aggravation of wall motion abnormalities and of LVF without rupture, once again in agreement with necropsy. Five clinical cases are presented for illustration of this issue. In the 44 fatal AMI cases of our study there was complete agreement between the ECOCG/DP and necropsy studies. In AMI patients, ECOCG/DP monitoring can in a routine basis, evaluate wall motion abnormalities and LVF. In an emergency setting ECOCG/DP can diagnose all the mechanic complications with a great certainty. Risk factors for rupture after an acute myocardial infarction include female gender, advanced age of the individual, first ischemic event, and a low body mass index. Other presenting signs associated with myocardial rupture include a pericardial friction rub, sluggish flow in the coronary artery after it is opened i.e. revascularized with an angioplasty, the left anterior descending artery being often the cause of the acute MI, and delay of revascularization greater than 2 hours. Diagnosis Due to the acute hemodynamic deterioration associated with myocardial rupture, the diagnosis is generally made based on physical examination, changes in the vital signs, and clinical suspicion. The diagnosis can be confirmed with echocardiography. The diagnosis is ultimately made at autopsy. Although a rare complication of acute myocardial infarction (AMI), ventricular rupture is a serious event associated with significant mortality and morbidity. Patients normally present with hemodynamic instability, often in cardiogenic shock. Despite improvements in surgical techniques and diagnostic tools, post-myocardial infarction ventricular rupture remains a difficult therapeutic challenge. There are three categories of ventricular rupture: free wall rupture (FWR), ventricular septal rupture (VSR), and papillary muscle rupture (PWR). The incidence of FWR occurs following up to 10% of myocardial infarctions. VSR and PWR have a lower incidence of 1-2% and 0.5-5%, respectively. Patients often present with single-vessel coronary artery disease and usually do not have a positive history for a previous myocardial infarction. The incidence of post infarction angina in these patients is significantly greater than in patients without ventricular rupture. Delay in treatment and continued physical activity post infarction increases the risk of ventricular rupture. Diagnostic tools such as two-dimensional echocardiography and cardiac catheterization confirm the diagnosis of ventricular rupture in only 45-88% of cases. Knowledge of the disease progression is necessary to insure accurate and timely diagnosis. Due to the rapid deterioration of these patients, there is a 50-80% mortality rate within the first week if untreated. With surgical correction, patients can extend their 5-year survival rates to 65%. A good example of the complex course of ventricular rupture is the case of a 71-year-old patient at our institution. The patient presented in cardiogenic shock following an AMI. Preoperative diagnosis was unsuccessful in determining the extent of the ventricular rupture. The correct diagnosis was determined in the operating room, and both a mitral valve replacement and closure of a ventricular septal defect were completed. The patient was successfully treated with this difficult pathology. Acute myocardial infarction (AMI) may culminate in sudden death by ventricular fibrillation, cardiogenic shock, and cardiac rupture. We present a case of postinfarction rupture treated by direct closure and coronary artery bypass grafting after thrombolytic therapy. A 67-year-old woman with cardiac risk factors of hypertension, diabetes mellitus, and being post-menopausal was admitted complaining of chest pain and sweating. Thrombolytic therapy with streptokinase was started due to acute myocardial infarction. But, reperfusion criteria were not achieved. Echocardiography revealed a moderate pericardial effusion with mild right chamber collapse and pericardial thrombus. Cardiac catheterization revealed totally occluded left anterior descending (LAD) and circumflex coronary arteries. She was taken to the operating-room immediately. The pericardium was opened and a large amount of blood with thrombus was removed. Her hemodynamic indices improved immediately. There was active bleeding from multiple sites with a 4 mm rupture. Cardiopulmonary bypass was established. Direct closure of rupture was carried out. Reversed autogenous saphenous vein bypass grafts were placed to the LAD and second obtuse margin coronary arteries. Postoperative recovery was uneventful and she was discharged from hospital in good condition. She remained asymptomatic during first year following the surgery. This case demonstrates that left ventricular free wall rupture is not always fatal and that early diagnosis and emergency surgical therapy may be successful. The combination of surgical repair with revascularization should be considered, because 80% of patients who experience LVFWR have multivessel coronary artery disease. Right ventricular assistance (RVA) using centrifugal pump in combination with IABP was used to treat a patient who was difficult to wean from a cardiopulmonary bypass following emergency coronary revascularization and resection of a ventricular aneurysm performed to treat acute right ventricular infarction due to a PTCA complication. After 131 hours of RVA at 3.2 to 4.8 l/min, it was possible to remove the pump. No heparin was administered during this time, changing the pump head twice, was used for 64 and 50 hour period, no thrombi were detected either time. After being weaned from RVA, the patient developed severe respiratory dysfunction, but on the 10th postoperative day (POD) IABP was weaned, and on the 13th POD the artificial respirator was withdrawn. The results of the postoperative cardiac catheterization were favorable, the patient was discharged on the 57th POD, and has returned to society at the present time. The indications for RVA include a central venous pressure &gt; 20 mmHg and a cardiac index &lt; 1.8 l/min/m2, and tissue perfusion pressure and general preoperative condition should severe as guides. The higher the assisted flow volume the more efficacious in relieving ventricular load, but, since there is a limit to how much the left ventricle and lungs can withstand, it should not exceed levels which ensure the maintainance of cardiac output and tissue perfusion pressure. Left ventricular wall rupture remains a major lethal complication of acute myocardial infarction and hypertension is a well-known predisposing factor of cardiac rupture after myocardial infarction. An 87-year-old man was admitted to our hospital, diagnosed as acute myocardial infarction (AMI). The echocardiogram showed 0.67-cm(2) aortic valve, consistent with severe aortic stenosis (AS). A coronary angiography showed a chronic occlusion of the proximal left circumflex artery and a 99 % stenosis and thrombus in the mid right coronary artery. During percutaneous angioplasty of the latter, transient hypotension and bradycardia developed at the time of balloon inflation, and low doses of noradrenaline and etilefrine were intravenously administered as needed. The patient suddenly lost consciousness and developed electro-mechanical dissociation. Cardio-pulmonary resuscitation followed by insertion of an intra-aortic balloon pump (IABP) and percutaneous cardiopulmonary support were initiated. The echocardiogram revealed moderate pericardial effusion, though the site of free wall rupture was not distinctly visible. A left ventriculogram clearly showed an infero-posterior apical wall rupture. Surgical treatment was withheld because of the interim development of brain death. In this patient, who presented with severe AS, the administration of catecholamine to stabilize the blood pressure probably increased the intraventricular pressures considerably despite apparently normal measurements of the central aortic pressure. IABP, temporary pacemaker, or both are recommended instead of intravenous catecholamines for patients with AMI complicated with significant AS to stabilize hemodynamic function during angioplasty. In the era before reperfusion therapy, ventricular septal rupture complicated 1approximate3% of acute myocardial infarctions (AMI) usually 3-5 days after onset. Studies have reported a positive correlation between the incidence of septal perforation and total occlusion of the coronary arteries. A 70-year old female patient was referred to the emergency room with the diagnosis of acute anterior myocardial infarction (MI) and recent cerebral infarction. The coronary angiogram showed a 90% stenosis at the mid-portion of the left anterior descending artery (LAD), and the lesion was successfully treated by percutaneous coronary intervention (PCI) with stent implantation. After PCI, the anterior wall motion improved on the follow-up echocardiogram. However, on the 20th hospital day, the patient condition deteriorated suddenly with pulmonary congestion. The echocardiography revealed a 1.3 cm ventricular septal defect at the apical septum with a left-to-right shunt. We report this rare case of delayed septal rupture in a patient with patent LAD after PCI and recovery of wall motion. We reported a case of a 70 year-old woman who suffered from right ventricular infarction with cardiogenic shock, detected clearly by transesophageal echocardiography. On admission, her pulse rate was 31 bpm and her blood pressure was unobtainable. Conscious level was III-1-2 and she was cold and clammy. The ECG showed complete AV block with junctional escape rhythm at a rate of 31 bpm which required temporary pacing and ST elevation in leads II, III, a VF, V4R, V3R, V1. An echocardiogram showed akinesis of RV free wall and paradoxical septal motion. Transesophageal echocardiography was performed safely on the 5th hospital day and detected RV wall motion abnormality clearly. A Swan-Ganz catheter was inserted. Mean PCW was 12 mmHg. PA pressure was 19/11 mmHg. Mean RA pressure was 13 mmHg. Cardiac index was 1.33 l/min/m2. SvO2 was 54%. Volume loading, administration of dopamine, dobutamine and nitroprusside were started. Cardiac index increased to 1.88 l/min/m2, and SvO2 increased to 59%. On the 4th hospital day, mean RA pressure increased to 29 mmHg and PA pressure increased to 47/31 mmHg acutely. Endotracheal intubation was done and PEEP 6 cmH2O was used and mean RA pressure and PA pressure decreased. On the 6th hospital day, cardiac index increased 4.08 l/min/m2. Cardiac catheterization done two months after acute myocardial infarction showed 75% stenosis of the proximal right coronary artery. Incomplete rupture of the ventricle free wall can occur after myocardial infarction. This occurs when an organized thrombus and the pericardium seal the ventricular perforation. This can progress to the formation of a left ventricle pseudoaneurysm (LVPA). A 70-year-old male with an antero-septal ST-elevation myocardial infarction (STEMI) underwent an emergent left heart catheterization which revealed severe three-vessel disease with occluded grafts, non-amenable to re-vascularization, and an apical thrombus. As he was high-risk for repeat coronary artery bypass graft, he was medically managed. Transthoracic echocardiogram (TTE) showed a normal left ventricle ejection fraction (LVEF), apical anterior and inferior wall akinesis, moderate sized apical thrombus, and pericardial thickening. On hospital day 7, examination revealed a new 3/6 to-and-fro murmur that was loudest at the apex. The patient was asymptomatic with normal vital signs. A repeat TTE revealed an apical wall rupture with flow into the pericardial cavity and absence of the apical thrombus. A LVPA was diagnosed and the patient was immediately referred for surgical repair. This case illustrates the potential for developing LVPA in STEMI patients and the importance of physical examination. If identified early a potential emergent situation in a previously asymptomatic patient can be averted, thereby preventing fatal consequences. &lt;<bLearning objective:</b With the growing use of diagnostic testing the importance of physical examination is being lost. However, with an astute cardiac examination, potential complications such as a left ventricular pseudoaneurysm can be identified and promptly managed. In addition, a ventricular pseudoaneurysm must be considered in the differential as a rare complication in post ST-elevation myocardial infarction patients with a new murmur.&gt;. An 80 years old man suffered a cardiac arrest shortly after arrival to his local health department. Basic Life Support was started promptly and nine minutes later, on evaluation by an Advanced Life Support team, the victim was defibrillated with a 200J shock. When orotracheal intubation was attempted, masseter muscle contraction was noticed: on reevaluation, the victim had pulse and spontaneous breathing.Thirty minutes later, the patient had been transferred to an emergency department. As he complained of chest pain, the ECG showed a ST segment depression in leads V4 to V6 and laboratory tests showed cardiac troponine I slightly elevated. A coronary angiography was performed urgently: significant left main plus three vessel coronary artery disease was disclosed.Eighteen hours after the cardiac arrest, a quadruple coronary artery bypass grafting operation was undertaken. During surgery, a fresh thrombus was removed from the middle left anterior descendent artery. Post-operative course was uneventful and the patient was discharged seven days after the procedure. Twenty four months later, he remains asymptomatic.In this case, the immediate call for the Advanced Life Support team, prompt basic life support and the successful defibrillation, altogether, contributed for the full recovery. Furthermore, the swiftness in the detection and treatment of the acute reversible cause (myocardial ischemia in this case) was crucial for long-term prognosis. Ventricular septal defect (VSD) is a severe complication of acute myocardial infarction and has a high mortality rate. This complication appears to have declined in the reperfusion era. It has mostly been reported in elderly or female patients who suffer from anterior wall infarction, patients with multivessel coronary artery disease (CAD) or occluded infarct-related artery (IRA) without collateral circulation, or patients who have had delayed reperfusion therapy. Here, we report the case of a 60-year-old male patient who presented with persistent chest pain and Killip I ST-segment-elevation myocardial infarction. Thrombolytic therapy was started 3 hours after the onset of chest pain. Based on the subsidence of chest pain, resolution of the elevated ST segment, and early peak of cardiac enzymes, reperfusion was thought to be successful. However, on the third day of admission, the patient complained of dyspnea after defecation and was found to have new-onset grade 3 pansystolic murmur over the left sternal border. Cardiac echography showed an apical VSD. A Swan-Ganz catheter was inserted into the right side of the heart; analysis of blood oxygen saturation revealed a 6% step-up of oxygen in the right ventricle. Coronary angiography showed only one-vessel CAD and TIMI 3 flow in the IRA. The patient received intensive medical management and underwent VSD repair and internal mammary artery bypass grafting to the left anterior descending artery. His recovery was uneventful. This case illustrates that VSD can be found in patients receiving early successful reperfusion therapy, with one-vessel CAD, and TIMI 3 flow in the IRA. Ventricular septal rupture is a potentially fatal complication of acute myocardial infarction. Its incidence has declined with modern reperfusion therapy. In the era of percutaneous coronary interventions, it occurs a median of 18-24 hours after myocardial infarction and is most commonly associated with anterior myocardial infarction. We present a case of delayed ventricular septal rupture complicating acute inferior wall myocardial infarction. A 53-year-old Caucasian male presented with epigastric pain for three days and electrocardiographic evidence for an acute inferior wall myocardial infarction. Coronary angiography revealed a total occlusion of the proximal right coronary artery. Reperfusion was achieved by balloon angioplasty followed by placement of a bare metal stent. On hospital day six, the patient developed acute respiratory distress, a new loud pansystolic murmur, and hemodynamic instability. Echocardiography revealed the presence of a large defect in the inferobasal interventricular septum with significant left-to-right shunt consistent with ventricular septal rupture. The patient underwent emergent surgical repair with a bovine pericardial patch. Ventricular septal rupture after myocardial infarction should be suspected in the presence of new physical findings and hemodynamic compromise regardless of revascularization therapy.\nHere is the question:\nCARDIOLOGY AND VASCULAR SURGERY: A 70-year-old female patient is admitted to the ICU after suffering anterior AMI treated by coronary angioplasty and stent placement in the anterior descending artery. Four days later she suddenly presented hypotension that required vigorous volume support, initiation of vasoactive drugs, orotracheal intubation and connection to mechanical ventilation. Physical examination revealed a murmur not previously present. Suspicion of a mechanical complication of the infarction led to transthoracic echocardiography showing pericardial effusion. Mark the CORRECT answer:\nHere are the potential choices:\n1. Mortality with medical treatment is 20%.\n2. In case of free wall rupture there is an oximetric jump in the right ventricle in the Swan-Ganz catheterization.\n3. In case of free wall rupture, there is no palpable frémito.\n4. Mechanical complications usually appear on the first post-infarction day.\nThe correct answer is: 3. In case of free wall rupture, there is no palpable frémito."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n To assess the efficacy and safety of mechanical fragmentation combined with intrapulmonary thrombolysis in massive pulmonary thromboembolism (PTE) with hemodynamic impairment. Fifty-nine patients diagnosed with massive PTE with hemodynamic impact were treated. The initial clinical symptoms were shock in 23 patients (38.9%), syncope in eight (13.5%), and dyspnea at rest in 28 (47.4%). Mean O2 saturation was 67.8%. Mean pulmonary artery pressure (PAP) was 42.1 mm Hg. During fragmentation, thrombolysis was administered in the form of a urokinase bolus of 200,000-500,000 U in 57 patients and 20 mg of recombinant tissue plasminogen activator (rt-PA) in two patients. The mean urokinase dose used was 2,500,000 IU, whereas the total dose of rt-PA was 100 mg. Heparin sodium infusion was performed to reach activated partial thromboplastin time ratios of 2. The follow-up consisted of clinical assessment, pulmonary scintigraphy, and echocardiography. The patients received treatment with dicoumarin for 6 months after the procedure. Clinical improvement was seen in 56 patients (94%). Three patients died. The mean PAP after the treatment was 21.8 mm Hg. The mean posttreatment Miller index was 0.35. Technical success was achieved in all cases and clinical symptoms improved in all cases except those in which the patients died. Pulmonary scintigraphy showed improved perfusion in all cases. Echocardiography was performed after 3-6 months, showing a mean pressure of 22.8 mm Hg (corrected values). There were no signs of recurrent PTE or arterial hypertension in the follow-up. The data provided confirm the efficacy and safety of mechanical fragmentation and pharmacologic thrombolysis in the treatment of massive PTE with hemodynamic impairment, showing improvement of symptoms and a decrease in PAP. A 79[correction of seventy]-year-old patient, who has been in bed a long time, suffered an episode of sudden dyspnea, tachycardia and tachypnea. An electrocardiogram registered at her admission in the coronary care unit showed a normal rhythm with right axis deviation and S1Q3T3 pattern and ST segment alterations. A ventilation-perfusion lung scanning demonstrated segmental perfusion defects with high probability of pulmonary embolism. She developed a low cardiac output syndrome, which neither responded to the volume expansion nor to the inotropic drugs. The bed-side hemodynamic measurements were a systolic pulmonary pressure of 60 mmHg, with a diastolic pressure of 18 mmHg and capillary wedge pressure of 13 mmHg with high pulmonary resistance. With this evidences, the diagnoses of massive pulmonary embolism was done, thrombolytic treatment was decided on. Two hundred and fifty thousands international units of streptokinase was administered, and then 100.000 UI/hour in 24 hours; after that with intravenous heparin. The low cardiac output syndrome disappeared. The patients recovered her systemic arterial pressure and her diuresis. The electrocardiographic signs vanished and both the pulmonary pressure and resistance decreased. We discussed the importance of intravenous thrombolytic treatment in massive pulmonary embolism. We concluded than this treatment is an useful strategy that not always needs a pulmonary arteriography, and could be used in low complexity centres, successfully in the massive pulmonary thromboembolism with severe hemodynamic damage. We report the case of a 65 year old woman with no prior cardiac or pulmonary disease, who suffered pulmonary embolism (PE); diagnosis was made on the basis of the existence of risk factors, clinical, radiographic and electrocardiographic features, and a lung scan with perfusion defects and normal ventilation. PE was considered massive because the patient developed acute respiratory failure that required tracheal intubation and mechanical ventilation as well as obstructive shock, electrocardiographic and echocardiographic data of right ventricle overload, and pulmonary hypertension, with pulmonary artery pressure of 38 mmHg. She received an initial treatment with high doses (1,500,000 UI) and rapid infusion (1 hr) of intravenous streptokinase (SK) followed by heparin anticoagulation. Thereafter the hemodynamic disturbances improved and pulmonary artery pressure post-thrombolysis was 23 mmHg. In this report SK at high doses and rapid infusion showed effectiveness and security. We emphasize the usefulness of echocardiography as a diagnostic aid in patients with a previously healthy cardiopulmonary system, as well as the possible role of electrocardiogram as an early indicator of pulmonary reperfusion. This could be the first report of successful thrombolysis with high doses and rapid infusion of SK in massive PE. Several animal studies have shown that regional lung perfusion could be effectively estimated by the hypertonic saline contrast electrical impedance tomography method. Here, we reported an application of this method to dynamically assess regional pulmonary perfusion defect in a patient with acute massive pulmonary embolism. A 68-year-old man experienced sudden dyspnea and cardiac arrest during out-of-bed physical activity on the first day after partial mediastinal tumor resection. Acute pulmonary embolism was suspected due to acute enlargement of right heart and fixed inferior venous cava measured with bedside ultrasound. The computed tomography pulmonary angiography further confirmed large embolism in both left and right main pulmonary arteries and branches. The regional time impedance curves, which were obtained by a bolus of 10 ml 10% NaCl through the central venous catheter, were then analyzed to quantitatively assess regional perfusion. Normal ventilation distribution with massive defects in regional perfusion in both lungs was observed, leading to a ventilation-perfusion mismatch and low oxygenation index (PaO<sub2</sub/FiO2 = 86 mmHg) at the first day of pulmonary embolism. The anticoagulation was performed with heparin, and the patient's condition (such as shock, dyspnea, hypoxemia, etc.), regional lung perfusion defect, and ventilation-perfusion mismatch continuously improved in the following days. In conclusion, this case implies that electrical impedance tomography might have the potential to assess and monitor regional perfusion for rapid diagnosis of fatal pulmonary embolism in clinical practice. Acute pulmonary embolism (APE) as a life-threatening illness may present with a wide range of manifestations. APE was diagnosed using computed tomographic pulmonary angiography (CTPA); however, transthoracic echocardiography (TTE) can reveal hemodynamic status. Early thrombolysis is the most effective therapy for the treatment of massive pulmonary embolism. Herein, we report a case of high-risk APE with a wide range of manifestations, including chest pain, dyspnea, low-blood pressure, and syncope. A 55-year-old, previously healthy woman, complained of dyspnea and pleuritic chest pain for 40 days, along with transitory (10 minutes) episodes of syncope that had occurred 2 days previously. Because of the high-risk APE, the patient received intravenous thrombolytic therapy with low-dose recombinant tissue plasminogen activator (rt-PA, 50 mg over 30 minutes) and an anticoagulant (subcutaneous low-molecular-weight heparin, once every 12 hours for 5 days). Five days after thrombolysis, bedside TTE revealed RV diastolic dimension decreased to 22 mm. Color ultrasonography revealed a significant decrease in systolic and mean pulmonary artery pressure. TTE may provide initial suspicion of APE and may help identify patients with unstable hemodynamic status before the onset of shock. Moreover, concomitant TTE signs of decreased RV load may predict better prognosis for high-risk APE patients. The authors describe a rare case of pulmonary thromboembolism with unusual clinical findings and emphasized the large difficulty encountered in formuling a correct diagnosis in a reasonable time. A man, 60 years old, was admitted to a Medical Division of our hospital for the appearance of chest pain and epigastric pain during effort in the last year. He smoked 20 cigarettes a day and drank wine (1 or 2 litres a day). He was affected by hypercholesterolemia and in the past reported relapsed thrombophlebitis in the left leg. Four years before admission to our hospital he underwent large and small left saphenectomy. He had no cardiac events in the past. After a non significant exercise stress test the patient was treated with nitrates and asa and was discharged from the hospital. At home the symptoms increased and after 8 months the patient was admitted again to the Cardiologic Division of the hospital. At admission he reported dyspnea and chest pain at rest, not only during effort and the ECG showed negative T waves in anterior and inferior leads. Intravenous heparine, nitrates and calcium antagonists stabilized the clinical picture. The following examinations revealed: reduction of the T wave negativity at the ECG registered during chest pain; mild enlargement of the heart at the chest roentgenogram; normal value of the left ventricle and apical and midseptal by ipokinesia at the transthoracic echocardiogram; normal coronary artery at the coronary arteriography. \"Vasospastic angina\" was diagnosed and the patient was discharged after 20 days, asymptomatic. After 15 days he returned to the hospital again for chest pain, dyspnea, hypotension and syncope despite therapy. At physical examination he showed a painful left tibio-tarsal tumefaction, an increased and splitting second heart sound in the pulmonary area and a systolic murmur in the third and fourth left interspace. The ECG showed a severe anterior ischemia, while a new transthoracic echocardiogram revealed a considerable dilatation of the right atrium, right ventricle and the main pulmonary artery with severe tricuspid regurgitation and pulmonary hypertension (mean PAP about 50 mmHg). The following pulmonary perfusion scintigraphy confirmed the diagnosis of pulmonary embolism and the selective right and left pulmonary arteriography exhibited multiple thrombi and large intravascular filling defects. The right heart catheterization confirmed a chronic precapillary pulmonary hypertension (mean PAP = 55 mmHg). About 24 hours after these examinations the patient died because of a cardiac arrest with electromechanical dissociation. Pulmonary thromboembolism is a potentially fatal disease characterized by a largely variable clinical presentation. Frequently pulmonary embolism diagnosis is difficult especially when clinical findings are unusual. In the case observed the \"typical\" chest and epigastric pains associated with the electrocardiographic findings directed diagnosis towards myocardial ischemia. Also after the coronary arteriography that showed normal coronary artery, the erroneous diagnosis persisted. Pulmonary embolism was correctly diagnosed too late to begin an effective therapy. These unusual clinical findings and diagnostic mistakes are stressed and critically reviewed in the article. Pulmonary embolism (PE) refers to the endogenous or exogenous emboli blocking pulmonary trunk or branches, causing clinical and pathophysiological syndrome of pulmonary circulation disorder, the incidence rate is high. Sometimes PE patients were lack of specific symptoms and signs, or without any symptoms, which often result in misdiagnosis, un-timely diagnosis, and the delay of treatment. A PE case with syncope, vomiting and shock, which was proved to be pulmonary artery trunk and branch wide embolism later, was presented so as to improve the understanding of the disease. Management Pulse oximetry can guide the use of supplemental oxygen to maintain oxygen saturation greater than 94%. Hyperoxia should be avoided as may be detrimental in stroke. Hypertension is common in an acute ischemic stroke. A low BP is uncommon and may indicate symptoms exacerbation of a previous stroke due to poor perfusion. Blood pressure of 220/120 mmHg should receive treatment. There is a consensus approach of allowing permissive hypertension up to 220/120 mmHg for patients that are not candidates for thrombolysis.[21] However, for a patient that is a potential candidate for alteplase, attempt to control BP should be made immediately as goal BP for initiation of IV alteplase is 185/110 mmHg. Usually, titratable short-acting intravenous hypotensive agents are recommended to avoid dropping the BP too much once the patient is at goal. Hypotensive agents that can be options include labetalol, nicardipine, clevidipine, hydralazine, enalaprilat.[21] Massive pulmonary thromboembolism has a high mortality. Early thrombolysis is the treatment of choice. We report a 79-year-old man admitted in shock. A chest angio-CAT scan showed a massive pulmonary thromboembolism. A transthoracic echocardiography showed a right cardiac dysfunction. Although the patient was in hemodynamic instability, he was subjected to thrombolysis with streptokinase, assisted with noradrenaline support and invasive mechanical ventilation. Parenteral anticoagulation was started thereafter. A second echocardiography, performed 72 hours later showed an improvement in right ventricular function. The patient had a nosocomial pneumonia that was treated. Noradrenalin and mechanical ventilation were discontinued nine and 15 days after thrombolysis. A new angio-CAT scan, 23 days after the procedure, was normal. The patient was discharged in good conditions 27 days after admission. A 50-year-old man presented with progressive dyspnea on exertion, but with no history of chest pain or syncope. Chronic pulmonary thromboembolism was suspected and he was referred to our hospital. On ausculation, a grade 3 systolic murmur was heard, that was loudest in the fifth intercostal space lateral to the right sternal border. Chest radiography showed mild cardiomegaly and ventilation-perfusion scan revealed absence of perfusion in the left lung and the upper field of the right lung. Contrast-enhanced helical CT showed large mural defects in both main pulmonary arteries, clearly delineated by contrast medium. The left pulmonary artery was nearly completely occluded, and eccentric defects were observed projecting into the lumen of the pulmonary trunk. A tumor originating in the pulmonary artery was suspected, but a definitive diagnosis of the mass could not be made with pulmonary angiography and magnetic resonance imaging. The mean pulmonary arterial pressure was 50 mmHg. Further radiologic examinations failed to reveal the source of the embolus or tumor. It was decided to attempt surgical excision under total cardiopulmonary bypass. At operation, a gelatinous, lustrous, yellowish mass was found partially occluding the right main pulmonary artery and completely occluding the left. The tumor adhered tightly to the intima of the vessel and was inoperable. The patient could not be weaned from percutaneous cardiopulmonary support and died 3 days after surgery. Histologic examination of the excised specimen revealed myxosarcoma. A 54-year-old man was admitted to our hospital complaining of sudden-onset dyspnea in shock. Chest computed tomography(CT) showed thrombi in the right main and left intermediate pulmonary arteries. The case was diagnosed as a massive acute pulmonary thromboembolism. Although his hemodynamic status was stable after catecholamine infusion, his dyspnea was still in progress. Emergency pulmonary embolectomy was performed and the life of patient was saved. It is thought that progressive dyspnea is an important sign of a deteriorating hemodynamic status and the predictive symptom indicating a surgical procedure in patients with massive acute pulmonary thromboembolism. We report a case of a 73-year-old man with pulmonary embolism due to idiopathic thrombosis of the inferior vena cava. He was referred to our hospital because of a fever and cough of 2 weeks' duration despite treatment with an oral antibiotic. Chest radiography on the first visit showed an infiltrate in the right middle lung field. He was diagnosed as having pneumonia and admitted to our hospital for treatment. Following administration of intravenous antibiotics, his symptoms disappeared and the chest radiography findings improved. The abdominal CT obtained in an attempt to visualize the cause of liver dysfunction serendipitously revealed thrombosis of the inferior vena cava, which was suspected to have caused the pulmonary embolism. A subsequent lung perfusion scan revealed marked perfusion defects in the right middle and lower lobes. Chest CT revealed an embolus located in the right pulmonary artery. Since thrombolytic therapy was not effective, the placement of a filter in the inferior vena cava was performed to prevent the recurrence of pulmonary embolism. The patient has been asymptomatic without recurrence of the disease since the filter insertion. Chronic pulmonary embolism is a rare disease which can occur at first with pulmonary hypertension. In these cases it may be difficult to distinguish between primary pulmonary hypertension. We examined nine patients with Chronic Pulmonary Embolism (CPE) (three females and six males, mean age 45 +/- 13 years, range 21-67 years) and ten patients with Primary Pulmonary Hypertension (PPH) (seven females and three males, mean age 35 +/- 13 years, range 10-56 years) who came to our attention during the years 1973-1986 (mean follow up 3 years). All patients had an electrocardiogram, chest x-ray, echocardiogram, cardiac catheterization with pulmonary angiography; seven patients with CPE and eight with PPH had perfusion lung scans. Progressive dyspnoea was the main feature in all the patients; four out of nine with CPE and none of the ones with PPH had a previous history of thrombophlebitis. In all the patients the electrocardiogram, chest x-ray and echocardiogram showed signs of pulmonary hypertension, so that a clear distinction between the two groups was not possible. Cardiac catheterization showed pulmonary pressure values higher in patients with PPH as compared to the ones with CPE (systolic pressure 96 mmHg vs 70 mmHg, diastolic pressure 49 mmHg vs 31 mmHg, mean pressure 65 mmHg vs 45 mmHg). Pulmonary angiography in more than half of the patients with CPE showed a \"cut off\" of two or more lobar branches of the pulmonary arteries. In the patients with PPH pulmonary angiography showed a dilatation of the main pulmonary artery and a diffuse bilateral hypoperfusion. Perfusion lung scan in all the cases of CPE showed zonal perfusion defects, while in all cases of PPH, with the exception of one, it was largely normal. Venograms in the districts of the inferior vena cava demonstrated thrombosis in two out of six patients with CPE. Negative venograms were found in the five patients with PPH who had this investigation performed. One patient with CPE had a surgical embolectomy, the other eight had anticoagulant oral treatment. During the follow-up period three patients with CPE and five with PPH died within five years and within fifteen months respectively, of the diagnosis.(ABSTRACT TRUNCATED AT 400 WORDS) In-hospital mortality is high when pulmonary embolism is complicated by hemodynamic instability and/or pulmonary hypertension. Death occurs frequently within the first hours after admission. This implies specific diagnostic and therapeutic management. Spiral CT seems to be an excellent diagnostic procedure in this setting. However, pulmonary angiography and perfusion lung scan can also be employed. Cardiac echography can help in the diagnosis and therapeutic decision making. Supportive therapy mainly includes correction of hypovolemia if present, a limited volume loading in other cases, and the use of dobutamine. Norepinephrine is the drug of choice when hypotension is present. Thrombolytic agents are indicated in case of hemodynamic instability. Modalities of administration and contra indications are currently well established. Surgical embolectomy should be performed in cases of uncontrolled shock, when thrombolysis is contra-indicated or uneffective. The diagnosis of major pulmonary embolism should be considered in case of acute respiratory distress, particularly when there is high thromboembolic risk. Although clinical symptoms are not specific, some are suggestive: syncope or dizziness with cyanosis and polypnoea, and especially arterial hypotension and cardiogenic shock. Diagnostic workup should be rapid and straight forward. Transthoracic echography is particularly useful to detect right heart thrombi and right ventricular overload. More information could be provided by helical computed tomography or perfusion lung scan or less commonly now by pulmonary angiography, depending on the patient's clinical condition and the available equipment. The mortality rate can reach 20 to 30%, and up to 65% after resuscitated cardiac arrest. Rapid desobstruction is justified through surgical embolectomy or intravenous thrombolysis favouring short duration protocols (alteplase over 2 h), in spite of the bleeding risk. We report a case of renal vein thrombosis (RVT) and pulmonary embolism associated with diffuse membranous glomerulonephritis. A 44-year-old Japanese male was referred to the Nephrology Department with heavy proteinuria. Renal biopsy revealed diffuse membranous glomerulonephritis and we administered PSL 30mg/day and dipyridamole 300mg/day. Three weeks later, he was admitted with severe chest pain, dyspnea and massive proteinuria. RVT and pulmonary embolism were detected on CT scan and perfusion lung scan. After a few days of continuous intravenous unfractionated heparin (UFH) therapy, we used 72 U (anti-FXa)/kg of intravenous low-molecular-weight heparin (LMWH) every 12 hours for 10 days. He also received urokinase at the dose of 120,000 U/day for 4 weeks and long-term therapy with warfarin potassium at the dose of 3 mg/day. One month later, the thrombi in the pulmonary arteries and inferior vena cava disappeared on CT scan and perfusion lung scan. LMWHs have a longer biological half-life and a lower bleeding tendency than UFH for an equivalent antithrombotic effect. This case indicates that intermittent intravenous LMWH administration combined with urokinase is effective against RVT and pulmonary embolism without any side effect. Pulmonary embolism (PE) is a clinical situation difficult to diagnose, at times of great clinical instability, above all when it is massive, which leads to difficulties in the approach and treatment of patients. The treatment has not had any major innovations in recent years, being conventional the use of heparin and more rarely embolectomy. Recently, some clinical trials have defended the use of thrombolytics. The objéctive of this paper is to present our experience, although the series is still small. From April 1996 to November 1997, 11 patients were admitted to our Cardiac Intensive Care Unit with the clinical suspicion of PE, 5 of which with great hemodynamic instability and suspicion of massive PE. The clinical presentation was sudden dyspnea and loss of consciousness in 2 patients, dyspnea and hypotension in 2 patients and shock and respiratory arrest in one case. Gasimetry revealed acute hypoxemia and hypocapnia in all cases, average partial blood pressure in O2 (pO2) of 59 mm Hg and CO2 (pCO2) of 19 mm Hg. ECC and thorax x-ray contributed to the diagnosis in 3 patients, transthoracic echocardiography was decisive for the diagnosis in 5 cases, with visualisation of the thrombus by transesophageal echocardiography in 3 patients. All patients were monitored by Swan-Ganz catheter, the average systolic pulmonary artery pressure (PAP) was 74 mm Hg. Thrombolysis with rTPA (10 mg bolus followed by 90 mg in perfusion in 2 hrs) was administered in 6 episodes in 5 patients. Only in the case of the patient in shock were other complications related to the use of thrombolytics namely high digestive hemorrhage. There was a clear clinical improvement in all cases with great relief of dyspnea reduction of cyanosis and jugular engurgitation. The patient in shock recovered systemic pressures and improved the hemodynamic state. A significant reduction in PAP was observed (average of 32.5 mm Hg). PE recurred in two cases: with one death and therapeutic thrombolytic was repeated in the other patient with good results. After discharge, all patients remained asymptomatic under oral anticoagulation. Despite this small series, the results favour the use of thrombolytics in PE with a clear clinical and hemodynamic improvement. 38-year-old man had chronic deep venous thrombosis (DVT) as a result of multiple injuries caused by an explosion of grenade 12 years ago, with recurrent pulmonary thromboembolisms and pulmonary hypertension which was unrecognized for a decade. Patient was admitted with a progressive dyspnea and exercise intolerance (NYHA II). The diagnosis was established according to clinical symptoms, transthoracic echocardiography, phlebography, lung scintigraphy and pulmonary angiography. Oral anticoagulant therapy was introduced and cava filter indicated to implant. During phlebography a floating thrombus was found in the inferior cava vein underneath renal vein. Implantation was delayed and patient received systemic fibrinolytic therapy with streptokinase (7500 000 UI within 4 days), followed by heparin infusion and warfarin. Post-fibrinolytic phlebography showed clear lumen of inferior vena cava. Fibrinolysis had also affected pulmonary hypertension-systolic pressure in the right ventricle measured by Doppler echocardiography decreased from 90 to 65 mmHg. Permanent intravenous cava filter was implanted. 12 patients (7 male and 5 female) with confirmed pulmonary embolism (PE) with: angiography-5 cases, conventional contrast-enhanced CT-2 cases, echocardiography-2 cases, autopsy-3 cases were diagnosed as clinically acute PE. Criteria of clinically acute PE were: cardiac arrest-1 case-2 cases, shock-1 case, acute cor pulmonale-9 cases and acute cor pulmonale with shock. All patients were treated with heparin, administered with therapeutic prolongation of aPTT. Clinically acute PE (if possible confirmed with angiography, TC and/or echocardiography) was treated with rtPA administered in 10 minutes lasting bolus in doses 0.6-0.8 mg per kg of body weight (50 mg of rtPA during 10 minutes administered into peripheral veins). In 9 patients with pulmonary hypertension, significant decrease of tricuspidal gradient (measured echocardiographically during several hours after administration of rtPA) was documented. Improvement in PaO2, SaO2 and decrease of heart rate and respiratory rate were also achieved. No serious bleeding complications were observed after mentioned treatment. Control investigations (conventional contrast-enhanced CT and spiral CT) performed several days after rtPA administration revealed thrombus in pulmonary artery. We conclude: I rtPA administered in bolus simultaneously with heparin significantly decreased pulmonaryhypertension; rtPA administered simultaneously with heparin is safe method of treatment of PE; hemodynamic improvement after administration of rtPA is not univocal with full fibrynolitic effect. Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease with a poor prognosis, characterized by chronic thromboembolic obstruction of the pulmonary arteries and pulmonary hypertension. Balloon pulmonary angioplasty (BPA) is a newly emergent treatment for CTEPH, which may substitute pulmonary endarterectomy, the standard but more invasive treatment for CTEPH. Here, we report the case of a CTEPH patient who underwent 2 noncardiac surgeries without complications after preoperative intervention of BPA. A 79-year-old man presented with severe osteoarthritis of bilateral knees, with adaptation of total knee arthroplasty (TKA). Transthoracic echocardiogram revealed severe pulmonary hypertension with estimated right ventricular systolic pressure of 140 mm Hg. Pulmonary arteriography revealed total occlusion of the upper branch of the right pulmonary artery, and ventilation/perfusion scan showed multiple mismatched perfusion defects. His pulmonary artery pressure (PAP) was as high as 89/25 (46) mm Hg with normal range of pulmonary capillary wedge pressure. He was diagnosed with CTEPH. Four BPA sessions for 8 branches of the bilateral pulmonary arteries were done, until the mean PAP (mPAP) went under 30 mm Hg. For the TKA, we selected spinal anesthesia in order to minimize intraoperative hemodynamic changes. Cardiac surgeons were standby in case extracorporeal membrane oxygenation (ECMO) initiation was required. With appropriate pain management and use of intravenous vasopressors, intraoperative vital signs were stable. No symptoms of hemodynamic collapse were observed postoperatively. The patient was discharged on the 46th postoperative day following rehabilitation. Two years later, left-side unicompartment knee arthroplasty (UKA) was scheduled. Right heart catheterization study revealed the mPAP was 30 mm Hg, nearly the same value as the last study. The operation was performed under spinal anesthesia with continuous arterial pressure monitoring without need for intraoperative vasopressor. He was discharged without complications on the 24th postoperative day. BPA can be an effective preoperative intervention for CTEPH patients undergoing noncardiac surgery.\nHere is the question:\nCRITICAL CARE AND EMERGENCIES: A 58-year-old man, three weeks after a severe ankle sprain presents, rapidly progressive, with dyspnea at rest, dizziness and syncope. On arrival at the hospital he has hypotension (systolic BP 80 mmHg, diastolic 40 mmHg) and poor perfusion. He is intubated and connected to mechanical ventilation and noradrenaline is started. Echocardiogram shows signs of pulmonary hypertension. Angio-CT shows multiple repletion defects occupying both main pulmonary arteries. Which of the following treatments would be associated with the most rapid hemodynamic improvement in this case?\nHere are the potential choices:\n1. Intravenous perfused sodium heparin.\n2. Thromboendartectomy.\n3. Systemic fibrinolysis with rt-PA (alteplase) 100 mg intravenous.\n4. Inferior vena cava filter.\nThe correct answer is: ",
        "gold_answer": "3 Systemic fibrinolysis with rt-PA (alteplase) 100 mg intravenous.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n To assess the efficacy and safety of mechanical fragmentation combined with intrapulmonary thrombolysis in massive pulmonary thromboembolism (PTE) with hemodynamic impairment. Fifty-nine patients diagnosed with massive PTE with hemodynamic impact were treated. The initial clinical symptoms were shock in 23 patients (38.9%), syncope in eight (13.5%), and dyspnea at rest in 28 (47.4%). Mean O2 saturation was 67.8%. Mean pulmonary artery pressure (PAP) was 42.1 mm Hg. During fragmentation, thrombolysis was administered in the form of a urokinase bolus of 200,000-500,000 U in 57 patients and 20 mg of recombinant tissue plasminogen activator (rt-PA) in two patients. The mean urokinase dose used was 2,500,000 IU, whereas the total dose of rt-PA was 100 mg. Heparin sodium infusion was performed to reach activated partial thromboplastin time ratios of 2. The follow-up consisted of clinical assessment, pulmonary scintigraphy, and echocardiography. The patients received treatment with dicoumarin for 6 months after the procedure. Clinical improvement was seen in 56 patients (94%). Three patients died. The mean PAP after the treatment was 21.8 mm Hg. The mean posttreatment Miller index was 0.35. Technical success was achieved in all cases and clinical symptoms improved in all cases except those in which the patients died. Pulmonary scintigraphy showed improved perfusion in all cases. Echocardiography was performed after 3-6 months, showing a mean pressure of 22.8 mm Hg (corrected values). There were no signs of recurrent PTE or arterial hypertension in the follow-up. The data provided confirm the efficacy and safety of mechanical fragmentation and pharmacologic thrombolysis in the treatment of massive PTE with hemodynamic impairment, showing improvement of symptoms and a decrease in PAP. A 79[correction of seventy]-year-old patient, who has been in bed a long time, suffered an episode of sudden dyspnea, tachycardia and tachypnea. An electrocardiogram registered at her admission in the coronary care unit showed a normal rhythm with right axis deviation and S1Q3T3 pattern and ST segment alterations. A ventilation-perfusion lung scanning demonstrated segmental perfusion defects with high probability of pulmonary embolism. She developed a low cardiac output syndrome, which neither responded to the volume expansion nor to the inotropic drugs. The bed-side hemodynamic measurements were a systolic pulmonary pressure of 60 mmHg, with a diastolic pressure of 18 mmHg and capillary wedge pressure of 13 mmHg with high pulmonary resistance. With this evidences, the diagnoses of massive pulmonary embolism was done, thrombolytic treatment was decided on. Two hundred and fifty thousands international units of streptokinase was administered, and then 100.000 UI/hour in 24 hours; after that with intravenous heparin. The low cardiac output syndrome disappeared. The patients recovered her systemic arterial pressure and her diuresis. The electrocardiographic signs vanished and both the pulmonary pressure and resistance decreased. We discussed the importance of intravenous thrombolytic treatment in massive pulmonary embolism. We concluded than this treatment is an useful strategy that not always needs a pulmonary arteriography, and could be used in low complexity centres, successfully in the massive pulmonary thromboembolism with severe hemodynamic damage. We report the case of a 65 year old woman with no prior cardiac or pulmonary disease, who suffered pulmonary embolism (PE); diagnosis was made on the basis of the existence of risk factors, clinical, radiographic and electrocardiographic features, and a lung scan with perfusion defects and normal ventilation. PE was considered massive because the patient developed acute respiratory failure that required tracheal intubation and mechanical ventilation as well as obstructive shock, electrocardiographic and echocardiographic data of right ventricle overload, and pulmonary hypertension, with pulmonary artery pressure of 38 mmHg. She received an initial treatment with high doses (1,500,000 UI) and rapid infusion (1 hr) of intravenous streptokinase (SK) followed by heparin anticoagulation. Thereafter the hemodynamic disturbances improved and pulmonary artery pressure post-thrombolysis was 23 mmHg. In this report SK at high doses and rapid infusion showed effectiveness and security. We emphasize the usefulness of echocardiography as a diagnostic aid in patients with a previously healthy cardiopulmonary system, as well as the possible role of electrocardiogram as an early indicator of pulmonary reperfusion. This could be the first report of successful thrombolysis with high doses and rapid infusion of SK in massive PE. Several animal studies have shown that regional lung perfusion could be effectively estimated by the hypertonic saline contrast electrical impedance tomography method. Here, we reported an application of this method to dynamically assess regional pulmonary perfusion defect in a patient with acute massive pulmonary embolism. A 68-year-old man experienced sudden dyspnea and cardiac arrest during out-of-bed physical activity on the first day after partial mediastinal tumor resection. Acute pulmonary embolism was suspected due to acute enlargement of right heart and fixed inferior venous cava measured with bedside ultrasound. The computed tomography pulmonary angiography further confirmed large embolism in both left and right main pulmonary arteries and branches. The regional time impedance curves, which were obtained by a bolus of 10 ml 10% NaCl through the central venous catheter, were then analyzed to quantitatively assess regional perfusion. Normal ventilation distribution with massive defects in regional perfusion in both lungs was observed, leading to a ventilation-perfusion mismatch and low oxygenation index (PaO<sub2</sub/FiO2 = 86 mmHg) at the first day of pulmonary embolism. The anticoagulation was performed with heparin, and the patient's condition (such as shock, dyspnea, hypoxemia, etc.), regional lung perfusion defect, and ventilation-perfusion mismatch continuously improved in the following days. In conclusion, this case implies that electrical impedance tomography might have the potential to assess and monitor regional perfusion for rapid diagnosis of fatal pulmonary embolism in clinical practice. Acute pulmonary embolism (APE) as a life-threatening illness may present with a wide range of manifestations. APE was diagnosed using computed tomographic pulmonary angiography (CTPA); however, transthoracic echocardiography (TTE) can reveal hemodynamic status. Early thrombolysis is the most effective therapy for the treatment of massive pulmonary embolism. Herein, we report a case of high-risk APE with a wide range of manifestations, including chest pain, dyspnea, low-blood pressure, and syncope. A 55-year-old, previously healthy woman, complained of dyspnea and pleuritic chest pain for 40 days, along with transitory (10 minutes) episodes of syncope that had occurred 2 days previously. Because of the high-risk APE, the patient received intravenous thrombolytic therapy with low-dose recombinant tissue plasminogen activator (rt-PA, 50 mg over 30 minutes) and an anticoagulant (subcutaneous low-molecular-weight heparin, once every 12 hours for 5 days). Five days after thrombolysis, bedside TTE revealed RV diastolic dimension decreased to 22 mm. Color ultrasonography revealed a significant decrease in systolic and mean pulmonary artery pressure. TTE may provide initial suspicion of APE and may help identify patients with unstable hemodynamic status before the onset of shock. Moreover, concomitant TTE signs of decreased RV load may predict better prognosis for high-risk APE patients. The authors describe a rare case of pulmonary thromboembolism with unusual clinical findings and emphasized the large difficulty encountered in formuling a correct diagnosis in a reasonable time. A man, 60 years old, was admitted to a Medical Division of our hospital for the appearance of chest pain and epigastric pain during effort in the last year. He smoked 20 cigarettes a day and drank wine (1 or 2 litres a day). He was affected by hypercholesterolemia and in the past reported relapsed thrombophlebitis in the left leg. Four years before admission to our hospital he underwent large and small left saphenectomy. He had no cardiac events in the past. After a non significant exercise stress test the patient was treated with nitrates and asa and was discharged from the hospital. At home the symptoms increased and after 8 months the patient was admitted again to the Cardiologic Division of the hospital. At admission he reported dyspnea and chest pain at rest, not only during effort and the ECG showed negative T waves in anterior and inferior leads. Intravenous heparine, nitrates and calcium antagonists stabilized the clinical picture. The following examinations revealed: reduction of the T wave negativity at the ECG registered during chest pain; mild enlargement of the heart at the chest roentgenogram; normal value of the left ventricle and apical and midseptal by ipokinesia at the transthoracic echocardiogram; normal coronary artery at the coronary arteriography. \"Vasospastic angina\" was diagnosed and the patient was discharged after 20 days, asymptomatic. After 15 days he returned to the hospital again for chest pain, dyspnea, hypotension and syncope despite therapy. At physical examination he showed a painful left tibio-tarsal tumefaction, an increased and splitting second heart sound in the pulmonary area and a systolic murmur in the third and fourth left interspace. The ECG showed a severe anterior ischemia, while a new transthoracic echocardiogram revealed a considerable dilatation of the right atrium, right ventricle and the main pulmonary artery with severe tricuspid regurgitation and pulmonary hypertension (mean PAP about 50 mmHg). The following pulmonary perfusion scintigraphy confirmed the diagnosis of pulmonary embolism and the selective right and left pulmonary arteriography exhibited multiple thrombi and large intravascular filling defects. The right heart catheterization confirmed a chronic precapillary pulmonary hypertension (mean PAP = 55 mmHg). About 24 hours after these examinations the patient died because of a cardiac arrest with electromechanical dissociation. Pulmonary thromboembolism is a potentially fatal disease characterized by a largely variable clinical presentation. Frequently pulmonary embolism diagnosis is difficult especially when clinical findings are unusual. In the case observed the \"typical\" chest and epigastric pains associated with the electrocardiographic findings directed diagnosis towards myocardial ischemia. Also after the coronary arteriography that showed normal coronary artery, the erroneous diagnosis persisted. Pulmonary embolism was correctly diagnosed too late to begin an effective therapy. These unusual clinical findings and diagnostic mistakes are stressed and critically reviewed in the article. Pulmonary embolism (PE) refers to the endogenous or exogenous emboli blocking pulmonary trunk or branches, causing clinical and pathophysiological syndrome of pulmonary circulation disorder, the incidence rate is high. Sometimes PE patients were lack of specific symptoms and signs, or without any symptoms, which often result in misdiagnosis, un-timely diagnosis, and the delay of treatment. A PE case with syncope, vomiting and shock, which was proved to be pulmonary artery trunk and branch wide embolism later, was presented so as to improve the understanding of the disease. Management Pulse oximetry can guide the use of supplemental oxygen to maintain oxygen saturation greater than 94%. Hyperoxia should be avoided as may be detrimental in stroke. Hypertension is common in an acute ischemic stroke. A low BP is uncommon and may indicate symptoms exacerbation of a previous stroke due to poor perfusion. Blood pressure of 220/120 mmHg should receive treatment. There is a consensus approach of allowing permissive hypertension up to 220/120 mmHg for patients that are not candidates for thrombolysis.[21] However, for a patient that is a potential candidate for alteplase, attempt to control BP should be made immediately as goal BP for initiation of IV alteplase is 185/110 mmHg. Usually, titratable short-acting intravenous hypotensive agents are recommended to avoid dropping the BP too much once the patient is at goal. Hypotensive agents that can be options include labetalol, nicardipine, clevidipine, hydralazine, enalaprilat.[21] Massive pulmonary thromboembolism has a high mortality. Early thrombolysis is the treatment of choice. We report a 79-year-old man admitted in shock. A chest angio-CAT scan showed a massive pulmonary thromboembolism. A transthoracic echocardiography showed a right cardiac dysfunction. Although the patient was in hemodynamic instability, he was subjected to thrombolysis with streptokinase, assisted with noradrenaline support and invasive mechanical ventilation. Parenteral anticoagulation was started thereafter. A second echocardiography, performed 72 hours later showed an improvement in right ventricular function. The patient had a nosocomial pneumonia that was treated. Noradrenalin and mechanical ventilation were discontinued nine and 15 days after thrombolysis. A new angio-CAT scan, 23 days after the procedure, was normal. The patient was discharged in good conditions 27 days after admission. A 50-year-old man presented with progressive dyspnea on exertion, but with no history of chest pain or syncope. Chronic pulmonary thromboembolism was suspected and he was referred to our hospital. On ausculation, a grade 3 systolic murmur was heard, that was loudest in the fifth intercostal space lateral to the right sternal border. Chest radiography showed mild cardiomegaly and ventilation-perfusion scan revealed absence of perfusion in the left lung and the upper field of the right lung. Contrast-enhanced helical CT showed large mural defects in both main pulmonary arteries, clearly delineated by contrast medium. The left pulmonary artery was nearly completely occluded, and eccentric defects were observed projecting into the lumen of the pulmonary trunk. A tumor originating in the pulmonary artery was suspected, but a definitive diagnosis of the mass could not be made with pulmonary angiography and magnetic resonance imaging. The mean pulmonary arterial pressure was 50 mmHg. Further radiologic examinations failed to reveal the source of the embolus or tumor. It was decided to attempt surgical excision under total cardiopulmonary bypass. At operation, a gelatinous, lustrous, yellowish mass was found partially occluding the right main pulmonary artery and completely occluding the left. The tumor adhered tightly to the intima of the vessel and was inoperable. The patient could not be weaned from percutaneous cardiopulmonary support and died 3 days after surgery. Histologic examination of the excised specimen revealed myxosarcoma. A 54-year-old man was admitted to our hospital complaining of sudden-onset dyspnea in shock. Chest computed tomography(CT) showed thrombi in the right main and left intermediate pulmonary arteries. The case was diagnosed as a massive acute pulmonary thromboembolism. Although his hemodynamic status was stable after catecholamine infusion, his dyspnea was still in progress. Emergency pulmonary embolectomy was performed and the life of patient was saved. It is thought that progressive dyspnea is an important sign of a deteriorating hemodynamic status and the predictive symptom indicating a surgical procedure in patients with massive acute pulmonary thromboembolism. We report a case of a 73-year-old man with pulmonary embolism due to idiopathic thrombosis of the inferior vena cava. He was referred to our hospital because of a fever and cough of 2 weeks' duration despite treatment with an oral antibiotic. Chest radiography on the first visit showed an infiltrate in the right middle lung field. He was diagnosed as having pneumonia and admitted to our hospital for treatment. Following administration of intravenous antibiotics, his symptoms disappeared and the chest radiography findings improved. The abdominal CT obtained in an attempt to visualize the cause of liver dysfunction serendipitously revealed thrombosis of the inferior vena cava, which was suspected to have caused the pulmonary embolism. A subsequent lung perfusion scan revealed marked perfusion defects in the right middle and lower lobes. Chest CT revealed an embolus located in the right pulmonary artery. Since thrombolytic therapy was not effective, the placement of a filter in the inferior vena cava was performed to prevent the recurrence of pulmonary embolism. The patient has been asymptomatic without recurrence of the disease since the filter insertion. Chronic pulmonary embolism is a rare disease which can occur at first with pulmonary hypertension. In these cases it may be difficult to distinguish between primary pulmonary hypertension. We examined nine patients with Chronic Pulmonary Embolism (CPE) (three females and six males, mean age 45 +/- 13 years, range 21-67 years) and ten patients with Primary Pulmonary Hypertension (PPH) (seven females and three males, mean age 35 +/- 13 years, range 10-56 years) who came to our attention during the years 1973-1986 (mean follow up 3 years). All patients had an electrocardiogram, chest x-ray, echocardiogram, cardiac catheterization with pulmonary angiography; seven patients with CPE and eight with PPH had perfusion lung scans. Progressive dyspnoea was the main feature in all the patients; four out of nine with CPE and none of the ones with PPH had a previous history of thrombophlebitis. In all the patients the electrocardiogram, chest x-ray and echocardiogram showed signs of pulmonary hypertension, so that a clear distinction between the two groups was not possible. Cardiac catheterization showed pulmonary pressure values higher in patients with PPH as compared to the ones with CPE (systolic pressure 96 mmHg vs 70 mmHg, diastolic pressure 49 mmHg vs 31 mmHg, mean pressure 65 mmHg vs 45 mmHg). Pulmonary angiography in more than half of the patients with CPE showed a \"cut off\" of two or more lobar branches of the pulmonary arteries. In the patients with PPH pulmonary angiography showed a dilatation of the main pulmonary artery and a diffuse bilateral hypoperfusion. Perfusion lung scan in all the cases of CPE showed zonal perfusion defects, while in all cases of PPH, with the exception of one, it was largely normal. Venograms in the districts of the inferior vena cava demonstrated thrombosis in two out of six patients with CPE. Negative venograms were found in the five patients with PPH who had this investigation performed. One patient with CPE had a surgical embolectomy, the other eight had anticoagulant oral treatment. During the follow-up period three patients with CPE and five with PPH died within five years and within fifteen months respectively, of the diagnosis.(ABSTRACT TRUNCATED AT 400 WORDS) In-hospital mortality is high when pulmonary embolism is complicated by hemodynamic instability and/or pulmonary hypertension. Death occurs frequently within the first hours after admission. This implies specific diagnostic and therapeutic management. Spiral CT seems to be an excellent diagnostic procedure in this setting. However, pulmonary angiography and perfusion lung scan can also be employed. Cardiac echography can help in the diagnosis and therapeutic decision making. Supportive therapy mainly includes correction of hypovolemia if present, a limited volume loading in other cases, and the use of dobutamine. Norepinephrine is the drug of choice when hypotension is present. Thrombolytic agents are indicated in case of hemodynamic instability. Modalities of administration and contra indications are currently well established. Surgical embolectomy should be performed in cases of uncontrolled shock, when thrombolysis is contra-indicated or uneffective. The diagnosis of major pulmonary embolism should be considered in case of acute respiratory distress, particularly when there is high thromboembolic risk. Although clinical symptoms are not specific, some are suggestive: syncope or dizziness with cyanosis and polypnoea, and especially arterial hypotension and cardiogenic shock. Diagnostic workup should be rapid and straight forward. Transthoracic echography is particularly useful to detect right heart thrombi and right ventricular overload. More information could be provided by helical computed tomography or perfusion lung scan or less commonly now by pulmonary angiography, depending on the patient's clinical condition and the available equipment. The mortality rate can reach 20 to 30%, and up to 65% after resuscitated cardiac arrest. Rapid desobstruction is justified through surgical embolectomy or intravenous thrombolysis favouring short duration protocols (alteplase over 2 h), in spite of the bleeding risk. We report a case of renal vein thrombosis (RVT) and pulmonary embolism associated with diffuse membranous glomerulonephritis. A 44-year-old Japanese male was referred to the Nephrology Department with heavy proteinuria. Renal biopsy revealed diffuse membranous glomerulonephritis and we administered PSL 30mg/day and dipyridamole 300mg/day. Three weeks later, he was admitted with severe chest pain, dyspnea and massive proteinuria. RVT and pulmonary embolism were detected on CT scan and perfusion lung scan. After a few days of continuous intravenous unfractionated heparin (UFH) therapy, we used 72 U (anti-FXa)/kg of intravenous low-molecular-weight heparin (LMWH) every 12 hours for 10 days. He also received urokinase at the dose of 120,000 U/day for 4 weeks and long-term therapy with warfarin potassium at the dose of 3 mg/day. One month later, the thrombi in the pulmonary arteries and inferior vena cava disappeared on CT scan and perfusion lung scan. LMWHs have a longer biological half-life and a lower bleeding tendency than UFH for an equivalent antithrombotic effect. This case indicates that intermittent intravenous LMWH administration combined with urokinase is effective against RVT and pulmonary embolism without any side effect. Pulmonary embolism (PE) is a clinical situation difficult to diagnose, at times of great clinical instability, above all when it is massive, which leads to difficulties in the approach and treatment of patients. The treatment has not had any major innovations in recent years, being conventional the use of heparin and more rarely embolectomy. Recently, some clinical trials have defended the use of thrombolytics. The objéctive of this paper is to present our experience, although the series is still small. From April 1996 to November 1997, 11 patients were admitted to our Cardiac Intensive Care Unit with the clinical suspicion of PE, 5 of which with great hemodynamic instability and suspicion of massive PE. The clinical presentation was sudden dyspnea and loss of consciousness in 2 patients, dyspnea and hypotension in 2 patients and shock and respiratory arrest in one case. Gasimetry revealed acute hypoxemia and hypocapnia in all cases, average partial blood pressure in O2 (pO2) of 59 mm Hg and CO2 (pCO2) of 19 mm Hg. ECC and thorax x-ray contributed to the diagnosis in 3 patients, transthoracic echocardiography was decisive for the diagnosis in 5 cases, with visualisation of the thrombus by transesophageal echocardiography in 3 patients. All patients were monitored by Swan-Ganz catheter, the average systolic pulmonary artery pressure (PAP) was 74 mm Hg. Thrombolysis with rTPA (10 mg bolus followed by 90 mg in perfusion in 2 hrs) was administered in 6 episodes in 5 patients. Only in the case of the patient in shock were other complications related to the use of thrombolytics namely high digestive hemorrhage. There was a clear clinical improvement in all cases with great relief of dyspnea reduction of cyanosis and jugular engurgitation. The patient in shock recovered systemic pressures and improved the hemodynamic state. A significant reduction in PAP was observed (average of 32.5 mm Hg). PE recurred in two cases: with one death and therapeutic thrombolytic was repeated in the other patient with good results. After discharge, all patients remained asymptomatic under oral anticoagulation. Despite this small series, the results favour the use of thrombolytics in PE with a clear clinical and hemodynamic improvement. 38-year-old man had chronic deep venous thrombosis (DVT) as a result of multiple injuries caused by an explosion of grenade 12 years ago, with recurrent pulmonary thromboembolisms and pulmonary hypertension which was unrecognized for a decade. Patient was admitted with a progressive dyspnea and exercise intolerance (NYHA II). The diagnosis was established according to clinical symptoms, transthoracic echocardiography, phlebography, lung scintigraphy and pulmonary angiography. Oral anticoagulant therapy was introduced and cava filter indicated to implant. During phlebography a floating thrombus was found in the inferior cava vein underneath renal vein. Implantation was delayed and patient received systemic fibrinolytic therapy with streptokinase (7500 000 UI within 4 days), followed by heparin infusion and warfarin. Post-fibrinolytic phlebography showed clear lumen of inferior vena cava. Fibrinolysis had also affected pulmonary hypertension-systolic pressure in the right ventricle measured by Doppler echocardiography decreased from 90 to 65 mmHg. Permanent intravenous cava filter was implanted. 12 patients (7 male and 5 female) with confirmed pulmonary embolism (PE) with: angiography-5 cases, conventional contrast-enhanced CT-2 cases, echocardiography-2 cases, autopsy-3 cases were diagnosed as clinically acute PE. Criteria of clinically acute PE were: cardiac arrest-1 case-2 cases, shock-1 case, acute cor pulmonale-9 cases and acute cor pulmonale with shock. All patients were treated with heparin, administered with therapeutic prolongation of aPTT. Clinically acute PE (if possible confirmed with angiography, TC and/or echocardiography) was treated with rtPA administered in 10 minutes lasting bolus in doses 0.6-0.8 mg per kg of body weight (50 mg of rtPA during 10 minutes administered into peripheral veins). In 9 patients with pulmonary hypertension, significant decrease of tricuspidal gradient (measured echocardiographically during several hours after administration of rtPA) was documented. Improvement in PaO2, SaO2 and decrease of heart rate and respiratory rate were also achieved. No serious bleeding complications were observed after mentioned treatment. Control investigations (conventional contrast-enhanced CT and spiral CT) performed several days after rtPA administration revealed thrombus in pulmonary artery. We conclude: I rtPA administered in bolus simultaneously with heparin significantly decreased pulmonaryhypertension; rtPA administered simultaneously with heparin is safe method of treatment of PE; hemodynamic improvement after administration of rtPA is not univocal with full fibrynolitic effect. Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease with a poor prognosis, characterized by chronic thromboembolic obstruction of the pulmonary arteries and pulmonary hypertension. Balloon pulmonary angioplasty (BPA) is a newly emergent treatment for CTEPH, which may substitute pulmonary endarterectomy, the standard but more invasive treatment for CTEPH. Here, we report the case of a CTEPH patient who underwent 2 noncardiac surgeries without complications after preoperative intervention of BPA. A 79-year-old man presented with severe osteoarthritis of bilateral knees, with adaptation of total knee arthroplasty (TKA). Transthoracic echocardiogram revealed severe pulmonary hypertension with estimated right ventricular systolic pressure of 140 mm Hg. Pulmonary arteriography revealed total occlusion of the upper branch of the right pulmonary artery, and ventilation/perfusion scan showed multiple mismatched perfusion defects. His pulmonary artery pressure (PAP) was as high as 89/25 (46) mm Hg with normal range of pulmonary capillary wedge pressure. He was diagnosed with CTEPH. Four BPA sessions for 8 branches of the bilateral pulmonary arteries were done, until the mean PAP (mPAP) went under 30 mm Hg. For the TKA, we selected spinal anesthesia in order to minimize intraoperative hemodynamic changes. Cardiac surgeons were standby in case extracorporeal membrane oxygenation (ECMO) initiation was required. With appropriate pain management and use of intravenous vasopressors, intraoperative vital signs were stable. No symptoms of hemodynamic collapse were observed postoperatively. The patient was discharged on the 46th postoperative day following rehabilitation. Two years later, left-side unicompartment knee arthroplasty (UKA) was scheduled. Right heart catheterization study revealed the mPAP was 30 mm Hg, nearly the same value as the last study. The operation was performed under spinal anesthesia with continuous arterial pressure monitoring without need for intraoperative vasopressor. He was discharged without complications on the 24th postoperative day. BPA can be an effective preoperative intervention for CTEPH patients undergoing noncardiac surgery.\nHere is the question:\nCRITICAL CARE AND EMERGENCIES: A 58-year-old man, three weeks after a severe ankle sprain presents, rapidly progressive, with dyspnea at rest, dizziness and syncope. On arrival at the hospital he has hypotension (systolic BP 80 mmHg, diastolic 40 mmHg) and poor perfusion. He is intubated and connected to mechanical ventilation and noradrenaline is started. Echocardiogram shows signs of pulmonary hypertension. Angio-CT shows multiple repletion defects occupying both main pulmonary arteries. Which of the following treatments would be associated with the most rapid hemodynamic improvement in this case?\nHere are the potential choices:\n1. Intravenous perfused sodium heparin.\n2. Thromboendartectomy.\n3. Systemic fibrinolysis with rt-PA (alteplase) 100 mg intravenous.\n4. Inferior vena cava filter.\nThe correct answer is: 3. Systemic fibrinolysis with rt-PA (alteplase) 100 mg intravenous."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A variety of tests may be performed in people presenting with cough and shortness of breath: A chest X-ray is useful to exclude pneumonia which is more common in those with a fever, fast heart rate, fast respiratory rate, or who are old. A sputum sample showing neutrophil granulocytes (inflammatory white blood cells) and culture showing that has pathogenic microorganisms such as Streptococcus species. A blood test would indicate inflammation (as indicated by a raised white blood cell count and elevated C-reactive protein). Decreased breath sounds, crackles, wheezing, and rhonchi that clears with coughs may be heard in the chest. Dullness to percussion and pleural rub suggest disease extension beyond the bronchi such as seen with pneumonia. Paroxysms of cough followed by inspiratory whoop and vomiting suggests pertussis. Pneumonia is a common illness in all parts of the world and is considered as a major cause of death among all age groups. Nevertheless, only about 5% of patients referring to their primary care physicians with acute respiratory symptoms will develop pneumonia. This study was performed to derive practical criteria for performing chest radiographs for the evaluation of community-acquired pneumonia (CAP). A total of 420 patients with acute respiratory symptoms and positive findings on chest radiograph were evaluated from December 2008 to December 2009. The subjects were referred to outpatient clinics or emergency departments of Birjand's medical university hospitals, Iran, and were enrolled as positive cases. A checklist was completed for each patient including their demographic information, clinical signs and symptoms (cough, sputum production, dyspnea, chest pain, fever, tachycardia, and tachypnea), abnormal findings in pulmonary auscultation and laboratory findings (erythrocyte sedimentation rate, C-reactive protein levels, and white blood cell count). An equal number of age-matched individuals with acute respiratory symptoms, but insignificant findings on chest radiography, were included as the control group. Finally, the diagnostic values of different findings were compared. The data showed that vital signs and physical examination findings are useful screening parameters for predicting chest radiograph findings in outpatient settings. Therefore, by implementing a prediction rule, we would be able to determine which patients would benefit from a chest X-Ray (sensitivity, 94% and specificity, 57%). This study's findings suggest that requesting chest radiographs might not be necessary in patients with acute respiratory symptoms unless the vital signs and/or physical examination findings are abnormal. Considering the 94% sensitivity of this rule for predicting CAP, a chest radiograph is required for patients with unreliable follow-ups or moderate to high likelihood of morbidity if CAP is not initially detected. The pulmonary examination or respiratory examination is the portion of the physical examination where the physician examines the respiratory system for signs of disease. It is performed as a part of a complete physical examination, or the physician may choose to perform a focused respiratory exam. Classically, it is performed after the HEENT examination, and consists of four stages: inspection, palpation, percussion, and auscultation. If there are signs of respiratory disease, the physician may order additional tests including medical imaging, such as a chest X-ray or CT scan, or laboratory tests, such as a complete blood count. The information gathered from the physical examination, along with the medical history, is synthesized in order to produce a differential diagnosis and treatment plan. References Medical treatments medical test is a medical procedure performed to detect, diagnose, or monitor diseases, disease processes, susceptibility, or to determine a course of treatment. The tests are classified by speciality field allowing to know in which ward of hospital or by which specialist doctor are usually these tests performed. This list is not exhaustive but might be useful as a guide. Where available, ICD-10 codes are listed. Consulting Room Tests These tests are usually performed in a consulting room by any doctor and require no advanced equipment. general Temperature measurement, with a thermometer Patient's Respiratory rate measurement Blood oxygen concentration measurement taking the patient's pulse weighing, and measuring height and girth measuring blood pressure specific: abdominal palpation cardiac ausculation HEENT examination digital rectal examination neurological examination psychiatric assessment pulmonary auscultation vaginal examination Hospitalization Some CAP patients require intensive care, with clinical prediction rules such as the pneumonia severity index and CURB-65 guiding the decision whether or not to hospitalize. Factors increasing the need for hospitalization include: Age greater than 65 Underlying chronic illnesses Respiratory rate greater than 30 per minute Systolic blood pressure less than 90 mmHg Heart rate greater than 125 per minute Temperature below 35 or over 40 °C Confusion Evidence of infection outside the lung Laboratory results indicating hospitalization include: Arterial oxygen tension less than 60 mm Hg Carbon dioxide over 50 mmHg or pH under 7.35 while breathing room air Hematocrit under 30 percent Creatinine over 1.2 mg/dl or blood urea nitrogen over 20 mg/dl White-blood-cell count under 4 × 10^9/L or over 30 × 10^9/L Neutrophil count under 1 x 10^9/L Diagnosis The diagnosis of acute chest syndrome is made difficult by its similarity in presentation with pneumonia. Both may present with a new opacification of the lung on chest x-ray. The presence of fevers, low oxygen levels in the blood, increased respiratory rate, chest pain, and cough are also common in acute chest syndrome. Diagnostic workup includes chest x-ray, complete cell count, reticulocyte count, ECG, and blood and sputum cultures. Patients may also require additional blood tests or imaging (e.g. a CT scan) to exclude a heart attack or other pulmonary pathology. Prevention Hydroxyurea is a medication that can help to prevent acute chest syndrome. It may cause a low white blood cell count, which can predispose the person to some types of infection. Treatment Broad spectrum antibiotics to cover common infections such as Streptococcus pneumoniae and mycoplasma, pain control, and blood transfusion. Acute chest syndrome is an indication for exchange transfusion. A case of miliary tuberculosis associated with acute respiratory failure during pregnancy was reported. A 39-year-old, 29-week pregnant woman was admitted to our hospital with complaints of nonproductive cough and fever on June 12. On admission, her temperature was 38.2 degrees C; pulse rate was 90/min., and blood pressure was 120/76 mmHg. Physical examination revealed moist rales at right lung basis. Chest X-ray showed small nodular infiltrates in right lower lung field. Laboratory data revealed positive CRP, accelerated ESR and increased level of alpha 2-globulin. The number of T-cells was markedly decreased (14/mm3). The PPD skin test was negative, and the sputum smears for acid-fast bacilli were negative. Suspected of bacterial or viral pneumonia, the patient was treated with antibiotics (CPM, EM and CAZ), which had no effects for her. On June 16, the Chest X-ray showed infiltrates throughout bilateral lung fields, and the patient became increasingly dyspneic. On June 18, the results of arterial blood gas, analysis under room air were: PaO2 26.7 Torr, PaCO2 29.0 Torr, pH 7.505. Because of severe hypoxemia, she was intubated and placed on a volume-cycled respirator. Hydrocortisone (1000 mg, daily) was added to treatment because ARDS was suspected. Since the smears of tracheobronchial secretions showed acid-fast bacilli on June 24, she was diagnosed to have miliary tuberculosis. Then the intensive therapy with antituberculosis drugs (isoniazid 400 mg, rifampicin 450 mg, and streptomycin 1g, daily) was started. The non specific antibiotics were discontinued; hydrocortisone was tapered and stopped. The next week, she became afebrile and hypoxemia steadily improved.(ABSTRACT TRUNCATED AT 250 WORDS) Physical exam Physical examination may sometimes reveal low blood pressure, high heart rate, or low oxygen saturation. The respiratory rate may be faster than normal, and this may occur a day or two before other signs. Examination of the chest may be normal, but it may show decreased expansion on the affected side. Harsh breath sounds from the larger airways that are transmitted through the inflamed lung are termed bronchial breathing and are heard on auscultation with a stethoscope. Crackles (rales) may be heard over the affected area during inspiration. Percussion may be dulled over the affected lung, and increased, rather than decreased, vocal resonance distinguishes pneumonia from a pleural effusion. Imaging A 24-year-old White man presented with 1-day complaints of progressive shortness of breath and fever. He recently underwent an open reduction and internal fixation of a left midshaft femur fracture from a skiing accident 4 days ago. He denied chest pain, skin rashes, hemoptysis, hematemesis, melena, or surgical site bleeding. On arrival, the patient appeared in mild respiratory distress with a respiratory rate of 23 breaths/min, temperature of 37.8°C, heart rate of 97 beats/min, BP of 95/54 mm Hg, and peripheral saturation of 97% on 6-L/min nasal canula. His initial peripheral saturation on room air was 67%. Physical examination was unremarkable, except for diffuse rhonchi on chest auscultation. Chest radiograph on admission showed alveolar opacities predominantly in bilateral lower lobes. A chest CT angiography revealed no evidence for pulmonary embolism. However, there were findings of diffuse bilateral ground-glass opacities with areas of patchy consolidation and innumerous micronodules in both lungs (Fig 1). Laboratory examination was significant for a drop of hemoglobin by 3 g/dL and hematocrit level by 7% since his hospital discharge 4 days earlier. His renal function and urine analysis were normal. Venous blood gas on admission showed pH of 7.39 and Pco<sub2</sub of 43 mm Hg. Because of unexplained acute anemia, nonspecific CT chest findings and progressive dyspnea, a bronchoscopy with BAL was performed. Four aliquots of 60 mL saline solution were injected for lavage with fluid return (Fig 2). BAL fluid showed WBC count of 0.411 × 10<sup3</sup/mm<sup3</sup, RBC count of 318 × 10<sup3</sup/mm<sup3</sup, 100% fresh RBCs, 73% neutrophil, 24% lymphocytes, 1% monocytes, and 2% eosinophils. BAL fluid cytologic condition is shown in Figure 3. A full vasculitis workup by rheumatology was unremarkable. Ophthalmologic and skin examination were unrevealing. In daily routine, physicians use history, physical examination and technology-based information such as laboratory tests and imaging studies to diagnose the patients' disease. We determined the diagnostic value of lung auscultation in patients admitted to the Medical emergency room with chest symptoms. Two-hundred-and forty-three consecutive patients (137 males), mean age 59.2 years were included. Internal Medicine registrars had to make a presumptive diagnosis, 1) after having taken the history and 2) after having auscultated the lungs. Thereafter, routine diagnostic procedures were performed. The estimated diagnosis was compared with the final diagnosis based on the written report to the Family Practitioner. Two-hundred-eighty-seven diagnoses were made. Eighteen percent of patients suffered from left heart failure, 13% from unexplained chest pain, 10.5% from chest wall pain, and 10.5% from pneumonia. Forty-one percent of the diagnoses were already correct when based only on the patient's history. Lung auscultation improved the diagnostic yield only in 1% and worsened it in another 3%. By multiple logistic regression, normal lung auscultation (OR 0.12 [95CI% 0.053-0.29]) was the independent predictor for not having a lung or heart disease. However, elevation of B-type natiuretic peptide (BNP) (OR 1.16 per 100 pg/ml (95CI% 1.004-1.35), wheezing (OR 0.023 [0.002-0.33]) and pCO2 (OR 0.25 (0.10-0.621) were independent predictors for having a heart disease, whereas wheezing (OR 7.41 [3.26-16.83]) and CRP (OR 1.008 per 10 units [1.003-1.014]) were risk factors for having a lung disease. In contrast to history taking, abnormal lung auscultation does not appear to contribute considerably to the final diagnosis in patients presenting with chest symptoms in an emergency room setting. However, normal lung auscultation is a valuable predictor for not having a lung or heart disease, whereas wheezing is a predictor for having a lung disease and not having a heart disease. Physical examination The general appearance of patients may vary according to the experienced symptoms; the patient may be comfortable, or restless and in severe distress with an increased respiratory rate. A cool and pale skin is common and points to vasoconstriction. Some patients have low-grade fever (38–39 °C). Blood pressure may be elevated or decreased, and the pulse can become irregular. If heart failure ensues, elevated jugular venous pressure and hepatojugular reflux, or swelling of the legs due to peripheral edema may be found on inspection. Rarely, a cardiac bulge with a pace different from the pulse rhythm can be felt on precordial examination. Various abnormalities can be found on auscultation, such as a third and fourth heart sound, systolic murmurs, paradoxical splitting of the second heart sound, a pericardial friction rub and rales over the lung. Electrocardiogram A 52-year-old man presented with unproductive cough, fever and chill in our emergency department. Self-medication with amoxicillin over 3 days failed to improve his condition. The patient was in poor general condition. His body temperature was 38.4 C, with a heart rate of 124/min, a blood pressure of 120/70 mmHg and a positive shock index. At auscultation of the chest fine rales were heard over both lungs with diminished percussion sounds basal. The respiratory rate was 30/min and the oxygen saturation of 84% at room air. Laboratory: signs of inflammation; blood gas analysis: pronounced hypoxemia. A chest radiogram revealed signs of extensive pulmonary infiltrates on both sides. The patient was admitted to our Intensive Care Unit. He received piperacillin, sulbactam and levoflaxacin, ample fluid and non-invasive ventilation as well as intermittent catecholamine treatment. As there was no clinical improvement the patient was intubated on day 3. On bronchoscopy viral etiology was suspected. At this time the respiratory situation deteriorated. Acute respiratory distress syndrome (ARDS) was diagnosed. An antifungal and antiviral treatment (voriconazol, oseltamivir) was started and a cortisone pulse was attempted. The patient was transferred to another clinic where extracorporeal membranoxygenation (ECMO) was performed on the same day. The following day influenza A/H1N1-test was confirmed. Ten days after transfer, the patient regained spontaneous respiration, and he most likely survives the infection. The incidence of influenza (A/H1N1) has increased in Germany and severe and lethal courses have occurred. Therefore, the diagnostic and treatment algorithms need to be reconsidered in order to rapidly diagnose and treat infections. To study the influence of the spectrum of patients on the usefulness of five clinical cues, \"very annoying dyspnoea\", \"strong lateral chest pain\", crackles, C-reactive protein analysis, and erythrocyte sedimentation rate in the diagnosis of pneumonia. Evaluating the diagnostic properties of the cues against radiographic pneumonia at four steps in the diagnostic process, associated with increasing prevalence of pneumonia: 1. in all the 581 patients included, 2. in 402 of these patients who underwent physical chest examination, 3. in 188 patients classified by the doctors as having a lower respiratory tract infection, and 4. in 79 patients referred for radiography by the doctors. The municipal emergency clinic in Tromsø, Norway. 581 adult patients with respiratory tract infection. Sensitivity, specificity, Likelihood Ratio, and Positive predictive value. A tendency of decreasing specificity and Likelihood Ratio with increasing prevalence of pneumonia was demonstrated for all test, except for C-reactive protein analysis. This tendency may be explained either by the emphasis laid on the tests by the doctors when selecting patients for the diagnostic steps, or by an association between the evaluated tests and those emphasized by the doctors. As the diagnostic value of symptoms and signs are strongly influenced by selection, caution should be shown when transferring diagnostic values from one clinical setting to another. According to the 2012 Berlin definition, adult ARDS is characterized by the following: lung injury of acute onset, within 1 week of an apparent clinical insult and with the progression of respiratory symptoms bilateral opacities on chest imaging (chest radiograph or CT) not explained by other lung pathology (e.g. effusion, lobar/lung collapse, or nodules) respiratory failure not explained by heart failure or volume overload decreased Pa/Fi ratio (a decreased Pa/Fi ratio indicates reduced arterial oxygenation from the available inhaled gas): mild ARDS: 201 – 300 mmHg (≤ 39.9 kPa) moderate ARDS: 101 – 200 mmHg (≤ 26.6 kPa) severe ARDS: ≤ 100 mmHg (≤ 13.3 kPa) Note that the Berlin definition requires a minimum positive end expiratory pressure (PEEP) of 5 cm for consideration of the Pa/Fi ratio. This degree of PEEP may be delivered noninvasively with CPAP to diagnose mild ARDS. Spirometry plays the major role in pulmonary diagnostics in the family practice, but is still used much too rarely on patients with respiratory symptoms. Every patient with shortness of breath or a chronic, persistent cough should have spirometry performed. Needless to say, taking a selective medical history and auscultation of the lungs and heart are additional, important pillars for making a diagnosis. Measurement of the peak expiratory flow (PEF) can be especially helpful in emergencies. Pulse oxymetry also aids in the assessment of acute situations and additionally, can provide valuable information in the follow-up treatment of chronic respiratory diseases. A 25-year-old young male patient presented in casualty department with severe respiratory distress on the fourth day from onset of symptoms. The patient was nonsmoker and had no antecedent medical or drug history. Prior to admission, patient had dry cough and bilateral pleuritic chest pain for the last three days. He was in severe respiratory distress with use of accessory muscles of respiration. On examination, he had heart rate of 120 beats/min, blood pressure (BP) of 150/80, respiratory rate of 48-52/min and central cyanosis present. On systemic examination, reduced intensity of breath sounds with extensive rhonchi and crepitation was found in both lung fields, with other examination being within normal limits. On pulse oximetry, oxygen saturation was 28% on room air, which increased up to 36% with the help of 4 L oxygen via nasal prongs. PaO2/FiO2 ratio was 100. Chest X-ray analysis was suggestive of non-cardiac pulmonary edema in view of bilateral fluffy opacity without cardiomegaly. In view of 2/3 positive criteria, his provisional diagnosis was Acute Respiratory Distress Syndrome (ARDS). He required mechanical ventilatory support and was gradually weaned over a period of 10 days. The patient was treated with broad spectrum antibiotics and other supportive measures. On re-evaluation of history, we found that he was a goldsmith by occupation, smelting silver and gold for the past 8-10 years. On the day of onset of symptoms, while smelting silver he was exposed to golden yellow fumes for around 15 minutes, with the quantum of exposure more than any other day earlier. From previous experience and analysis of similar silver metals, he was able to tell us that the silver was adulterated with large amount of cadmium on that day than before. Serum level of cadmium was 2.9 μg/L 6 days after initial exposure. At the time of discharge, he had residual opacities in the chest radiograph and resting oxygen saturation was 94% on room air.  The auscultation of the lungs is - among anamnesis - the most important part in the assessment of patients presenting with pulmonary symptoms. The lung auscultation is reproducible, cost efficient and very helpful to distinguish between differential diagnoses, in particular in emergency situations. Detection and description of lung sounds requires experience and should be performed by strict adherence to the internationally accepted terminology.  Venous or pulmonary air embolism occurs when air enters the systemic veins and is transported to the right side of the heart and from there into the pulmonary arteries, where it may lodge, blocking or reducing blood flow. Gas in the venous circulation can cause cardiac problems by obstructing the pulmonary circulation or forming an air-lock which raises central venous pressure and reduces pulmonary and systemic arterial pressures. Experiments on animals show that the amount of gas necessary for this to happen is quite variable. Human case reports suggest that injecting more than 100 mL of air into the venous system at rates greater than 100 mL/s can be fatal. Very large and symptomatic amounts of venous air emboli may also occur in rapid decompression in severe diving or decompression accidents, where they may interfere with circulation in the lungs and result in respiratory distress and hypoxia. The World Health Organization's global programme for the control of acute respiratory infections relies on counting respiratory rate (RR) by observing abdominal and chest movements in order to diagnose pneumonia. However, few studies on the reliability of the observation method have been published. We counted RR simultaneously by observation and auscultation in 100 healthy infants at 1, 2, 4, 6 and 8 weeks of age for 15, 30 and 60 sec, and compared RRs obtained by the two methods. In all the age groups studied, the co-efficients of variation for the RRs recorded by observation or auscultation were similar. The mean RR by observation was higher by 1-3 breaths/min than mean RR by auscultation (p &lt; 0.001). The 95% confidence interval (+/-2 SD) for the difference between RR by the two methods ranged from +5 to -8 breaths/min for RR counted for 1 full minute. Our data support the assumption that observation is as reliable as auscultation for counting RR. \"Dabbing\", a relatively new form of THC use which utilizes Butane Hash Oil (BHO), an extraction of dried cannabis containing high levels of butane and terpene byproducts. The extraction process yields a waxy substance that is heated, vaporized and inhaled. We describe a lung injury as a result of BHO use. A previously healthy 18-year-old female presented to the ED with shortness of breath for 3-4 days. Initial oxygen saturation was 79% on room air. She was refractory to bronchodilators, steroids and supplemental O<sub2</sub. She has a 1-pack year smoking history and daily BHO abuse. Chest x-ray was positive for bilateral patchy infiltrates with mild hyperinflation. CT was negative for Pulmonary Embolus or other acute pathologic process. Sputum gram stain and blood cultures were negative. Arterial blood gases confirmed a pO2 of 73 mmHg. On physical exam she was tachycardic and tachypneic. Respiratory auscultation showed decreased air entry bilaterally with diffuse expiratory wheezing, bilateral rhonchi and a prolonged expiratory phase. We concluded her severe pneumonitis was secondary to daily BHO inhalation. Heating BHO to high temperatures, releases up to 75% of THC, compared to 5-20% THC in traditional smoked cannabis. At 978°F terpenes degrade into methacrolein and benzene. Methacrolein is structurally similar to acrolein, a pulmonary irritant, which causes acute lung injury and pulmonary edema in laboratory animals. We hypothesize a mechanism of lung injury and acute respiratory failure secondary to inhalation of high levels of methacrolein and benzene related to relatively novel phenomena of BHO use. Lung auscultation is an essential part of the physical examination for diagnosing respiratory diseases. The terminology standardization for lung sounds, in addition to advances in their analysis through new technologies, have improved the use of this technique. However, traditional auscultation has been questioned due to the limited concordance among health professionals. Despite the revolu tionary use of new diagnostic tools of imaging and lung function tests allowing diagnostic accuracy in respiratory diseases, no technology can replace lung auscultation to guide the diagnostic process. Lung auscultation allows identifying those patients who may benefit from a specific test. Moreover, this technique can be performed many times to make clinical decisions, and often with no need for- complicated and sometimes unavailable tests. This review describes the current state-of-the-art of lung auscultation and its efficacy based on the current respiratory sound terminology. In addition, it describes the main evidence on respiratory sound concordance studies among health professionals and its objective analysis through new technology. Other tests of auscultation The Surviving Sepsis Campaign has recommended 30 ml/kg of fluid to be given in adults in the first three hours followed by fluid titration according to blood pressure, urine output, respiratory rate, and oxygen saturation with a target mean arterial pressure (MAP) of 65 mmHg. In children an initial amount of 20 ml/kg is reasonable in shock. In cases of severe sepsis and septic shock where a central venous catheter is used to measure blood pressures dynamically, fluids should be administered until the central venous pressure reaches 8–12 mmHg. Once these goals are met, the central venous oxygen saturation (ScvO2), i.e., the oxygen saturation of venous blood as it returns to the heart as measured at the vena cava, is optimized. If the ScvO2 is less than 70%, blood may be given to reach a hemoglobin of 10 g/dL and then inotropes are added until the ScvO2 is optimized. In those with acute respiratory distress syndrome (ARDS) and sufficient tissue blood fluid, more fluids should be given Auscultation of the lungs has been a central element in clinical examination since the early part of the nineteenth century. However, the role of the stethoscope in our diagnostic work-up has more and more been challenged by newer diagnostic equipment. Research carried out over the last 30 years has given us new knowledge about the physical basis of lung sounds and the meaning of the sounds. Electronic stethoscopes and computer-based analysis of digital lung sounds are now available. Lungs auscultation findings should be interpreted with caution and be related to the case history and other clinical findings. Because of lower respiratory infection that was treated with antibiotics on the suspicion of pneumonia, 71 patients aged 15 years or more were referred to the study by general practitioners. Using a positive chest X-ray as a \"gold standard\", 15% had pneumonia. The diagnostic value of variables from history, physical examination and blood tests was evaluated by calculating the likelihood ratio (LR). A duration of illness less than 24 hours before consulting the general practitioner was the variable from the history with the highest LR, 13.5. The white blood cell count and particularly the C-reactive protein analysis had a high diagnostic value, CRP greater than 50 mg/l had an LR of 37. In this selected material pulmonary symptoms and lung findings were of minor value in differentiating patients with and without pneumonia, with no LR exceeding 2.3. This can be explained to some extent by selection bias. Lung cancers may extend along or grow through the pulmonary veins to invade or lie within the left atrium (LA). A 62-year-old man, previously healthy, presented with 1-month ventilatory-independent right hemithorax back pain, dry cough and large effort dyspnea. He also referred weight loss of 12 kg in 10 months and denied hemoptysis. As antecedents, he smoked for 40 years and moderate daily alcoholism. On physical examination, the patient was in good general condition, hydrated and regular respiration at rest [blood pressure (BP) =120/80 mmHg; heart rate (HR) =90 bpm; respiratory rate (RR) =16 rpm]. Cardiac auscultation revealed two standard rhythmic sounds without murmurs. Pulmonary auscultation revealed a slightly diminished vesicular murmur in the lower 1/3 of the right hemithorax without adventitious noises. Chest radiography showed a mass over the right lower lung. A CT scan confirmed the radiography image with the mass extending along the right inferior pulmonary vein and a tumor in the LA. Transthoracic and transesophageal echocardiography revealed large mass within the LA (occupying almost the entire cavity), measuring about 10 cm × 3 cm at its largest diameter, prolapsing into the left ventricle. Bronchoscopy, head CT scan, and whole-body bone scintigraphy investigation did not show any distant metastasis. The patient was successfully operated removing the intracardiac and inferior pulmonary vein tumor with the aid of cardiopulmonary bypass, followed by a right inferior lobectomy carried out after 25 days. After 30 days from surgery presented seizures associated a brain metastasis evidenced by CT when adjuvant radio and chemotherapy was started. During the next 90 days, the clinical conditions worsened, and the patient died 4 months after the surgical treatment. The case report has two primary justifications, even considering the poor outcome: (I) rarity and (II) the possibility of the surgical treatment.\nHere is the question:\nPEDIATRICS: 6-month-old infant presenting to the emergency department for respiratory distress. Examination: axillary temperature 37.2°C, respiratory rate 40 rpm, heart rate 160 bpm, blood pressure 90/45 mmHg, SatO2 95% on room air. He shows moderate respiratory distress with intercostal and subcostal retraction. Pulmonary auscultation: scattered expiratory rhonchi, elongated expiration and slight decrease in air entry in both lung fields. Cardiac auscultation: no murmurs. It is decided to keep the patient under observation in the hospital for a few hours. What do you consider the most appropriate attitude at this time with regard to the complementary tests?\nHere are the potential choices:\n1. Request venous blood gas, leukocyte count and acute phase reactants.\n2. Request chest X-ray.\n3. Request arterial blood gases and acute phase reactants.\n4. Do not request complementary tests.\nThe correct answer is: ",
        "gold_answer": "4 Do not request complementary tests.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A variety of tests may be performed in people presenting with cough and shortness of breath: A chest X-ray is useful to exclude pneumonia which is more common in those with a fever, fast heart rate, fast respiratory rate, or who are old. A sputum sample showing neutrophil granulocytes (inflammatory white blood cells) and culture showing that has pathogenic microorganisms such as Streptococcus species. A blood test would indicate inflammation (as indicated by a raised white blood cell count and elevated C-reactive protein). Decreased breath sounds, crackles, wheezing, and rhonchi that clears with coughs may be heard in the chest. Dullness to percussion and pleural rub suggest disease extension beyond the bronchi such as seen with pneumonia. Paroxysms of cough followed by inspiratory whoop and vomiting suggests pertussis. Pneumonia is a common illness in all parts of the world and is considered as a major cause of death among all age groups. Nevertheless, only about 5% of patients referring to their primary care physicians with acute respiratory symptoms will develop pneumonia. This study was performed to derive practical criteria for performing chest radiographs for the evaluation of community-acquired pneumonia (CAP). A total of 420 patients with acute respiratory symptoms and positive findings on chest radiograph were evaluated from December 2008 to December 2009. The subjects were referred to outpatient clinics or emergency departments of Birjand's medical university hospitals, Iran, and were enrolled as positive cases. A checklist was completed for each patient including their demographic information, clinical signs and symptoms (cough, sputum production, dyspnea, chest pain, fever, tachycardia, and tachypnea), abnormal findings in pulmonary auscultation and laboratory findings (erythrocyte sedimentation rate, C-reactive protein levels, and white blood cell count). An equal number of age-matched individuals with acute respiratory symptoms, but insignificant findings on chest radiography, were included as the control group. Finally, the diagnostic values of different findings were compared. The data showed that vital signs and physical examination findings are useful screening parameters for predicting chest radiograph findings in outpatient settings. Therefore, by implementing a prediction rule, we would be able to determine which patients would benefit from a chest X-Ray (sensitivity, 94% and specificity, 57%). This study's findings suggest that requesting chest radiographs might not be necessary in patients with acute respiratory symptoms unless the vital signs and/or physical examination findings are abnormal. Considering the 94% sensitivity of this rule for predicting CAP, a chest radiograph is required for patients with unreliable follow-ups or moderate to high likelihood of morbidity if CAP is not initially detected. The pulmonary examination or respiratory examination is the portion of the physical examination where the physician examines the respiratory system for signs of disease. It is performed as a part of a complete physical examination, or the physician may choose to perform a focused respiratory exam. Classically, it is performed after the HEENT examination, and consists of four stages: inspection, palpation, percussion, and auscultation. If there are signs of respiratory disease, the physician may order additional tests including medical imaging, such as a chest X-ray or CT scan, or laboratory tests, such as a complete blood count. The information gathered from the physical examination, along with the medical history, is synthesized in order to produce a differential diagnosis and treatment plan. References Medical treatments medical test is a medical procedure performed to detect, diagnose, or monitor diseases, disease processes, susceptibility, or to determine a course of treatment. The tests are classified by speciality field allowing to know in which ward of hospital or by which specialist doctor are usually these tests performed. This list is not exhaustive but might be useful as a guide. Where available, ICD-10 codes are listed. Consulting Room Tests These tests are usually performed in a consulting room by any doctor and require no advanced equipment. general Temperature measurement, with a thermometer Patient's Respiratory rate measurement Blood oxygen concentration measurement taking the patient's pulse weighing, and measuring height and girth measuring blood pressure specific: abdominal palpation cardiac ausculation HEENT examination digital rectal examination neurological examination psychiatric assessment pulmonary auscultation vaginal examination Hospitalization Some CAP patients require intensive care, with clinical prediction rules such as the pneumonia severity index and CURB-65 guiding the decision whether or not to hospitalize. Factors increasing the need for hospitalization include: Age greater than 65 Underlying chronic illnesses Respiratory rate greater than 30 per minute Systolic blood pressure less than 90 mmHg Heart rate greater than 125 per minute Temperature below 35 or over 40 °C Confusion Evidence of infection outside the lung Laboratory results indicating hospitalization include: Arterial oxygen tension less than 60 mm Hg Carbon dioxide over 50 mmHg or pH under 7.35 while breathing room air Hematocrit under 30 percent Creatinine over 1.2 mg/dl or blood urea nitrogen over 20 mg/dl White-blood-cell count under 4 × 10^9/L or over 30 × 10^9/L Neutrophil count under 1 x 10^9/L Diagnosis The diagnosis of acute chest syndrome is made difficult by its similarity in presentation with pneumonia. Both may present with a new opacification of the lung on chest x-ray. The presence of fevers, low oxygen levels in the blood, increased respiratory rate, chest pain, and cough are also common in acute chest syndrome. Diagnostic workup includes chest x-ray, complete cell count, reticulocyte count, ECG, and blood and sputum cultures. Patients may also require additional blood tests or imaging (e.g. a CT scan) to exclude a heart attack or other pulmonary pathology. Prevention Hydroxyurea is a medication that can help to prevent acute chest syndrome. It may cause a low white blood cell count, which can predispose the person to some types of infection. Treatment Broad spectrum antibiotics to cover common infections such as Streptococcus pneumoniae and mycoplasma, pain control, and blood transfusion. Acute chest syndrome is an indication for exchange transfusion. A case of miliary tuberculosis associated with acute respiratory failure during pregnancy was reported. A 39-year-old, 29-week pregnant woman was admitted to our hospital with complaints of nonproductive cough and fever on June 12. On admission, her temperature was 38.2 degrees C; pulse rate was 90/min., and blood pressure was 120/76 mmHg. Physical examination revealed moist rales at right lung basis. Chest X-ray showed small nodular infiltrates in right lower lung field. Laboratory data revealed positive CRP, accelerated ESR and increased level of alpha 2-globulin. The number of T-cells was markedly decreased (14/mm3). The PPD skin test was negative, and the sputum smears for acid-fast bacilli were negative. Suspected of bacterial or viral pneumonia, the patient was treated with antibiotics (CPM, EM and CAZ), which had no effects for her. On June 16, the Chest X-ray showed infiltrates throughout bilateral lung fields, and the patient became increasingly dyspneic. On June 18, the results of arterial blood gas, analysis under room air were: PaO2 26.7 Torr, PaCO2 29.0 Torr, pH 7.505. Because of severe hypoxemia, she was intubated and placed on a volume-cycled respirator. Hydrocortisone (1000 mg, daily) was added to treatment because ARDS was suspected. Since the smears of tracheobronchial secretions showed acid-fast bacilli on June 24, she was diagnosed to have miliary tuberculosis. Then the intensive therapy with antituberculosis drugs (isoniazid 400 mg, rifampicin 450 mg, and streptomycin 1g, daily) was started. The non specific antibiotics were discontinued; hydrocortisone was tapered and stopped. The next week, she became afebrile and hypoxemia steadily improved.(ABSTRACT TRUNCATED AT 250 WORDS) Physical exam Physical examination may sometimes reveal low blood pressure, high heart rate, or low oxygen saturation. The respiratory rate may be faster than normal, and this may occur a day or two before other signs. Examination of the chest may be normal, but it may show decreased expansion on the affected side. Harsh breath sounds from the larger airways that are transmitted through the inflamed lung are termed bronchial breathing and are heard on auscultation with a stethoscope. Crackles (rales) may be heard over the affected area during inspiration. Percussion may be dulled over the affected lung, and increased, rather than decreased, vocal resonance distinguishes pneumonia from a pleural effusion. Imaging A 24-year-old White man presented with 1-day complaints of progressive shortness of breath and fever. He recently underwent an open reduction and internal fixation of a left midshaft femur fracture from a skiing accident 4 days ago. He denied chest pain, skin rashes, hemoptysis, hematemesis, melena, or surgical site bleeding. On arrival, the patient appeared in mild respiratory distress with a respiratory rate of 23 breaths/min, temperature of 37.8°C, heart rate of 97 beats/min, BP of 95/54 mm Hg, and peripheral saturation of 97% on 6-L/min nasal canula. His initial peripheral saturation on room air was 67%. Physical examination was unremarkable, except for diffuse rhonchi on chest auscultation. Chest radiograph on admission showed alveolar opacities predominantly in bilateral lower lobes. A chest CT angiography revealed no evidence for pulmonary embolism. However, there were findings of diffuse bilateral ground-glass opacities with areas of patchy consolidation and innumerous micronodules in both lungs (Fig 1). Laboratory examination was significant for a drop of hemoglobin by 3 g/dL and hematocrit level by 7% since his hospital discharge 4 days earlier. His renal function and urine analysis were normal. Venous blood gas on admission showed pH of 7.39 and Pco<sub2</sub of 43 mm Hg. Because of unexplained acute anemia, nonspecific CT chest findings and progressive dyspnea, a bronchoscopy with BAL was performed. Four aliquots of 60 mL saline solution were injected for lavage with fluid return (Fig 2). BAL fluid showed WBC count of 0.411 × 10<sup3</sup/mm<sup3</sup, RBC count of 318 × 10<sup3</sup/mm<sup3</sup, 100% fresh RBCs, 73% neutrophil, 24% lymphocytes, 1% monocytes, and 2% eosinophils. BAL fluid cytologic condition is shown in Figure 3. A full vasculitis workup by rheumatology was unremarkable. Ophthalmologic and skin examination were unrevealing. In daily routine, physicians use history, physical examination and technology-based information such as laboratory tests and imaging studies to diagnose the patients' disease. We determined the diagnostic value of lung auscultation in patients admitted to the Medical emergency room with chest symptoms. Two-hundred-and forty-three consecutive patients (137 males), mean age 59.2 years were included. Internal Medicine registrars had to make a presumptive diagnosis, 1) after having taken the history and 2) after having auscultated the lungs. Thereafter, routine diagnostic procedures were performed. The estimated diagnosis was compared with the final diagnosis based on the written report to the Family Practitioner. Two-hundred-eighty-seven diagnoses were made. Eighteen percent of patients suffered from left heart failure, 13% from unexplained chest pain, 10.5% from chest wall pain, and 10.5% from pneumonia. Forty-one percent of the diagnoses were already correct when based only on the patient's history. Lung auscultation improved the diagnostic yield only in 1% and worsened it in another 3%. By multiple logistic regression, normal lung auscultation (OR 0.12 [95CI% 0.053-0.29]) was the independent predictor for not having a lung or heart disease. However, elevation of B-type natiuretic peptide (BNP) (OR 1.16 per 100 pg/ml (95CI% 1.004-1.35), wheezing (OR 0.023 [0.002-0.33]) and pCO2 (OR 0.25 (0.10-0.621) were independent predictors for having a heart disease, whereas wheezing (OR 7.41 [3.26-16.83]) and CRP (OR 1.008 per 10 units [1.003-1.014]) were risk factors for having a lung disease. In contrast to history taking, abnormal lung auscultation does not appear to contribute considerably to the final diagnosis in patients presenting with chest symptoms in an emergency room setting. However, normal lung auscultation is a valuable predictor for not having a lung or heart disease, whereas wheezing is a predictor for having a lung disease and not having a heart disease. Physical examination The general appearance of patients may vary according to the experienced symptoms; the patient may be comfortable, or restless and in severe distress with an increased respiratory rate. A cool and pale skin is common and points to vasoconstriction. Some patients have low-grade fever (38–39 °C). Blood pressure may be elevated or decreased, and the pulse can become irregular. If heart failure ensues, elevated jugular venous pressure and hepatojugular reflux, or swelling of the legs due to peripheral edema may be found on inspection. Rarely, a cardiac bulge with a pace different from the pulse rhythm can be felt on precordial examination. Various abnormalities can be found on auscultation, such as a third and fourth heart sound, systolic murmurs, paradoxical splitting of the second heart sound, a pericardial friction rub and rales over the lung. Electrocardiogram A 52-year-old man presented with unproductive cough, fever and chill in our emergency department. Self-medication with amoxicillin over 3 days failed to improve his condition. The patient was in poor general condition. His body temperature was 38.4 C, with a heart rate of 124/min, a blood pressure of 120/70 mmHg and a positive shock index. At auscultation of the chest fine rales were heard over both lungs with diminished percussion sounds basal. The respiratory rate was 30/min and the oxygen saturation of 84% at room air. Laboratory: signs of inflammation; blood gas analysis: pronounced hypoxemia. A chest radiogram revealed signs of extensive pulmonary infiltrates on both sides. The patient was admitted to our Intensive Care Unit. He received piperacillin, sulbactam and levoflaxacin, ample fluid and non-invasive ventilation as well as intermittent catecholamine treatment. As there was no clinical improvement the patient was intubated on day 3. On bronchoscopy viral etiology was suspected. At this time the respiratory situation deteriorated. Acute respiratory distress syndrome (ARDS) was diagnosed. An antifungal and antiviral treatment (voriconazol, oseltamivir) was started and a cortisone pulse was attempted. The patient was transferred to another clinic where extracorporeal membranoxygenation (ECMO) was performed on the same day. The following day influenza A/H1N1-test was confirmed. Ten days after transfer, the patient regained spontaneous respiration, and he most likely survives the infection. The incidence of influenza (A/H1N1) has increased in Germany and severe and lethal courses have occurred. Therefore, the diagnostic and treatment algorithms need to be reconsidered in order to rapidly diagnose and treat infections. To study the influence of the spectrum of patients on the usefulness of five clinical cues, \"very annoying dyspnoea\", \"strong lateral chest pain\", crackles, C-reactive protein analysis, and erythrocyte sedimentation rate in the diagnosis of pneumonia. Evaluating the diagnostic properties of the cues against radiographic pneumonia at four steps in the diagnostic process, associated with increasing prevalence of pneumonia: 1. in all the 581 patients included, 2. in 402 of these patients who underwent physical chest examination, 3. in 188 patients classified by the doctors as having a lower respiratory tract infection, and 4. in 79 patients referred for radiography by the doctors. The municipal emergency clinic in Tromsø, Norway. 581 adult patients with respiratory tract infection. Sensitivity, specificity, Likelihood Ratio, and Positive predictive value. A tendency of decreasing specificity and Likelihood Ratio with increasing prevalence of pneumonia was demonstrated for all test, except for C-reactive protein analysis. This tendency may be explained either by the emphasis laid on the tests by the doctors when selecting patients for the diagnostic steps, or by an association between the evaluated tests and those emphasized by the doctors. As the diagnostic value of symptoms and signs are strongly influenced by selection, caution should be shown when transferring diagnostic values from one clinical setting to another. According to the 2012 Berlin definition, adult ARDS is characterized by the following: lung injury of acute onset, within 1 week of an apparent clinical insult and with the progression of respiratory symptoms bilateral opacities on chest imaging (chest radiograph or CT) not explained by other lung pathology (e.g. effusion, lobar/lung collapse, or nodules) respiratory failure not explained by heart failure or volume overload decreased Pa/Fi ratio (a decreased Pa/Fi ratio indicates reduced arterial oxygenation from the available inhaled gas): mild ARDS: 201 – 300 mmHg (≤ 39.9 kPa) moderate ARDS: 101 – 200 mmHg (≤ 26.6 kPa) severe ARDS: ≤ 100 mmHg (≤ 13.3 kPa) Note that the Berlin definition requires a minimum positive end expiratory pressure (PEEP) of 5 cm for consideration of the Pa/Fi ratio. This degree of PEEP may be delivered noninvasively with CPAP to diagnose mild ARDS. Spirometry plays the major role in pulmonary diagnostics in the family practice, but is still used much too rarely on patients with respiratory symptoms. Every patient with shortness of breath or a chronic, persistent cough should have spirometry performed. Needless to say, taking a selective medical history and auscultation of the lungs and heart are additional, important pillars for making a diagnosis. Measurement of the peak expiratory flow (PEF) can be especially helpful in emergencies. Pulse oxymetry also aids in the assessment of acute situations and additionally, can provide valuable information in the follow-up treatment of chronic respiratory diseases. A 25-year-old young male patient presented in casualty department with severe respiratory distress on the fourth day from onset of symptoms. The patient was nonsmoker and had no antecedent medical or drug history. Prior to admission, patient had dry cough and bilateral pleuritic chest pain for the last three days. He was in severe respiratory distress with use of accessory muscles of respiration. On examination, he had heart rate of 120 beats/min, blood pressure (BP) of 150/80, respiratory rate of 48-52/min and central cyanosis present. On systemic examination, reduced intensity of breath sounds with extensive rhonchi and crepitation was found in both lung fields, with other examination being within normal limits. On pulse oximetry, oxygen saturation was 28% on room air, which increased up to 36% with the help of 4 L oxygen via nasal prongs. PaO2/FiO2 ratio was 100. Chest X-ray analysis was suggestive of non-cardiac pulmonary edema in view of bilateral fluffy opacity without cardiomegaly. In view of 2/3 positive criteria, his provisional diagnosis was Acute Respiratory Distress Syndrome (ARDS). He required mechanical ventilatory support and was gradually weaned over a period of 10 days. The patient was treated with broad spectrum antibiotics and other supportive measures. On re-evaluation of history, we found that he was a goldsmith by occupation, smelting silver and gold for the past 8-10 years. On the day of onset of symptoms, while smelting silver he was exposed to golden yellow fumes for around 15 minutes, with the quantum of exposure more than any other day earlier. From previous experience and analysis of similar silver metals, he was able to tell us that the silver was adulterated with large amount of cadmium on that day than before. Serum level of cadmium was 2.9 μg/L 6 days after initial exposure. At the time of discharge, he had residual opacities in the chest radiograph and resting oxygen saturation was 94% on room air.  The auscultation of the lungs is - among anamnesis - the most important part in the assessment of patients presenting with pulmonary symptoms. The lung auscultation is reproducible, cost efficient and very helpful to distinguish between differential diagnoses, in particular in emergency situations. Detection and description of lung sounds requires experience and should be performed by strict adherence to the internationally accepted terminology.  Venous or pulmonary air embolism occurs when air enters the systemic veins and is transported to the right side of the heart and from there into the pulmonary arteries, where it may lodge, blocking or reducing blood flow. Gas in the venous circulation can cause cardiac problems by obstructing the pulmonary circulation or forming an air-lock which raises central venous pressure and reduces pulmonary and systemic arterial pressures. Experiments on animals show that the amount of gas necessary for this to happen is quite variable. Human case reports suggest that injecting more than 100 mL of air into the venous system at rates greater than 100 mL/s can be fatal. Very large and symptomatic amounts of venous air emboli may also occur in rapid decompression in severe diving or decompression accidents, where they may interfere with circulation in the lungs and result in respiratory distress and hypoxia. The World Health Organization's global programme for the control of acute respiratory infections relies on counting respiratory rate (RR) by observing abdominal and chest movements in order to diagnose pneumonia. However, few studies on the reliability of the observation method have been published. We counted RR simultaneously by observation and auscultation in 100 healthy infants at 1, 2, 4, 6 and 8 weeks of age for 15, 30 and 60 sec, and compared RRs obtained by the two methods. In all the age groups studied, the co-efficients of variation for the RRs recorded by observation or auscultation were similar. The mean RR by observation was higher by 1-3 breaths/min than mean RR by auscultation (p &lt; 0.001). The 95% confidence interval (+/-2 SD) for the difference between RR by the two methods ranged from +5 to -8 breaths/min for RR counted for 1 full minute. Our data support the assumption that observation is as reliable as auscultation for counting RR. \"Dabbing\", a relatively new form of THC use which utilizes Butane Hash Oil (BHO), an extraction of dried cannabis containing high levels of butane and terpene byproducts. The extraction process yields a waxy substance that is heated, vaporized and inhaled. We describe a lung injury as a result of BHO use. A previously healthy 18-year-old female presented to the ED with shortness of breath for 3-4 days. Initial oxygen saturation was 79% on room air. She was refractory to bronchodilators, steroids and supplemental O<sub2</sub. She has a 1-pack year smoking history and daily BHO abuse. Chest x-ray was positive for bilateral patchy infiltrates with mild hyperinflation. CT was negative for Pulmonary Embolus or other acute pathologic process. Sputum gram stain and blood cultures were negative. Arterial blood gases confirmed a pO2 of 73 mmHg. On physical exam she was tachycardic and tachypneic. Respiratory auscultation showed decreased air entry bilaterally with diffuse expiratory wheezing, bilateral rhonchi and a prolonged expiratory phase. We concluded her severe pneumonitis was secondary to daily BHO inhalation. Heating BHO to high temperatures, releases up to 75% of THC, compared to 5-20% THC in traditional smoked cannabis. At 978°F terpenes degrade into methacrolein and benzene. Methacrolein is structurally similar to acrolein, a pulmonary irritant, which causes acute lung injury and pulmonary edema in laboratory animals. We hypothesize a mechanism of lung injury and acute respiratory failure secondary to inhalation of high levels of methacrolein and benzene related to relatively novel phenomena of BHO use. Lung auscultation is an essential part of the physical examination for diagnosing respiratory diseases. The terminology standardization for lung sounds, in addition to advances in their analysis through new technologies, have improved the use of this technique. However, traditional auscultation has been questioned due to the limited concordance among health professionals. Despite the revolu tionary use of new diagnostic tools of imaging and lung function tests allowing diagnostic accuracy in respiratory diseases, no technology can replace lung auscultation to guide the diagnostic process. Lung auscultation allows identifying those patients who may benefit from a specific test. Moreover, this technique can be performed many times to make clinical decisions, and often with no need for- complicated and sometimes unavailable tests. This review describes the current state-of-the-art of lung auscultation and its efficacy based on the current respiratory sound terminology. In addition, it describes the main evidence on respiratory sound concordance studies among health professionals and its objective analysis through new technology. Other tests of auscultation The Surviving Sepsis Campaign has recommended 30 ml/kg of fluid to be given in adults in the first three hours followed by fluid titration according to blood pressure, urine output, respiratory rate, and oxygen saturation with a target mean arterial pressure (MAP) of 65 mmHg. In children an initial amount of 20 ml/kg is reasonable in shock. In cases of severe sepsis and septic shock where a central venous catheter is used to measure blood pressures dynamically, fluids should be administered until the central venous pressure reaches 8–12 mmHg. Once these goals are met, the central venous oxygen saturation (ScvO2), i.e., the oxygen saturation of venous blood as it returns to the heart as measured at the vena cava, is optimized. If the ScvO2 is less than 70%, blood may be given to reach a hemoglobin of 10 g/dL and then inotropes are added until the ScvO2 is optimized. In those with acute respiratory distress syndrome (ARDS) and sufficient tissue blood fluid, more fluids should be given Auscultation of the lungs has been a central element in clinical examination since the early part of the nineteenth century. However, the role of the stethoscope in our diagnostic work-up has more and more been challenged by newer diagnostic equipment. Research carried out over the last 30 years has given us new knowledge about the physical basis of lung sounds and the meaning of the sounds. Electronic stethoscopes and computer-based analysis of digital lung sounds are now available. Lungs auscultation findings should be interpreted with caution and be related to the case history and other clinical findings. Because of lower respiratory infection that was treated with antibiotics on the suspicion of pneumonia, 71 patients aged 15 years or more were referred to the study by general practitioners. Using a positive chest X-ray as a \"gold standard\", 15% had pneumonia. The diagnostic value of variables from history, physical examination and blood tests was evaluated by calculating the likelihood ratio (LR). A duration of illness less than 24 hours before consulting the general practitioner was the variable from the history with the highest LR, 13.5. The white blood cell count and particularly the C-reactive protein analysis had a high diagnostic value, CRP greater than 50 mg/l had an LR of 37. In this selected material pulmonary symptoms and lung findings were of minor value in differentiating patients with and without pneumonia, with no LR exceeding 2.3. This can be explained to some extent by selection bias. Lung cancers may extend along or grow through the pulmonary veins to invade or lie within the left atrium (LA). A 62-year-old man, previously healthy, presented with 1-month ventilatory-independent right hemithorax back pain, dry cough and large effort dyspnea. He also referred weight loss of 12 kg in 10 months and denied hemoptysis. As antecedents, he smoked for 40 years and moderate daily alcoholism. On physical examination, the patient was in good general condition, hydrated and regular respiration at rest [blood pressure (BP) =120/80 mmHg; heart rate (HR) =90 bpm; respiratory rate (RR) =16 rpm]. Cardiac auscultation revealed two standard rhythmic sounds without murmurs. Pulmonary auscultation revealed a slightly diminished vesicular murmur in the lower 1/3 of the right hemithorax without adventitious noises. Chest radiography showed a mass over the right lower lung. A CT scan confirmed the radiography image with the mass extending along the right inferior pulmonary vein and a tumor in the LA. Transthoracic and transesophageal echocardiography revealed large mass within the LA (occupying almost the entire cavity), measuring about 10 cm × 3 cm at its largest diameter, prolapsing into the left ventricle. Bronchoscopy, head CT scan, and whole-body bone scintigraphy investigation did not show any distant metastasis. The patient was successfully operated removing the intracardiac and inferior pulmonary vein tumor with the aid of cardiopulmonary bypass, followed by a right inferior lobectomy carried out after 25 days. After 30 days from surgery presented seizures associated a brain metastasis evidenced by CT when adjuvant radio and chemotherapy was started. During the next 90 days, the clinical conditions worsened, and the patient died 4 months after the surgical treatment. The case report has two primary justifications, even considering the poor outcome: (I) rarity and (II) the possibility of the surgical treatment.\nHere is the question:\nPEDIATRICS: 6-month-old infant presenting to the emergency department for respiratory distress. Examination: axillary temperature 37.2°C, respiratory rate 40 rpm, heart rate 160 bpm, blood pressure 90/45 mmHg, SatO2 95% on room air. He shows moderate respiratory distress with intercostal and subcostal retraction. Pulmonary auscultation: scattered expiratory rhonchi, elongated expiration and slight decrease in air entry in both lung fields. Cardiac auscultation: no murmurs. It is decided to keep the patient under observation in the hospital for a few hours. What do you consider the most appropriate attitude at this time with regard to the complementary tests?\nHere are the potential choices:\n1. Request venous blood gas, leukocyte count and acute phase reactants.\n2. Request chest X-ray.\n3. Request arterial blood gases and acute phase reactants.\n4. Do not request complementary tests.\nThe correct answer is: 4. Do not request complementary tests."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 36 year-old man suffered from fever, fatigue, pleurodynia and precordial discomfort. His family physician suspected febrile tracheobronchitis and treated it with ampicillin for 5 days. Because symptoms persisted an ECG was done which suggested acute myocardial infarction. The patient underwent an emergency coronary angiography which excluded coronary artery disease and aortic dissection. Pericarditis was suspected and the patient put on aspirin, 500 mg/d. Because of persisting cardiac symptoms an echocardiography was performed which revealed systolic separation between epi- and pericardium, characteristic of a small pericardial effusion after acute pericarditis. The symptoms improved after one week of treatment with diclofenac and the ECG had become normal. Two months later the patient was seen at our cardiac outpatient clinic. He had night sweats, sporadic precordial pain and severe dyspnoe. Further investigations revealed tachycardia (120/min), hypotension (95/70 mm Hg), pulsus paradoxus and jugular vein sustension. Echocardiography revealed a large pericardial effusion (\"swinging heart\"), which explained the low voltage and the electrical alternans in the ECG. Pericardiocentesis was carried out the same day to relieve the tamponade. It was followed by pericardioscopy and epi- as well as pericardial biopsy. 485 ml of a serous effusion were drained. Cytology and histology demonstrated a lymphocytic fibrinous pericarditis. Polymerase chain reaction (PCR) on viral and bacterial RNA and DNA of potentially cardiotropic agents remained negative. The pigtail catheter was left in place and 80 mg of gentamycin were given intrapericardially on day 1 and 2, followed by 500 mg of crystalloid triamcinolone acetate after the PCR was found to be negative. Oral treatment with 0.5 mg colchicine three times a day (off-label use) was started and maintained for 6 months. After 9 months no effusion was detected and the patient was free of symptoms. After exclusion of bacterial and viral pericardial infection, a high single dose of intrapericardial triamcinolone combined with long-term oral colchicine has proven to be a highly efficacious treatment of autoreactive pericarditis which will avoid relapses in most cases. PRESENTING FEATURES: A 70-year-old African American man was admitted with a history of fever, chills, and malaise of several days' duration. His past medical history was notable for end-stage renal disease requiring hemodialysis, coronary artery disease, and aortic stenosis requiring a bioprosthetic aortic valve replacement. On the day of admission, the patient was noted to have a shaking chill while undergoing dialysis through his catheter and was admitted to the hospital. He complained of pain at the catheter insertion site, shortness of breath, and dyspnea on exertion, but denied chest pain. On physical examination, the patient had a temperature of 100.4 degrees F, with a heart rate of 64 beats per minute, blood pressure of 127/72 mm Hg, and an oxygen saturation of 97% on room air. He was a mildly obese man in no apparent distress. He had shotty cervical lymphadenopathy and a right subclavian dialysis catheter in place, with erythema and pus at the entry site. His jugular venous pressure was 10 cm H(2)O. Lung examination showed bibasilar rales. Heart sounds were normal, with no rub or gallop. He had a 2/6 systolic ejection murmur best heart at the left sternal border as well as a 3/6 holosystolic murmur at the apex that radiated to his left axilla. Examination of the abdomen and extremities was unremarkable. The patient's neurological examination was unremarkable, and he was alert and oriented to person, place, and time. Laboratory studies showed an elevated white blood cell count of 16,700 cells/microL. His blood urea nitrogen level was 43 mg/dL and his serum creatinine level was 4.9 mg/dL. Multiple blood cultures grew methicillin-resistant Staphylococcus aureus. An admission, chest radiograph showed no infiltrate. An admission electrocardiogram showed normal sinus rhythm with first degree atrioventricular block, left anterior fascicular block, and left ventricular hypertrophy. shows rhythm strips from lead II electrocardiograms 5 months before admission (top), on admission (middle) and 5 days after admission (bottom). What is the diagnosis? Intracardiac shunts or moderate to severe valvular insufficiency Co-existing disease that significantly increases left or right ventricular diastolic pressure such severe systemic hypertension, aortic stenosis, or cor pulmonale Aortic dissection resulting in pericardial effusion/tamponade Cardiac tamponade in hypovolemia Patients with cardiac tamponade present similar to patients with other forms of cardiogenic or obstructive shock. They may endorse vague symptoms of chest pain, palpitations, shortness of breath, or in more severe cases, dizziness, syncope, and altered mental status.  They may also present in a pulseless electrical activity cardiac arrest. The classic physical findings in cardiac tamponade included in Beck’s triad are hypotension, jugular venous distension, and muffled heart sounds. Pulsus paradoxus, which is a decrease in systolic blood pressure by more than 10 mm Hg with inspiration is an important physical exam finding that suggests a pericardial effusion is causing cardiac tamponade. Pulsus paradoxus may be absent in patients with ASD, elevated diastolic pressures, pulmonary hypertension and aortic regurgitation. The Kussmaul sign - a paradoxical elevated in JVP and pressure during inspiration is sometimes seen in cardiac tamponade. Aortic regurgitation when acute and/or severe can be suspected when the patient has a wide pulse pressure, and a low pitched early diastolic murmur is auscultated again over the right sternal border at the second intercostal space. Accentuated P2 may also be noticed due to elevated pressures in the pulmonary vasculature. Chronic aortic regurgitation may illicit a blowing diastolic decrescendo murmur with a positive correlation between the duration of murmur and the severity of the disease. Often auscultation of a laterally and inferiorly displaced apical impulse is present and sustained. Often there is the phenomenon of Corrigan pulse (water hammer), a bounding and forceful pulse that rapidly increases and collapses. Other less common physical exam findings include the de Musset sign, which is subtle head bobbing with a pulse, as well as the Quincke sign and Muller sign (pulsations on the fingernails and uvula, respectively). Similar physical exam findings to aortic stenosis can also be seen late in disease progression. Acute aortic regurgitation will present differently depending on the etiology. If a patient presents with tearing severe chest pain along with physical exam findings such as variation in blood pressure between the right and left extremities, consider aortic dissection as a cause. If the patient presented with a history of streptococcal infection along with fevers, swollen and tender joints, skin nodules, new onset of rash, then rheumatic heart disease would be high on the differential. Causes The differential diagnoses of Kussmaul's sign includes constrictive pericarditis, restrictive cardiomyopathy, pericardial effusion, and severe right-sided heart failure. With cardiac tamponade, jugular veins are distended and typically show a prominent x descent and an absent y descent as opposed to patients with constrictive pericarditis (prominent x and y descent), see Beck's triad. Other possible causes of Kussmaul's sign include: Right ventricular infarction - low ventricular compliance Right heart failure Cardiac tumours Tricuspid stenosis Restrictive cardiomyopathy Pulmonary embolism Constrictive pericarditis History Kussmaul's sign is named after the German doctor who first described it, Adolph Kussmaul (1822-1902). He is also credited with describing Kussmaul breathing. See also Pulsus paradoxus References Symptoms and signs: Vascular Physical examinations The classic sign of pericarditis is a friction rub heard with a stethoscope on the cardiovascular examination, usually on the lower left sternal border. Other physical signs include a person in distress, positional chest pain, diaphoresis (excessive sweating); possibility of heart failure in form of pericardial tamponade causing pulsus paradoxus, and the Beck's triad of low blood pressure (due to decreased cardiac output), distant (muffled) heart sounds, and distension of the jugular vein (JVD). Pericardial disease The sac which surrounds the heart, called the pericardium, can become inflamed in a condition known as pericarditis. This condition typically causes chest pain that may spread to the back, and is often caused by a viral infection (glandular fever, cytomegalovirus, or coxsackievirus). Fluid can build up within the pericardial sac, referred to as a pericardial effusion. Pericardial effusions often occur secondary to pericarditis, kidney failure, or tumours, and frequently do not cause any symptoms. However, large effusions or effusions which accumulate rapidly can compress the heart in a condition known as cardiac tamponade, causing breathlessness and potentially fatal low blood pressure. Fluid can be removed from the pericardial space for diagnosis or to relieve tamponade using a syringe in a procedure called pericardiocentesis. Congenital heart disease A careful physical exam will assess heart rate and rhythm. Any abnormalities will increase suspicion of cardiac arrhythmia. In addition, an elevated respiratory rate or hypoxia will increase suspicion of a pulmonary embolism. Jugular venous distention and hypotension are suggestive signs of an obstructive mechanical cardiac etiology. Pathological cardiac murmurs, specifically new ones, will clue one into a valvular etiology, hypertrophic cardiomyopathy, or an obstructive intracardiac lesion. Muffled sounds can be heard with pericardial tamponade. Pedal edema or other evidence of deep venous thrombosis increases a patient's risk of pulmonary embolism. [10] Diagnosis Due to the unstable condition of these patients, supportive therapy must be initiated simultaneously with diagnostic evaluation (Fig. 326-2). A focused history and physical examination should be performed, blood specimens sent to the laboratory, and an electrocardiogram (ECG) and chest x-ray obtained. Etiologies of Cardiogenic Shock or Pulmonary Edema Acute myocardial infarction/ischemia LV failure Ventricular septal rupture Papillary muscle/chordal rupture–severe MR Ventricular free wall rupture with subacute tamponade Other conditions complicating large MIs Post-cardiac arrest Post-cardiotomy Refractory sustained tachyarrhythmias Acute fulminant myocarditis End-stage cardiomyopathy LV apical ballooning Takotsubo’s cardiomyopathy Hypertrophic cardiomyopathy with severe outflow obstruction Aortic dissection with aortic insufficiency or tamponade Severe valvular heart disease Other Etiologies of Cardiogenic Shockb RV failure due to: Purulent pericarditis is an extremely rare entity with only a few reported cases so far. This condition deserves prompt diagnosis because of its significant mortality rate if left untreated. A 76-year-old man with a past medical history of coronary artery disease (CAD) with percutaneous coronary intervention (PCI) to the left anterior descending artery (LAD) and right circumflex artery (RCA), ischemic cardiomyopathy with moderately reduced ejection fraction (EF 45-50%), peripheral artery disease (PAD), COVID-19 pneumonia complicated by fibrotic lung disease (on 3 liters of home oxygen), type-2 diabetes mellitus (T2DM), hypertension (HTN), hyperlipidemia (HLD), and chronic kidney disease (CKD) stage III presented with complaints of pleuritic chest pain and shortness of breath. On hospital day 1, he was afebrile and hemodynamically stable with physical exam remarkable for bibasilar crackles and dry gangrene of his right first toe. He developed progressive altered mental status, hypotension, oliguric renal failure, and respiratory distress on hospital day 6. On exam at this time, he had an elevated jugular venous distension (JVD) of 12-14 cm water, pericardial friction rub with decreased heart sounds, and orthopnea; all were consistent with cardiac tamponade clinically. An electrocardiogram (EKG) showed new ST elevations in leads I, II, and aVL with ST depression in aVR and V1 with only mild elevation in troponin I to 0.07 ng/mL. A transthoracic echocardiogram (TTE) was done on hospital day 7 and showed a moderate sized pericardial effusion with inferior vena cava (IVC) enlargement but no atrial collapse, ventricular collapse, IVC collapse, or respiratory variation in the mitral and tricuspid inflow velocities. Blood cultures grew methicillin-resistant <iStaphylococcus aureus</i (MRSA) on hospital day 6, and he was started on intravenous (IV) vancomycin. The differential diagnosis for his enlarging pericardial effusion included purulent pericarditis, uremic pericarditis, or hemorrhagic effusion. He had urgent diagnostic and therapeutic pericardiocentesis with removal of 350 milliliters of fluid. The pericardial fluid was cloudy, tan-brown with a gram stain showing gram-positive cocci in clusters and cultures growing MRSA, which confirmed the diagnosis of purulent pericarditis secondary to MRSA infection. After the pericardiocentesis, his blood pressure, respiratory distress, and renal failure improved. The source of the bacteremia was from osteomyelitis of his gangrenous, right toe with bone biopsy growing both MRSA and <iStreptococcus anginosus</i. He underwent toe amputation for definitive source control. He was discharged on hospital day 24 with a plan to complete 6 weeks of IV vancomycin. Additional clues to the etiology and importance of a heart murmur can be gleaned from the history and other physical examination findings. Symptoms suggestive of cardiovascular, neurologic, or pulmonary disease help focus the differential diagnosis, as do findings relevant to the jugular venous pressure and waveforms, the arterial pulses, other heart sounds, the lungs, the abdomen, the skin, and the extremities. In many instances, laboratory studies, an ECG, and/or a chest x-ray may have been obtained earlier and may contain valuable information. A patient with suspected infective endocarditis, for example, may have a murmur in the setting of fever, chills, anorexia, fatigue, dyspnea, splenomegaly, petechiae, and positive blood cultures. A new systolic murmur in a patient with a marked fall in blood pressure after a recent MI suggests myocardial rupture. By contrast, an isolated grade 1 or 2 mid-systolic murmur at the left sternal border in a healthy, active, and asymptomatic young or absence of a third heart sound (S3). Accurate characterization of cardiac murmurs provides important insight into the natural history of many valvular and congenital heart lesions. Finally, the important role played by the physical examination in enhancing the clinician-patient relationship cannot be overestimated. THE GENERAL PHYSICAL EXAMINATION Any examination begins with an assessment of the general appear-ance of the patient, with notation of age, posture, demeanor, and 267 SEC Tion 2 DiAgnoSiS oF CARDiovASCulAR DiSoRDERS overall health status. Is the patient in pain or resting quietly, dyspneic or diaphoretic? Does the patient choose to avoid certain body positions to reduce or eliminate pain, as might be the case with suspected acute pericarditis? Are there clues indicating that dyspnea may have a pulmonary cause, such as a barrel chest deformity with an increased anterior-posterior diameter, tachypnea, and pursed-lip breathing? Skin pallor, cyanosis, and jaundice can be The acquired aortic stenosis manifests with exertional dyspnea, syncope, angina, and, ultimately, heart failure. [17] [18] Typically, symptoms begin at the age of 50 to 70 years in patients with the bicuspid aortic valve and in greater than 70 years in patients with tri-leaflet valve calcific stenosis. Patients progressively experience a gradual decrease in exercise tolerance, dyspnea on exertion, and fatigue. Severe exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, and pulmonary edema show various degrees of pulmonary venous hypertension. Angina results from the combination of the need for increased oxygen in hypertrophied myocardium and reduction of oxygen delivery secondary to the excessive compression of coronary vessels. Syncope is caused by the decrease in cerebral perfusion occurring during exertion when the arterial pressure declines due to systemic vasodilation and an inadequate increase in cardiac output related to stenosis. It is also due to the malfunction of the baroreceptor mechanism in severe aortic stenosis. Non-cardiac symptoms include gastrointestinal (GI) bleeding and cerebral emboli. GI bleeding is observed in patients with severe aortic stenosis and is often associated with angiodysplasia or other vascular malformations. It manifests from shear stress-induced platelet aggregation and reduction in the von Willebrand factor. [19] Cerebral emboli occur due to microthrombi formation on thickened bicuspid valves. There is also an observed increase in the risk of infective endocarditis in patients with aortic valve disease, especially with a bicuspid valve. On examination, carotid upstroke can be observed on palpation. A slow-rising, late-peaking, and a low-amplitude carotid impulse, pulsus parvus et tardus, is an expected finding in severe aortic stenosis and, when present, is specific to aortic stenosis. On auscultation, the second heart sound may lack a split and can be heard as a single sound during inspiration. It can also become paradoxical when the closure of the aortic valve gets delayed than the pulmonic valve. A mid-systolic ejection murmur, heard best over the right second intercostal space, with radiation into the right neck. However, high-frequency components may radiate to the apex in calcified aortic valves, and this phenomenon is called the Gallavardin phenomenon. The murmur becomes softer in LV failure and when there is a fall of stroke volume. HIV infection and ART likely contribute to increased cardiovascular disease in patients. Common presenting symptoms may include chest pain, shortness of breath, or fatigue. The examination should proceed as one would when assessing for acute coronary syndrome or valvular disease, palpating for chest wall pain, observing for jugular venous distension and peripheral edema, and auscultating for abnormal heart sounds, murmurs, or evidence of pulmonary edema. Cardiovascular AIDS-related illnesses could include purulent pericarditis or cardiac tamponade caused by Mycobacterium tuberculosis . If these conditions are suspected, observing for Beck’s triad of low blood pressure, jugular venous distension, and muffled heart sounds may confirm a compressive pericardial effusion. Chronic constrictive pericarditis (CCP) is a disease that has multiple possible causes and is associated with variable clinical findings, depending on its severity. It develops insidiously, and in many cases, particularly in developed countries, no antecedent diagnosis can be found. These cases are termed idiopathic. Tuberculosis is the leading cause of constrictive pericarditis in developing nations but represents only a small minority in developed countries. Here the authors describe two different case reports where tuberculosis was the probable cause of CCP. A 21-year-old man born in Cape Verde living in Europe for 4 years and a 24-year-old man born in Guiné Bissau were both admitted due to intense precordial pain and syncope after exertion. Interestingly both had fatigability, dyspnea, chest discomfort and palpitations on exertion, as well as progressive involuntary weight loss and decubitus cough. On physical examination they had tachycardia, jaundice, cachexia, elevated jugular venous pressure, hepatomegaly and ascites. Both electrocardiograms showed prominent P waves and chest X-ray showed bilateral pulmonary interstitial infiltrates and enlargement of the right cavities. Analytically, elevated bilirubin, leukopenia and thrombocytopenia was also found in both. Echocardiography revealed findings, in both cases, compatible with CCP including less common signs as annulus reversus and annulus paradoxus. Thoraco-abdomino-pelvic CT from both patients revealed chronic liver disease with congestion, pleural effusion, pericardial calcifications, ascites and massive mediastinal and abdominal adenopathies. Blood cultures and IGRA test were negative. However, given the presumptive diagnosis of tuberculosis (TB), anti-TB therapy was started. Despite the diagnosis of \"end-stage\" CCP with very high operative risk multidisciplinary team decided after informed consent, to perform total anterior pericardiectomy, that occurred without complications. Pericardial and mediastinal biopsies, pericardial/pleural fluid cultures/ immune-phenotyping were inconclusive. Anti- tuberculosis therapy was maintained. After surgery, the patients had a remarkable clinical improvement (NYHA I) that persisted in 6- month follow-up. These two case reports illustrate that despite the markedly elevated operative risk of pericardiectomy in \"end-stage\" forms of disease after patients informed consent must be a considered option. The other point to consider is that, despite rare, tuberculosis still is a possible diagnosis to consider in CCP in Portugal. Corticosteroids are usually used in those cases that are clearly refractory to NSAIDs and colchicine and a specific cause has not been found. Systemic corticosteroids are usually reserved for those with autoimmune disease. Prognosis One of the most feared complications of acute pericarditis is cardiac tamponade. Cardiac tamponade is accumulation of enough fluid in the pericardial space --- pericardial effusion --- to cause serious obstruction to the inflow of blood to the heart. Signs of cardiac tamponade include distended neck veins, muffled heart sounds when listening with a stethoscope, and low blood pressure (together known as Beck's triad). This condition can be fatal if not immediately treated. Pericarditis as a presenting sign of infective endocarditis is rare. Here we describe 2 cases and an additional 19 cases of pericarditis as a presenting sign of infective endocarditis reported during the last 40 y. 71% of patients were young males (mean age 43.2 y). The most commonly reported underlying conditions were diabetes mellitus type 2 (5 patients, 24%), and substance or alcohol abuse (4 patients, 19%). The native aortic valve was the most frequently involved valve. The most common symptoms were fever, cough or dyspnoea, and chest pain. Overt tamponade was diagnosed in 47% of the patients. However, pulsus paradoxus and pericardial friction rub were rare. A heart murmur was heard in 12 patients (57%). Staphylococcus aureus was the most commonly isolated pathogen concomitantly from blood and pericardial fluid. 16 patients (76%) were operated. Six underwent a pericardial procedure, 5 underwent valve replacement, 4 both, and 1 patient was operated for pseudoaneurysm. Mortality rates were 60% and 31% of patients treated with antibiotics alone versus antibiotics and surgical intervention, respectively. In patients presenting with pericarditis with or without cardiac tamponade, the possibility of infective endocarditis should be considered. Optimal therapy should consist of antibiotics and surgical intervention. An important thing to keep in mind when considering pulsus paradoxus while discerning between pericardial and non-pericardial disease is the following: pulsus paradoxus in non-pericardial disease will usually manifest with a drop in systolic and diastolic pressures. This is in contrast to pericardial disease in which the drop is mainly in systolic pressure, diastolic pressure is usually minimally affected, and thus pulse pressure will be narrower. Other critical clinical signs to be aware of are signs of tamponade such as raised jugular venous pressure (JVP), muffled heart sounds, and decreased blood pressure. If pericardial tamponade is concerned, checking for a pulsus paradoxus is recommended. It is defined as a drop of systolic blood pressure by more than 10 mm hg during inspiration. Suspected severe valve disease in symptomatic patients—dyspnea, angina, heart failure, syncope Infective endocarditis with need for cardiac surgery Asymptomatic patients with aortic regurgitation and cardiac enlargement or Prior to cardiac surgery in patients with suspected coronary artery disease New onset with angina or suspected undiagnosed coronary artery disease New-onset cardiomyopathy of uncertain cause or suspected to be due to coronary artery disease Prior to surgical correction, when symptoms or noninvasive testing suggests coronary disease Symptomatic patients with suspected cardiac tamponade or constrictive pericarditis Hypertrophic cardiomyopathy with angina Diseases of the aorta when knowledge of coronary artery involvement is necessary for management Complications Complications include pericarditis, pericardial effusion, pleuritis, pulmonary infiltration, and very rarely pericardial tamponade. Of these cardiac tamponade is the most life-threatening complication. The pericardial fluid increases intra-pericardial pressure therefore preventing complete expansion of the atria and the ventricles upon the diastole. This causes equilibration of the pressure in all four heart chambers, and results in the common findings of the tamponade which are pulsus paradoxus, Beck's triad of hypotension, muffled heart sounds, and raised jugular venous pressure, as well as EKG or Holter monitor findings such as electrical alternans. Physically the patients who progress to severe pericardial tamponade obtundate, become mentally altered, and lethargic. If left untreated, severe decrease in cardiac output, vascular collapse, and hypoperfusion of body including the brain results in death. The early and late results were retrospectively evaluated in 57 cases of double or triple valve replacement or repair performed in 1970-1983. The causes of the valvular lesions were rheumatic fever (43 cases), bacterial endocarditis (6), syphilis (1) and unknown (7 cases). The preoperative NYHA classification was III in 29 patients and IV in 28, due mainly to dyspnea of effort. Cardiomegaly (mean radiologic volume 880 cm3/m2) and atrial fibrillation were the dominant clinical findings. Surgery was on emergency indications in five cases. Cold cardioplegia combined with external cardiac cooling has been used for myocardial protection since 1977. The valve replacements were 56 aortic, 50 mitral and 2 tricuspid. In addition there were three closed and two open mitral commissurotomies, two mitral plastic repairs, three tricuspid valve anuloplasties (DeVega) and one aortic anuloplasty. Follow-up (0.3-13, mean 3.5 years) was supplemented with a check-up including two-dimensional echophonocardiography and hematologic tests. The operative mortality (10/57 patients) fell from 26% in 1970-1976 to 12% in 1977-1983. The causes of death were low cardiac output in preoperatively ill patients (5), myocardial infarction (2), technical failure (2) and sepsis (1 case). There were 11 late deaths (6.7/100 patient-years of observation), the commonest cause (5 patients) being congestive heart failure. The respective incidences of thromboembolism, paravalvular leak and postoperative endocarditis were 2.1, 4.2 and 2.1 episodes/100 patient-years.(ABSTRACT TRUNCATED AT 250 WORDS) Complications Pericarditis can progress to pericardial effusion and eventually cardiac tamponade. This can be seen in people who are experiencing the classic signs of pericarditis but then show signs of relief, and progress to show signs of cardiac tamponade which include decreased alertness and lethargy, pulsus paradoxus (decrease of at least 10 mmHg of the systolic blood pressure upon inspiration), low blood pressure (due to decreased cardiac index), (jugular vein distention from right sided heart failure and fluid overload), distant heart sounds on auscultation, and equilibration of all the diastolic blood pressures on cardiac catheterization due to the constriction of the pericardium by the fluid. Early symptoms included precordial chest pain, fatigue, dyspnea, palpitations, and fever. Patients may give symptoms suggestive of a viral prodrome (a runny nose, arthralgia, low-grade fever) 1 to 2 weeks preceding the presentation. In predominant pericardial involvement, they can describe the pain as sharp, worse with a cough or inspiration and relieved by sitting forward. If there is significant myocardial involvement, there may be a continuous pain, and sometimes, it is hard to differentiate from myocardial ischemia pain, especially in people with cardiovascular risk factors. They may also have predominant heart failure symptoms such as shortness of breath, orthopnea, pedal edema, and fatigue. Rare symptoms include arrhythmias, syncope, and sudden cardiac arrest. Physical examination findings can be variable, but common findings may include fever, pericardial friction rub and features of heart failure. Look for other signs of systemic illness which may contribute to the etiology.\nHere is the question:\nANESTHESIOLOGY, CRITICAL CARE AND EMERGENCIES: A patient with a history of fever and chest pain comes to the hospital with dyspnea and tachypnea. On physical examination, the blood pressure cyphrads are low, jugular venous pressure is elevated with a deep descending sinus X, and he has a pulsus paradoxus. What pathology should be suspected?\nHere are the potential choices:\n1. Ischemic heart disease.\n2. Dilated cardiomyopathy.\n3. Severe aortic valve stenosis.\n4. Constrictive pericarditis.\n5. Pericardial effusion with cardiac tamponade.\nThe correct answer is: ",
        "gold_answer": "5 Pericardial effusion with cardiac tamponade.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 36 year-old man suffered from fever, fatigue, pleurodynia and precordial discomfort. His family physician suspected febrile tracheobronchitis and treated it with ampicillin for 5 days. Because symptoms persisted an ECG was done which suggested acute myocardial infarction. The patient underwent an emergency coronary angiography which excluded coronary artery disease and aortic dissection. Pericarditis was suspected and the patient put on aspirin, 500 mg/d. Because of persisting cardiac symptoms an echocardiography was performed which revealed systolic separation between epi- and pericardium, characteristic of a small pericardial effusion after acute pericarditis. The symptoms improved after one week of treatment with diclofenac and the ECG had become normal. Two months later the patient was seen at our cardiac outpatient clinic. He had night sweats, sporadic precordial pain and severe dyspnoe. Further investigations revealed tachycardia (120/min), hypotension (95/70 mm Hg), pulsus paradoxus and jugular vein sustension. Echocardiography revealed a large pericardial effusion (\"swinging heart\"), which explained the low voltage and the electrical alternans in the ECG. Pericardiocentesis was carried out the same day to relieve the tamponade. It was followed by pericardioscopy and epi- as well as pericardial biopsy. 485 ml of a serous effusion were drained. Cytology and histology demonstrated a lymphocytic fibrinous pericarditis. Polymerase chain reaction (PCR) on viral and bacterial RNA and DNA of potentially cardiotropic agents remained negative. The pigtail catheter was left in place and 80 mg of gentamycin were given intrapericardially on day 1 and 2, followed by 500 mg of crystalloid triamcinolone acetate after the PCR was found to be negative. Oral treatment with 0.5 mg colchicine three times a day (off-label use) was started and maintained for 6 months. After 9 months no effusion was detected and the patient was free of symptoms. After exclusion of bacterial and viral pericardial infection, a high single dose of intrapericardial triamcinolone combined with long-term oral colchicine has proven to be a highly efficacious treatment of autoreactive pericarditis which will avoid relapses in most cases. PRESENTING FEATURES: A 70-year-old African American man was admitted with a history of fever, chills, and malaise of several days' duration. His past medical history was notable for end-stage renal disease requiring hemodialysis, coronary artery disease, and aortic stenosis requiring a bioprosthetic aortic valve replacement. On the day of admission, the patient was noted to have a shaking chill while undergoing dialysis through his catheter and was admitted to the hospital. He complained of pain at the catheter insertion site, shortness of breath, and dyspnea on exertion, but denied chest pain. On physical examination, the patient had a temperature of 100.4 degrees F, with a heart rate of 64 beats per minute, blood pressure of 127/72 mm Hg, and an oxygen saturation of 97% on room air. He was a mildly obese man in no apparent distress. He had shotty cervical lymphadenopathy and a right subclavian dialysis catheter in place, with erythema and pus at the entry site. His jugular venous pressure was 10 cm H(2)O. Lung examination showed bibasilar rales. Heart sounds were normal, with no rub or gallop. He had a 2/6 systolic ejection murmur best heart at the left sternal border as well as a 3/6 holosystolic murmur at the apex that radiated to his left axilla. Examination of the abdomen and extremities was unremarkable. The patient's neurological examination was unremarkable, and he was alert and oriented to person, place, and time. Laboratory studies showed an elevated white blood cell count of 16,700 cells/microL. His blood urea nitrogen level was 43 mg/dL and his serum creatinine level was 4.9 mg/dL. Multiple blood cultures grew methicillin-resistant Staphylococcus aureus. An admission, chest radiograph showed no infiltrate. An admission electrocardiogram showed normal sinus rhythm with first degree atrioventricular block, left anterior fascicular block, and left ventricular hypertrophy. shows rhythm strips from lead II electrocardiograms 5 months before admission (top), on admission (middle) and 5 days after admission (bottom). What is the diagnosis? Intracardiac shunts or moderate to severe valvular insufficiency Co-existing disease that significantly increases left or right ventricular diastolic pressure such severe systemic hypertension, aortic stenosis, or cor pulmonale Aortic dissection resulting in pericardial effusion/tamponade Cardiac tamponade in hypovolemia Patients with cardiac tamponade present similar to patients with other forms of cardiogenic or obstructive shock. They may endorse vague symptoms of chest pain, palpitations, shortness of breath, or in more severe cases, dizziness, syncope, and altered mental status.  They may also present in a pulseless electrical activity cardiac arrest. The classic physical findings in cardiac tamponade included in Beck’s triad are hypotension, jugular venous distension, and muffled heart sounds. Pulsus paradoxus, which is a decrease in systolic blood pressure by more than 10 mm Hg with inspiration is an important physical exam finding that suggests a pericardial effusion is causing cardiac tamponade. Pulsus paradoxus may be absent in patients with ASD, elevated diastolic pressures, pulmonary hypertension and aortic regurgitation. The Kussmaul sign - a paradoxical elevated in JVP and pressure during inspiration is sometimes seen in cardiac tamponade. Aortic regurgitation when acute and/or severe can be suspected when the patient has a wide pulse pressure, and a low pitched early diastolic murmur is auscultated again over the right sternal border at the second intercostal space. Accentuated P2 may also be noticed due to elevated pressures in the pulmonary vasculature. Chronic aortic regurgitation may illicit a blowing diastolic decrescendo murmur with a positive correlation between the duration of murmur and the severity of the disease. Often auscultation of a laterally and inferiorly displaced apical impulse is present and sustained. Often there is the phenomenon of Corrigan pulse (water hammer), a bounding and forceful pulse that rapidly increases and collapses. Other less common physical exam findings include the de Musset sign, which is subtle head bobbing with a pulse, as well as the Quincke sign and Muller sign (pulsations on the fingernails and uvula, respectively). Similar physical exam findings to aortic stenosis can also be seen late in disease progression. Acute aortic regurgitation will present differently depending on the etiology. If a patient presents with tearing severe chest pain along with physical exam findings such as variation in blood pressure between the right and left extremities, consider aortic dissection as a cause. If the patient presented with a history of streptococcal infection along with fevers, swollen and tender joints, skin nodules, new onset of rash, then rheumatic heart disease would be high on the differential. Causes The differential diagnoses of Kussmaul's sign includes constrictive pericarditis, restrictive cardiomyopathy, pericardial effusion, and severe right-sided heart failure. With cardiac tamponade, jugular veins are distended and typically show a prominent x descent and an absent y descent as opposed to patients with constrictive pericarditis (prominent x and y descent), see Beck's triad. Other possible causes of Kussmaul's sign include: Right ventricular infarction - low ventricular compliance Right heart failure Cardiac tumours Tricuspid stenosis Restrictive cardiomyopathy Pulmonary embolism Constrictive pericarditis History Kussmaul's sign is named after the German doctor who first described it, Adolph Kussmaul (1822-1902). He is also credited with describing Kussmaul breathing. See also Pulsus paradoxus References Symptoms and signs: Vascular Physical examinations The classic sign of pericarditis is a friction rub heard with a stethoscope on the cardiovascular examination, usually on the lower left sternal border. Other physical signs include a person in distress, positional chest pain, diaphoresis (excessive sweating); possibility of heart failure in form of pericardial tamponade causing pulsus paradoxus, and the Beck's triad of low blood pressure (due to decreased cardiac output), distant (muffled) heart sounds, and distension of the jugular vein (JVD). Pericardial disease The sac which surrounds the heart, called the pericardium, can become inflamed in a condition known as pericarditis. This condition typically causes chest pain that may spread to the back, and is often caused by a viral infection (glandular fever, cytomegalovirus, or coxsackievirus). Fluid can build up within the pericardial sac, referred to as a pericardial effusion. Pericardial effusions often occur secondary to pericarditis, kidney failure, or tumours, and frequently do not cause any symptoms. However, large effusions or effusions which accumulate rapidly can compress the heart in a condition known as cardiac tamponade, causing breathlessness and potentially fatal low blood pressure. Fluid can be removed from the pericardial space for diagnosis or to relieve tamponade using a syringe in a procedure called pericardiocentesis. Congenital heart disease A careful physical exam will assess heart rate and rhythm. Any abnormalities will increase suspicion of cardiac arrhythmia. In addition, an elevated respiratory rate or hypoxia will increase suspicion of a pulmonary embolism. Jugular venous distention and hypotension are suggestive signs of an obstructive mechanical cardiac etiology. Pathological cardiac murmurs, specifically new ones, will clue one into a valvular etiology, hypertrophic cardiomyopathy, or an obstructive intracardiac lesion. Muffled sounds can be heard with pericardial tamponade. Pedal edema or other evidence of deep venous thrombosis increases a patient's risk of pulmonary embolism. [10] Diagnosis Due to the unstable condition of these patients, supportive therapy must be initiated simultaneously with diagnostic evaluation (Fig. 326-2). A focused history and physical examination should be performed, blood specimens sent to the laboratory, and an electrocardiogram (ECG) and chest x-ray obtained. Etiologies of Cardiogenic Shock or Pulmonary Edema Acute myocardial infarction/ischemia LV failure Ventricular septal rupture Papillary muscle/chordal rupture–severe MR Ventricular free wall rupture with subacute tamponade Other conditions complicating large MIs Post-cardiac arrest Post-cardiotomy Refractory sustained tachyarrhythmias Acute fulminant myocarditis End-stage cardiomyopathy LV apical ballooning Takotsubo’s cardiomyopathy Hypertrophic cardiomyopathy with severe outflow obstruction Aortic dissection with aortic insufficiency or tamponade Severe valvular heart disease Other Etiologies of Cardiogenic Shockb RV failure due to: Purulent pericarditis is an extremely rare entity with only a few reported cases so far. This condition deserves prompt diagnosis because of its significant mortality rate if left untreated. A 76-year-old man with a past medical history of coronary artery disease (CAD) with percutaneous coronary intervention (PCI) to the left anterior descending artery (LAD) and right circumflex artery (RCA), ischemic cardiomyopathy with moderately reduced ejection fraction (EF 45-50%), peripheral artery disease (PAD), COVID-19 pneumonia complicated by fibrotic lung disease (on 3 liters of home oxygen), type-2 diabetes mellitus (T2DM), hypertension (HTN), hyperlipidemia (HLD), and chronic kidney disease (CKD) stage III presented with complaints of pleuritic chest pain and shortness of breath. On hospital day 1, he was afebrile and hemodynamically stable with physical exam remarkable for bibasilar crackles and dry gangrene of his right first toe. He developed progressive altered mental status, hypotension, oliguric renal failure, and respiratory distress on hospital day 6. On exam at this time, he had an elevated jugular venous distension (JVD) of 12-14 cm water, pericardial friction rub with decreased heart sounds, and orthopnea; all were consistent with cardiac tamponade clinically. An electrocardiogram (EKG) showed new ST elevations in leads I, II, and aVL with ST depression in aVR and V1 with only mild elevation in troponin I to 0.07 ng/mL. A transthoracic echocardiogram (TTE) was done on hospital day 7 and showed a moderate sized pericardial effusion with inferior vena cava (IVC) enlargement but no atrial collapse, ventricular collapse, IVC collapse, or respiratory variation in the mitral and tricuspid inflow velocities. Blood cultures grew methicillin-resistant <iStaphylococcus aureus</i (MRSA) on hospital day 6, and he was started on intravenous (IV) vancomycin. The differential diagnosis for his enlarging pericardial effusion included purulent pericarditis, uremic pericarditis, or hemorrhagic effusion. He had urgent diagnostic and therapeutic pericardiocentesis with removal of 350 milliliters of fluid. The pericardial fluid was cloudy, tan-brown with a gram stain showing gram-positive cocci in clusters and cultures growing MRSA, which confirmed the diagnosis of purulent pericarditis secondary to MRSA infection. After the pericardiocentesis, his blood pressure, respiratory distress, and renal failure improved. The source of the bacteremia was from osteomyelitis of his gangrenous, right toe with bone biopsy growing both MRSA and <iStreptococcus anginosus</i. He underwent toe amputation for definitive source control. He was discharged on hospital day 24 with a plan to complete 6 weeks of IV vancomycin. Additional clues to the etiology and importance of a heart murmur can be gleaned from the history and other physical examination findings. Symptoms suggestive of cardiovascular, neurologic, or pulmonary disease help focus the differential diagnosis, as do findings relevant to the jugular venous pressure and waveforms, the arterial pulses, other heart sounds, the lungs, the abdomen, the skin, and the extremities. In many instances, laboratory studies, an ECG, and/or a chest x-ray may have been obtained earlier and may contain valuable information. A patient with suspected infective endocarditis, for example, may have a murmur in the setting of fever, chills, anorexia, fatigue, dyspnea, splenomegaly, petechiae, and positive blood cultures. A new systolic murmur in a patient with a marked fall in blood pressure after a recent MI suggests myocardial rupture. By contrast, an isolated grade 1 or 2 mid-systolic murmur at the left sternal border in a healthy, active, and asymptomatic young or absence of a third heart sound (S3). Accurate characterization of cardiac murmurs provides important insight into the natural history of many valvular and congenital heart lesions. Finally, the important role played by the physical examination in enhancing the clinician-patient relationship cannot be overestimated. THE GENERAL PHYSICAL EXAMINATION Any examination begins with an assessment of the general appear-ance of the patient, with notation of age, posture, demeanor, and 267 SEC Tion 2 DiAgnoSiS oF CARDiovASCulAR DiSoRDERS overall health status. Is the patient in pain or resting quietly, dyspneic or diaphoretic? Does the patient choose to avoid certain body positions to reduce or eliminate pain, as might be the case with suspected acute pericarditis? Are there clues indicating that dyspnea may have a pulmonary cause, such as a barrel chest deformity with an increased anterior-posterior diameter, tachypnea, and pursed-lip breathing? Skin pallor, cyanosis, and jaundice can be The acquired aortic stenosis manifests with exertional dyspnea, syncope, angina, and, ultimately, heart failure. [17] [18] Typically, symptoms begin at the age of 50 to 70 years in patients with the bicuspid aortic valve and in greater than 70 years in patients with tri-leaflet valve calcific stenosis. Patients progressively experience a gradual decrease in exercise tolerance, dyspnea on exertion, and fatigue. Severe exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, and pulmonary edema show various degrees of pulmonary venous hypertension. Angina results from the combination of the need for increased oxygen in hypertrophied myocardium and reduction of oxygen delivery secondary to the excessive compression of coronary vessels. Syncope is caused by the decrease in cerebral perfusion occurring during exertion when the arterial pressure declines due to systemic vasodilation and an inadequate increase in cardiac output related to stenosis. It is also due to the malfunction of the baroreceptor mechanism in severe aortic stenosis. Non-cardiac symptoms include gastrointestinal (GI) bleeding and cerebral emboli. GI bleeding is observed in patients with severe aortic stenosis and is often associated with angiodysplasia or other vascular malformations. It manifests from shear stress-induced platelet aggregation and reduction in the von Willebrand factor. [19] Cerebral emboli occur due to microthrombi formation on thickened bicuspid valves. There is also an observed increase in the risk of infective endocarditis in patients with aortic valve disease, especially with a bicuspid valve. On examination, carotid upstroke can be observed on palpation. A slow-rising, late-peaking, and a low-amplitude carotid impulse, pulsus parvus et tardus, is an expected finding in severe aortic stenosis and, when present, is specific to aortic stenosis. On auscultation, the second heart sound may lack a split and can be heard as a single sound during inspiration. It can also become paradoxical when the closure of the aortic valve gets delayed than the pulmonic valve. A mid-systolic ejection murmur, heard best over the right second intercostal space, with radiation into the right neck. However, high-frequency components may radiate to the apex in calcified aortic valves, and this phenomenon is called the Gallavardin phenomenon. The murmur becomes softer in LV failure and when there is a fall of stroke volume. HIV infection and ART likely contribute to increased cardiovascular disease in patients. Common presenting symptoms may include chest pain, shortness of breath, or fatigue. The examination should proceed as one would when assessing for acute coronary syndrome or valvular disease, palpating for chest wall pain, observing for jugular venous distension and peripheral edema, and auscultating for abnormal heart sounds, murmurs, or evidence of pulmonary edema. Cardiovascular AIDS-related illnesses could include purulent pericarditis or cardiac tamponade caused by Mycobacterium tuberculosis . If these conditions are suspected, observing for Beck’s triad of low blood pressure, jugular venous distension, and muffled heart sounds may confirm a compressive pericardial effusion. Chronic constrictive pericarditis (CCP) is a disease that has multiple possible causes and is associated with variable clinical findings, depending on its severity. It develops insidiously, and in many cases, particularly in developed countries, no antecedent diagnosis can be found. These cases are termed idiopathic. Tuberculosis is the leading cause of constrictive pericarditis in developing nations but represents only a small minority in developed countries. Here the authors describe two different case reports where tuberculosis was the probable cause of CCP. A 21-year-old man born in Cape Verde living in Europe for 4 years and a 24-year-old man born in Guiné Bissau were both admitted due to intense precordial pain and syncope after exertion. Interestingly both had fatigability, dyspnea, chest discomfort and palpitations on exertion, as well as progressive involuntary weight loss and decubitus cough. On physical examination they had tachycardia, jaundice, cachexia, elevated jugular venous pressure, hepatomegaly and ascites. Both electrocardiograms showed prominent P waves and chest X-ray showed bilateral pulmonary interstitial infiltrates and enlargement of the right cavities. Analytically, elevated bilirubin, leukopenia and thrombocytopenia was also found in both. Echocardiography revealed findings, in both cases, compatible with CCP including less common signs as annulus reversus and annulus paradoxus. Thoraco-abdomino-pelvic CT from both patients revealed chronic liver disease with congestion, pleural effusion, pericardial calcifications, ascites and massive mediastinal and abdominal adenopathies. Blood cultures and IGRA test were negative. However, given the presumptive diagnosis of tuberculosis (TB), anti-TB therapy was started. Despite the diagnosis of \"end-stage\" CCP with very high operative risk multidisciplinary team decided after informed consent, to perform total anterior pericardiectomy, that occurred without complications. Pericardial and mediastinal biopsies, pericardial/pleural fluid cultures/ immune-phenotyping were inconclusive. Anti- tuberculosis therapy was maintained. After surgery, the patients had a remarkable clinical improvement (NYHA I) that persisted in 6- month follow-up. These two case reports illustrate that despite the markedly elevated operative risk of pericardiectomy in \"end-stage\" forms of disease after patients informed consent must be a considered option. The other point to consider is that, despite rare, tuberculosis still is a possible diagnosis to consider in CCP in Portugal. Corticosteroids are usually used in those cases that are clearly refractory to NSAIDs and colchicine and a specific cause has not been found. Systemic corticosteroids are usually reserved for those with autoimmune disease. Prognosis One of the most feared complications of acute pericarditis is cardiac tamponade. Cardiac tamponade is accumulation of enough fluid in the pericardial space --- pericardial effusion --- to cause serious obstruction to the inflow of blood to the heart. Signs of cardiac tamponade include distended neck veins, muffled heart sounds when listening with a stethoscope, and low blood pressure (together known as Beck's triad). This condition can be fatal if not immediately treated. Pericarditis as a presenting sign of infective endocarditis is rare. Here we describe 2 cases and an additional 19 cases of pericarditis as a presenting sign of infective endocarditis reported during the last 40 y. 71% of patients were young males (mean age 43.2 y). The most commonly reported underlying conditions were diabetes mellitus type 2 (5 patients, 24%), and substance or alcohol abuse (4 patients, 19%). The native aortic valve was the most frequently involved valve. The most common symptoms were fever, cough or dyspnoea, and chest pain. Overt tamponade was diagnosed in 47% of the patients. However, pulsus paradoxus and pericardial friction rub were rare. A heart murmur was heard in 12 patients (57%). Staphylococcus aureus was the most commonly isolated pathogen concomitantly from blood and pericardial fluid. 16 patients (76%) were operated. Six underwent a pericardial procedure, 5 underwent valve replacement, 4 both, and 1 patient was operated for pseudoaneurysm. Mortality rates were 60% and 31% of patients treated with antibiotics alone versus antibiotics and surgical intervention, respectively. In patients presenting with pericarditis with or without cardiac tamponade, the possibility of infective endocarditis should be considered. Optimal therapy should consist of antibiotics and surgical intervention. An important thing to keep in mind when considering pulsus paradoxus while discerning between pericardial and non-pericardial disease is the following: pulsus paradoxus in non-pericardial disease will usually manifest with a drop in systolic and diastolic pressures. This is in contrast to pericardial disease in which the drop is mainly in systolic pressure, diastolic pressure is usually minimally affected, and thus pulse pressure will be narrower. Other critical clinical signs to be aware of are signs of tamponade such as raised jugular venous pressure (JVP), muffled heart sounds, and decreased blood pressure. If pericardial tamponade is concerned, checking for a pulsus paradoxus is recommended. It is defined as a drop of systolic blood pressure by more than 10 mm hg during inspiration. Suspected severe valve disease in symptomatic patients—dyspnea, angina, heart failure, syncope Infective endocarditis with need for cardiac surgery Asymptomatic patients with aortic regurgitation and cardiac enlargement or Prior to cardiac surgery in patients with suspected coronary artery disease New onset with angina or suspected undiagnosed coronary artery disease New-onset cardiomyopathy of uncertain cause or suspected to be due to coronary artery disease Prior to surgical correction, when symptoms or noninvasive testing suggests coronary disease Symptomatic patients with suspected cardiac tamponade or constrictive pericarditis Hypertrophic cardiomyopathy with angina Diseases of the aorta when knowledge of coronary artery involvement is necessary for management Complications Complications include pericarditis, pericardial effusion, pleuritis, pulmonary infiltration, and very rarely pericardial tamponade. Of these cardiac tamponade is the most life-threatening complication. The pericardial fluid increases intra-pericardial pressure therefore preventing complete expansion of the atria and the ventricles upon the diastole. This causes equilibration of the pressure in all four heart chambers, and results in the common findings of the tamponade which are pulsus paradoxus, Beck's triad of hypotension, muffled heart sounds, and raised jugular venous pressure, as well as EKG or Holter monitor findings such as electrical alternans. Physically the patients who progress to severe pericardial tamponade obtundate, become mentally altered, and lethargic. If left untreated, severe decrease in cardiac output, vascular collapse, and hypoperfusion of body including the brain results in death. The early and late results were retrospectively evaluated in 57 cases of double or triple valve replacement or repair performed in 1970-1983. The causes of the valvular lesions were rheumatic fever (43 cases), bacterial endocarditis (6), syphilis (1) and unknown (7 cases). The preoperative NYHA classification was III in 29 patients and IV in 28, due mainly to dyspnea of effort. Cardiomegaly (mean radiologic volume 880 cm3/m2) and atrial fibrillation were the dominant clinical findings. Surgery was on emergency indications in five cases. Cold cardioplegia combined with external cardiac cooling has been used for myocardial protection since 1977. The valve replacements were 56 aortic, 50 mitral and 2 tricuspid. In addition there were three closed and two open mitral commissurotomies, two mitral plastic repairs, three tricuspid valve anuloplasties (DeVega) and one aortic anuloplasty. Follow-up (0.3-13, mean 3.5 years) was supplemented with a check-up including two-dimensional echophonocardiography and hematologic tests. The operative mortality (10/57 patients) fell from 26% in 1970-1976 to 12% in 1977-1983. The causes of death were low cardiac output in preoperatively ill patients (5), myocardial infarction (2), technical failure (2) and sepsis (1 case). There were 11 late deaths (6.7/100 patient-years of observation), the commonest cause (5 patients) being congestive heart failure. The respective incidences of thromboembolism, paravalvular leak and postoperative endocarditis were 2.1, 4.2 and 2.1 episodes/100 patient-years.(ABSTRACT TRUNCATED AT 250 WORDS) Complications Pericarditis can progress to pericardial effusion and eventually cardiac tamponade. This can be seen in people who are experiencing the classic signs of pericarditis but then show signs of relief, and progress to show signs of cardiac tamponade which include decreased alertness and lethargy, pulsus paradoxus (decrease of at least 10 mmHg of the systolic blood pressure upon inspiration), low blood pressure (due to decreased cardiac index), (jugular vein distention from right sided heart failure and fluid overload), distant heart sounds on auscultation, and equilibration of all the diastolic blood pressures on cardiac catheterization due to the constriction of the pericardium by the fluid. Early symptoms included precordial chest pain, fatigue, dyspnea, palpitations, and fever. Patients may give symptoms suggestive of a viral prodrome (a runny nose, arthralgia, low-grade fever) 1 to 2 weeks preceding the presentation. In predominant pericardial involvement, they can describe the pain as sharp, worse with a cough or inspiration and relieved by sitting forward. If there is significant myocardial involvement, there may be a continuous pain, and sometimes, it is hard to differentiate from myocardial ischemia pain, especially in people with cardiovascular risk factors. They may also have predominant heart failure symptoms such as shortness of breath, orthopnea, pedal edema, and fatigue. Rare symptoms include arrhythmias, syncope, and sudden cardiac arrest. Physical examination findings can be variable, but common findings may include fever, pericardial friction rub and features of heart failure. Look for other signs of systemic illness which may contribute to the etiology.\nHere is the question:\nANESTHESIOLOGY, CRITICAL CARE AND EMERGENCIES: A patient with a history of fever and chest pain comes to the hospital with dyspnea and tachypnea. On physical examination, the blood pressure cyphrads are low, jugular venous pressure is elevated with a deep descending sinus X, and he has a pulsus paradoxus. What pathology should be suspected?\nHere are the potential choices:\n1. Ischemic heart disease.\n2. Dilated cardiomyopathy.\n3. Severe aortic valve stenosis.\n4. Constrictive pericarditis.\n5. Pericardial effusion with cardiac tamponade.\nThe correct answer is: 5. Pericardial effusion with cardiac tamponade."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n In genetic endocrine diseases, genetic testing is necessary for a precise diagnosis, which will provide a better knowledge of the evolution and prognosis and also indicate the adequate therapy, targeting the precise etiopathogenesis of the disease. Genetic testing in endocrinology is often based on classical cytogenetic techniques, molecular cytogenetic analysis or molecular biology techniques. Genetic testing in disorders of sex development includes the karyotype and SRY gene analysis and depending on the presence of associated clinical signs and on the observations at paraclinical examination, these tests will be followed by chromosomal array techniques and NGS sequencing. In short stature, the decision to perform a genetic test is taken depending on clinical, paraclinical and imaging signs. In case of a short stature associated with a low weight/length for gestational age, genetic testing is proposed to evaluate a Russell-Silver syndrome or if the short stature is associated with other clinical signs (e.g. intellectual disability), chromosomal analysis by microarray is proposed. If the short stature is disproportionate, it is indicated to perform a next generation sequencing (NGS) of a panel of genes involved in skeletal dysplasia. If an endocrine cause for short stature is observed at the hormonal evaluation, it is indicated to test a panel of genes involved in these pathways. In genetic obesity, depending on clinical signs associated to obesity, it will be a more targeted genetic testing. If obesity is associated with intellectual disability or other nonspecific neurological changes, a chromosomal analysis by microarray will be indicated. If monogenic obesity is suspected, NGS testing will be indicated (as genes panel or whole exome or genome analysis). Genetic testing in endocrine diseases brings an etiological diagnosis, but a favorable cost-benefit ratio derives from an adequate indication of these tests, generally proposed in expert centers for rare endocrine diseases. Diagnosis Diagnosis of 48,XXXY is usually done by a standard karyotype. A karyotype is a chromosomal analysis in which a full set of chromosomes can be seen for an individual. The presence of the additional 2 X chromosomes on the karyotype are indicative of XXXY syndrome. Another way to diagnosis 48,XXXY is by chromosomal microarray showing the presence of extra X chromosomes. Chromosomal microarray (CMA) is used to detect extra or missing chromosomal segments or whole chromosomes. CMA uses microchip-based testing to analyze many pieces of DNA. Males with 48,XXXY are diagnosed anywhere from before birth to adulthood as a result of the range in the severity of symptoms. The age range at diagnosis is likely due to the fact that XXXY is a rare syndrome, and does not cause as extreme phenotypes as other variants of Klinefelter syndrome (such as XXXXY). Copy number variants (CNVs) are responsible for many patients with short stature of unknown etiology. This study aims to analyze clinical phenotypes and identify pathogenic CNVs in a patient with short stature, intellectual disability, craniofacial deformities, and anal imperforation. G-banded karyotyping and chromosomal microarray analysis (CMA) was used on the patient to identify pathogenic causes. Fluorescence in situ hybridization (FISH) was applied to explore the abnormal genetic origin. Literatures were searched using identified CNVs as keywords in the PubMed database to perform genotype-phenotype analysis. Cytogenetic analysis revealed a normal karyotype 46,XY. CMA detected a 6.1 Mb duplication at 8q24.3 and a 3.6 Mb deletion at 21q22.3. FISH confirmed that the abnormal chromosomes were inherited from paternal balanced translocation. We compared phenotypes of our patient with 6 patients with 8q24.3 duplication and 7 cases with 21q22.3 deletion respectively. A novel 8q24.3 duplication and 21q22.3 deletion was identified in a Chinese patient. Genotype-phenotype analysis demonstrated that patients with 8q24.3 duplication and 21q22.3 deletion had specific facial features, intellectual disability, short stature, and multiple malformations. To conduct genetic testing and prenatal diagnosis for a pregnant women with growth retardation, severe mental retardation, and a history of adverse pregnancies. G-banded chromosome analysis, fluorescence in situ hybridization (FISH), and whole genome DNA microarray were used to analyze the patient and her fetus. The women was found to be a chimera containing two cell lines with 47 and 46 chromosomes, respectively. Both have involved deletion of 18q21.2q23. FISH analysis suggested that the cell line containing 47 chromosomes has harbored a chromosome marker derived from chromosome 15. The marker has contained chromosome 15p involving the SNRPN locus and part of 15q, which gave rise to a karyotype of 47,XX,del18q21.3,+ish mar D15Z1+ SNRPN+[82]/46,XX,del18q21.3[18]. Whole genome DNA microarray confirmed that a 3.044 Mb fragment from 15q11.2q12 was duplicated, which involved NIPA1, SNRPN and other 17 OMIM genes. Duplication of this region has been characterized by low mental retardation, autism, developmental delay. Meanwhile, there was a 17.992 Mb deletion at 18q21.33q23, which contained 39 OMIM genes including TNFRSF11A and PHLPP1. This fragment was characterized by mental retardation, developmental delay, short stature, and cleft palate. Whole genome microarray analysis confirmed that there was a 17.9 Mb deletion at 18q21.33q23, which has been implemented with mental retardation, general growth retardation, short stature, and cleft palate. After genetic counseling, the family decided to terminate the pregnancy at 21st week. Combined chromosome karyotyping, FISH, and whole genome DNA microarray can determine the origin of marker chromosomes and facilitate delineation of its correlation with the clinical phenotype. <bPurpose</b  Turner syndrome is a sex chromosomal aberration where majority of the patients have 45,X karyotype, while several patients are mosaic involving 45,X/46,XX; 46,X,i(Xq); and other variants. Cytogenetic analysis, karyotyping, is considered to be the \"gold standard\" to detect numerical and structural chromosomal abnormalities. In the recent years, alternative approaches, such as array comparative genomic hybridization (aCGH), have been widely used in genetic analysis to detect numerical abnormalities as well as unbalanced structural rearrangements. In this study, we report the use of karyotyping as well as aCGH in detecting a possible Turner syndrome variant. <bMethods</b  An apparent 16-year-old female was clinically diagnosed as Turner syndrome with premature ovarian failure and short stature. The genetic diagnosis was performed for the patient and the parents by karyotyping analysis. aCGH was also performed for the patient. <bMain Findings</b  Cytogenetic analysis of the patient was performed showing variant Turner syndrome (46,X,i(X)(q10)[26]/46,X,del(X)(q11.2)[11]/45,X[8]/46,XX[5]). The patient's aCGH result revealed that she has a deletion of 57,252kb of Xp22.33-p11.21 region; arr[GRCh37] Xp22.33-p11.21 (310,932-57,563-078)X1. Both aCGH and fluorescence in situ hybridization (FISH) results suggested that <ishort stature Homeobox-containing</i ( <iSHOX</i ) gene, which is located on Xp22.33, was deleted, though FISH result indicated that this was in a mosaic pattern. <bConclusion</b  In the recent years, aCGH has become the preferred method in detecting numerical abnormalities and unbalanced chromosomal rearrangements. However, its use is hindered by its failure of detecting mosaicism, especially low-level partial mosaicism. Therefore, although the resolution of the aCGH is higher, the cytogenetic investigation is still the first in line to detect mosaicism. Diagnosis and management Clinical genetics and genetic testing Genetic testing is necessary to confirm the diagnosis of PMS. A prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small to detect with this method. Chromosomal microarray should be ordered in children with suspected developmental delays or ASD. Most cases will be identified by microarray; however, small variations in genes might be missed. The falling cost for whole exome sequencing may replace DNA microarray technology for candidate gene evaluation. Biological parents should be tested with fluorescence in situ hybridization (FISH) to rule out balanced translocations or inversions. Balanced translocation in a parent increases the risk for recurrence and heritability within families (figure 3). Genetic testing for a variety of disorders has seen many advances starting with cytogenetics to evaluate human chromosomes for aneuploidy and other chromosome abnormalities. The development of molecular cytogenetics involving techniques such as fluorescence in situ hybridization (FISH) followed, permitting the detection of more subtle changes in the karyotype. Techniques to determine the precise sequence of nucleotides in DNA by DNA sequencing, notably Sanger sequencing was developed in the 1970s. In the 1980s the DNA microarray appeared, permitting laboratories to find copy number variants associated with disease that are below the level of detection of cytogenetics but too large to be detected by DNA sequencing. In recent years the development of high-throughput or next-generation sequencing has dramatically lowered the cost of DNA sequencing permitting laboratories to evaluate all 20,000 genes of the human genome at once through exome sequencing and whole genome sequencing. A Prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small. The availability of DNA microarray technology for revealing multiple genetic problems simultaneously has been the diagnostic tool of choice. The falling cost for the whole exome sequencing and, eventually, whole genome sequencing, may replace DNA microarray technology for candidate evaluation. However, fluorescence in situ hybridization (FISH) tests remain valuable for diagnosing cases of mosaicism (mosaic genetics) and chromosomal rearrangements (e.g., ring chromosome, unbalanced chromosomal translocation). Although early researchers sought a monogenic (single gene genetic disorder) explanation, recent studies have not supported that hypothesis (see Etiology). Signs and symptoms Short stature is associated with several disorders including wide variations of chromosomal disorders and single gene disorders. The objective of this report is to present the cytogenetic findings in Indonesian patients with short stature. G-banding and interphase/metaphase FISH were performed on short stature patients with and without other clinical features who were referred by clinicians all over Indonesia to our laboratory during the year 2003-2009. The results of chromosomal analysis of ninety seven patients (mean age: 10.7 years old) were collected. The group of patients with other clinical features showed sex chromosome abnormalities in 45% (18/40) and autosomal abnormalities in 10% (4/40), whereas those with short stature only, 42.1% (24/57) had sex chromosome abnormalities and 1.75% (1/57) had autosomal abnormalities. The autosomal chromosomal abnormalities involved mostly subtelomeric regions. Results discrepancies between karyotype and FISH were found in 10 patients, including detection of low-level monosomy X mosaicism in 6 patients with normal karyotype, and detection of mosaic aneuploidy chromosome 18 in 1 patient with 45,XX,rob(13;14)(q10;q10).Statistical analysis showed no significant association between the groups and the type of chromosomal abnormalities. Chromosome abnormalities account for about 50% of the short stature patients. Wide variations of both sex and autosomal chromosomes abnormalities were detected in the study. Since three out of five patients had autosomal structural abnormalities involving the subtelomeric regions, thus in the future, subtelomeric FISH or even a more sensitive method such as genomic/SNP microarray is needed to confirm deletions of subtelomeric regions of chromosome 9, 11 and 18. Low-level mosaicism in normal karyotype patients indicates interphase FISH need to be routinely carried out in short stature patients as an adjunct to karyotyping. Genetics 18p- describes a deletion of the short arm of chromosome 18. About half of the people with deletions have a breakpoint at the centromere. Those with it are said to have centromeric 18p-, and those without are said to have non-centromeric 18p-. Diagnosis Suspicion of a chromosome abnormality is typically raised due to the presence of developmental delays or birth defects. Diagnosis of 18p- is usually made via a blood sample. A routine chromosome analysis, or karyotype, is usually used to make the initial diagnosis, although it may also be made by microarray analysis. Increasingly, microarray analysis is also being used to clarify breakpoints. Prenatal diagnosis is possible via amniocentesis of chorionic villus sampling. MRI In some children without \"classic\" holoprosencephaly, microforms of holoprosencephaly may be noted on MRI, including missing olfactory tracts and bulbs and absent or hypoplastic corpus callosum. Treatment Diagnosis Suspicion of a chromosome abnormality is typically raised due to the presence of developmental delays or birth defects. Diagnosis of distal 18q- is usually made from a blood sample. A routine chromosome analysis, or karyotype, is usually used to make the initial diagnosis, although it may also be made by microarray analysis. Increasingly, microarray analysis is also being used to clarify breakpoints. Prenatal diagnosis is possible using amniocentesis or chorionic villus sampling. Treatment At present, treatment for distal 18q- is symptomatic, meaning the focus is on treating the signs and symptoms of the conditions as they arise. To ensure early diagnosis and treatment, people with distal 18q- are suggested to undergo routine screenings for thyroid, hearing, and vision problems. History Data and studies based on exome sequencing for the genetic evaluation of short stature are limited, and more large-scale studies are warranted. Some factors increase the likelihood of a monogenic cause of short stature, including skeletal dysplasia, severe short stature, and small for gestational age (SGA) without catch-up growth. However, whether these factors can serve as predictors of molecular diagnosis remains unknown. We aimed to explore the diagnostic efficiency of the associated risk factors and their exome sequences for screening. We defined and applied factors that increased the likelihood of monogenic causes of short stature in diagnostic genetic tests based on next-generation sequencing (NGS) in 814 patients with short stature and at least 1 other factor. Pathogenic/likely pathogenic (P/LP) variants in genes, copy number variations, and chromosomal abnormalities were identified in 361 patients. We found P/LP variants among 111 genes, and RASopathies comprised the most important etiology. Short stature combined with other phenotypes significantly increased the likelihood of a monogenic cause, including skeletal dysplasia, facial dysmorphism, and intellectual disability, compared with simple severe short stature (&lt;-3 SD scores). We report novel candidate pathogenic genes, KMT2C for unequivocal growth hormone insensitivity and GATA6 for SGA. Our study identified the diagnostic characteristics of NGS in short stature with different risk factors. Our study provides novel insights into the current understanding of the etiology of short stature in patients with different phenotypes. To explore the genetic cause for a child featuring growth and mental retardation. Following conventional karyotyping analysis of the trio family, next generation sequencing (NGS) was carried out to explore the origin of the supernumerary marker chromosome. Fluorescence in situ hybridization (FISH) was used to confirm the result. The karyotypes of both parents were normal, while the proband was found to be 47,XX,+mar. NGS showed that the supernumerary marker has originated from chromosome 9p13.1p24.3 with a size of 39.77 Mb. FISH has confirmed the above finding. The 9p13.1-p24.3 trisomy probably underlies the abnormal phenotypes of the child. Cytogenetic analysis combined with NGS and FISH can provide accurate diagnosis for such disorders. The majority of mutations are considered de novo, however cases of inheritance from both somatic mosaic and germ-line mosaic parents have been reported. Diagnosis Diagnosis is based on genetic testing, with the recommended testing approach being Chromosomal Microarray Analysis followed by an Intellectual Disability multigene panel or Whole Exome Sequencing. A diagnosis is established following the identification of a heterozygous pathogenic (or likely pathogenic) point mutation of the SYNGAP1 gene (present in approximately 89% of patients), a micro deletion of chromosome 6 incorporating SYNGAP1 (approximately 11% of patients), or a balanced translocation disrupting SYNGAP1. EEG monitoring frequently shows generalized epilepsy, predominantly in the occipital regions. Seizure onset usually occurs around 2 years of age. MRI is usually normal. The aim of this study was to explore the source and morphology of a small supernumerary marker chromosome (sSMC) from karyotype analysis of a patient with a unique case of mosaic Turner syndrome. The study findings will provide technical reference and genetic counseling for similar cases. A female patient with 46,X,+mar karyotype was diagnosed by genetic karyotype analysis. Genetic methods including fluorescence <iin situ</i hybridization (FISH) and copy number variation sequencing (CNV-seq) based on low-depth whole-genome sequencing were used to explore the source and morphology of sSMC. FISH technology showed that 56.5% of the cells were X and 43.5% of the cells were XY. CNV-seq detection found that the sSMC was chrY, implying that the patient's karyotype was mos 45,X[58.6%]/46,XY[41.4%]. Retrospective karyotype analysis indicated that the female patient's sSMC was inherited from her father's small chrY. Customized FISH probe of Yq12 microdeletion was positive, indicating that the sSMC was a del(Y)(q12). Based on the results of genetic diagnosis, the specialist doctor gave a comprehensive genetic consultation and ordered regular follow-up examinations. The findings of the current study showed that the chromosome description of the unique Turner case was mos 45,X[56.5%]/46,X,del(Y)(q12)[43.5%]. FISH technology played a key role in diagnosis of mosaicism. The terminal deletion of mosaic chrY provided a scientific and an accurate explanation for masculinity failure and abnormal sexual development of the current case. Microduplication at 17p13.3 and microdeletion at 21q22 are both rare chromosomal aberrations. The presence of both genomic imbalances in one patient has not been previously reported in literature. In this study, we performed a molecular diagnostic testing with a whole genome microarray on a 3-year-old boy with developmental delay, mental retardation and multiple malformations. A routine G-banding karyotype analysis was performed using peripheral lymphocytes. Chromosome microarray analysis (CMA) was done using Affymetrix CytoScan™ HD array. Genomic imbalances were further confirmed by multiple ligation-dependent probe amplification (MLPA). The result of karyotyping was normal but CMA detected a 9.8 Mb microduplication at 17p13.3-13.1 (chr17: 1-9,875,545) and a 2.8 Mb microdeletion involving 21q22.3-qter (chr21: 45,239,077-48,097,372). The imbalances were due to a balanced translocation present in patient's mother. The patient was characterized with short stature, profound developmental delay, non-verbal, intellectual disability as well as craniofacial dysmorphism, subtle brain structural anomaly and sparse scalp hair. This is the first patient reported with a combination of a microduplication at 17p13.3-13.1 and a microdeletion at 21q22.3-qter. Both genomic imbalances were undetected by conventional karyotyping but were delineated with CMA test. Synergistic effect from the two rare genomic imbalances is likely responsible for the severe clinical phenotypes observed in this patient. Copy number variation (CNV) is a kind of malfunction of DNA polymerase to produce extra genetic material which leads to more number of repeats in genes. The CNVs have been associated with different clinical phenotypes such as learning disabilities, short stature, and intellectual disability. The chromosomal microarray analysis is an effective diagnostic method for identifying new CNVs and understanding their clinical effects. In this case report, a variation that has not been reported previously in the literature is presented. This case report will contribute to increasing the knowledge. The CNV (arr [hg19] 2q12.1q12.3 (103,368,824-107,946,062) x3) detected in the index case was also detected in her father and male sibling. Key Words: DNA, Copy number variation, Chromosomal duplication, Intellectual disabilities. Trisomy 14 mosaicism is a rare chromosomal abnormality. It is associated with multiple congenital anomalies. We report a 15 year-old female with an unusual karyotype with three cell lines: 47,XX,+mar/47,XX,+14/46,XX. At six months old she had short stature, cleft palate, hyperpigmented linear spots in arms and legs and developmental delay. At present, she has mild facial dysmorphism and moderate mental retardation. Cytogenetic analysis was performed in peripheral blood lymphocytes and in the light and dark skin following standard methods. DNAarray - Oligo 180 k was carried out using Agilent Technologies and FISH analysis was accomplished using DNA BACs probes to confirm the result obtained by DNAarray. Methylation-Specific PCR (MS-PCR) of the MEG3 promoter and microsatellite analysis were performed. Microarray analysis confirmed partial trisomy 14 mosaicism; the marker chromosome was found to be from chromosome 14, the result was confirmed with FISH. Methylation (14q32.3) and microsatellite (14q11-14q32.33) analysis were carried out and UPD was discarded. The global result was: mos 47,XX,+del(14)(q11.2)[45]/47,XX,+14[10]/46,XX[45]. This is a unique case because of the coexistence of two abnormal cell lines, including one with +14 and another with +del(14)(q11.2). To our knowledge, only three patients have been reported with trisomy 14 and another abnormal cell line. The array analysis identified the marker chromosome and characterized the breakpoint. The del(14)(q11.2) does not seem to be related to any particular phenotypic characteristic of the patient; the clinical features of our patient observed until now, can be attributed to trisomy 14 mosaicism. Nevertheless, we cannot discard the manifestation of new symptoms related to her karyotype in the future. Trisomy 8 mosaicism has a wide phenotypic variability, ranging from mild dysmorphic features to severe malformations. This report concluded a female pregnant woman with trisomy 8 mosaicism, and carefully cytogenetic diagnoses were performed to give her prenatal diagnostic information. This report also provides more knowledge about trisomy 8 mosaicism and the prenatal diagnostic for clinicians. In this present study, we reported one case of pregnancy woman with trisomy 8 mosaicism. Noninvasive prenatal testing prompted an abnormal Z-score, but further three dimension color ultrasound result suggested a single live fetus with no abnormality. The phenotypic of the pregnant woman was normal. Based on our results, there were no abnormal initial myeloid cells (&lt; 10<sup- 4</sup), which suggested that the patient had no blood diseases. The peripheral blood karyotype of the patient was 47,XX,+ 8[67]/46,XX [13], and karyotype of amniotic fluid was 46, XX. The next generation sequencing (NGS) result suggested that the proportions of trisomy 8 in different tissues were obviously different; and 0% in amniotic fluid. Last, the chromosomes of the patient and her baby were confirmed using chromosome microarray analysis (CMA), and the results were arr[GRCh37](8) × 3,11p15.5p13(230750-33,455,733) × 2 hmz and normal. This pregnancy woman was trisomy 8 mosaicism, but the phenotypic was normal, and also the fetus was normal. Carefully cytogenetic diagnoses should be performed for prenatal diagnose. Genotype-first assessment is becoming the standard approach for clinical diagnosis of complex heterogeneous diseases. Microduplication and microdeletion syndromes have a range of characteristics, including intellectual disability and developmental delay, which vary in severity making patients with these syndromes very difficult to diagnose. Since the development of next-generation sequencing technologies, clinicians have been able to use a genotype-first approach to group these patients based on their microdeletion or duplication and document the disease features present in these groups. Chromosomal microarray analysis, in particular, is being used clinically to assist in diagnosing patients with microdeletion and microdulplication syndromes. In diseases, such as Autism spectrum disorder (ASD), where differentiating patients into disease subtype groups based on phenotype is challenging, genotype-first studies allow the classification of patients into subtypes based on their genetics. To emphasize the clinical significance of copy number variations (CNVs) detection by describing a case misdiagnosed as trisomy 21 syndrome by G-banded chromosomal karyotype analysis. A girl with obesity and short stature was diagnosed as trisomy 21 syndrome by G-banded chromosomal karyotype analysis. Considering the discrepancy of her karyotype with her phenotype, genomic CNVs was detected by next-generation sequencing and the result was verified by quantitative PCR (qPCR). A microduplication of 16p11.2: 29 642 339-29 775 631 (133.292 kb) was detected. qPCR assay for QPRT and SPN located in the duplicated region confirmed the finding of CNVs assay. Meanwhile, her parents did not present similar duplication in 16p11.2. The 16p11.2 microduplication was a novel genomic structural variation in the girl, though it may not be associated with her clinical manifestations. Chromosomal microarray or next-generation sequencing-based CNVs detection can accurately determine the origin of small supernumerary marker chromosome and reduce the chance of misdiagnosis. To explore the genetic cause for a patient with intellectual disability, short stature and multiple congenital anomalies, and to correlate the result with the clinical phenotype. Routine karyotyping analysis was carried out on GTG-banded metaphase chromosomes. Single nucleotide polymorphism (SNP) microarray was used to detect microdeletions or microduplications in the patient. Fluorescence in situ hybridization (FISH) was used to ascertain the origin of aberrant chromosomes. The karyotype of the patient was 46,XY,der(18), while both of his parents had a normal karyotype. SNP array identified a 1.23 Mb deletion at 18p11.32-pter (chr18: 136 227-1 370 501, hg19) and a 33.76 Mb duplication at 18q21.1-qter (chr18: 44 250 359-78 013 728, hg19) in the patient. Above finding was confirmed by dual-color FISH with one color for 18p and another for 18q. The patient presented with some common features of 18p deletion and 18q duplication including intellectual disability and growth retardation, in addition with some features of 18p deletion including pectus excavatum, short stature and growth hormone (GH) deficiency. The patient showed progressive improvement of stature with GH therapy. Comparison of patients with previously reported dup(18q)+del(18p) recombinations suggested that, even for patients with similar breakpoints, their phenotypes have ranged from normal to severe and there were no consistent findings. As aberrations involving double chromosomal segments often result in phenotypic variability, it has been difficult to correlate the genotype of our patient with his phenotype. To assess the value of chromosomal microarray analysis (CMA) for the diagnosis of children with intellectual disability/developmental delay (ID/DD) but a normal karytype. Peripheral blood samples from 92 ID/DD patients were analyzed with CMA using Affymetrix CytoScan 750K arrays. The results were analyzed by ChAS v3.0 software. Eighteen cases (19.57%) were detected with abnormalities by CMA, among which 10 cases were diagnosed with microdeletion/microduplication syndromes. These included 2 Williams-Beuren syndromes, 2 Angelman syndromes, 2 Russell-Silver syndromes, 1 Smith-Magenis syndromes, 1 Wolf-Hirschhorn syndromes, 1 15q26 overgrowth syndrome and 1 Xq28 (MECP2) duplication syndrome. In addition, 8 cases were diagnosed with pathogenic copy number variations (pCNV). CMA can significantly improve the diagnostic rate for patients with ID/DD, which is of great value for the treatment of such children and guidance of reproduction for their parents. Therefore, CMA should become the first-line diagnostic test for patients with ID/DD.\nHere is the question:\nGENETICS: 15-year-old female presenting with delayed menarche and short stature. She does not have intellectual disability. Which of the following genetic tests would be routinely used for the diagnosis of this patient:\nHere are the potential choices:\n1. Massive sequencing (NGS).\n2. FISH.\n3. DNA and/or RNA microarrays.\n4. Karyotype.\nThe correct answer is: ",
        "gold_answer": "4 Karyotype.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n In genetic endocrine diseases, genetic testing is necessary for a precise diagnosis, which will provide a better knowledge of the evolution and prognosis and also indicate the adequate therapy, targeting the precise etiopathogenesis of the disease. Genetic testing in endocrinology is often based on classical cytogenetic techniques, molecular cytogenetic analysis or molecular biology techniques. Genetic testing in disorders of sex development includes the karyotype and SRY gene analysis and depending on the presence of associated clinical signs and on the observations at paraclinical examination, these tests will be followed by chromosomal array techniques and NGS sequencing. In short stature, the decision to perform a genetic test is taken depending on clinical, paraclinical and imaging signs. In case of a short stature associated with a low weight/length for gestational age, genetic testing is proposed to evaluate a Russell-Silver syndrome or if the short stature is associated with other clinical signs (e.g. intellectual disability), chromosomal analysis by microarray is proposed. If the short stature is disproportionate, it is indicated to perform a next generation sequencing (NGS) of a panel of genes involved in skeletal dysplasia. If an endocrine cause for short stature is observed at the hormonal evaluation, it is indicated to test a panel of genes involved in these pathways. In genetic obesity, depending on clinical signs associated to obesity, it will be a more targeted genetic testing. If obesity is associated with intellectual disability or other nonspecific neurological changes, a chromosomal analysis by microarray will be indicated. If monogenic obesity is suspected, NGS testing will be indicated (as genes panel or whole exome or genome analysis). Genetic testing in endocrine diseases brings an etiological diagnosis, but a favorable cost-benefit ratio derives from an adequate indication of these tests, generally proposed in expert centers for rare endocrine diseases. Diagnosis Diagnosis of 48,XXXY is usually done by a standard karyotype. A karyotype is a chromosomal analysis in which a full set of chromosomes can be seen for an individual. The presence of the additional 2 X chromosomes on the karyotype are indicative of XXXY syndrome. Another way to diagnosis 48,XXXY is by chromosomal microarray showing the presence of extra X chromosomes. Chromosomal microarray (CMA) is used to detect extra or missing chromosomal segments or whole chromosomes. CMA uses microchip-based testing to analyze many pieces of DNA. Males with 48,XXXY are diagnosed anywhere from before birth to adulthood as a result of the range in the severity of symptoms. The age range at diagnosis is likely due to the fact that XXXY is a rare syndrome, and does not cause as extreme phenotypes as other variants of Klinefelter syndrome (such as XXXXY). Copy number variants (CNVs) are responsible for many patients with short stature of unknown etiology. This study aims to analyze clinical phenotypes and identify pathogenic CNVs in a patient with short stature, intellectual disability, craniofacial deformities, and anal imperforation. G-banded karyotyping and chromosomal microarray analysis (CMA) was used on the patient to identify pathogenic causes. Fluorescence in situ hybridization (FISH) was applied to explore the abnormal genetic origin. Literatures were searched using identified CNVs as keywords in the PubMed database to perform genotype-phenotype analysis. Cytogenetic analysis revealed a normal karyotype 46,XY. CMA detected a 6.1 Mb duplication at 8q24.3 and a 3.6 Mb deletion at 21q22.3. FISH confirmed that the abnormal chromosomes were inherited from paternal balanced translocation. We compared phenotypes of our patient with 6 patients with 8q24.3 duplication and 7 cases with 21q22.3 deletion respectively. A novel 8q24.3 duplication and 21q22.3 deletion was identified in a Chinese patient. Genotype-phenotype analysis demonstrated that patients with 8q24.3 duplication and 21q22.3 deletion had specific facial features, intellectual disability, short stature, and multiple malformations. To conduct genetic testing and prenatal diagnosis for a pregnant women with growth retardation, severe mental retardation, and a history of adverse pregnancies. G-banded chromosome analysis, fluorescence in situ hybridization (FISH), and whole genome DNA microarray were used to analyze the patient and her fetus. The women was found to be a chimera containing two cell lines with 47 and 46 chromosomes, respectively. Both have involved deletion of 18q21.2q23. FISH analysis suggested that the cell line containing 47 chromosomes has harbored a chromosome marker derived from chromosome 15. The marker has contained chromosome 15p involving the SNRPN locus and part of 15q, which gave rise to a karyotype of 47,XX,del18q21.3,+ish mar D15Z1+ SNRPN+[82]/46,XX,del18q21.3[18]. Whole genome DNA microarray confirmed that a 3.044 Mb fragment from 15q11.2q12 was duplicated, which involved NIPA1, SNRPN and other 17 OMIM genes. Duplication of this region has been characterized by low mental retardation, autism, developmental delay. Meanwhile, there was a 17.992 Mb deletion at 18q21.33q23, which contained 39 OMIM genes including TNFRSF11A and PHLPP1. This fragment was characterized by mental retardation, developmental delay, short stature, and cleft palate. Whole genome microarray analysis confirmed that there was a 17.9 Mb deletion at 18q21.33q23, which has been implemented with mental retardation, general growth retardation, short stature, and cleft palate. After genetic counseling, the family decided to terminate the pregnancy at 21st week. Combined chromosome karyotyping, FISH, and whole genome DNA microarray can determine the origin of marker chromosomes and facilitate delineation of its correlation with the clinical phenotype. <bPurpose</b  Turner syndrome is a sex chromosomal aberration where majority of the patients have 45,X karyotype, while several patients are mosaic involving 45,X/46,XX; 46,X,i(Xq); and other variants. Cytogenetic analysis, karyotyping, is considered to be the \"gold standard\" to detect numerical and structural chromosomal abnormalities. In the recent years, alternative approaches, such as array comparative genomic hybridization (aCGH), have been widely used in genetic analysis to detect numerical abnormalities as well as unbalanced structural rearrangements. In this study, we report the use of karyotyping as well as aCGH in detecting a possible Turner syndrome variant. <bMethods</b  An apparent 16-year-old female was clinically diagnosed as Turner syndrome with premature ovarian failure and short stature. The genetic diagnosis was performed for the patient and the parents by karyotyping analysis. aCGH was also performed for the patient. <bMain Findings</b  Cytogenetic analysis of the patient was performed showing variant Turner syndrome (46,X,i(X)(q10)[26]/46,X,del(X)(q11.2)[11]/45,X[8]/46,XX[5]). The patient's aCGH result revealed that she has a deletion of 57,252kb of Xp22.33-p11.21 region; arr[GRCh37] Xp22.33-p11.21 (310,932-57,563-078)X1. Both aCGH and fluorescence in situ hybridization (FISH) results suggested that <ishort stature Homeobox-containing</i ( <iSHOX</i ) gene, which is located on Xp22.33, was deleted, though FISH result indicated that this was in a mosaic pattern. <bConclusion</b  In the recent years, aCGH has become the preferred method in detecting numerical abnormalities and unbalanced chromosomal rearrangements. However, its use is hindered by its failure of detecting mosaicism, especially low-level partial mosaicism. Therefore, although the resolution of the aCGH is higher, the cytogenetic investigation is still the first in line to detect mosaicism. Diagnosis and management Clinical genetics and genetic testing Genetic testing is necessary to confirm the diagnosis of PMS. A prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small to detect with this method. Chromosomal microarray should be ordered in children with suspected developmental delays or ASD. Most cases will be identified by microarray; however, small variations in genes might be missed. The falling cost for whole exome sequencing may replace DNA microarray technology for candidate gene evaluation. Biological parents should be tested with fluorescence in situ hybridization (FISH) to rule out balanced translocations or inversions. Balanced translocation in a parent increases the risk for recurrence and heritability within families (figure 3). Genetic testing for a variety of disorders has seen many advances starting with cytogenetics to evaluate human chromosomes for aneuploidy and other chromosome abnormalities. The development of molecular cytogenetics involving techniques such as fluorescence in situ hybridization (FISH) followed, permitting the detection of more subtle changes in the karyotype. Techniques to determine the precise sequence of nucleotides in DNA by DNA sequencing, notably Sanger sequencing was developed in the 1970s. In the 1980s the DNA microarray appeared, permitting laboratories to find copy number variants associated with disease that are below the level of detection of cytogenetics but too large to be detected by DNA sequencing. In recent years the development of high-throughput or next-generation sequencing has dramatically lowered the cost of DNA sequencing permitting laboratories to evaluate all 20,000 genes of the human genome at once through exome sequencing and whole genome sequencing. A Prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small. The availability of DNA microarray technology for revealing multiple genetic problems simultaneously has been the diagnostic tool of choice. The falling cost for the whole exome sequencing and, eventually, whole genome sequencing, may replace DNA microarray technology for candidate evaluation. However, fluorescence in situ hybridization (FISH) tests remain valuable for diagnosing cases of mosaicism (mosaic genetics) and chromosomal rearrangements (e.g., ring chromosome, unbalanced chromosomal translocation). Although early researchers sought a monogenic (single gene genetic disorder) explanation, recent studies have not supported that hypothesis (see Etiology). Signs and symptoms Short stature is associated with several disorders including wide variations of chromosomal disorders and single gene disorders. The objective of this report is to present the cytogenetic findings in Indonesian patients with short stature. G-banding and interphase/metaphase FISH were performed on short stature patients with and without other clinical features who were referred by clinicians all over Indonesia to our laboratory during the year 2003-2009. The results of chromosomal analysis of ninety seven patients (mean age: 10.7 years old) were collected. The group of patients with other clinical features showed sex chromosome abnormalities in 45% (18/40) and autosomal abnormalities in 10% (4/40), whereas those with short stature only, 42.1% (24/57) had sex chromosome abnormalities and 1.75% (1/57) had autosomal abnormalities. The autosomal chromosomal abnormalities involved mostly subtelomeric regions. Results discrepancies between karyotype and FISH were found in 10 patients, including detection of low-level monosomy X mosaicism in 6 patients with normal karyotype, and detection of mosaic aneuploidy chromosome 18 in 1 patient with 45,XX,rob(13;14)(q10;q10).Statistical analysis showed no significant association between the groups and the type of chromosomal abnormalities. Chromosome abnormalities account for about 50% of the short stature patients. Wide variations of both sex and autosomal chromosomes abnormalities were detected in the study. Since three out of five patients had autosomal structural abnormalities involving the subtelomeric regions, thus in the future, subtelomeric FISH or even a more sensitive method such as genomic/SNP microarray is needed to confirm deletions of subtelomeric regions of chromosome 9, 11 and 18. Low-level mosaicism in normal karyotype patients indicates interphase FISH need to be routinely carried out in short stature patients as an adjunct to karyotyping. Genetics 18p- describes a deletion of the short arm of chromosome 18. About half of the people with deletions have a breakpoint at the centromere. Those with it are said to have centromeric 18p-, and those without are said to have non-centromeric 18p-. Diagnosis Suspicion of a chromosome abnormality is typically raised due to the presence of developmental delays or birth defects. Diagnosis of 18p- is usually made via a blood sample. A routine chromosome analysis, or karyotype, is usually used to make the initial diagnosis, although it may also be made by microarray analysis. Increasingly, microarray analysis is also being used to clarify breakpoints. Prenatal diagnosis is possible via amniocentesis of chorionic villus sampling. MRI In some children without \"classic\" holoprosencephaly, microforms of holoprosencephaly may be noted on MRI, including missing olfactory tracts and bulbs and absent or hypoplastic corpus callosum. Treatment Diagnosis Suspicion of a chromosome abnormality is typically raised due to the presence of developmental delays or birth defects. Diagnosis of distal 18q- is usually made from a blood sample. A routine chromosome analysis, or karyotype, is usually used to make the initial diagnosis, although it may also be made by microarray analysis. Increasingly, microarray analysis is also being used to clarify breakpoints. Prenatal diagnosis is possible using amniocentesis or chorionic villus sampling. Treatment At present, treatment for distal 18q- is symptomatic, meaning the focus is on treating the signs and symptoms of the conditions as they arise. To ensure early diagnosis and treatment, people with distal 18q- are suggested to undergo routine screenings for thyroid, hearing, and vision problems. History Data and studies based on exome sequencing for the genetic evaluation of short stature are limited, and more large-scale studies are warranted. Some factors increase the likelihood of a monogenic cause of short stature, including skeletal dysplasia, severe short stature, and small for gestational age (SGA) without catch-up growth. However, whether these factors can serve as predictors of molecular diagnosis remains unknown. We aimed to explore the diagnostic efficiency of the associated risk factors and their exome sequences for screening. We defined and applied factors that increased the likelihood of monogenic causes of short stature in diagnostic genetic tests based on next-generation sequencing (NGS) in 814 patients with short stature and at least 1 other factor. Pathogenic/likely pathogenic (P/LP) variants in genes, copy number variations, and chromosomal abnormalities were identified in 361 patients. We found P/LP variants among 111 genes, and RASopathies comprised the most important etiology. Short stature combined with other phenotypes significantly increased the likelihood of a monogenic cause, including skeletal dysplasia, facial dysmorphism, and intellectual disability, compared with simple severe short stature (&lt;-3 SD scores). We report novel candidate pathogenic genes, KMT2C for unequivocal growth hormone insensitivity and GATA6 for SGA. Our study identified the diagnostic characteristics of NGS in short stature with different risk factors. Our study provides novel insights into the current understanding of the etiology of short stature in patients with different phenotypes. To explore the genetic cause for a child featuring growth and mental retardation. Following conventional karyotyping analysis of the trio family, next generation sequencing (NGS) was carried out to explore the origin of the supernumerary marker chromosome. Fluorescence in situ hybridization (FISH) was used to confirm the result. The karyotypes of both parents were normal, while the proband was found to be 47,XX,+mar. NGS showed that the supernumerary marker has originated from chromosome 9p13.1p24.3 with a size of 39.77 Mb. FISH has confirmed the above finding. The 9p13.1-p24.3 trisomy probably underlies the abnormal phenotypes of the child. Cytogenetic analysis combined with NGS and FISH can provide accurate diagnosis for such disorders. The majority of mutations are considered de novo, however cases of inheritance from both somatic mosaic and germ-line mosaic parents have been reported. Diagnosis Diagnosis is based on genetic testing, with the recommended testing approach being Chromosomal Microarray Analysis followed by an Intellectual Disability multigene panel or Whole Exome Sequencing. A diagnosis is established following the identification of a heterozygous pathogenic (or likely pathogenic) point mutation of the SYNGAP1 gene (present in approximately 89% of patients), a micro deletion of chromosome 6 incorporating SYNGAP1 (approximately 11% of patients), or a balanced translocation disrupting SYNGAP1. EEG monitoring frequently shows generalized epilepsy, predominantly in the occipital regions. Seizure onset usually occurs around 2 years of age. MRI is usually normal. The aim of this study was to explore the source and morphology of a small supernumerary marker chromosome (sSMC) from karyotype analysis of a patient with a unique case of mosaic Turner syndrome. The study findings will provide technical reference and genetic counseling for similar cases. A female patient with 46,X,+mar karyotype was diagnosed by genetic karyotype analysis. Genetic methods including fluorescence <iin situ</i hybridization (FISH) and copy number variation sequencing (CNV-seq) based on low-depth whole-genome sequencing were used to explore the source and morphology of sSMC. FISH technology showed that 56.5% of the cells were X and 43.5% of the cells were XY. CNV-seq detection found that the sSMC was chrY, implying that the patient's karyotype was mos 45,X[58.6%]/46,XY[41.4%]. Retrospective karyotype analysis indicated that the female patient's sSMC was inherited from her father's small chrY. Customized FISH probe of Yq12 microdeletion was positive, indicating that the sSMC was a del(Y)(q12). Based on the results of genetic diagnosis, the specialist doctor gave a comprehensive genetic consultation and ordered regular follow-up examinations. The findings of the current study showed that the chromosome description of the unique Turner case was mos 45,X[56.5%]/46,X,del(Y)(q12)[43.5%]. FISH technology played a key role in diagnosis of mosaicism. The terminal deletion of mosaic chrY provided a scientific and an accurate explanation for masculinity failure and abnormal sexual development of the current case. Microduplication at 17p13.3 and microdeletion at 21q22 are both rare chromosomal aberrations. The presence of both genomic imbalances in one patient has not been previously reported in literature. In this study, we performed a molecular diagnostic testing with a whole genome microarray on a 3-year-old boy with developmental delay, mental retardation and multiple malformations. A routine G-banding karyotype analysis was performed using peripheral lymphocytes. Chromosome microarray analysis (CMA) was done using Affymetrix CytoScan™ HD array. Genomic imbalances were further confirmed by multiple ligation-dependent probe amplification (MLPA). The result of karyotyping was normal but CMA detected a 9.8 Mb microduplication at 17p13.3-13.1 (chr17: 1-9,875,545) and a 2.8 Mb microdeletion involving 21q22.3-qter (chr21: 45,239,077-48,097,372). The imbalances were due to a balanced translocation present in patient's mother. The patient was characterized with short stature, profound developmental delay, non-verbal, intellectual disability as well as craniofacial dysmorphism, subtle brain structural anomaly and sparse scalp hair. This is the first patient reported with a combination of a microduplication at 17p13.3-13.1 and a microdeletion at 21q22.3-qter. Both genomic imbalances were undetected by conventional karyotyping but were delineated with CMA test. Synergistic effect from the two rare genomic imbalances is likely responsible for the severe clinical phenotypes observed in this patient. Copy number variation (CNV) is a kind of malfunction of DNA polymerase to produce extra genetic material which leads to more number of repeats in genes. The CNVs have been associated with different clinical phenotypes such as learning disabilities, short stature, and intellectual disability. The chromosomal microarray analysis is an effective diagnostic method for identifying new CNVs and understanding their clinical effects. In this case report, a variation that has not been reported previously in the literature is presented. This case report will contribute to increasing the knowledge. The CNV (arr [hg19] 2q12.1q12.3 (103,368,824-107,946,062) x3) detected in the index case was also detected in her father and male sibling. Key Words: DNA, Copy number variation, Chromosomal duplication, Intellectual disabilities. Trisomy 14 mosaicism is a rare chromosomal abnormality. It is associated with multiple congenital anomalies. We report a 15 year-old female with an unusual karyotype with three cell lines: 47,XX,+mar/47,XX,+14/46,XX. At six months old she had short stature, cleft palate, hyperpigmented linear spots in arms and legs and developmental delay. At present, she has mild facial dysmorphism and moderate mental retardation. Cytogenetic analysis was performed in peripheral blood lymphocytes and in the light and dark skin following standard methods. DNAarray - Oligo 180 k was carried out using Agilent Technologies and FISH analysis was accomplished using DNA BACs probes to confirm the result obtained by DNAarray. Methylation-Specific PCR (MS-PCR) of the MEG3 promoter and microsatellite analysis were performed. Microarray analysis confirmed partial trisomy 14 mosaicism; the marker chromosome was found to be from chromosome 14, the result was confirmed with FISH. Methylation (14q32.3) and microsatellite (14q11-14q32.33) analysis were carried out and UPD was discarded. The global result was: mos 47,XX,+del(14)(q11.2)[45]/47,XX,+14[10]/46,XX[45]. This is a unique case because of the coexistence of two abnormal cell lines, including one with +14 and another with +del(14)(q11.2). To our knowledge, only three patients have been reported with trisomy 14 and another abnormal cell line. The array analysis identified the marker chromosome and characterized the breakpoint. The del(14)(q11.2) does not seem to be related to any particular phenotypic characteristic of the patient; the clinical features of our patient observed until now, can be attributed to trisomy 14 mosaicism. Nevertheless, we cannot discard the manifestation of new symptoms related to her karyotype in the future. Trisomy 8 mosaicism has a wide phenotypic variability, ranging from mild dysmorphic features to severe malformations. This report concluded a female pregnant woman with trisomy 8 mosaicism, and carefully cytogenetic diagnoses were performed to give her prenatal diagnostic information. This report also provides more knowledge about trisomy 8 mosaicism and the prenatal diagnostic for clinicians. In this present study, we reported one case of pregnancy woman with trisomy 8 mosaicism. Noninvasive prenatal testing prompted an abnormal Z-score, but further three dimension color ultrasound result suggested a single live fetus with no abnormality. The phenotypic of the pregnant woman was normal. Based on our results, there were no abnormal initial myeloid cells (&lt; 10<sup- 4</sup), which suggested that the patient had no blood diseases. The peripheral blood karyotype of the patient was 47,XX,+ 8[67]/46,XX [13], and karyotype of amniotic fluid was 46, XX. The next generation sequencing (NGS) result suggested that the proportions of trisomy 8 in different tissues were obviously different; and 0% in amniotic fluid. Last, the chromosomes of the patient and her baby were confirmed using chromosome microarray analysis (CMA), and the results were arr[GRCh37](8) × 3,11p15.5p13(230750-33,455,733) × 2 hmz and normal. This pregnancy woman was trisomy 8 mosaicism, but the phenotypic was normal, and also the fetus was normal. Carefully cytogenetic diagnoses should be performed for prenatal diagnose. Genotype-first assessment is becoming the standard approach for clinical diagnosis of complex heterogeneous diseases. Microduplication and microdeletion syndromes have a range of characteristics, including intellectual disability and developmental delay, which vary in severity making patients with these syndromes very difficult to diagnose. Since the development of next-generation sequencing technologies, clinicians have been able to use a genotype-first approach to group these patients based on their microdeletion or duplication and document the disease features present in these groups. Chromosomal microarray analysis, in particular, is being used clinically to assist in diagnosing patients with microdeletion and microdulplication syndromes. In diseases, such as Autism spectrum disorder (ASD), where differentiating patients into disease subtype groups based on phenotype is challenging, genotype-first studies allow the classification of patients into subtypes based on their genetics. To emphasize the clinical significance of copy number variations (CNVs) detection by describing a case misdiagnosed as trisomy 21 syndrome by G-banded chromosomal karyotype analysis. A girl with obesity and short stature was diagnosed as trisomy 21 syndrome by G-banded chromosomal karyotype analysis. Considering the discrepancy of her karyotype with her phenotype, genomic CNVs was detected by next-generation sequencing and the result was verified by quantitative PCR (qPCR). A microduplication of 16p11.2: 29 642 339-29 775 631 (133.292 kb) was detected. qPCR assay for QPRT and SPN located in the duplicated region confirmed the finding of CNVs assay. Meanwhile, her parents did not present similar duplication in 16p11.2. The 16p11.2 microduplication was a novel genomic structural variation in the girl, though it may not be associated with her clinical manifestations. Chromosomal microarray or next-generation sequencing-based CNVs detection can accurately determine the origin of small supernumerary marker chromosome and reduce the chance of misdiagnosis. To explore the genetic cause for a patient with intellectual disability, short stature and multiple congenital anomalies, and to correlate the result with the clinical phenotype. Routine karyotyping analysis was carried out on GTG-banded metaphase chromosomes. Single nucleotide polymorphism (SNP) microarray was used to detect microdeletions or microduplications in the patient. Fluorescence in situ hybridization (FISH) was used to ascertain the origin of aberrant chromosomes. The karyotype of the patient was 46,XY,der(18), while both of his parents had a normal karyotype. SNP array identified a 1.23 Mb deletion at 18p11.32-pter (chr18: 136 227-1 370 501, hg19) and a 33.76 Mb duplication at 18q21.1-qter (chr18: 44 250 359-78 013 728, hg19) in the patient. Above finding was confirmed by dual-color FISH with one color for 18p and another for 18q. The patient presented with some common features of 18p deletion and 18q duplication including intellectual disability and growth retardation, in addition with some features of 18p deletion including pectus excavatum, short stature and growth hormone (GH) deficiency. The patient showed progressive improvement of stature with GH therapy. Comparison of patients with previously reported dup(18q)+del(18p) recombinations suggested that, even for patients with similar breakpoints, their phenotypes have ranged from normal to severe and there were no consistent findings. As aberrations involving double chromosomal segments often result in phenotypic variability, it has been difficult to correlate the genotype of our patient with his phenotype. To assess the value of chromosomal microarray analysis (CMA) for the diagnosis of children with intellectual disability/developmental delay (ID/DD) but a normal karytype. Peripheral blood samples from 92 ID/DD patients were analyzed with CMA using Affymetrix CytoScan 750K arrays. The results were analyzed by ChAS v3.0 software. Eighteen cases (19.57%) were detected with abnormalities by CMA, among which 10 cases were diagnosed with microdeletion/microduplication syndromes. These included 2 Williams-Beuren syndromes, 2 Angelman syndromes, 2 Russell-Silver syndromes, 1 Smith-Magenis syndromes, 1 Wolf-Hirschhorn syndromes, 1 15q26 overgrowth syndrome and 1 Xq28 (MECP2) duplication syndrome. In addition, 8 cases were diagnosed with pathogenic copy number variations (pCNV). CMA can significantly improve the diagnostic rate for patients with ID/DD, which is of great value for the treatment of such children and guidance of reproduction for their parents. Therefore, CMA should become the first-line diagnostic test for patients with ID/DD.\nHere is the question:\nGENETICS: 15-year-old female presenting with delayed menarche and short stature. She does not have intellectual disability. Which of the following genetic tests would be routinely used for the diagnosis of this patient:\nHere are the potential choices:\n1. Massive sequencing (NGS).\n2. FISH.\n3. DNA and/or RNA microarrays.\n4. Karyotype.\nThe correct answer is: 4. Karyotype."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Anti-glomerular basement membrane (GBM) glomerulonephritis does not usually coexist with another glomerulonephritis such as IgA nephropathy. We present a rare case having a combination of these two diseases, and furthermore, histological evaluation could be performed before and after the development of anti-GBM glomerulonephritis over a period of only10 months. A 66-year-old woman was admitted with complaints of microscopic hematuria and mild proteinuria for the past 3 years. Serum creatinine level was normal at that time. The first renal biopsy was performed. Light microscopy revealed mesangial proliferative glomerulonephritis with fibro-cellular crescents in one out of 18 glomeruli, excluding one global sclerotic glomerulus. Immunofluorescence (IF) showed IgA and C3 deposition in the mesangium. Therefore, the diagnosis was IgA nephropathy. Eight months later, the patient's serum creatinine suddenly rose to 4.53 mg/dL and urinalysis showed 100 red blood cells per high power field with nephrotic range proteinuria (12.3 g/g<subCr</sub). The serological tests revealed the presence of anti-GBM antibody at the titer of 116 IU/mL. Treatments were begun after admission, consisting of hemodialysis, plasma exchange, and intravenous methylprednisolone pulse therapy. At 4 weeks after admission, the second renal biopsy was performed. Light microscopy revealed crescents in 18 of 25 glomeruli, excluding six global sclerotic glomeruli. IF showed linear IgG deposition along the GBM in addition to granular IgA and C3 deposition. Based on these findings, the diagnosis of anti-GBM glomerulonephritis and IgA nephropathy was confirmed. Renal function was not restored despite treatment, but alveolar hemorrhage was prevented. We report a patient with a diagnosis of anti-GBM disease during the course of IgA nephropathy. This case strongly suggests that the presence of autoantibodies should be checked to rule out overlapping autoimmune conditions even in patient who have previously been diagnosed with chronic glomerulonephritis, such as IgA nephropathy, who present an unusually rapid clinical course. Smoking in young men may trigger anti-GBM disease manifesting with hemoptysis. We present a male adolescent in whom hemoptysis was mistaken to be a sign of airway infection for several months and who later on underwent an unusual antibody-negative relapse. The 16-year-old patient had a history of smoking and therapy-refractant hemoptysis and, later, acute macrohematuria with renal insufficiency necessitating hemodialysis (initial creatinine 4.2 mg/ dl). Chest X-ray showed diffuse lung infiltration. Renal biopsy revealed linear IgG deposits along the glomerular basement membrane (GBM) and cellular crescents in 13/16 glomeruli, simultaneously increased anti-GBM antibodies were detected. Thus, anti-GBM glomerulonephritis was diagnosed. After treatment with prednisone, oral cyclophosphamide and plasmapheresis, chest X-ray and hemoptysis improved, but renal failure persisted. Anti-GBM antibodies were negative. 4 weeks later, the patient presented again with a clinical relapse of severe hemoptysis and respiratory insufficiency after smoke exposition. Despite negative anti-GBM antibodies, he was treated similarly to a relapse and after the second course of plasmapheresis the patients' general condition improved and hemoptysis subsided. During the next 10 months the patient was stable with negative antibodies. He was under intermittent hemodialysis until laboratory measurements showed improved renal function. Now, 30 months after the acute episode, the patient is off dialysis for 17 months with stable creatinine values of 1.9 - 2.4 mg/dl, and is currently being treated with antihypertensive medicaments, calcitriol, calciumacetate, natriumhydrogencarbonate and allopurinol. The prognosis of anti-GBM glomerulonephritis depends on serum creatinine and the need of dialysis at initial presentation. In these patients, one-year survival rate is 67% and 5% for kidney function. Of note, despite the unfavorable prognosis in our patient, renal function recovered after 1 year of hemodialysis treatment. It is important to consider that in patients with anti-GBM disease antibody-negative relapses are possible. The prognosis for renal function in anti-GBM glomerulonephritis (anti-GBM GN) is extremely poor, and when renal impairment progresses severely, it is difficult to expect improvement. In addition, it is also known that once the disease activity can be controlled by aggressive treatment, its recurrence is rare. We experienced an anti-GBM GN that improved from severe renal dysfunction and relapsed. A possible cause was the superimpose of nephrotic syndrome due to minimal change disease (MCD). A 30-year-old man was admitted to our hospital because of general malaise, fever, oliguria and renal dysfunction. The patient's laboratory data showed serum creatinine as high as 6.6 mg/dl, and severe inflammation (C-reactive protein 20.6 mg/dl). Anti-glomerular basement membrane antibody (anti-GBM Ab) was detected in his serum, which led to the diagnosis of anti-GBM GN. Treatment was initiated with high-dose glucocorticoid (GC) and plasma exchange therapy (PE), and the patient's renal function and oliguria improved rapidly and he was discharged 40 days after admission. Renal biopsy findings showed cellular crescents associated with linear IgG depositions along the glomerular tufts compatible with anti-GBM GN, but only about one-third of the glomeruli was involved, suggesting that it still remains an early stage of the disease. However, 2 months after discharge, he had a relapse and was readmitted due to severe proteinuria with positive anti-GBM Ab. On the second admission, after high-dose GC and PE combined with intravenous cyclophosphamide, and remission was achieved. Despite the relatively minor renal biopsy findings, the patient showed rapid renal dysfunction and relatively rapid improvement with our treatment. Electron microscopy of the renal biopsy tissue showed significant foot process effacement on podocytes in the apparently normal glomeruli, without electron dense deposits. On the basis of clinical course and renal pathology, it is suggested that the present case was a rare complication of an early stage of anti-GBM GN and minimal change nephrotic syndrome. Although the simultaneous development of anti-GBM GN and MCD with anti-GBM antibody is unclear, it might have been precipitated by influenza infection or some unknown factor. We report a case of endstage renal disease due to simultaneous occurrence of membranous nephropathy and crescentic glomerulonephritis associated with anti-GBM antibodies. The patient was a 60-year-old male and was hospitalized for prolonged anorexia and general malaise. On admission, his body temperature was 38.5 degrees C. Urinalysis revealed 3+ proteinuria and the sediment contained abundant erythrocytes. The urea nitrogen was 142.4 mg/dl, the creatinine 19.5 mg/dl, the potassium 6.47 mEq/dl and CRP 10.1 mg/dl. Anti-GBM antibodies were 1000EU/ml. Immediately after initiating hemodialysis, pulse steroid therapy, plasma exchange and continuous heparinization were performed. However, renal function had been impaired and maintenance hemodialysis was required. Histological examination of the renal specimen revealed marked epithelial crescent formation, whereas thickening of basement membrane and mesangial proliferation were not observed. By immunofluorescent staining, both bright linear and fine granular fixation of IgG and fine granular fixations of C3 along the glomerular capillary walls were observed. Electron microscopy showed subepithelial electron lucent deposits and thickening of the glomerular basement membrane, diagnostic of the advanced membranous nephropathy (stage IV). Goodpasture's syndrome, a rare disease, is an organ-specific autoimmune disease mediated by anti-glomerular basement membrane antibodies. Its pathology is characterized by crescentic glomerulonephritis with linear immunofluorescent staining for immunoglobulin G on the glomerular basement membrane. Although rare, a few cases with absence of circulating anti-glomerular membrane antibodies have been described. The objective of this clinical case report is to describe and discuss a case of a 27-year-old white man who was hospitalized with a 1-year history of weight loss and a 1-month history of hemoptysis, with aggravation  the day before, having developed dyspnea and cough in the previous 24 hours. An analytical study showed normocytic normochromic anemia with a hemoglobin level of 7.2 g/dL and leukocytosis with normal renal function and coagulation times. A blood transfusion was performed without complications. Chest computed tomography revealed a reticulonodular infiltrate of both lungs. Bronchoscopy showed no apparent lesions. Sputum cultures, rapid urine antigens for Legionella pneumophila and Streptococcus pneumoniae, studies for Influenza, virologic markers and serologic studies for autoimmunity were all negative. At the end of the tenth day his general state deteriorated with fatigue, hematuria, and in 3 days he developed aggravation of renal function with recurrent hemoptysis and anemia. Immunosuppression with daily prednisolone 1 g administered intravenously was initiated. An urgent bronchoscopy showed no lesions. A kidney biopsy showed fibrinoid necrosis and cellular crescents. Immunofluorescence revealed a linear immunoglobulin G deposition compatible with Goodpasture's syndrome. Immunosuppressive therapy with daily cyclophosphamide 120 mg orally was added. Subsequently he was transferred to a referral center at which 21 sessions of plasmapheresis and four sessions of hemodialysis were performed with good response; he currently has no need of hemodialysis. The absence of circulating anti-glomerular basement membrane antibodies in Goodpasture's syndrome adds complexity to the diagnosis creating an unusual setting in a rare disease. In our case a kidney biopsy was essential for diagnosis and clinical approach. Studies have shown that early aggressive therapy leads to an improved prognosis. Physicians should consider tissue diagnoses such as bronchoscopy and kidney biopsy in pulmonary renal syndrome. We present the case of a 56-year-old woman with anti-glomerular basement membrane (anti-GBM) antibody disease accompanied by granulomatous reaction in the kidney. Three months prior to admission to our kidney center, she had suffered from interstitial pneumonia and had a slightly elevated level of MPO-ANCA (13 EU). Her serum level of creatinine was normal (0.72 mg/dl) but proteinuria (1+) and hematuria (2+, 1-4/HF) were present. She was admitted to our hospital because of general fatigue, loss of appetite, high fever (over 38.5 degrees C) and a rapid decline in renal function (creatinine 8.50 mg/dl). Hemodialysis therapy was started immediately after admission. The serological study was negative for MPO-ANCA and PR3-ANCA but positive for anti-GBM antibody (139 EU). Renal biopsy demonstrated necrotizing glomeruli, cellular crescents and grauloma formation with multinucleated giant cells. Immunofluorescence microscopy revealed linear staining of IgG and C3. We diagnosed graulomatous, crescentic and necrotizing glomerulonephritis, patho-logically. She was diagnosed as having anti-GBM antibody disease because alveolar hemorrhage was absent. Steroid therapy including methylprednisolone pulse therapy (500 mg/day, 3 days) and 2 courses of plasma exchange were effective in reducing the fever, anti-GBM antibody titer and C-reactive protein level. Her renal function recovered and she was able to quit hemodialysis therapy 68 days after the start of hemodialysis and she has shown no signs of pulmonary alveolar hemorrhage to date. The present case suggests that intensive therapy may restore renal function in anti-GBM disease even though renal function was sufficiently damaged and required hemodialysis therapy and active pathological changes were observed in renal biopsy specimens. The Goodpasture syndrome is an extremely rare disease, with renal and pulmonary manifestations, and is mediated by anti-glomerular basement membrane (anti-GBM) antibodies. Renal pathological changes are mainly characterized by glomerular crescent formation and linear immunofluorescent staining for immunoglobulin G on the GBM. There are few reports on the atypical course of the syndrome involving serum-negative anti-GBM antibodies. Therefore, we present a case of Goodpasture syndrome that presented with nephrotic-range proteinuria and was seronegative for anti-GBM antibodies. A 38-year-old Chinese man presented with a lung lesion that was discovered by physical examination a month prior to presentation. The chief concern was occasional hemoptysis without fever, cough, chest pain, and edema. Laboratory testing revealed that the urinary protein level and urine erythrocyte count were 7.4 g/24 hours and 144/high-power field (HPF), respectively. Serological testing for anti-GBM antibodies was negative. Chest computed tomography revealed multiple exudative lesions in both lungs, indicating alveolar infiltration and hemorrhage. Electronic bronchoscopy and pathological examination of the alveolar lavage fluid indicated no abnormalities. However, kidney biopsy suggested cellular crescent formation and segmental necrosis of the globuli, with linear IgG and complement C3 deposition on the GBM. These findings were consistent with the diagnosis of anti-GBM antibody nephritis. The patient underwent 7 sessions of double filtration plasmapheresis. He was also administered with intravenous methylprednisolone and cyclophosphamide. After renal function stabilization, he was discharged under an immunosuppressive regimen comprising of glucocorticoids and cyclophosphamides. Three months later, follow-up examination revealed that the 24-hour urine protein had increased to 13 g. Furthermore, the urine erythrocyte count was 243/HPF. After a 6-month follow-up, the patient achieved partial remission, with a proteinuria level of 3.9 g/24 hours and a urine erythrocyte count of 187/HPF. This extremely rare case of Goodpasture syndrome manifested with seronegativity for anti-GBM antibodies and nephrotic-range proteinuria. Our findings emphasize the importance of renal biopsy for the clinical diagnosis of atypical cases. Furthermore, because renal involvement achieved only partial remission despite therapy, early detection and active treatment of the Goodpasture syndrome is necessary to improve the prognosis of patients. Anti-glomerular basement membrane (GBM) disease is mediated by circulating autoantibodies, principally IgG, targeted at the type IV collagen of GBM. The IgA variant of anti-GBM disease has rarely been described. We report a 65-year-old man with uremia, undergoing hemodialysis, who was referred because of hemoptysis. A chest X-ray showed diffuse infiltration in the right lung field. Laboratory data were remarkable for renal failure, anemia, and thrombocytopenia. Furthermore, laboratory evidence of microangiopathic hemolytic anemia was present. A kidney biopsy revealed diffuse crescentic glomerulonephritis. Circulating IgA anti-GBM antibody was found, as well as the presence of significant IgA deposition in a linear pattern along the GBM, suggesting an anti-GBM antibody-mediated disease. The patient was treated with plasmapheresis and pulse steroid therapy, which resulted in an immediate improvement in the pulmonary hemorrhage and hematological abnormalities. However, the patient did not regain renal function and remained on hemodialysis.  A 56-year-old female developed rapidly progressive glomerulonephritis in the course of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated pachymeningitis that had been found four years previously. On admission, her serum creatinine increased from 0.8 mg dL to 1.84 mg dL and to 3.66 mg dL every 3 to 4 weeks. Urinalysis revealed that urinary protein excretion was 1.25 g day and 3+ hematuria. MPO-ANCA titer was found to be 50 EU and anti-glomerular basement membrane (GBM) antibody was also elevated to as high as 174 EU. Renal pathology revealed cellular to fibrocellular crescents in 21 out of 23 glomeruli with interstitial inflammation and fibrosis. Immunohistochemistry with anti IgG antibody showed linear staining along the glomerular capillary walls. Following plasma exchange and methylprednisolone pulse therapy, oral prednisolone at a dose of 50 mg day was instituted, but without significant effect. Subsequent cyclophosphamide pulse therapy was effective, resulting in the stabilization of serum creatinine at 2 mg dL and disappearance of urine abnormalities. In addition, the MPO-ANCA titer and anti-GBM antibody titer of the patient decreased to within the normal range in one month and three months, respectively. Pulmonary lesions were not found throughout the course. Recently the emergence of anti-GBM antibody-associated crescentic glomemrulonephritis in the course of MPO-ANCA-associated vasculitis has increasingly been reported. Accumulation of such cases may unravel the pathogenesis of these diseases. one month and three months, respectively. Pulmonary lesions were not found throughout the course. Recently the emergence of anti-GBM antibody-associated crescentic glomemrulonephritis in the course of MPO-ANCA-associated vasculitis has increasingly been reported. Accumulation of such cases may unravel the pathogenesis of these diseases. A 22-year-old woman was admitted to our hospital for evaluation of fever, renal dysfunction, and a 3-month-history of macrohematuria. Laboratory evaluation revealed proteinuria (1.8 g/day), hypoproteinemia, microcytic microchromic anemia, renal failure (blood urea nitrogen 30.3 mg/dl, serum creatinine 4.0 mg/dl), and positive serum antiglomerular basement membrane (anti-GBM) antibody. Renal biopsy revealed cellular crescents in all 8 glomeruli and partial rupture of the GBM. The interstitium showed severe inflammatory cell infiltration. Immunofluorescent examination revealed linear deposits of IgG and C3 along the GBM. Pulmonary biopsy revealed linear deposits of IgG along the alveolar basement membrane in the immunofluorescent examination. A diagnosis of Goodpasture's syndrome was made because all of the diagnostic criteria were fulfilled. After admission, the patient's renal function deteriorated rapidly. Hemodialysis was started, and the patient was treated with methylprednisolone pulse therapy and oral prednisolone with double filtration plasma pheresis (DFPP). However, her renal function did not improve. On the 30th hospital day, she showed hemoptysis, and a chest X-ray and CT revealed massive bilateral pulmonary hemorrhage. Despite treatment with pulsed methylprednisolone, oral prednisolone (80 mg/day), and DFPP, the pulmonary hemorrhage improved only transiently, worsening again 5 days later. Cyclophosphamide pulse therapy was administered. After this treatment, the patient's pulmonary manifestations and pulmonary hemorrhage improved. At the present time she is on maintenance dialysis therapy without pulmonary manifestations. These findings suggest that cyclophosphamide pulse therapy is effective against Goodpasture's syndrome with massive pulmonary hemorrhage showing resistance to other conventional therapy. A 70-year-old man with uremia was referred because of hemoptysis. A chest X-ray showed diffuse infiltration in the right lung field. Laboratory data were remarkable for renal failure, anemia, and thrombocytopenia. Furthermore, laboratory evidence of microangiopathic hemolytic anemia was present. A kidney biopsy revealed diffuse crescentic glomerulonephritis with linear staining of IgA along the glomerular basement membrane (GBM). No thrombotic microangiopathy was noted on renal biopsy. Circulating IgG anti-GBM antibody was not detected, and IgA anti-GBM antibody was not tested. The patient was treated with plasmapheresis and pulse steroid therapy, which resulted in an immediate improvement in the pulmonary hemorrhage and hematological abnormalities. However, the patient did not regain renal function and remained on hemodialysis. Some cases of postinfectious glomerulonephritis initially are oligoanuric. Renal biopsy is essential to distinguish the purely endocapillary and exsudative form from that with endo- and extracapillary proliferation. The former characterises spontaneously regressive poststreptococcal glomerulonephritis, which is now rare, whilst the latter is caused by various strains of gram-positive and gram-negative strains and entails a much less favourable outcome in terms of renal and patient survival. Acute renal failure is a common complication of angiitis, mainly polyarteris nodosa (PAN) and Wegener granulomatosis. A third variety of crescentic glomerulonephritis is due to anti-glomerular basement membrane (GBM) antibodies, with or without pulmonary haemorrhage. Glomerular immunofluorescence discloses a typical pattern of linear IgG deposits along the GBMs. Treatment based on plasma exchanges, corticosteroids and alkylating agents can prevent end stage renal failure when undertaken early. Other glomerulopathies may be complicated with acute renal failure, including haematuric forms of IgA nephropathy. A case of 49-year-old man with anti-GBM antibody and who manifested pulmonary and renal symptoms at divergent times. Thirty-six years previously, renal disease with unneglectable degree of proteinuria was noticed. One month before admission, he was found by chance to have elevated serum creatine (Scr); 3.4 mg/dl. At admission, his Scr was 13.7 mg/dl and Hb 12.7 g/dl, TP 5.2 g/dl with 3+ proteinuria and no glucosuria. He was a heavy smoker and remained so while admitted. Renal biopsy presented fibrocellular crescents in 100% of glomeruli with striking tubulointerstitial involvement. Immunofluorescence showed linear IgG deposition along the glomerular capillary wall. Hemodialysis was instituted, and after 13 hospital days, anti-GBM antibody at admission was high at 128 U, with negative PANCA. Plasmapheresis was also performed, but on the next day pulmonary hemorrhage occurred with a concomitant rise of anti-GBM to 250 U. Thus, steroid pulse therapy was conducted in combination with plasmapheresis. Pulmonary hemorrhage subsided along with lowering of anti-GBM (48 U), but renal failure persisted. The patient died of septicemia. Based on the clinical course of the case, the term \"anti-BM mediated disease\" may more properly delineate the entity of the disease rather than the classical eponym \"Goodpasture's disease\" which requires coexistence of pulmo- and renal manifestations for definition. Goodpasture syndrome (GS) is an autoimmune disorder characterized by the association of pulmonary hemorrhage and rapidly progressive glomerulonephritis. The pathogenesis of GS is still unknown, but was shown to be the result that antibodies directed against glomerular basement membrane (GBM) antigens could injure both glomerular and pulmonary alveolar basement membrane. And membranous glomerulonephritis (MGN) is a glomerular disease characterized by epimembranous immune deposits and basement membrane thickening. MGN typically presents with the onset of nephrotic syndrome, but it often presents with only asymptomatic proteinuria. We reported an autopsy case of GS preceded with MGN. A 70-year-old man was admitted to our hospital with acute renal failure in May 2, 1996. Percutaneous renal biopsy demonstrated a crescentic glomerulonephritis associated with MGN and linear immunofluorescent staining of the basement membrane with antibodies to IgG. Two weeks later on admission he began to develop slight hemoptysis and chest X-ray showed pulmonary hemorrhage, Furthermore, his serum anti-GBM antibodies titer was very high. He was diagnosed as GS associated with MGN and treated with plasma exchange, glucocorticoid, and cyclophosphamide. Though his symptom was improved for intensive support, he suddenly died on June 22. Autopsied lungs showed focal pulmonary hemorrhage, but were not considered to be life-threatening. The cause of the death remained unclear. A 68-year-old woman was admitted to Kinki University Hospital because of progressive renal failure. She had been well until two months before admission. Laboratory data were as follows: serum creatinine 4.1 mg/dl, BUN 69 mg/dl, MPO-ANCA 33 EU, anti-glomerular basement membrane antibodies (AGBMA) 118 U. Histological findings showed cellular and fibrocellular crescents in many glomeruli. Therefore, we diagnosed rapidly progressive glomerulonephritis (RPGN) due to MPO-ANCA and anti-GBM associated renal disease. The patient was started on prednisolone and double filtration plasmapheresis (DFPP) therapy. Subsequently, the values of MPO-ANCA and AGBMA decreased. However, the patient's condition suddenly worsened and she died of interstitial pneumonia. Autopsy examination revealed crescentic glomerulonephritis and alveolar hemorrhage with linear deposition of IgG along the glomerular and alveolar capillary walls by immunofluorescence studies. We considered this to be a rare case of Goodpasture's syndrome associated with not only anti-GBM antibodies, but also MPO-ANCA. Anti-glomerular basement membrane (anti-GBM) disease is an autoimmune disorder characterized by the production of circulating immunoglobulin G (IgG) antibodies that affect the kidneys and lungs, mainly in the form of rapidly progressive crescentic glomerulonephritis and pulmonary hemorrhage. Typically diagnosed on tissue biopsy, findings mainly include glomerular crescent formation, bright linear staining of GBM for IgG on direct immunofluorescence (IF), and the serologic presence of circulating anti-GBM antibodies. Variation in the laboratory results, where histological findings of linear IgG IF staining were present in the absence of circulating anti-GBM antibodies, have recently led to the use of the term \"atypical anti-GBM disease,\" which usually has a distinct benign clinical outcome as compared to typical anti-GBM disease. We report a case of a middle-aged woman who presented with renal failure without lung involvement. Upon further investigation, the patient was found to have strongly positive serum anti-GBM antibodies, but the tissue biopsy did not show typical findings of the anti-GBM disease. The patient showed modest improvement after multiple sessions of plasmapheresis and steroids, with stabilization of her renal parameters after the initial response. In our case, we will address the possibilities of the discrepancies between the serological and histopathological findings. A 28 years old male patient presented, after a history of previous recurrent hemoptysis, with diffuse bilateral air space consolidation at chest radiography (CXR). Within 48 hours, partial respiratory insufficiency developed and required intubation. On a clinical and roentgenographic basis, the diagnosis of a Goodpasture syndrome was suspected. Plasmapheresis and immunosuppressive therapy with prednisone and cyclophosphamide were started immediately. Three days after admission, macrohematuria developed and serum creatinine began to rise to a maximum of 3.9 mg/dl. Totally, 13 plasmaphereses were performed within 27 days. Clinical, laboratory and radiological findings improved markedly. 30 days after admission, the patient was discharged and followed on an outpatient basis. Serum creatinine eventually decreased to 1.1 mg/dl. Initially, circulating antibodies against glomerular basement membrane (GBM) were positive, controls remained negative. Renal biopsy was performed after the acute phase and showed glomerulonephritis and linear immunoglobulin deposition along the GBM. Radiologic findings at CXR and high resolution computed tomography are demonstrated. A 66-year-old man with uremia and on hemodialysis was referred to our hospital because of hemoptysis. A chest radiograph showed diffuse infiltration in the right lung field. Laboratory data were remarkable for renal failure accompanied by hematuria and proteinuria. A kidney biopsy revealed diffuse crescentic glomerulonephritis with linear staining of IgG along the glomerular basement membrane (GBM). Circulating IgG anti-GBM antibody was not detected. Because the findings of renal biopsy suggested anti-GBM disease, the patient was treated with plasmapheresis and pulse steroid therapy, which resulted in a rapid resolution of his pulmonary symptoms and chest radiograph abnormalities. However, sputum culture submitted on admission yielded Mycobacterium tuberculosis 3 weeks later. Therefore, immunosuppressive agents were discontinued and antituberculous agents were administrated. No relapse of pulmonary hemorrhage occurred during the next 1-year period of follow-up, but the patient did not regain renal function and remained on hemodialysis.\nHere is the question:\nNEPHROLOGY: A 38-year-old man consults for dyspnea and hemoptysis. Blood tests show creatinine 7 mg/dL, urea 250 mg/dL and high titer positive anti-GBM (anti-glomerular basement membrane antibodies). Renal biopsy shows crescents in 75% of the glomeruli and immunofluorescence shows a linear Ig deposition pattern. Which of the following is the correct answer?\nHere are the potential choices:\n1. It is an IgA nephropathy with acute renal failure.\n2. Plasmapheresis would be indicated.\n3. It is a membranous glomerulonephritis.\n4. Mycophenolate mofetil is the initial treatment of choice.\n5. Glomerular involvement is caused by the presence of circulating immunocomplexes.\nThe correct answer is: ",
        "gold_answer": "2 Plasmapheresis would be indicated.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Anti-glomerular basement membrane (GBM) glomerulonephritis does not usually coexist with another glomerulonephritis such as IgA nephropathy. We present a rare case having a combination of these two diseases, and furthermore, histological evaluation could be performed before and after the development of anti-GBM glomerulonephritis over a period of only10 months. A 66-year-old woman was admitted with complaints of microscopic hematuria and mild proteinuria for the past 3 years. Serum creatinine level was normal at that time. The first renal biopsy was performed. Light microscopy revealed mesangial proliferative glomerulonephritis with fibro-cellular crescents in one out of 18 glomeruli, excluding one global sclerotic glomerulus. Immunofluorescence (IF) showed IgA and C3 deposition in the mesangium. Therefore, the diagnosis was IgA nephropathy. Eight months later, the patient's serum creatinine suddenly rose to 4.53 mg/dL and urinalysis showed 100 red blood cells per high power field with nephrotic range proteinuria (12.3 g/g<subCr</sub). The serological tests revealed the presence of anti-GBM antibody at the titer of 116 IU/mL. Treatments were begun after admission, consisting of hemodialysis, plasma exchange, and intravenous methylprednisolone pulse therapy. At 4 weeks after admission, the second renal biopsy was performed. Light microscopy revealed crescents in 18 of 25 glomeruli, excluding six global sclerotic glomeruli. IF showed linear IgG deposition along the GBM in addition to granular IgA and C3 deposition. Based on these findings, the diagnosis of anti-GBM glomerulonephritis and IgA nephropathy was confirmed. Renal function was not restored despite treatment, but alveolar hemorrhage was prevented. We report a patient with a diagnosis of anti-GBM disease during the course of IgA nephropathy. This case strongly suggests that the presence of autoantibodies should be checked to rule out overlapping autoimmune conditions even in patient who have previously been diagnosed with chronic glomerulonephritis, such as IgA nephropathy, who present an unusually rapid clinical course. Smoking in young men may trigger anti-GBM disease manifesting with hemoptysis. We present a male adolescent in whom hemoptysis was mistaken to be a sign of airway infection for several months and who later on underwent an unusual antibody-negative relapse. The 16-year-old patient had a history of smoking and therapy-refractant hemoptysis and, later, acute macrohematuria with renal insufficiency necessitating hemodialysis (initial creatinine 4.2 mg/ dl). Chest X-ray showed diffuse lung infiltration. Renal biopsy revealed linear IgG deposits along the glomerular basement membrane (GBM) and cellular crescents in 13/16 glomeruli, simultaneously increased anti-GBM antibodies were detected. Thus, anti-GBM glomerulonephritis was diagnosed. After treatment with prednisone, oral cyclophosphamide and plasmapheresis, chest X-ray and hemoptysis improved, but renal failure persisted. Anti-GBM antibodies were negative. 4 weeks later, the patient presented again with a clinical relapse of severe hemoptysis and respiratory insufficiency after smoke exposition. Despite negative anti-GBM antibodies, he was treated similarly to a relapse and after the second course of plasmapheresis the patients' general condition improved and hemoptysis subsided. During the next 10 months the patient was stable with negative antibodies. He was under intermittent hemodialysis until laboratory measurements showed improved renal function. Now, 30 months after the acute episode, the patient is off dialysis for 17 months with stable creatinine values of 1.9 - 2.4 mg/dl, and is currently being treated with antihypertensive medicaments, calcitriol, calciumacetate, natriumhydrogencarbonate and allopurinol. The prognosis of anti-GBM glomerulonephritis depends on serum creatinine and the need of dialysis at initial presentation. In these patients, one-year survival rate is 67% and 5% for kidney function. Of note, despite the unfavorable prognosis in our patient, renal function recovered after 1 year of hemodialysis treatment. It is important to consider that in patients with anti-GBM disease antibody-negative relapses are possible. The prognosis for renal function in anti-GBM glomerulonephritis (anti-GBM GN) is extremely poor, and when renal impairment progresses severely, it is difficult to expect improvement. In addition, it is also known that once the disease activity can be controlled by aggressive treatment, its recurrence is rare. We experienced an anti-GBM GN that improved from severe renal dysfunction and relapsed. A possible cause was the superimpose of nephrotic syndrome due to minimal change disease (MCD). A 30-year-old man was admitted to our hospital because of general malaise, fever, oliguria and renal dysfunction. The patient's laboratory data showed serum creatinine as high as 6.6 mg/dl, and severe inflammation (C-reactive protein 20.6 mg/dl). Anti-glomerular basement membrane antibody (anti-GBM Ab) was detected in his serum, which led to the diagnosis of anti-GBM GN. Treatment was initiated with high-dose glucocorticoid (GC) and plasma exchange therapy (PE), and the patient's renal function and oliguria improved rapidly and he was discharged 40 days after admission. Renal biopsy findings showed cellular crescents associated with linear IgG depositions along the glomerular tufts compatible with anti-GBM GN, but only about one-third of the glomeruli was involved, suggesting that it still remains an early stage of the disease. However, 2 months after discharge, he had a relapse and was readmitted due to severe proteinuria with positive anti-GBM Ab. On the second admission, after high-dose GC and PE combined with intravenous cyclophosphamide, and remission was achieved. Despite the relatively minor renal biopsy findings, the patient showed rapid renal dysfunction and relatively rapid improvement with our treatment. Electron microscopy of the renal biopsy tissue showed significant foot process effacement on podocytes in the apparently normal glomeruli, without electron dense deposits. On the basis of clinical course and renal pathology, it is suggested that the present case was a rare complication of an early stage of anti-GBM GN and minimal change nephrotic syndrome. Although the simultaneous development of anti-GBM GN and MCD with anti-GBM antibody is unclear, it might have been precipitated by influenza infection or some unknown factor. We report a case of endstage renal disease due to simultaneous occurrence of membranous nephropathy and crescentic glomerulonephritis associated with anti-GBM antibodies. The patient was a 60-year-old male and was hospitalized for prolonged anorexia and general malaise. On admission, his body temperature was 38.5 degrees C. Urinalysis revealed 3+ proteinuria and the sediment contained abundant erythrocytes. The urea nitrogen was 142.4 mg/dl, the creatinine 19.5 mg/dl, the potassium 6.47 mEq/dl and CRP 10.1 mg/dl. Anti-GBM antibodies were 1000EU/ml. Immediately after initiating hemodialysis, pulse steroid therapy, plasma exchange and continuous heparinization were performed. However, renal function had been impaired and maintenance hemodialysis was required. Histological examination of the renal specimen revealed marked epithelial crescent formation, whereas thickening of basement membrane and mesangial proliferation were not observed. By immunofluorescent staining, both bright linear and fine granular fixation of IgG and fine granular fixations of C3 along the glomerular capillary walls were observed. Electron microscopy showed subepithelial electron lucent deposits and thickening of the glomerular basement membrane, diagnostic of the advanced membranous nephropathy (stage IV). Goodpasture's syndrome, a rare disease, is an organ-specific autoimmune disease mediated by anti-glomerular basement membrane antibodies. Its pathology is characterized by crescentic glomerulonephritis with linear immunofluorescent staining for immunoglobulin G on the glomerular basement membrane. Although rare, a few cases with absence of circulating anti-glomerular membrane antibodies have been described. The objective of this clinical case report is to describe and discuss a case of a 27-year-old white man who was hospitalized with a 1-year history of weight loss and a 1-month history of hemoptysis, with aggravation  the day before, having developed dyspnea and cough in the previous 24 hours. An analytical study showed normocytic normochromic anemia with a hemoglobin level of 7.2 g/dL and leukocytosis with normal renal function and coagulation times. A blood transfusion was performed without complications. Chest computed tomography revealed a reticulonodular infiltrate of both lungs. Bronchoscopy showed no apparent lesions. Sputum cultures, rapid urine antigens for Legionella pneumophila and Streptococcus pneumoniae, studies for Influenza, virologic markers and serologic studies for autoimmunity were all negative. At the end of the tenth day his general state deteriorated with fatigue, hematuria, and in 3 days he developed aggravation of renal function with recurrent hemoptysis and anemia. Immunosuppression with daily prednisolone 1 g administered intravenously was initiated. An urgent bronchoscopy showed no lesions. A kidney biopsy showed fibrinoid necrosis and cellular crescents. Immunofluorescence revealed a linear immunoglobulin G deposition compatible with Goodpasture's syndrome. Immunosuppressive therapy with daily cyclophosphamide 120 mg orally was added. Subsequently he was transferred to a referral center at which 21 sessions of plasmapheresis and four sessions of hemodialysis were performed with good response; he currently has no need of hemodialysis. The absence of circulating anti-glomerular basement membrane antibodies in Goodpasture's syndrome adds complexity to the diagnosis creating an unusual setting in a rare disease. In our case a kidney biopsy was essential for diagnosis and clinical approach. Studies have shown that early aggressive therapy leads to an improved prognosis. Physicians should consider tissue diagnoses such as bronchoscopy and kidney biopsy in pulmonary renal syndrome. We present the case of a 56-year-old woman with anti-glomerular basement membrane (anti-GBM) antibody disease accompanied by granulomatous reaction in the kidney. Three months prior to admission to our kidney center, she had suffered from interstitial pneumonia and had a slightly elevated level of MPO-ANCA (13 EU). Her serum level of creatinine was normal (0.72 mg/dl) but proteinuria (1+) and hematuria (2+, 1-4/HF) were present. She was admitted to our hospital because of general fatigue, loss of appetite, high fever (over 38.5 degrees C) and a rapid decline in renal function (creatinine 8.50 mg/dl). Hemodialysis therapy was started immediately after admission. The serological study was negative for MPO-ANCA and PR3-ANCA but positive for anti-GBM antibody (139 EU). Renal biopsy demonstrated necrotizing glomeruli, cellular crescents and grauloma formation with multinucleated giant cells. Immunofluorescence microscopy revealed linear staining of IgG and C3. We diagnosed graulomatous, crescentic and necrotizing glomerulonephritis, patho-logically. She was diagnosed as having anti-GBM antibody disease because alveolar hemorrhage was absent. Steroid therapy including methylprednisolone pulse therapy (500 mg/day, 3 days) and 2 courses of plasma exchange were effective in reducing the fever, anti-GBM antibody titer and C-reactive protein level. Her renal function recovered and she was able to quit hemodialysis therapy 68 days after the start of hemodialysis and she has shown no signs of pulmonary alveolar hemorrhage to date. The present case suggests that intensive therapy may restore renal function in anti-GBM disease even though renal function was sufficiently damaged and required hemodialysis therapy and active pathological changes were observed in renal biopsy specimens. The Goodpasture syndrome is an extremely rare disease, with renal and pulmonary manifestations, and is mediated by anti-glomerular basement membrane (anti-GBM) antibodies. Renal pathological changes are mainly characterized by glomerular crescent formation and linear immunofluorescent staining for immunoglobulin G on the GBM. There are few reports on the atypical course of the syndrome involving serum-negative anti-GBM antibodies. Therefore, we present a case of Goodpasture syndrome that presented with nephrotic-range proteinuria and was seronegative for anti-GBM antibodies. A 38-year-old Chinese man presented with a lung lesion that was discovered by physical examination a month prior to presentation. The chief concern was occasional hemoptysis without fever, cough, chest pain, and edema. Laboratory testing revealed that the urinary protein level and urine erythrocyte count were 7.4 g/24 hours and 144/high-power field (HPF), respectively. Serological testing for anti-GBM antibodies was negative. Chest computed tomography revealed multiple exudative lesions in both lungs, indicating alveolar infiltration and hemorrhage. Electronic bronchoscopy and pathological examination of the alveolar lavage fluid indicated no abnormalities. However, kidney biopsy suggested cellular crescent formation and segmental necrosis of the globuli, with linear IgG and complement C3 deposition on the GBM. These findings were consistent with the diagnosis of anti-GBM antibody nephritis. The patient underwent 7 sessions of double filtration plasmapheresis. He was also administered with intravenous methylprednisolone and cyclophosphamide. After renal function stabilization, he was discharged under an immunosuppressive regimen comprising of glucocorticoids and cyclophosphamides. Three months later, follow-up examination revealed that the 24-hour urine protein had increased to 13 g. Furthermore, the urine erythrocyte count was 243/HPF. After a 6-month follow-up, the patient achieved partial remission, with a proteinuria level of 3.9 g/24 hours and a urine erythrocyte count of 187/HPF. This extremely rare case of Goodpasture syndrome manifested with seronegativity for anti-GBM antibodies and nephrotic-range proteinuria. Our findings emphasize the importance of renal biopsy for the clinical diagnosis of atypical cases. Furthermore, because renal involvement achieved only partial remission despite therapy, early detection and active treatment of the Goodpasture syndrome is necessary to improve the prognosis of patients. Anti-glomerular basement membrane (GBM) disease is mediated by circulating autoantibodies, principally IgG, targeted at the type IV collagen of GBM. The IgA variant of anti-GBM disease has rarely been described. We report a 65-year-old man with uremia, undergoing hemodialysis, who was referred because of hemoptysis. A chest X-ray showed diffuse infiltration in the right lung field. Laboratory data were remarkable for renal failure, anemia, and thrombocytopenia. Furthermore, laboratory evidence of microangiopathic hemolytic anemia was present. A kidney biopsy revealed diffuse crescentic glomerulonephritis. Circulating IgA anti-GBM antibody was found, as well as the presence of significant IgA deposition in a linear pattern along the GBM, suggesting an anti-GBM antibody-mediated disease. The patient was treated with plasmapheresis and pulse steroid therapy, which resulted in an immediate improvement in the pulmonary hemorrhage and hematological abnormalities. However, the patient did not regain renal function and remained on hemodialysis.  A 56-year-old female developed rapidly progressive glomerulonephritis in the course of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated pachymeningitis that had been found four years previously. On admission, her serum creatinine increased from 0.8 mg dL to 1.84 mg dL and to 3.66 mg dL every 3 to 4 weeks. Urinalysis revealed that urinary protein excretion was 1.25 g day and 3+ hematuria. MPO-ANCA titer was found to be 50 EU and anti-glomerular basement membrane (GBM) antibody was also elevated to as high as 174 EU. Renal pathology revealed cellular to fibrocellular crescents in 21 out of 23 glomeruli with interstitial inflammation and fibrosis. Immunohistochemistry with anti IgG antibody showed linear staining along the glomerular capillary walls. Following plasma exchange and methylprednisolone pulse therapy, oral prednisolone at a dose of 50 mg day was instituted, but without significant effect. Subsequent cyclophosphamide pulse therapy was effective, resulting in the stabilization of serum creatinine at 2 mg dL and disappearance of urine abnormalities. In addition, the MPO-ANCA titer and anti-GBM antibody titer of the patient decreased to within the normal range in one month and three months, respectively. Pulmonary lesions were not found throughout the course. Recently the emergence of anti-GBM antibody-associated crescentic glomemrulonephritis in the course of MPO-ANCA-associated vasculitis has increasingly been reported. Accumulation of such cases may unravel the pathogenesis of these diseases. one month and three months, respectively. Pulmonary lesions were not found throughout the course. Recently the emergence of anti-GBM antibody-associated crescentic glomemrulonephritis in the course of MPO-ANCA-associated vasculitis has increasingly been reported. Accumulation of such cases may unravel the pathogenesis of these diseases. A 22-year-old woman was admitted to our hospital for evaluation of fever, renal dysfunction, and a 3-month-history of macrohematuria. Laboratory evaluation revealed proteinuria (1.8 g/day), hypoproteinemia, microcytic microchromic anemia, renal failure (blood urea nitrogen 30.3 mg/dl, serum creatinine 4.0 mg/dl), and positive serum antiglomerular basement membrane (anti-GBM) antibody. Renal biopsy revealed cellular crescents in all 8 glomeruli and partial rupture of the GBM. The interstitium showed severe inflammatory cell infiltration. Immunofluorescent examination revealed linear deposits of IgG and C3 along the GBM. Pulmonary biopsy revealed linear deposits of IgG along the alveolar basement membrane in the immunofluorescent examination. A diagnosis of Goodpasture's syndrome was made because all of the diagnostic criteria were fulfilled. After admission, the patient's renal function deteriorated rapidly. Hemodialysis was started, and the patient was treated with methylprednisolone pulse therapy and oral prednisolone with double filtration plasma pheresis (DFPP). However, her renal function did not improve. On the 30th hospital day, she showed hemoptysis, and a chest X-ray and CT revealed massive bilateral pulmonary hemorrhage. Despite treatment with pulsed methylprednisolone, oral prednisolone (80 mg/day), and DFPP, the pulmonary hemorrhage improved only transiently, worsening again 5 days later. Cyclophosphamide pulse therapy was administered. After this treatment, the patient's pulmonary manifestations and pulmonary hemorrhage improved. At the present time she is on maintenance dialysis therapy without pulmonary manifestations. These findings suggest that cyclophosphamide pulse therapy is effective against Goodpasture's syndrome with massive pulmonary hemorrhage showing resistance to other conventional therapy. A 70-year-old man with uremia was referred because of hemoptysis. A chest X-ray showed diffuse infiltration in the right lung field. Laboratory data were remarkable for renal failure, anemia, and thrombocytopenia. Furthermore, laboratory evidence of microangiopathic hemolytic anemia was present. A kidney biopsy revealed diffuse crescentic glomerulonephritis with linear staining of IgA along the glomerular basement membrane (GBM). No thrombotic microangiopathy was noted on renal biopsy. Circulating IgG anti-GBM antibody was not detected, and IgA anti-GBM antibody was not tested. The patient was treated with plasmapheresis and pulse steroid therapy, which resulted in an immediate improvement in the pulmonary hemorrhage and hematological abnormalities. However, the patient did not regain renal function and remained on hemodialysis. Some cases of postinfectious glomerulonephritis initially are oligoanuric. Renal biopsy is essential to distinguish the purely endocapillary and exsudative form from that with endo- and extracapillary proliferation. The former characterises spontaneously regressive poststreptococcal glomerulonephritis, which is now rare, whilst the latter is caused by various strains of gram-positive and gram-negative strains and entails a much less favourable outcome in terms of renal and patient survival. Acute renal failure is a common complication of angiitis, mainly polyarteris nodosa (PAN) and Wegener granulomatosis. A third variety of crescentic glomerulonephritis is due to anti-glomerular basement membrane (GBM) antibodies, with or without pulmonary haemorrhage. Glomerular immunofluorescence discloses a typical pattern of linear IgG deposits along the GBMs. Treatment based on plasma exchanges, corticosteroids and alkylating agents can prevent end stage renal failure when undertaken early. Other glomerulopathies may be complicated with acute renal failure, including haematuric forms of IgA nephropathy. A case of 49-year-old man with anti-GBM antibody and who manifested pulmonary and renal symptoms at divergent times. Thirty-six years previously, renal disease with unneglectable degree of proteinuria was noticed. One month before admission, he was found by chance to have elevated serum creatine (Scr); 3.4 mg/dl. At admission, his Scr was 13.7 mg/dl and Hb 12.7 g/dl, TP 5.2 g/dl with 3+ proteinuria and no glucosuria. He was a heavy smoker and remained so while admitted. Renal biopsy presented fibrocellular crescents in 100% of glomeruli with striking tubulointerstitial involvement. Immunofluorescence showed linear IgG deposition along the glomerular capillary wall. Hemodialysis was instituted, and after 13 hospital days, anti-GBM antibody at admission was high at 128 U, with negative PANCA. Plasmapheresis was also performed, but on the next day pulmonary hemorrhage occurred with a concomitant rise of anti-GBM to 250 U. Thus, steroid pulse therapy was conducted in combination with plasmapheresis. Pulmonary hemorrhage subsided along with lowering of anti-GBM (48 U), but renal failure persisted. The patient died of septicemia. Based on the clinical course of the case, the term \"anti-BM mediated disease\" may more properly delineate the entity of the disease rather than the classical eponym \"Goodpasture's disease\" which requires coexistence of pulmo- and renal manifestations for definition. Goodpasture syndrome (GS) is an autoimmune disorder characterized by the association of pulmonary hemorrhage and rapidly progressive glomerulonephritis. The pathogenesis of GS is still unknown, but was shown to be the result that antibodies directed against glomerular basement membrane (GBM) antigens could injure both glomerular and pulmonary alveolar basement membrane. And membranous glomerulonephritis (MGN) is a glomerular disease characterized by epimembranous immune deposits and basement membrane thickening. MGN typically presents with the onset of nephrotic syndrome, but it often presents with only asymptomatic proteinuria. We reported an autopsy case of GS preceded with MGN. A 70-year-old man was admitted to our hospital with acute renal failure in May 2, 1996. Percutaneous renal biopsy demonstrated a crescentic glomerulonephritis associated with MGN and linear immunofluorescent staining of the basement membrane with antibodies to IgG. Two weeks later on admission he began to develop slight hemoptysis and chest X-ray showed pulmonary hemorrhage, Furthermore, his serum anti-GBM antibodies titer was very high. He was diagnosed as GS associated with MGN and treated with plasma exchange, glucocorticoid, and cyclophosphamide. Though his symptom was improved for intensive support, he suddenly died on June 22. Autopsied lungs showed focal pulmonary hemorrhage, but were not considered to be life-threatening. The cause of the death remained unclear. A 68-year-old woman was admitted to Kinki University Hospital because of progressive renal failure. She had been well until two months before admission. Laboratory data were as follows: serum creatinine 4.1 mg/dl, BUN 69 mg/dl, MPO-ANCA 33 EU, anti-glomerular basement membrane antibodies (AGBMA) 118 U. Histological findings showed cellular and fibrocellular crescents in many glomeruli. Therefore, we diagnosed rapidly progressive glomerulonephritis (RPGN) due to MPO-ANCA and anti-GBM associated renal disease. The patient was started on prednisolone and double filtration plasmapheresis (DFPP) therapy. Subsequently, the values of MPO-ANCA and AGBMA decreased. However, the patient's condition suddenly worsened and she died of interstitial pneumonia. Autopsy examination revealed crescentic glomerulonephritis and alveolar hemorrhage with linear deposition of IgG along the glomerular and alveolar capillary walls by immunofluorescence studies. We considered this to be a rare case of Goodpasture's syndrome associated with not only anti-GBM antibodies, but also MPO-ANCA. Anti-glomerular basement membrane (anti-GBM) disease is an autoimmune disorder characterized by the production of circulating immunoglobulin G (IgG) antibodies that affect the kidneys and lungs, mainly in the form of rapidly progressive crescentic glomerulonephritis and pulmonary hemorrhage. Typically diagnosed on tissue biopsy, findings mainly include glomerular crescent formation, bright linear staining of GBM for IgG on direct immunofluorescence (IF), and the serologic presence of circulating anti-GBM antibodies. Variation in the laboratory results, where histological findings of linear IgG IF staining were present in the absence of circulating anti-GBM antibodies, have recently led to the use of the term \"atypical anti-GBM disease,\" which usually has a distinct benign clinical outcome as compared to typical anti-GBM disease. We report a case of a middle-aged woman who presented with renal failure without lung involvement. Upon further investigation, the patient was found to have strongly positive serum anti-GBM antibodies, but the tissue biopsy did not show typical findings of the anti-GBM disease. The patient showed modest improvement after multiple sessions of plasmapheresis and steroids, with stabilization of her renal parameters after the initial response. In our case, we will address the possibilities of the discrepancies between the serological and histopathological findings. A 28 years old male patient presented, after a history of previous recurrent hemoptysis, with diffuse bilateral air space consolidation at chest radiography (CXR). Within 48 hours, partial respiratory insufficiency developed and required intubation. On a clinical and roentgenographic basis, the diagnosis of a Goodpasture syndrome was suspected. Plasmapheresis and immunosuppressive therapy with prednisone and cyclophosphamide were started immediately. Three days after admission, macrohematuria developed and serum creatinine began to rise to a maximum of 3.9 mg/dl. Totally, 13 plasmaphereses were performed within 27 days. Clinical, laboratory and radiological findings improved markedly. 30 days after admission, the patient was discharged and followed on an outpatient basis. Serum creatinine eventually decreased to 1.1 mg/dl. Initially, circulating antibodies against glomerular basement membrane (GBM) were positive, controls remained negative. Renal biopsy was performed after the acute phase and showed glomerulonephritis and linear immunoglobulin deposition along the GBM. Radiologic findings at CXR and high resolution computed tomography are demonstrated. A 66-year-old man with uremia and on hemodialysis was referred to our hospital because of hemoptysis. A chest radiograph showed diffuse infiltration in the right lung field. Laboratory data were remarkable for renal failure accompanied by hematuria and proteinuria. A kidney biopsy revealed diffuse crescentic glomerulonephritis with linear staining of IgG along the glomerular basement membrane (GBM). Circulating IgG anti-GBM antibody was not detected. Because the findings of renal biopsy suggested anti-GBM disease, the patient was treated with plasmapheresis and pulse steroid therapy, which resulted in a rapid resolution of his pulmonary symptoms and chest radiograph abnormalities. However, sputum culture submitted on admission yielded Mycobacterium tuberculosis 3 weeks later. Therefore, immunosuppressive agents were discontinued and antituberculous agents were administrated. No relapse of pulmonary hemorrhage occurred during the next 1-year period of follow-up, but the patient did not regain renal function and remained on hemodialysis.\nHere is the question:\nNEPHROLOGY: A 38-year-old man consults for dyspnea and hemoptysis. Blood tests show creatinine 7 mg/dL, urea 250 mg/dL and high titer positive anti-GBM (anti-glomerular basement membrane antibodies). Renal biopsy shows crescents in 75% of the glomeruli and immunofluorescence shows a linear Ig deposition pattern. Which of the following is the correct answer?\nHere are the potential choices:\n1. It is an IgA nephropathy with acute renal failure.\n2. Plasmapheresis would be indicated.\n3. It is a membranous glomerulonephritis.\n4. Mycophenolate mofetil is the initial treatment of choice.\n5. Glomerular involvement is caused by the presence of circulating immunocomplexes.\nThe correct answer is: 2. Plasmapheresis would be indicated."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Premature thelarche Premature thelarche is a benign condition in which a young female has breast development before the age of 8 without any accompanied pubertal changes. Individuals undergoing isolated premature thelarche do not experience menstruation, pubic hair growth (pubarche), or the bone growth characteristic of puberty. Initial breast development can be bilateral or unilateral and usually begins with a firm, disc-like area of tissue under the areola which can be mistaken for a mass but is almost always a normal, physiologic process. The breast is often tender and palpation is sometimes painful but breast discharge is absent. Usually, the breasts do not develop past stage 3 on the Tanner Scale, hence maintaining adolescent nipples. Moreover, in 90% of patients with isolated premature thelarche, breast enlargement will resolve 6 months to 6 years after diagnosis. A nineteen years old woman with ambiguous external genitalia was studied. This condition had been previously identified as a newborn, but her parents refused medical attention and it was reared as a girl. At 12-years, she began spontaneous mammary development, appearing pubic and axillary hair, and clitoral enlargement. The menarche occurred at 15-years and it was followed by irregular periods. Physical examination, showed absence of hirsutism and acne, normal mammary development equivalent to grade V of Tanner. The external genitalia showed fused labio-scrotal folds with an small introitus. The urethral meatus was absent and was later located inside the introitus. There was a big phallus similar to an adult penis with a normal glans, flexed by a chordee. Hormonal determinations discarded congenital adrenal hyperplasia. The karyotype was 46,XX and testosterone levels were in adult male range. Pelvic ultrasonography disclosed a normal uterus and both gonads in confirmed by laparoscopy identifying bilateral ovotestis. Testicular tissue was removed and plastic reconstruction of female genitals was done. Pubic hair Pubic hair is often the second noticeable change in puberty, usually within a few months of thelarche. It is referred to as pubarche. The pubic hairs are usually visible first along the labia. The first few hairs are described as Tanner stage 2. Stage 3 is usually reached within another 6–12 months, when the hairs are too numerous to count and appear on the pubic mound as well. By stage 4, the pubic hairs densely fill the \"pubic triangle.\" Stage 5 refers to spread of pubic hair to the thighs and sometimes as abdominal hair upward towards the navel. In about 15% of girls, the earliest pubic hair appears before breast development begins. Underarm hair, also known as axillary hair, is the hair in the underarm area (axilla). Development and function Underarm hair, as human body hair, usually starts to appear at the beginning of puberty, with growth usually completed by the end of the teenage years. Axillary hair goes through four stages of development, driven by weak androgens produced by the adrenal in males and females during adrenarche, and testosterone from the testicle in males during puberty. Like Tanner Staging for pubic hair, axillary hair can be staged according to the Wolfsdorf Staging system, named for pediatric endocrinologist Joseph Wolfsdorf, as follows: Wolfsdorf Stage 1 – no axillary hair Wolfsdorf Stage 2 – scant axillary hair (usually coinciding with onset of adrenarche) Wolfsdorf Stage 3 – coarse axillary hair, less than full-adult Wolfsdorf Stage 4 – full adult axillary hair Staging a patient's axillary hair will allow the physician to track the child's development longitudinally. Linear growth acceleration is one of the important features of early puberty. So the exact height, weight, growth velocity (cm/year) and BMI should be documented.  In females, accurate Tanner staging of the breast should take place, which is particularly challenging in obese or overweight girls to differentiate between adipose tissue and the glandular breast tissue. In males, an orchidometer should be used to determine the testicular volume. Volumes of more than 4 ml confirm pubertal development.  In males and females with pubic hair and body odor, the absence of increased testicular volume and breast development should prompt investigation of peripheral causes. Unilateral testicular enlargement is likely due to testicular tumors. Breast ultrasound is a complementary study of mammography. In many women the tissue that makes up the breast is very dense, representing fibrous tissue and glandular tissue, which produces milk during lactation. This limits the radiologist interpreting the study, so, in these cases, the ultrasound is helpful, since this is capable of distinguishing tumors in women with dense breast tissue, where identification is otherwise difficult. Additionally, it is advisable to follow up a mammogram that shows indications of tumors with an ultrasound, to confirm, before more invasive procedures are undertaken. Pelvic exam The pelvic exam is part of the physical examination of the internal pelvic organs (uterus, cervix, ovaries), vagina, and external genitalia. This exam often includes three parts: Inspection of the external genitalia Bimanual examination Inspection of the cervix and vagina using a speculum. In females, the normal onset of puberty ranges from 8 to 13 years old, averaging age 10 years in White Americans and age 8.9 years in African-Americans. Puberty in females begins with the development of breast buds under the areola, also known as thelarche, and represents entry into Tanner Stage 2. As puberty progresses, the glandular tissue of the breast increases in size and changes in contour. In females, thelarche is followed in 1 to 1.5 years by the onset of sexual hair (pubic and axillary), known as pubarche. Menarche, the onset of menses, arrives on average at age 12.5 years, regardless of ethnicity, following thelarche on average by 2.5 years (range 0.5 to 3 years).  Between Tanner Stage 2 and 3 breast development, females experience peak height velocity. African-American females have closer to 3 years between their thelarche and menarche, accounting for greater height potential. In the months and years following the appearance of pubic hair, other areas of skin that respond to androgens may develop androgenic hair. The usual sequence is: underarm (axillary) hair, perianal hair, upper lip hair, sideburn (preauricular) hair, periareolar hair, and the beard area. As with most human biological processes, this specific order may vary among some individuals. Arm, leg, chest, abdominal, and back hair become heavier more gradually. There is a large range in amount of body hair among adult men, and significant differences in timing and quantity of hair growth among different racial groups. Facial hair is often present in late adolescence, but may not appear until significantly later. Facial hair will continue to get coarser, darker and thicker for another 2–4 years after puberty. Some men do not develop full facial hair for up to 10 years after the completion of puberty. Chest hair may appear during puberty or years after, though not all men develop it. As females develop, a universal means to classify where they are in puberty is known as Tanner stages. Stage one is prepubertal females. They will have no breast tissue or pubic hair. Stage two is when the breast bud begins to protrude with enlargement of the areola and the sparse presence of pubic hair. [2] Female typically experience their ‘growth spurt’ during Tanner stage two. [1] Continued breast and areola enlargement without distinct separation of the contour and darkening pubic hair along the mons pubis is known as Tanner stage three. Stage four is classified when a secondary mound above the breast forms and the pubic hair thickens but is not on the thigh. Menarche occurs in stage three or four. Stage five is the adult female body. It is when the nipple projects out of the areola and the pubic hairs reach the medial thigh. [3] accounts for the greatest num-ber of malpractice claims for errors in diagnosis and for the largest number of paid claims. Litigation often involves younger women, whose physical examination and mammogram may be misleading. If a young woman (≤45 years) presents with a palpable breast mass and equivocal mammographic findings, ultrasound examination and biopsy are used to avoid a delay in diagnosis.ExaminationInspection. The clinician inspects the woman’s breast with her arms by her side (Fig. 17-18A), with her arms straight up in the air (Fig. 17-18B), and with her hands on her hips (with and without pectoral muscle contraction).135,136 Symmetry, size, and shape of the breast are recorded, as well as any evidence of edema (peau d’orange), nipple or skin retraction, or erythema. With the arms extended forward and in a sitting position, the woman leans forward to accentuate any skin retraction.Figure 17-18. Examination of the breast. A. Inspection of the breast with arms at sides. B. Background: Premature ovarian failure (POF) is often associated with autoimmune disorders. The 47,XXX karyotype has also been associated with POF and other genitourinary abnormalities. Following is a case of a 17 year old with immune thrombocytopenic purpura (ITP), POF, 47, XXX and a positive antinuclear antibody (ANA).Case Report: A 17 year old Caucasian female was referred to the Adolescent Health Clinic for evaluation of oligomenorrhea with secondary amenorrhea. Thelarche occurred at 12 years, and menarche at 13 years of age. Since then she had a total of five menstrual periods, spaced 1-15 months apart and lasting 3-5 days. Her last menstrual period was six months prior to presentation. Past medical history was significant for chronic ITP diagnosed seven months prior to presentation, when she developed easy bruising. She was treated with IV gamma globulin and had a moderate response, but relapsed several weeks later. She was started on oral prednisone and had a good response, but continued to relapse whenever steroids were tapered. She was therefore maintained on prednisone 10 mg QOD. There was no family history of irregular menses or autoimmune disease. Physical exam revealed a well-appearing, slightly Cushingoid 17 year old. Physical and cognitive development were age-appropriate. There were no stigmata of Turner Syndrome. The thyroid was normal. Breasts were Tanner 5; public hair was Tanner 3. The external genitalia were normal and appeared well-estrogenized. The remainder of the exam was unremarkable. Pelvic ultrasound demonstrated a normal uterus and ovaries. Laboratory evaluation was significant for elevated gonadotropins and nondetectable estradiol. ANA was positive at 1:320 with a speckled pattern. Blood counts, serologies, complement levels, and coagulation studies were otherwise normal. Cytogenetic studies revealed a 47,XXX karyotype. The patient was placed on an estrogen/norethindrone hormone replacement patch for premature ovarian failure. To date, she has developed no further symptoms, and does not meet criteria for a diagnosis of systemic lupus erythematosis.Conclusions: A 47,XXX karyotype was found in a 17 year old with POF and ITP with a positive ANA. The presence of known autoimmune disease in a woman with POF should not dissuade the physician from evaluating for a potential genetic cause. Sexual ambiguities are due to varied congenital or hormonal causes. A retrospective study carried out from January 1995 to December 2000 and followed by a prospective study from January 2001 to September 2002 sought to describe the clinical aspects of sexual ambiguities in Internal Medicine in a tertiary hospital Mali. Among 12 patients out of 2223 consultants identified (0.54 percent), 10 of them were phenotypically feminine and 2 phenotypically masculine. The average age of the patients was 14.3+- 8.9 years. Clinically, 3 out of the 10 phenotypically feminine patients presented an anomaly of the external genital organs; 5 out of the 10 had low axillary and pubic hair growth; 4 out of the 10 had delayed puberty; 6 out of the 10 had primary amenorrhoea; 7 out of 10 had hypoplasia of the mammary glands; and3 out of 10 had an inguinal mass. For the the 2 phenotypically masculine patients, one had a bilateral gynecomastia, a macroskelia of 2m04, a low axillary and pubic hair growth and the other had an anomaly of the external genital organs. Trichotillomania (TTM) is defined by the Diagnostics and Statistic Manual of Mental Disorders, 4th edition (DMS-IV) as hair loss from a patient`s repetitive self-pulling of hair. The disorder is included under anxiety disorders because it shares some obsessive-compulsive features. Patients have the tendency towards feelings of unattractiveness, body dissatisfaction, and low self-esteem (1,2). It is a major psychiatric problem, but many patients with this disorder first present to a dermatologist. An 11-year-old girl came to our department with a 2-month history of diffuse hair loss on the frontoparietal and parietotemporal area (Figure 1). She had originally been examined by a pediatrician with the diagnosis of alopecia areata. The patient`s personal history included hay fever and shortsightedness, and she suffered from varicella and mononucleosis. Nobody in the family history suffered from alopecia areata, but her father has male androgenetic alopecia (Norwood/Hamilton MAGA C3F3). The mother noticed that the child had had changeable mood for about 2 months and did not want to communicate with other persons in the family. The family did not have any pet at home. At school, her favorite subjects were Math and Computer Studies. She did not like Physical Education and did not participate in any sport activities during her free time. This was very strange because she was obese (body-mass index (BMI) 24.69). She was sometimes angry with her 13-year-old sister who had better results at school. The girl had suddenly started to wear a blue scarf. The parents did not notice that she pulled out her hair at home. Dermatological examination of the capillitium found a zone of incomplete alopecia in the frontoparietal and parietotemporal area, without inflammation, desquamation, and scaring. Hairs were of variable length (Figure 1). There was a patch of incomplete alopecia above the forehead between two stripes of hair of variable length (Figure 2). The hair pull test was negative along the edges of the alopecia. Mycological examination from the skin capillitium was negative. The trichoscopy and skin biopsy of the parietotemporal region of the capillitium (Figure 3) confirmed trichotillomania. Laboratory tests (blood count, iron, ferritin, transferrin, selenium, zinc, vitamin B12, folic acid, serology and hormones of thyroid gland) were negative. We referred the girl for ophthalmologic and psychological examination. Ophthalmologic examination proved that there was no need to add any more diopters. The psychological examination provided us with a picture in which she drew her family (Figure 4). The strongest authority in the family was the mother because she looked after the girls for most of the day. She was in the first place in the picture. The father had longer working hours and spent more time outside the home. He worked as a long vehicle driver. He was in the second place in the picture. There was sibling rivalry between the girls, but the parents did not notice this problem and preferred the older daughter. She was successful at school and was prettier (slim, higher, curly brown hair, without spectacles). Our 11-years-old patient noticed all these differences between them, but at her level of mental development was not able to cope with this problem. She wanted to be her sister's equal. The sister is drawn in the picture in the third place next to father, while the patient's own figure was drawn larger and slim even though she was obese. Notably, all three female figures had very nice long brown hair. It seemed that the mother and our patient had better quality of hair and more intense color than the sister in the drawing. The only hairless person in the picture was the father. The girl did not want to talk about her problems and feelings at home. Then it was confirmed that our patient was very sensitive, anxious, willful, and withdrawn. She was interested in her body and very perceptive of her physical appearance. From the psychological point of view, the parents started to pay more interest to their younger daughter and tried to understand and help her. After consultation with the psychiatrist, we did not start psychopharmacologic therapy for trichotillomania; instead, we started treatment with cognitive behavioral therapy, mild shampoo, mild topical steroids (e.g. hydrocortisone butyrate 0.1%) in solution and methionine in capsules. With parents' cooperation, the treatment was successful. The name trichotillomania was first employed by the French dermatologist Francois Henri Hallopeau in 1889, who described a young man pulling his hair out in tufts (3-5). The word is derived from the Greek thrix (hair), tillein (to pull), and mania (madness) (5). The prevalence of TTM in the general adult population ranges from 0.6% to 4%, and 2-4% of the general psychiatric outpatient population meet the criteria for TTM (2-5). The prevalence among children and adolescents has been estimated at less than 1% (5). The disease can occur at any age and in any sex. The age of onset of hair pulling is significantly later for men than for women (3). There are three subsets of age: preschool children, preadolescents to young adults, and adults. The mean age of onset is pre-pubertal. It ranges from 8 to 13 years (on average 11.3 years) (2-5). The occurrence of hair-pulling in the first year of life is a rare event, probably comprising &lt;1% of cases (5). The etiology of TTM is complex and may be triggered by a psychosocial stressor within the family, such as separation from an attachment figure, hospitalization of the child or parent, birth of a younger sibling, sibling rivalry, moving to a new house, or problems with school performance. It has been hypothesized that the habit may begin with \"playing\" with the hair, with later chronic pulling resulting in obvious hair loss (2). Environment is a factor because children usually pull their hair when alone and in relaxed surroundings. The bedroom, bathroom, or family room are \"high-risk\" situations for hair-pulling (5). Men and women also differed in terms of the hair pulling site (men pull hair from the stomach/back and the moustache/beard areas, while women pull from the scalp) (3). Pulling hair from siblings, pets, dolls, and stuffed animals has also been documented, often occurring in the same pattern as in the patient (5). Genetic factors contributing to the development of TTM are mutations of the SLITRK1 gene, which plays a role in cortex development and neuronal growth. The protein SAPAP3 has been present in 4.2% of TTM cases and patients with obsessive-compulsive disorder (OCD). It may be involved in the development of the spectrum of OCD. A significantly different concordance rate for TTM was found in monozygotic (38.1%) compared with dizygotic (0%) twins in 34 pairs (3). The core diagnostic feature is the repetitive pulling of hairs from one`s own body, resulting in hair loss. The targeted hair is mostly on the scalp (75%), but may also be from the eyebrows (42%), eyelashes (53%), beard (10%), and pubic area (17%) (3,5). There are three subtypes of hair pulling - early onset, automatic, and focused. Diagnostic criteria for TTM according to DSM-IV criteria are (2,3,5): 1) recurrent pulling of one`s hair resulting in noticeable hair loss; 2) an increasing sense of tension immediately prior to pulling out the hair or when attempting to resist the behavior; 3) pleasure, gratification, or relief when pulling out the hair; 4) the disturbance is not better accounted for by another mental disorder and is not due to a general medical condition (e.g., a dermatologic condition); 5) the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. The differential diagnosis includes alopecia areata (Table 1) (6), tinea capitis, telogen effluvium, secondary syphilis, traction alopecia, loose anagen syndrome, lichen planopilaris, alopecia mucinosa, and scleroderma (2-5). Biopsy of an involved area (ideally from a recent site of hair loss) can help to confirm the diagnosis (5). On histologic examination, there are typically increased numbers of catagen and telogen hairs without evidence of inflammation. Chronic hair pulling induces a catagen phase, and more hairs will be telogen hairs. Pigment casts and empty anagen follicles are often seen. Perifollicular hemorrhage near the hair bulb is an indicator of TTM (2). Complications of TTM are rare, but they comprise secondary bacterial infections with regional lymphadenopathy as a result of picking and scratching at the scalp. Many patients play with and ingest the pulled hairs (e.g. touching the hair to lips, biting, and chewing). Trichophagia (ingestion of the hair) can lead to a rare complication named trichobezoar (a \"hair ball\" in stomach). This habit is present in approximately 5% to 30% of adult patients, but it is less frequent in children. Patient with trichophagia present with pallor, nausea, vomiting, anorexia, and weight loss. Radiologic examination and gastroscopy should not be delayed (2,4,5). The management of the disease is difficult and requires strong cooperation between the physician, patient, and parents. The dermatologist cannot take part in the therapy, strictly speaking, but without the psychological, psychopharmacologic, and topic dermatologic treatment a vicious circle will be perpetuated.  A Paladin paperback followed, with cover art by British artist John Holmes, influenced by René Magritte, showing a female torso as a suit hanging from a rail, a handle on each hip. Clive Hamilton regarded it as \"perhaps the most memorable and unnerving book cover ever created\". Likening the torso to \"some fibreglass cast on an industrial production line\", Christine Wallace wrote that Holmes's first version was a faceless, breastless, naked woman, \"unmistakably Germaine ... hair fashionably afro-frizzed, waist-deep in a pile of stylised breasts, presumably amputated in the creation of a 'female eunuch' based on an assumed equivalence of testicles and mammary glands\". The book was reissued in 2001 by Farrar, Straus & Giroux at the instigation of Jennifer Baumgardner, a leading third-wave feminist and editor of the publisher's Feminist Classics series. According to Justyna Wlodarczyk, Greer emerged as \"the third wave's favorite second-wave feminist\". Arguments History and physical examination remain the most effective methods of follow-up in patients treated for endometrial cancer (392–394). Patients should be examined every 3 to 4 months during the first 2 years and every 6 months thereafter. About one-half of patients discovered to have recurrent cancer have symptoms, and 75% to 80% of recurrences are detected initially on physical examination. Particular attention should be given to peripheral lymph nodes, the abdomen, and the pelvis. Very few asymptomatic recurrences are detected by vaginal cytology. Chest x-ray every 12 months is an important method of posttreatment surveillance. Almost one-half of all asymptomatic recurrences are detected by chest x-ray. Other radiologic studies, such as CT scans, are not indicated for routine follow-up of patients who do not have symptoms. Diagnosis To diagnose gynecomastia, a thorough history and physical examination are obtained by a physician. Important aspects of the physical examination include evaluation of the male breast tissue with palpation to evaluate for breast cancer and pseudogynecomastia (male breast tissue enlargement solely due to excess fatty tissue), evaluation of penile size and development, evaluation of testicular development and an assessment for masses that raise suspicion for testicular cancer, and proper development of secondary sex characteristics such as the amount and distribution of pubic and underarm hair. Gynecomastia usually presents with bilateral involvement of the breast tissue but may occur unilaterally as well. A 40-year-old female presented with primary amenorrhoea at 17 years of age. She was tall at 98th centile for height with eunuchoidal body habitus. Her breast development was Tanner stage 3, pubic and axillary hair Tanner stage 4 with normal external genitalia. Her bone age was 13.4 years at a chronological age of 17.8 years. Gonadotrophins were elevated indicating primary ovarian failure. A diagnostic laparotomy revealed hypoplastic, infantile uterus with bilateral streak gonads. Chromosomal analysis showed a balanced reciprocal translocation 46X, t(X; 2) (q22 p13). She became pregnant by in vitro fertilization with egg donation at the age of 36 years. At 13 weeks of gestation, she presented with intractable vomiting. She had raised corrected serum calcium and parathyroid hormone concentrations consistent with the diagnosis of primary hyperparathyroidism (PHPT). She underwent parathyroidectomy at 24 weeks of gestation with removal of a large left inferior parathyroid adenoma which normalized her serum calcium. Multipoint linkage from a genome-wide screen has identified a region of suggestive linkage on chromosome 2p13.3-14 in some cases of familial isolated hyperparathyroidism (FIHP). To our knowledge, this is the first case of primary amenorrhoea due to reciprocal translocation involving chromosome 2 and the X chromosome associated with PHPT. PHPT in this case is most likely to be as a result of chromosome 2 involvement where a locus for FIHP has been identified. Identification of the gene involved on chromosome 2p13.3-14 will be of considerable interest. Clinical examination of a breast lump is the first stage in the triple-assessment approach. Both breasts and axillae should be examined meticulously by the clinician, as well as carrying out a physical examination of other body systems as indicated by the history. Although it can be tempting to bypass the physical examination in favor of other, more targeted investigation modalities such as mammography or sonography, the findings of the physical examination are crucial for the effective diagnosis and management of breast disease. [16] Repeated studies have indicated that only by combining all three assessments can optimal sensitivity and specificity be achieved. [4] [16] An astute clinician has an appreciation of the wide variation possible in normal breasts, but anticipates that the palpation of the breasts of an individual woman will be determined by basic facts concerning typical relative distribution of gland tissue, breast symmetry, the influence of life history, and possibly previous surgery. If the findings of a CBE are not as anticipated, the clinician must find out why this is so. This is a different frame of reference from asking whether a given lump or area should be considered suspicious for cancer. The basic questions are whether the findings of a CBE are consistent with typical breast structure and anatomy and in the context of the woman's life history. If these questions can be answered in the affirmative, the examination is complete; if not, further evaluation is necessary. An 11-year-old girl presented to the pediatric gastroenterology outpatient department of our institution with gradually increasing painless abdominal distention. The distention started 2 years earlier and was not associated with any other constitutional symptoms, vomiting, diarrhea, jaundice, hematemesis, or melaena. She reported early satiety and heaviness in the lower abdomen. The abdominal swelling was predominantly in the infraumbilical region and was soft at palpation. She was the first child of nonconsanguineous parents and had an uneventful perinatal course after a normal vaginal delivery. Her developmental milestones were normal. She had an average scholastic performance at school. There was no history of visual problems, seizures, or inappropriate behaviors. She had an early menarche 2 years previously. Her menstrual cycles were regular, and there was no abnormal vaginal discharge. Her breast development was normal (Tanner stage III), while pubic and axillary hair were absent (Tanner stage I). She was short for her age (104 cm; normal range, 120-154 cm). There was no history of short stature among her siblings or parents. Laboratory investigations were performed to measure thyroid-stimulating hormone (1354.34 μIU/mL; normal range, 0.35-5.5 μIU/mL), triiodothyronine (&lt;2.5 ng/dL [0.0385 pmol/L]; normal range, 100-200 ng/dL [1.54-3.08 pmol/L]), thyroxine (1.35 μg/dL [17.37 nmol/L]; normal range, 5-12 μg/dL [64.35-154.44 nmol/L]), β-human chorionic gonadotropin (&lt;1.2 mIU/mL; normal, &lt;5 mIU/mL), luteinizing hormone (0.08 mIU/mL; normal range, 0.1-6.0 mIU/mL), and follicle-stimulating hormone (6.93 mIU/mL; normal range, 0.3-2.0 mIU/mL) levels. Complete blood count was normal. An abdominal mass was suspected, and abdominopelvic CT was performed and followed by US; these examinations revealed multiple large cysts in both ovaries (Figs 1, 2A, 2B). The uterus was pubertal in shape, and endometrial thickness was 9 mm, representing normal follicular phase measurement. Serum CA-125 and inhibin levels were normal. To evaluate short stature, radiographs of the hand (Fig 3) and pelvis (Fig 3B) were obtained as part of a limited skeletal survey, keeping in mind the possible skeletal changes associated with hypothyroidism. In view of the hypothyroidism, US of neck was also performed (Fig 4). Treatment was started based on the clinical and radiologic parameters, and the child's condition improved with medical treatment.\nHere is the question:\nPEDIATRICS: A woman comes to the office with her 3 year old daughter because she has detected a slight mammary development since 3 months without taking any medication or any relevant history. Indeed, the physical examination shows a Tanner stage IV, with no growth of pubic or axillary hair. The external genitalia are normal. Ultrasonography reveals a small uterus and radiology reveals a bone age of 3 years. What attitude should be adopted?\nHere are the potential choices:\n1. Follow-up every 3-4 months, as this is a temporary condition that often resolves on its own.\n2. Breast biopsy.\n3. Mammography.\n4. Administration of GnRh analogues.\nThe correct answer is: ",
        "gold_answer": "1 Follow-up every 3-4 months, as this is a temporary condition that often resolves on its own.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Premature thelarche Premature thelarche is a benign condition in which a young female has breast development before the age of 8 without any accompanied pubertal changes. Individuals undergoing isolated premature thelarche do not experience menstruation, pubic hair growth (pubarche), or the bone growth characteristic of puberty. Initial breast development can be bilateral or unilateral and usually begins with a firm, disc-like area of tissue under the areola which can be mistaken for a mass but is almost always a normal, physiologic process. The breast is often tender and palpation is sometimes painful but breast discharge is absent. Usually, the breasts do not develop past stage 3 on the Tanner Scale, hence maintaining adolescent nipples. Moreover, in 90% of patients with isolated premature thelarche, breast enlargement will resolve 6 months to 6 years after diagnosis. A nineteen years old woman with ambiguous external genitalia was studied. This condition had been previously identified as a newborn, but her parents refused medical attention and it was reared as a girl. At 12-years, she began spontaneous mammary development, appearing pubic and axillary hair, and clitoral enlargement. The menarche occurred at 15-years and it was followed by irregular periods. Physical examination, showed absence of hirsutism and acne, normal mammary development equivalent to grade V of Tanner. The external genitalia showed fused labio-scrotal folds with an small introitus. The urethral meatus was absent and was later located inside the introitus. There was a big phallus similar to an adult penis with a normal glans, flexed by a chordee. Hormonal determinations discarded congenital adrenal hyperplasia. The karyotype was 46,XX and testosterone levels were in adult male range. Pelvic ultrasonography disclosed a normal uterus and both gonads in confirmed by laparoscopy identifying bilateral ovotestis. Testicular tissue was removed and plastic reconstruction of female genitals was done. Pubic hair Pubic hair is often the second noticeable change in puberty, usually within a few months of thelarche. It is referred to as pubarche. The pubic hairs are usually visible first along the labia. The first few hairs are described as Tanner stage 2. Stage 3 is usually reached within another 6–12 months, when the hairs are too numerous to count and appear on the pubic mound as well. By stage 4, the pubic hairs densely fill the \"pubic triangle.\" Stage 5 refers to spread of pubic hair to the thighs and sometimes as abdominal hair upward towards the navel. In about 15% of girls, the earliest pubic hair appears before breast development begins. Underarm hair, also known as axillary hair, is the hair in the underarm area (axilla). Development and function Underarm hair, as human body hair, usually starts to appear at the beginning of puberty, with growth usually completed by the end of the teenage years. Axillary hair goes through four stages of development, driven by weak androgens produced by the adrenal in males and females during adrenarche, and testosterone from the testicle in males during puberty. Like Tanner Staging for pubic hair, axillary hair can be staged according to the Wolfsdorf Staging system, named for pediatric endocrinologist Joseph Wolfsdorf, as follows: Wolfsdorf Stage 1 – no axillary hair Wolfsdorf Stage 2 – scant axillary hair (usually coinciding with onset of adrenarche) Wolfsdorf Stage 3 – coarse axillary hair, less than full-adult Wolfsdorf Stage 4 – full adult axillary hair Staging a patient's axillary hair will allow the physician to track the child's development longitudinally. Linear growth acceleration is one of the important features of early puberty. So the exact height, weight, growth velocity (cm/year) and BMI should be documented.  In females, accurate Tanner staging of the breast should take place, which is particularly challenging in obese or overweight girls to differentiate between adipose tissue and the glandular breast tissue. In males, an orchidometer should be used to determine the testicular volume. Volumes of more than 4 ml confirm pubertal development.  In males and females with pubic hair and body odor, the absence of increased testicular volume and breast development should prompt investigation of peripheral causes. Unilateral testicular enlargement is likely due to testicular tumors. Breast ultrasound is a complementary study of mammography. In many women the tissue that makes up the breast is very dense, representing fibrous tissue and glandular tissue, which produces milk during lactation. This limits the radiologist interpreting the study, so, in these cases, the ultrasound is helpful, since this is capable of distinguishing tumors in women with dense breast tissue, where identification is otherwise difficult. Additionally, it is advisable to follow up a mammogram that shows indications of tumors with an ultrasound, to confirm, before more invasive procedures are undertaken. Pelvic exam The pelvic exam is part of the physical examination of the internal pelvic organs (uterus, cervix, ovaries), vagina, and external genitalia. This exam often includes three parts: Inspection of the external genitalia Bimanual examination Inspection of the cervix and vagina using a speculum. In females, the normal onset of puberty ranges from 8 to 13 years old, averaging age 10 years in White Americans and age 8.9 years in African-Americans. Puberty in females begins with the development of breast buds under the areola, also known as thelarche, and represents entry into Tanner Stage 2. As puberty progresses, the glandular tissue of the breast increases in size and changes in contour. In females, thelarche is followed in 1 to 1.5 years by the onset of sexual hair (pubic and axillary), known as pubarche. Menarche, the onset of menses, arrives on average at age 12.5 years, regardless of ethnicity, following thelarche on average by 2.5 years (range 0.5 to 3 years).  Between Tanner Stage 2 and 3 breast development, females experience peak height velocity. African-American females have closer to 3 years between their thelarche and menarche, accounting for greater height potential. In the months and years following the appearance of pubic hair, other areas of skin that respond to androgens may develop androgenic hair. The usual sequence is: underarm (axillary) hair, perianal hair, upper lip hair, sideburn (preauricular) hair, periareolar hair, and the beard area. As with most human biological processes, this specific order may vary among some individuals. Arm, leg, chest, abdominal, and back hair become heavier more gradually. There is a large range in amount of body hair among adult men, and significant differences in timing and quantity of hair growth among different racial groups. Facial hair is often present in late adolescence, but may not appear until significantly later. Facial hair will continue to get coarser, darker and thicker for another 2–4 years after puberty. Some men do not develop full facial hair for up to 10 years after the completion of puberty. Chest hair may appear during puberty or years after, though not all men develop it. As females develop, a universal means to classify where they are in puberty is known as Tanner stages. Stage one is prepubertal females. They will have no breast tissue or pubic hair. Stage two is when the breast bud begins to protrude with enlargement of the areola and the sparse presence of pubic hair. [2] Female typically experience their ‘growth spurt’ during Tanner stage two. [1] Continued breast and areola enlargement without distinct separation of the contour and darkening pubic hair along the mons pubis is known as Tanner stage three. Stage four is classified when a secondary mound above the breast forms and the pubic hair thickens but is not on the thigh. Menarche occurs in stage three or four. Stage five is the adult female body. It is when the nipple projects out of the areola and the pubic hairs reach the medial thigh. [3] accounts for the greatest num-ber of malpractice claims for errors in diagnosis and for the largest number of paid claims. Litigation often involves younger women, whose physical examination and mammogram may be misleading. If a young woman (≤45 years) presents with a palpable breast mass and equivocal mammographic findings, ultrasound examination and biopsy are used to avoid a delay in diagnosis.ExaminationInspection. The clinician inspects the woman’s breast with her arms by her side (Fig. 17-18A), with her arms straight up in the air (Fig. 17-18B), and with her hands on her hips (with and without pectoral muscle contraction).135,136 Symmetry, size, and shape of the breast are recorded, as well as any evidence of edema (peau d’orange), nipple or skin retraction, or erythema. With the arms extended forward and in a sitting position, the woman leans forward to accentuate any skin retraction.Figure 17-18. Examination of the breast. A. Inspection of the breast with arms at sides. B. Background: Premature ovarian failure (POF) is often associated with autoimmune disorders. The 47,XXX karyotype has also been associated with POF and other genitourinary abnormalities. Following is a case of a 17 year old with immune thrombocytopenic purpura (ITP), POF, 47, XXX and a positive antinuclear antibody (ANA).Case Report: A 17 year old Caucasian female was referred to the Adolescent Health Clinic for evaluation of oligomenorrhea with secondary amenorrhea. Thelarche occurred at 12 years, and menarche at 13 years of age. Since then she had a total of five menstrual periods, spaced 1-15 months apart and lasting 3-5 days. Her last menstrual period was six months prior to presentation. Past medical history was significant for chronic ITP diagnosed seven months prior to presentation, when she developed easy bruising. She was treated with IV gamma globulin and had a moderate response, but relapsed several weeks later. She was started on oral prednisone and had a good response, but continued to relapse whenever steroids were tapered. She was therefore maintained on prednisone 10 mg QOD. There was no family history of irregular menses or autoimmune disease. Physical exam revealed a well-appearing, slightly Cushingoid 17 year old. Physical and cognitive development were age-appropriate. There were no stigmata of Turner Syndrome. The thyroid was normal. Breasts were Tanner 5; public hair was Tanner 3. The external genitalia were normal and appeared well-estrogenized. The remainder of the exam was unremarkable. Pelvic ultrasound demonstrated a normal uterus and ovaries. Laboratory evaluation was significant for elevated gonadotropins and nondetectable estradiol. ANA was positive at 1:320 with a speckled pattern. Blood counts, serologies, complement levels, and coagulation studies were otherwise normal. Cytogenetic studies revealed a 47,XXX karyotype. The patient was placed on an estrogen/norethindrone hormone replacement patch for premature ovarian failure. To date, she has developed no further symptoms, and does not meet criteria for a diagnosis of systemic lupus erythematosis.Conclusions: A 47,XXX karyotype was found in a 17 year old with POF and ITP with a positive ANA. The presence of known autoimmune disease in a woman with POF should not dissuade the physician from evaluating for a potential genetic cause. Sexual ambiguities are due to varied congenital or hormonal causes. A retrospective study carried out from January 1995 to December 2000 and followed by a prospective study from January 2001 to September 2002 sought to describe the clinical aspects of sexual ambiguities in Internal Medicine in a tertiary hospital Mali. Among 12 patients out of 2223 consultants identified (0.54 percent), 10 of them were phenotypically feminine and 2 phenotypically masculine. The average age of the patients was 14.3+- 8.9 years. Clinically, 3 out of the 10 phenotypically feminine patients presented an anomaly of the external genital organs; 5 out of the 10 had low axillary and pubic hair growth; 4 out of the 10 had delayed puberty; 6 out of the 10 had primary amenorrhoea; 7 out of 10 had hypoplasia of the mammary glands; and3 out of 10 had an inguinal mass. For the the 2 phenotypically masculine patients, one had a bilateral gynecomastia, a macroskelia of 2m04, a low axillary and pubic hair growth and the other had an anomaly of the external genital organs. Trichotillomania (TTM) is defined by the Diagnostics and Statistic Manual of Mental Disorders, 4th edition (DMS-IV) as hair loss from a patient`s repetitive self-pulling of hair. The disorder is included under anxiety disorders because it shares some obsessive-compulsive features. Patients have the tendency towards feelings of unattractiveness, body dissatisfaction, and low self-esteem (1,2). It is a major psychiatric problem, but many patients with this disorder first present to a dermatologist. An 11-year-old girl came to our department with a 2-month history of diffuse hair loss on the frontoparietal and parietotemporal area (Figure 1). She had originally been examined by a pediatrician with the diagnosis of alopecia areata. The patient`s personal history included hay fever and shortsightedness, and she suffered from varicella and mononucleosis. Nobody in the family history suffered from alopecia areata, but her father has male androgenetic alopecia (Norwood/Hamilton MAGA C3F3). The mother noticed that the child had had changeable mood for about 2 months and did not want to communicate with other persons in the family. The family did not have any pet at home. At school, her favorite subjects were Math and Computer Studies. She did not like Physical Education and did not participate in any sport activities during her free time. This was very strange because she was obese (body-mass index (BMI) 24.69). She was sometimes angry with her 13-year-old sister who had better results at school. The girl had suddenly started to wear a blue scarf. The parents did not notice that she pulled out her hair at home. Dermatological examination of the capillitium found a zone of incomplete alopecia in the frontoparietal and parietotemporal area, without inflammation, desquamation, and scaring. Hairs were of variable length (Figure 1). There was a patch of incomplete alopecia above the forehead between two stripes of hair of variable length (Figure 2). The hair pull test was negative along the edges of the alopecia. Mycological examination from the skin capillitium was negative. The trichoscopy and skin biopsy of the parietotemporal region of the capillitium (Figure 3) confirmed trichotillomania. Laboratory tests (blood count, iron, ferritin, transferrin, selenium, zinc, vitamin B12, folic acid, serology and hormones of thyroid gland) were negative. We referred the girl for ophthalmologic and psychological examination. Ophthalmologic examination proved that there was no need to add any more diopters. The psychological examination provided us with a picture in which she drew her family (Figure 4). The strongest authority in the family was the mother because she looked after the girls for most of the day. She was in the first place in the picture. The father had longer working hours and spent more time outside the home. He worked as a long vehicle driver. He was in the second place in the picture. There was sibling rivalry between the girls, but the parents did not notice this problem and preferred the older daughter. She was successful at school and was prettier (slim, higher, curly brown hair, without spectacles). Our 11-years-old patient noticed all these differences between them, but at her level of mental development was not able to cope with this problem. She wanted to be her sister's equal. The sister is drawn in the picture in the third place next to father, while the patient's own figure was drawn larger and slim even though she was obese. Notably, all three female figures had very nice long brown hair. It seemed that the mother and our patient had better quality of hair and more intense color than the sister in the drawing. The only hairless person in the picture was the father. The girl did not want to talk about her problems and feelings at home. Then it was confirmed that our patient was very sensitive, anxious, willful, and withdrawn. She was interested in her body and very perceptive of her physical appearance. From the psychological point of view, the parents started to pay more interest to their younger daughter and tried to understand and help her. After consultation with the psychiatrist, we did not start psychopharmacologic therapy for trichotillomania; instead, we started treatment with cognitive behavioral therapy, mild shampoo, mild topical steroids (e.g. hydrocortisone butyrate 0.1%) in solution and methionine in capsules. With parents' cooperation, the treatment was successful. The name trichotillomania was first employed by the French dermatologist Francois Henri Hallopeau in 1889, who described a young man pulling his hair out in tufts (3-5). The word is derived from the Greek thrix (hair), tillein (to pull), and mania (madness) (5). The prevalence of TTM in the general adult population ranges from 0.6% to 4%, and 2-4% of the general psychiatric outpatient population meet the criteria for TTM (2-5). The prevalence among children and adolescents has been estimated at less than 1% (5). The disease can occur at any age and in any sex. The age of onset of hair pulling is significantly later for men than for women (3). There are three subsets of age: preschool children, preadolescents to young adults, and adults. The mean age of onset is pre-pubertal. It ranges from 8 to 13 years (on average 11.3 years) (2-5). The occurrence of hair-pulling in the first year of life is a rare event, probably comprising &lt;1% of cases (5). The etiology of TTM is complex and may be triggered by a psychosocial stressor within the family, such as separation from an attachment figure, hospitalization of the child or parent, birth of a younger sibling, sibling rivalry, moving to a new house, or problems with school performance. It has been hypothesized that the habit may begin with \"playing\" with the hair, with later chronic pulling resulting in obvious hair loss (2). Environment is a factor because children usually pull their hair when alone and in relaxed surroundings. The bedroom, bathroom, or family room are \"high-risk\" situations for hair-pulling (5). Men and women also differed in terms of the hair pulling site (men pull hair from the stomach/back and the moustache/beard areas, while women pull from the scalp) (3). Pulling hair from siblings, pets, dolls, and stuffed animals has also been documented, often occurring in the same pattern as in the patient (5). Genetic factors contributing to the development of TTM are mutations of the SLITRK1 gene, which plays a role in cortex development and neuronal growth. The protein SAPAP3 has been present in 4.2% of TTM cases and patients with obsessive-compulsive disorder (OCD). It may be involved in the development of the spectrum of OCD. A significantly different concordance rate for TTM was found in monozygotic (38.1%) compared with dizygotic (0%) twins in 34 pairs (3). The core diagnostic feature is the repetitive pulling of hairs from one`s own body, resulting in hair loss. The targeted hair is mostly on the scalp (75%), but may also be from the eyebrows (42%), eyelashes (53%), beard (10%), and pubic area (17%) (3,5). There are three subtypes of hair pulling - early onset, automatic, and focused. Diagnostic criteria for TTM according to DSM-IV criteria are (2,3,5): 1) recurrent pulling of one`s hair resulting in noticeable hair loss; 2) an increasing sense of tension immediately prior to pulling out the hair or when attempting to resist the behavior; 3) pleasure, gratification, or relief when pulling out the hair; 4) the disturbance is not better accounted for by another mental disorder and is not due to a general medical condition (e.g., a dermatologic condition); 5) the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. The differential diagnosis includes alopecia areata (Table 1) (6), tinea capitis, telogen effluvium, secondary syphilis, traction alopecia, loose anagen syndrome, lichen planopilaris, alopecia mucinosa, and scleroderma (2-5). Biopsy of an involved area (ideally from a recent site of hair loss) can help to confirm the diagnosis (5). On histologic examination, there are typically increased numbers of catagen and telogen hairs without evidence of inflammation. Chronic hair pulling induces a catagen phase, and more hairs will be telogen hairs. Pigment casts and empty anagen follicles are often seen. Perifollicular hemorrhage near the hair bulb is an indicator of TTM (2). Complications of TTM are rare, but they comprise secondary bacterial infections with regional lymphadenopathy as a result of picking and scratching at the scalp. Many patients play with and ingest the pulled hairs (e.g. touching the hair to lips, biting, and chewing). Trichophagia (ingestion of the hair) can lead to a rare complication named trichobezoar (a \"hair ball\" in stomach). This habit is present in approximately 5% to 30% of adult patients, but it is less frequent in children. Patient with trichophagia present with pallor, nausea, vomiting, anorexia, and weight loss. Radiologic examination and gastroscopy should not be delayed (2,4,5). The management of the disease is difficult and requires strong cooperation between the physician, patient, and parents. The dermatologist cannot take part in the therapy, strictly speaking, but without the psychological, psychopharmacologic, and topic dermatologic treatment a vicious circle will be perpetuated.  A Paladin paperback followed, with cover art by British artist John Holmes, influenced by René Magritte, showing a female torso as a suit hanging from a rail, a handle on each hip. Clive Hamilton regarded it as \"perhaps the most memorable and unnerving book cover ever created\". Likening the torso to \"some fibreglass cast on an industrial production line\", Christine Wallace wrote that Holmes's first version was a faceless, breastless, naked woman, \"unmistakably Germaine ... hair fashionably afro-frizzed, waist-deep in a pile of stylised breasts, presumably amputated in the creation of a 'female eunuch' based on an assumed equivalence of testicles and mammary glands\". The book was reissued in 2001 by Farrar, Straus & Giroux at the instigation of Jennifer Baumgardner, a leading third-wave feminist and editor of the publisher's Feminist Classics series. According to Justyna Wlodarczyk, Greer emerged as \"the third wave's favorite second-wave feminist\". Arguments History and physical examination remain the most effective methods of follow-up in patients treated for endometrial cancer (392–394). Patients should be examined every 3 to 4 months during the first 2 years and every 6 months thereafter. About one-half of patients discovered to have recurrent cancer have symptoms, and 75% to 80% of recurrences are detected initially on physical examination. Particular attention should be given to peripheral lymph nodes, the abdomen, and the pelvis. Very few asymptomatic recurrences are detected by vaginal cytology. Chest x-ray every 12 months is an important method of posttreatment surveillance. Almost one-half of all asymptomatic recurrences are detected by chest x-ray. Other radiologic studies, such as CT scans, are not indicated for routine follow-up of patients who do not have symptoms. Diagnosis To diagnose gynecomastia, a thorough history and physical examination are obtained by a physician. Important aspects of the physical examination include evaluation of the male breast tissue with palpation to evaluate for breast cancer and pseudogynecomastia (male breast tissue enlargement solely due to excess fatty tissue), evaluation of penile size and development, evaluation of testicular development and an assessment for masses that raise suspicion for testicular cancer, and proper development of secondary sex characteristics such as the amount and distribution of pubic and underarm hair. Gynecomastia usually presents with bilateral involvement of the breast tissue but may occur unilaterally as well. A 40-year-old female presented with primary amenorrhoea at 17 years of age. She was tall at 98th centile for height with eunuchoidal body habitus. Her breast development was Tanner stage 3, pubic and axillary hair Tanner stage 4 with normal external genitalia. Her bone age was 13.4 years at a chronological age of 17.8 years. Gonadotrophins were elevated indicating primary ovarian failure. A diagnostic laparotomy revealed hypoplastic, infantile uterus with bilateral streak gonads. Chromosomal analysis showed a balanced reciprocal translocation 46X, t(X; 2) (q22 p13). She became pregnant by in vitro fertilization with egg donation at the age of 36 years. At 13 weeks of gestation, she presented with intractable vomiting. She had raised corrected serum calcium and parathyroid hormone concentrations consistent with the diagnosis of primary hyperparathyroidism (PHPT). She underwent parathyroidectomy at 24 weeks of gestation with removal of a large left inferior parathyroid adenoma which normalized her serum calcium. Multipoint linkage from a genome-wide screen has identified a region of suggestive linkage on chromosome 2p13.3-14 in some cases of familial isolated hyperparathyroidism (FIHP). To our knowledge, this is the first case of primary amenorrhoea due to reciprocal translocation involving chromosome 2 and the X chromosome associated with PHPT. PHPT in this case is most likely to be as a result of chromosome 2 involvement where a locus for FIHP has been identified. Identification of the gene involved on chromosome 2p13.3-14 will be of considerable interest. Clinical examination of a breast lump is the first stage in the triple-assessment approach. Both breasts and axillae should be examined meticulously by the clinician, as well as carrying out a physical examination of other body systems as indicated by the history. Although it can be tempting to bypass the physical examination in favor of other, more targeted investigation modalities such as mammography or sonography, the findings of the physical examination are crucial for the effective diagnosis and management of breast disease. [16] Repeated studies have indicated that only by combining all three assessments can optimal sensitivity and specificity be achieved. [4] [16] An astute clinician has an appreciation of the wide variation possible in normal breasts, but anticipates that the palpation of the breasts of an individual woman will be determined by basic facts concerning typical relative distribution of gland tissue, breast symmetry, the influence of life history, and possibly previous surgery. If the findings of a CBE are not as anticipated, the clinician must find out why this is so. This is a different frame of reference from asking whether a given lump or area should be considered suspicious for cancer. The basic questions are whether the findings of a CBE are consistent with typical breast structure and anatomy and in the context of the woman's life history. If these questions can be answered in the affirmative, the examination is complete; if not, further evaluation is necessary. An 11-year-old girl presented to the pediatric gastroenterology outpatient department of our institution with gradually increasing painless abdominal distention. The distention started 2 years earlier and was not associated with any other constitutional symptoms, vomiting, diarrhea, jaundice, hematemesis, or melaena. She reported early satiety and heaviness in the lower abdomen. The abdominal swelling was predominantly in the infraumbilical region and was soft at palpation. She was the first child of nonconsanguineous parents and had an uneventful perinatal course after a normal vaginal delivery. Her developmental milestones were normal. She had an average scholastic performance at school. There was no history of visual problems, seizures, or inappropriate behaviors. She had an early menarche 2 years previously. Her menstrual cycles were regular, and there was no abnormal vaginal discharge. Her breast development was normal (Tanner stage III), while pubic and axillary hair were absent (Tanner stage I). She was short for her age (104 cm; normal range, 120-154 cm). There was no history of short stature among her siblings or parents. Laboratory investigations were performed to measure thyroid-stimulating hormone (1354.34 μIU/mL; normal range, 0.35-5.5 μIU/mL), triiodothyronine (&lt;2.5 ng/dL [0.0385 pmol/L]; normal range, 100-200 ng/dL [1.54-3.08 pmol/L]), thyroxine (1.35 μg/dL [17.37 nmol/L]; normal range, 5-12 μg/dL [64.35-154.44 nmol/L]), β-human chorionic gonadotropin (&lt;1.2 mIU/mL; normal, &lt;5 mIU/mL), luteinizing hormone (0.08 mIU/mL; normal range, 0.1-6.0 mIU/mL), and follicle-stimulating hormone (6.93 mIU/mL; normal range, 0.3-2.0 mIU/mL) levels. Complete blood count was normal. An abdominal mass was suspected, and abdominopelvic CT was performed and followed by US; these examinations revealed multiple large cysts in both ovaries (Figs 1, 2A, 2B). The uterus was pubertal in shape, and endometrial thickness was 9 mm, representing normal follicular phase measurement. Serum CA-125 and inhibin levels were normal. To evaluate short stature, radiographs of the hand (Fig 3) and pelvis (Fig 3B) were obtained as part of a limited skeletal survey, keeping in mind the possible skeletal changes associated with hypothyroidism. In view of the hypothyroidism, US of neck was also performed (Fig 4). Treatment was started based on the clinical and radiologic parameters, and the child's condition improved with medical treatment.\nHere is the question:\nPEDIATRICS: A woman comes to the office with her 3 year old daughter because she has detected a slight mammary development since 3 months without taking any medication or any relevant history. Indeed, the physical examination shows a Tanner stage IV, with no growth of pubic or axillary hair. The external genitalia are normal. Ultrasonography reveals a small uterus and radiology reveals a bone age of 3 years. What attitude should be adopted?\nHere are the potential choices:\n1. Follow-up every 3-4 months, as this is a temporary condition that often resolves on its own.\n2. Breast biopsy.\n3. Mammography.\n4. Administration of GnRh analogues.\nThe correct answer is: 1. Follow-up every 3-4 months, as this is a temporary condition that often resolves on its own."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Trigeminal autonomic cephalalgias include cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, and rhinorrhea (SUNCT). Conventional pharmacological therapy can be successful in the majority of trigeminal autonomic cephalalgias patients. Most cluster headache attacks respond to 100% oxygen inhalation, or 6 mg subcutaneous sumatriptan. Nasal spray of sumatriptan (20 mg) or zolmitriptan (5 mg) are recommended as second choice. The bouts can be brought under control by a short course of corticosteroids (oral prednisone: 60-100 mg/day, or intravenous methylprednisolone: 250-500 mg/day, for 5 days, followed by tapering off the dosage), or by long-term prophylaxis with verapamil (at least 240 mg/day). Alternative long-term preventive medications include lithium carbonate (800-1600 mg/day), methylergonovine (0.4-1.2 mg/day), and topiramate (100-200 mg/day). As a rule, paroxysmal hemicrania responds to preventive treatment with indomethacin (75-150 mg/day). A short course of intravenous lidocaine (1-4 mg/kg/hour) can reduce the flow of attacks during exacerbations of SUNCT. Lamotrigine (100-300 mg/day) is the preventive drug of choice for SUNCT. Gabapentin (800-2700 mg/day), topiramate (50-300 mg/day), and carbamazepine (200-1600 mg/day) may be of help.  We described three cases of hypnic headache with successful treatment by lithium carbonate or caffeine. This is the first detail report of Japanese cases. An endocrinological test and rhythm analyses of ambulatory blood pressure (ABP) and heart rate variability in a case suggested possible association between hypnic headache and hypothalamic-pituitary dysfunction. Case 1: A 48-year-old female migraineur complained of new-onset nocturnal headaches. Her headache awakened her from sleep between 1 AM and 2 AM. The headache occurred 3-4 times per week and lasted from 1 hour to 2 hours. The headache were moderate intensity and bilateral dull throbbing pain that located in the forehead to temples. There was no accompanying symptoms such as nausea, phonophobia, photophobia, nor the other autonomic features including conjunctival injection or tearing during the headache attacks. Physical and neurological examinations showed normal results except slight weakness and mild dysesthesia of the left arm due to a vertebral disk herniation at C5/6 level. In the pituitary endocrinological test, the prolactin level remarkably increased in response to the TRH loading. The single cosinor analysis demonstrated significant circadian rhythm of ABP parameters. However, the analysis did not demonstrate any significant circadian rhythm of Holter ECG parameters of time domain analysis and frequency analysis. Receiving 200 mg lithium bicarbonate before sleep, her nocturnal headache completely disappeared. Case 2: A 68-year-old woman had been followed up by her chronic tension-type headache since her forties. At her 66-years, she suffered from a new nocturnal headache. She awoke from sleep by the headache about 3 AM and the headache lasted 30 min. Moderate, dull headache located on her left temple to parietal head, 3-4 times/week. She was able to go back asleep without any medication after spontaneous headache cessation. She first complained the nocturnal headache at the 10 months later of the new headache appearance. She received 200 mg caffeine just before sleep and her headache has been disappeared. Case 3: 70-year-old women had been regularly visited our clinics for her migraine and chronic tension-type headache. She received amitriptyline and her headaches was well controlled. At her 69 years, she complained nocturnal headache. It occured every other day. The headache was moderate pulsative dull pain on the occipital region and lasted 90 minutes without any autonomic symptoms. Headache began between midnight and 1 AM. She told us her new nocturnal headache one year later of the onset. Oral caffeine (200 mg) just before sleep did not improve her headache and caused insomnia. Receiving 100 mg lithium before sleep, her hypnic headache disappeared completely. These three cases are compatible with the diagnostic criteria proposed in ICHD-II. There were some patients with hypnic headache in Japan and neurologists should pay attentions to this form of benign headache, because some beneficial treatments are currently available. Trigeminal autonomic cephalgias (TAC) are characterized by severe and strictly unilateral headaches with a frontotemporal and periorbital preponderance in combination with ipsilateral cranial autonomic symptoms, such as lacrimation, conjunctival injection, rhinorrhea, nasal congestion, and restlessness or agitation. One main differentiating factor is the duration of painful attacks. While attacks typically last 5 s to 10 min in SUNCT syndrome (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing), paroxysmal hemicrania lasts 2-30 min and cluster headaches 15-180 min. Hemicrania continua represents a continuous TAC variant. From a therapeutic view, TACs differ substantially. Lamotrigine is used as first-choice prevention in SUNCT syndrome and indometacin in paroxysmal hemicrania. For cluster headaches, acute therapy with inhaled pure oxygen and fast-acting triptans (sumatriptan s.c. and intranasal zolmitriptan) is equally important to short-term preventive therapy with methysergide and cortisone and long-term prophylactic treatment comprising verapamil as drug of first choice and lithium carbonate and topiramate as drugs of second choice. In refractory cases of chronic cluster headache, neuromodulatory approaches such as occipital nerve stimulation and sphenopalatine ganglion stimulation are increasingly applied.  The management of cluster headache (CH) may be challenging. We report a 50-year-old male with recurrent attacks of dull and severe unilateral periorbital pain, lasting 30-45 minutes, twice a day, exclusively during sleep, and accompanied by ipsilateral rhinorrhea and lacrimation. The pain switched sides within every attack. CH treatment was initiated but the patient maintained recurrence rates compatible with chronic CH, even after increasing verapamil to 460 mg/day. Afterwards we decided to add lithium (800 mg/day). With this treatment the severity and recurrence of CH substantially decreased, despite the patient's autonomous decision to take lithium only during the acute phase of the cluster. The exclusively alternating location and the excellent response to short cycles of lithium represent two unique features of CH. Primary Ninety percent of all headaches are primary headaches. Primary headaches usually first start when people are between 20 and 40 years old. The most common types of primary headaches are migraines and tension-type headaches. They have different characteristics. Migraines typically present with pulsing head pain, nausea, photophobia (sensitivity to light) and phonophobia (sensitivity to sound) Tension-type headaches usually present with non-pulsing \"bandlike\" pressure on both sides of the head, not accompanied by other symptoms. Such kind of headaches maybe further classified into-episodic and chronic tension type headaches Other very rare types of primary headaches include: cluster headaches: short episodes (15–180 minutes) of severe pain, usually around one eye, with autonomic symptoms (tearing, red eye, nasal congestion) which occur at the same time every day. Cluster headaches can be treated with triptans and prevented with prednisone, ergotamine or lithium. Cluster headache is characterised by attacks of excruciating unilateral headache or facial pain lasting 15 min to 3 h and is seen as one of the most intense forms of pain. Cluster headache attacks are accompanied by ipsilateral autonomic symptoms such as ptosis, miosis, redness or flushing of the face, nasal congestion, rhinorrhoea, peri-orbital swelling and/or restlessness or agitation. Cluster headache treatment entails fast-acting abortive treatment, transitional treatment and preventive treatment. The primary goal of prophylactic and transitional treatment is to achieve attack freedom, although this is not always possible. Subcutaneous sumatriptan and high-flow oxygen are the most proven abortive treatments for cluster headache attacks, but other treatment options such as intranasal triptans may be effective. Verapamil and lithium are the preventive drugs of first choice and the most widely used in first-line preventive treatment. Given its possible cardiac side effects, electrocardiogram (ECG) is recommended before treating with verapamil. Liver and kidney functioning should be evaluated before and during treatment with lithium. If verapamil and lithium are ineffective, contraindicated or discontinued because of side effects, the second choice is topiramate. If all these drugs fail, other options with lower levels of evidence are available (e.g. melatonin, clomiphene, dihydroergotamine, pizotifen). However, since the evidence level is low, we also recommend considering one of several neuromodulatory options in patients with refractory chronic cluster headache. A new addition to the preventive treatment options in episodic cluster headache is galcanezumab, although the long-term effects remain unknown. Since effective preventive treatment can take several weeks to titrate, transitional treatment can be of great importance in the treatment of cluster headache. At present, greater occipital nerve injection is the most proven transitional treatment. Other options are high-dose prednisone or frovatriptan. The prevalence of cluster headache is 0.1% and cluster headache is often not diagnosed or misdiagnosed as migraine or sinusitis. In cluster headache there is often a considerable diagnostic delay - an average of 7 years in a population-based survey. Cluster headache is characterized by very severe or severe orbital or periorbital pain with a duration of 15-180 minutes. The cluster headache attacks are accompanied by characteristic associated unilateral symptoms such as tearing, nasal congestion and/or rhinorrhoea, eyelid oedema, miosis and/or ptosis. In addition, there is a sense of restlessness and agitation. Patients may have up to eight attacks per day. Episodic cluster headache (ECH) occurs in clusters of weeks to months duration, whereas chronic cluster headache (CCH) attacks occur for more than 1 year without remissions. Management of cluster headache is divided into acute attack treatment and prophylactic treatment. In ECH and CCH the attacks can be treated with oxygen (12 L/min) or subcutaneous sumatriptan 6 mg. For both oxygen and sumatriptan there are two randomized, placebo-controlled trials demonstrating efficacy. In both ECH and CCH, verapamil is the prophylactic drug of choice. Verapamil 360 mg/day was found to be superior to placebo in one clinical trial. In clinical practice, daily doses of 480-720 mg are mostly used. Thus, the dose of verapamil used in cluster headache treatment may be double the dose used in cardiology, and with the higher doses the PR interval should be checked with an ECG. At the start of a cluster, transitional preventive treatment such as corticosteroids or greater occipital nerve blockade can be given. In CCH and in long-standing clusters of ECH, lithium, methysergide, topiramate, valproic acid and ergotamine tartrate can be used as add-on prophylactic treatment. In drug-resistant CCH, neuromodulation with either occipital nerve stimulation or deep brain stimulation of the hypothalamus is an alternative treatment strategy. For most cluster headache patients there are fairly good treatment options both for acute attacks and for prophylaxis. The big problem is the diagnosis of cluster headache as demonstrated by the diagnostic delay of 7 years. However, the relatively short-lasting attack of pain in one eye with typical associated symptoms should lead the family doctor to suspect cluster headache resulting in a referral to a neurologist or a headache centre with experience in the treatment of cluster headache. Two patients with cluster-tic syndrome are reported. The first, a 43-years-old man, complaining of trigeminal pain in the right side of the face, accompanied by homolateral autonomic signs, such as ocular injection, sweating and drooped eyelid. The cluster attack was triggered by chewing, shaving and washing the face. The periodicity of bouts was six months. The pain was relieved by carbamazepine (800 mg/day). The second patient, a 43-year-old man, with an excruciant, neuralgic pain in the left side of the face, accompanied by tearing, conjuntival injection, drooped eyelid, rhinorrhea, photophobia and phonophobia. The neurologic examination showed triggered points in the first and second division of the trigeminal nerve. The patient was treated with verapamil (160 mg/day) and prednisone (60 mg/day), with relief of his symptoms. The periodicity of bouts was once a year. The literature was reviewed and 37 cases previosly reported are considered. We conclude that there are two different groups of patients. In the first group, the patients had cluster and trigeminal bouts in different time. In the second group, with only nine cases, the patients presented both cluster and trigeminal type of pain at the same time, as in the two cases reported here. Hypnic headache (HH) is a rare benign disorder described initially by Raskin in 1988. It is characterized by recurrent nocturnal episodes of headache that periodically awaken the sleeping patient and usually occur in the elderly. This review aimed to describe the clinical features of the HH cases published in the literature from 1988 to 2018. Based on literature search in the major medical databases (LiLacs, SciELO, Bireme, Medline, Embase, Current Contents, Scopus, EBSCO and PubMed), we have analyzed the case reports on HH that have been published from 1988 to 2018. We described 343 adults (69.0% women and 31.0% men) and 5 children (3 girls and 2 boys) diagnosed with HH. Average age for adults and children was, respectively, 58.0 ± 13.1 years (ranging from 15 to 85 years) and 9 years (ranging from 7 to 11 years). The diagnosis was made 7.6 ± 14.2 years (range 0.1 to 39 years) after onset of headache. Pain occurred during nocturnal sleep (94.8%), with an average duration of 90 min, bilaterally located (55.5%), having a dull character (74.4%), and moderate intensity (61.5%). In 94.5% of the patients, headache occurred for 10 or more days per month (mean of 21 days). Autonomic manifestations occurred in 7.6% of the patients, predominantly lacrimation (61.1%) and rhinorrhea (16.7%). Caffeine presented the best therapeutic response in acute treatment. In prophylaxis, lithium, caffeine and indomethacin were effective drugs in 77.8% of the patients. In 56.7% of the patients there was remission with treatment and in 72.7% of them, without recurrence. HH is a rare disease that usually occurs for the first time in older women but may begin in childhood. Lithium and caffeine are effective drugs for pain prophylaxis, but randomized clinical trials are required. Treatments Lithium carbonate 200–600 mg at bedtime is an effective treatment for most patients but for those that can not tolerate Lithium, Verapamil, indomethacin, melatonin or methysergide may be tried. Two patients have also responded to flunarizine 5 mg. It has also been shown that 1–2 cups of coffee or 100–200 mg of caffeine before bed can prevent hypnic headaches. A recent review of 348 cases available in the literature has been recently published. References External links Headaches Treatments A ten-patient study conducted by Pareja et al. found that all patients diagnosed with CPH were responsive to indomethacin and were able to completely control their symptoms. Doses of the drug ranged from 25 mg per day to 150 mg per day with a median dose of 75 mg per 24-hour period. Almost all cases of CPH respond positively and effectively to indometacin, but as much as 25 percent of patients discontinued use of the drug due to adverse side effects, namely complications in the gastrointestinal tract. According to a case study by Milanlioglu et al., 100mg of lamotrigine, an antiepileptic drug, administered twice daily alleviated all painful symptoms. No side effects were noted after two months of treatment. Dosage of lamotrigine was decreased to 50mg a day after the first two months, and no symptoms or side-effects were recorded after a three-month followup. Many experts favor verapamil as the first-line preventive treatment for patients with chronic cluster headache or prolonged bouts. While verapamil compares favorably with lithium in practice, some patients require verapamil doses far in excess of those administered for cardiac disorders. The initial dose range is 40–80 mg twice daily; effective doses may be as high as 960 mg/d. Side effects such as constipation and leg swelling can be problematic. Of paramount concern, however, is the cardiovascular safety of verapamil, particularly Prednisone 1 mg/kg up to Verapamil 160–960 mg/d 60 mg qd, tapering over 21 days Gabapentinb 1200–3600 mg/d Melatoninb 9–12 mg/d aNot available worldwide. bUnproven but of potential benefit. We reported a 36-year-old man, who suffered from cluster headache (CH) associated with hemicrania continua (HC). The continuous, dull or pressure-type headache appeared on the same side of the CH during the third month of a prolonged cluster period, and fluctuated in the severity of pain. This headache was aggravated when the CH was ameliorated by the administration of lithium carbonate. This converse relationship between CH and HC persisted during an on-off trial of the lithium carbonate, and the HC was exacerbated again after the complete cessation of CH. Retrobulbar pain and nasal congestion were present as components of HC similarly to CH, but they subsided gradually and the pressure-type vascular headache over the temporal area predominated later. The continuous headache lasted more than 3 months, and responded significantly to the indomethacin at a dose of 75mg/d. The clinical course of this patient suggests that HC and CH have a common pathomechanism including hyperactivation of the trigemino-vascular reflex, and may be different in the involvement of other central pathway of pain generation. Indomethacin may deserve consideration for the treatment of continuous headache that appears during an atypical course of other primary headaches. Three grown-up males with a long-lasting history of rather uniform, unilateral headache in the ocular-periocular area, in cluster fashion, are examined. Pain paroxysms of short duration (15-60 sec) appear up to 5-30 times per h. The headache is unilateral without side shift. Conjunctival injection appears at the very beginning of the attack and is partly massive, lasting the entire duration of the attack, and fading away at the end of it. Tearing (massive), forehead sweating (subclinical) and rhinorrhea, all on the symptomatic side, accompany the attack. In the youngest patient, the headache became chronic after clustering for six months initially, and after approximately 3 1/2 years it became bilateral. However, even in this patient, a clear unilateral pain preponderance prevails, and the autonomic disturbances are all on the original pain side. Attacks can partly be precipitated by chewing, eating (e.g. citrus fruits), moving the head, etc. The headache is completely refractory to drug therapy, including indomethacin. The authors used lithium carbonate in treatment of 7 patients with Horton's headaches of primarily or secondarily chronic character. In all patients the blood level of lithium was determined and it was found to reach therapeutic levels. Disappearance of attacks was achieved in 3 cases, significant improvement in 2, and in 2 cases treatment was ineffective. The mechanism of lithium action in this disease is discussed. The authors recommend lithium as worthy of use since other drugs are ineffective in this disease or they cannot be used, eg. steroids or indomethacin, in view of frequent coexistence of paptic ulcer. Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome is a very rare disorder characterized by short-lasting neuralgiform unilateral pain affecting the orbital-periorbital area and associated with autonomic phenomena consisting mainly of conjunctival injection, tearing, and rhinorrhea. Treatment of this condition is difficult; many drugs and surgical procedures have been tried with variable results. In the literature, two cases have been described with short-term response to microvascular decompression of the trigeminal root. We present the case of a patient with short-lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome who remains asymptomatic 2 years after microvascular decompression. A 56-year-old woman was referred to our clinic because she had experienced pain in the distribution of the first left trigeminal branch during the previous 2 years. She experienced paroxysms lasting from a few seconds to 1 to 2 minutes superimposed over a dull sensation of pain involving the same territory. The paroxysms had no refractory period and were triggered by touching the eye or the left side of the face, chewing, yawning, washing her hair, and even by light. Although the paroxysms were triggered by light touch or chewing, she was able to talk or touch herself while having the paroxysm. During pain attacks, she experienced tearing and ipsilateral conjunctival injection, eyelid edema and rhinorrhea, as well as intense photophobia. A magnetic resonance imaging scan revealed a vascular structure distorting and compressing the trigeminal root. The patient underwent microvascular decompression of the trigeminal root. At surgery, there was clear compression of the trigeminal root by a superior cerebellar artery loop that was resolved by interposing a Teflon patch. The patient awoke from the operation without pain, and all the accompanying signs and symptoms, such as photophobia, disappeared. The postoperative course was uneventful, and 2 years after treatment, the patient remains asymptomatic. Microvascular decompression could be an alternative therapeutic approach to this rare syndrome. Episodic paroxysmal hemicrania (EPH) is a rare disorder characterized by frequent, daily attacks of short-lived, unilateral headache with accompanying ipsilateral autonomic features. EPH has attack periods which last weeks to months separated by remission intervals lasting months to years, however, a seasonal variation has never been reported in EPH. We report a new case of EPH with a clear seasonal pattern: a 32-year-old woman with a right-sided headache for 17 years. Pain occurred with a seasonal variation, with bouts lasting one month (usually in the first months of the year) and remission periods lasting around 11 months. During these periods she had headache from three to five times per day, lasting from 15 to 30 minutes, without any particular period preference. There were no precipitating or aggravating factors. Tearing and conjunctival injection accompanied ipsilaterally the pain. Previous treatments provided no pain relief. She completely responded to indomethacin 75 mg daily. After three years, the pain recurred with longer attack duration and was just relieved with prednisone. We also propose a new hypothesis: the EPH-cluster headache continuum. Paroxysmal hemicrania is a well-defined clinical condition about which many articles have been published. Attempts have been made to explain the response of this illness to indomethacin, suggesting its possible cervical origin. In some patients it is set off by stimulation of certain trigger zones situated in this region. The exceptional radiation of the pain seen in our patient clearly supports this theory. A 34 year old man with a past history of a similar but briefer episode 5 years previously presented to us. He complained of repeated episodes of stabbing pain with no obvious cause. The pain started at the base of the neck and radiated along the right carotid vessels to the cheek, base of the nose and ipsilateral eye. This was accompanied by injection of the conjunctivae, tears, nasal congestion and nasal discharge. Each episode lasted 15 to 30 minutes and was repeated 20 to 25 times a day without any particular relation to the time of day. The neurological examination, MR and angio-MR were normal. Before being seen by us he had been treated with prednisone and verpamil without effect. Indomethacin at a dose of 100 mg/day controlled the problem completely. We report a case of paroxysmal hemicrania with a spontaneous description of pain starting at the base of the neck and radiating along the carotid vessels. We consider this clinical description to be of interest since it supports the theories of a cervicogenic origin of this type of headache. A 23-year old woman developed headache and papilledema due to benign intracranial hypertension (BIH) while taking lithium carbonate for only seven months because of manic-depressive disease. Having discarded other causes, drug ingestion was the most likely etiology of the syndrome since it was observed that symptoms improved upon lithium withdrawal and worsened when the treatment was restarted. This report shows that BIH may appear as a side-effect of relatively short-term therapy with lithium and, therefore, funduscopic exams should be performed in every patient receiving this drug. The elderly as a whole suffer fewer headaches than the young. For the majority headache will represent a minor annoyance to be endured or treated with any available drug in the medicine chest. For some, migraine headaches or tension-type headaches become entwined with every daily activity. With the advent of modern pharmacology, headache can often be treated successfully. Trigeminal neuralgia is a source of particularly high morbidity among the elderly, but may be treated very satisfactorily with carbamazepine or baclofen. Paroxysmal hemicrania is exquisitely sensitive to indomethacin, while cluster headache patients receive relief from oxygen inhalation, corticosteroids or lithium. Headache may be the signature of the disease which leads to serious morbidity and mortality. The 'sentinel' headache of subarachnoid haemorrhage is evaluated by a physician in 15% of patients who will eventually rupture an intracranial aneurysm. Morning headache with nausea and vomiting may represent increased intracranial pressure caused by a tumour, haematoma or abscess. The elderly patient with a new headache needs emergency evaluation for temporal arteritis and rapid corticosteroid treatment if the diagnosis is confirmed, to prevent blindness. The broad spectrum of headache, at times a benign aggravation, while at others the harbinger of death, makes the careful evaluation of each headache imperative. This article attempts to make the difficult evaluation of head pain a little easier. For twelve years, the subject of this report, a 38-year-old man, presented a clinical condition compatible with the SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) syndrome. He presented a stabbing and intense daily pain located in the left pre-auricular and temporal regions. Each of these intense pain attacks lasted around one minute and presented a frequency of two to eight times per day. The pain was associated with ipsilateral lacrimation, conjunctival injection and rhinorrhea. MRI revealed a pituitary tumor with little suprasellar extent. The subjects serial assays of prolactin, GH, TSH and ACTH were within normal levels. Following transsphenoidal hypophysectomy, with complete removal of the tumor, the subject no more presented pain. The pathological diagnosis was non-secreting adenoma. Fourteen months after the surgery, he remains symptom-free. Lithium is widely used in the prophylaxis of episodic cluster headache without formal evidence of efficacy. Placebo-controlled clinical trials are not easy in conditions characterized by frequent severe pain. In this study, it was assumed that lithium would work quickly if at all, and placebo response would be zero. Strict diagnostic criteria excluded uncertain or atypical cases. Patients were male in so-far untreated episodes expected to last for at least 3 weeks more. In a double-blind, placebo-controlled comparison of matched parallel groups, treatment was either slow-release lithium carbonate, 800 mg/day, or placebo. After 7 days, compliance was estimated by tablet count, blood was taken for lithium assay, efficacy was assessed (attacks stopped or substantially improved) and adverse reactions were recorded. The study was stopped after planned sequential analysis of the 27th patient (13 on lithium, 14 on placebo). Estimated compliance was usually but not always good. Plasma lithium levels were mostly in the range 0.5-0.6 mmol/l on lithium, zero on placebo. Cessation of attacks within 1 week occurred in two patients in each group, substantial improvement in 6/14 (43%) on placebo, 8/13 (62%; NS) on lithium. Only minor adverse events were reported. Lithium treatment was therefore associated with a useful subjective improvement rate but the assumptions made at outset had proved wrong. The trial was stopped because superiority over placebo could not be demonstrated. There were lessons for future trials.\nHere is the question:\nNEUROLOGY: A 40-year-old woman consults for approximately 20 episodes per day of intense left periocular pain lasting 15 minutes, accompanied by intense tearing and rhinorrhea. Her examination and MRI are normal. His treatment of choice would be:\nHere are the potential choices:\n1. Indomethacin.\n2. Lamotrigine.\n3. Verapamil.\n4. Prednisone.\n5. Lithium carbonate.\nThe correct answer is: ",
        "gold_answer": "1 Indomethacin.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Trigeminal autonomic cephalalgias include cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, and rhinorrhea (SUNCT). Conventional pharmacological therapy can be successful in the majority of trigeminal autonomic cephalalgias patients. Most cluster headache attacks respond to 100% oxygen inhalation, or 6 mg subcutaneous sumatriptan. Nasal spray of sumatriptan (20 mg) or zolmitriptan (5 mg) are recommended as second choice. The bouts can be brought under control by a short course of corticosteroids (oral prednisone: 60-100 mg/day, or intravenous methylprednisolone: 250-500 mg/day, for 5 days, followed by tapering off the dosage), or by long-term prophylaxis with verapamil (at least 240 mg/day). Alternative long-term preventive medications include lithium carbonate (800-1600 mg/day), methylergonovine (0.4-1.2 mg/day), and topiramate (100-200 mg/day). As a rule, paroxysmal hemicrania responds to preventive treatment with indomethacin (75-150 mg/day). A short course of intravenous lidocaine (1-4 mg/kg/hour) can reduce the flow of attacks during exacerbations of SUNCT. Lamotrigine (100-300 mg/day) is the preventive drug of choice for SUNCT. Gabapentin (800-2700 mg/day), topiramate (50-300 mg/day), and carbamazepine (200-1600 mg/day) may be of help.  We described three cases of hypnic headache with successful treatment by lithium carbonate or caffeine. This is the first detail report of Japanese cases. An endocrinological test and rhythm analyses of ambulatory blood pressure (ABP) and heart rate variability in a case suggested possible association between hypnic headache and hypothalamic-pituitary dysfunction. Case 1: A 48-year-old female migraineur complained of new-onset nocturnal headaches. Her headache awakened her from sleep between 1 AM and 2 AM. The headache occurred 3-4 times per week and lasted from 1 hour to 2 hours. The headache were moderate intensity and bilateral dull throbbing pain that located in the forehead to temples. There was no accompanying symptoms such as nausea, phonophobia, photophobia, nor the other autonomic features including conjunctival injection or tearing during the headache attacks. Physical and neurological examinations showed normal results except slight weakness and mild dysesthesia of the left arm due to a vertebral disk herniation at C5/6 level. In the pituitary endocrinological test, the prolactin level remarkably increased in response to the TRH loading. The single cosinor analysis demonstrated significant circadian rhythm of ABP parameters. However, the analysis did not demonstrate any significant circadian rhythm of Holter ECG parameters of time domain analysis and frequency analysis. Receiving 200 mg lithium bicarbonate before sleep, her nocturnal headache completely disappeared. Case 2: A 68-year-old woman had been followed up by her chronic tension-type headache since her forties. At her 66-years, she suffered from a new nocturnal headache. She awoke from sleep by the headache about 3 AM and the headache lasted 30 min. Moderate, dull headache located on her left temple to parietal head, 3-4 times/week. She was able to go back asleep without any medication after spontaneous headache cessation. She first complained the nocturnal headache at the 10 months later of the new headache appearance. She received 200 mg caffeine just before sleep and her headache has been disappeared. Case 3: 70-year-old women had been regularly visited our clinics for her migraine and chronic tension-type headache. She received amitriptyline and her headaches was well controlled. At her 69 years, she complained nocturnal headache. It occured every other day. The headache was moderate pulsative dull pain on the occipital region and lasted 90 minutes without any autonomic symptoms. Headache began between midnight and 1 AM. She told us her new nocturnal headache one year later of the onset. Oral caffeine (200 mg) just before sleep did not improve her headache and caused insomnia. Receiving 100 mg lithium before sleep, her hypnic headache disappeared completely. These three cases are compatible with the diagnostic criteria proposed in ICHD-II. There were some patients with hypnic headache in Japan and neurologists should pay attentions to this form of benign headache, because some beneficial treatments are currently available. Trigeminal autonomic cephalgias (TAC) are characterized by severe and strictly unilateral headaches with a frontotemporal and periorbital preponderance in combination with ipsilateral cranial autonomic symptoms, such as lacrimation, conjunctival injection, rhinorrhea, nasal congestion, and restlessness or agitation. One main differentiating factor is the duration of painful attacks. While attacks typically last 5 s to 10 min in SUNCT syndrome (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing), paroxysmal hemicrania lasts 2-30 min and cluster headaches 15-180 min. Hemicrania continua represents a continuous TAC variant. From a therapeutic view, TACs differ substantially. Lamotrigine is used as first-choice prevention in SUNCT syndrome and indometacin in paroxysmal hemicrania. For cluster headaches, acute therapy with inhaled pure oxygen and fast-acting triptans (sumatriptan s.c. and intranasal zolmitriptan) is equally important to short-term preventive therapy with methysergide and cortisone and long-term prophylactic treatment comprising verapamil as drug of first choice and lithium carbonate and topiramate as drugs of second choice. In refractory cases of chronic cluster headache, neuromodulatory approaches such as occipital nerve stimulation and sphenopalatine ganglion stimulation are increasingly applied.  The management of cluster headache (CH) may be challenging. We report a 50-year-old male with recurrent attacks of dull and severe unilateral periorbital pain, lasting 30-45 minutes, twice a day, exclusively during sleep, and accompanied by ipsilateral rhinorrhea and lacrimation. The pain switched sides within every attack. CH treatment was initiated but the patient maintained recurrence rates compatible with chronic CH, even after increasing verapamil to 460 mg/day. Afterwards we decided to add lithium (800 mg/day). With this treatment the severity and recurrence of CH substantially decreased, despite the patient's autonomous decision to take lithium only during the acute phase of the cluster. The exclusively alternating location and the excellent response to short cycles of lithium represent two unique features of CH. Primary Ninety percent of all headaches are primary headaches. Primary headaches usually first start when people are between 20 and 40 years old. The most common types of primary headaches are migraines and tension-type headaches. They have different characteristics. Migraines typically present with pulsing head pain, nausea, photophobia (sensitivity to light) and phonophobia (sensitivity to sound) Tension-type headaches usually present with non-pulsing \"bandlike\" pressure on both sides of the head, not accompanied by other symptoms. Such kind of headaches maybe further classified into-episodic and chronic tension type headaches Other very rare types of primary headaches include: cluster headaches: short episodes (15–180 minutes) of severe pain, usually around one eye, with autonomic symptoms (tearing, red eye, nasal congestion) which occur at the same time every day. Cluster headaches can be treated with triptans and prevented with prednisone, ergotamine or lithium. Cluster headache is characterised by attacks of excruciating unilateral headache or facial pain lasting 15 min to 3 h and is seen as one of the most intense forms of pain. Cluster headache attacks are accompanied by ipsilateral autonomic symptoms such as ptosis, miosis, redness or flushing of the face, nasal congestion, rhinorrhoea, peri-orbital swelling and/or restlessness or agitation. Cluster headache treatment entails fast-acting abortive treatment, transitional treatment and preventive treatment. The primary goal of prophylactic and transitional treatment is to achieve attack freedom, although this is not always possible. Subcutaneous sumatriptan and high-flow oxygen are the most proven abortive treatments for cluster headache attacks, but other treatment options such as intranasal triptans may be effective. Verapamil and lithium are the preventive drugs of first choice and the most widely used in first-line preventive treatment. Given its possible cardiac side effects, electrocardiogram (ECG) is recommended before treating with verapamil. Liver and kidney functioning should be evaluated before and during treatment with lithium. If verapamil and lithium are ineffective, contraindicated or discontinued because of side effects, the second choice is topiramate. If all these drugs fail, other options with lower levels of evidence are available (e.g. melatonin, clomiphene, dihydroergotamine, pizotifen). However, since the evidence level is low, we also recommend considering one of several neuromodulatory options in patients with refractory chronic cluster headache. A new addition to the preventive treatment options in episodic cluster headache is galcanezumab, although the long-term effects remain unknown. Since effective preventive treatment can take several weeks to titrate, transitional treatment can be of great importance in the treatment of cluster headache. At present, greater occipital nerve injection is the most proven transitional treatment. Other options are high-dose prednisone or frovatriptan. The prevalence of cluster headache is 0.1% and cluster headache is often not diagnosed or misdiagnosed as migraine or sinusitis. In cluster headache there is often a considerable diagnostic delay - an average of 7 years in a population-based survey. Cluster headache is characterized by very severe or severe orbital or periorbital pain with a duration of 15-180 minutes. The cluster headache attacks are accompanied by characteristic associated unilateral symptoms such as tearing, nasal congestion and/or rhinorrhoea, eyelid oedema, miosis and/or ptosis. In addition, there is a sense of restlessness and agitation. Patients may have up to eight attacks per day. Episodic cluster headache (ECH) occurs in clusters of weeks to months duration, whereas chronic cluster headache (CCH) attacks occur for more than 1 year without remissions. Management of cluster headache is divided into acute attack treatment and prophylactic treatment. In ECH and CCH the attacks can be treated with oxygen (12 L/min) or subcutaneous sumatriptan 6 mg. For both oxygen and sumatriptan there are two randomized, placebo-controlled trials demonstrating efficacy. In both ECH and CCH, verapamil is the prophylactic drug of choice. Verapamil 360 mg/day was found to be superior to placebo in one clinical trial. In clinical practice, daily doses of 480-720 mg are mostly used. Thus, the dose of verapamil used in cluster headache treatment may be double the dose used in cardiology, and with the higher doses the PR interval should be checked with an ECG. At the start of a cluster, transitional preventive treatment such as corticosteroids or greater occipital nerve blockade can be given. In CCH and in long-standing clusters of ECH, lithium, methysergide, topiramate, valproic acid and ergotamine tartrate can be used as add-on prophylactic treatment. In drug-resistant CCH, neuromodulation with either occipital nerve stimulation or deep brain stimulation of the hypothalamus is an alternative treatment strategy. For most cluster headache patients there are fairly good treatment options both for acute attacks and for prophylaxis. The big problem is the diagnosis of cluster headache as demonstrated by the diagnostic delay of 7 years. However, the relatively short-lasting attack of pain in one eye with typical associated symptoms should lead the family doctor to suspect cluster headache resulting in a referral to a neurologist or a headache centre with experience in the treatment of cluster headache. Two patients with cluster-tic syndrome are reported. The first, a 43-years-old man, complaining of trigeminal pain in the right side of the face, accompanied by homolateral autonomic signs, such as ocular injection, sweating and drooped eyelid. The cluster attack was triggered by chewing, shaving and washing the face. The periodicity of bouts was six months. The pain was relieved by carbamazepine (800 mg/day). The second patient, a 43-year-old man, with an excruciant, neuralgic pain in the left side of the face, accompanied by tearing, conjuntival injection, drooped eyelid, rhinorrhea, photophobia and phonophobia. The neurologic examination showed triggered points in the first and second division of the trigeminal nerve. The patient was treated with verapamil (160 mg/day) and prednisone (60 mg/day), with relief of his symptoms. The periodicity of bouts was once a year. The literature was reviewed and 37 cases previosly reported are considered. We conclude that there are two different groups of patients. In the first group, the patients had cluster and trigeminal bouts in different time. In the second group, with only nine cases, the patients presented both cluster and trigeminal type of pain at the same time, as in the two cases reported here. Hypnic headache (HH) is a rare benign disorder described initially by Raskin in 1988. It is characterized by recurrent nocturnal episodes of headache that periodically awaken the sleeping patient and usually occur in the elderly. This review aimed to describe the clinical features of the HH cases published in the literature from 1988 to 2018. Based on literature search in the major medical databases (LiLacs, SciELO, Bireme, Medline, Embase, Current Contents, Scopus, EBSCO and PubMed), we have analyzed the case reports on HH that have been published from 1988 to 2018. We described 343 adults (69.0% women and 31.0% men) and 5 children (3 girls and 2 boys) diagnosed with HH. Average age for adults and children was, respectively, 58.0 ± 13.1 years (ranging from 15 to 85 years) and 9 years (ranging from 7 to 11 years). The diagnosis was made 7.6 ± 14.2 years (range 0.1 to 39 years) after onset of headache. Pain occurred during nocturnal sleep (94.8%), with an average duration of 90 min, bilaterally located (55.5%), having a dull character (74.4%), and moderate intensity (61.5%). In 94.5% of the patients, headache occurred for 10 or more days per month (mean of 21 days). Autonomic manifestations occurred in 7.6% of the patients, predominantly lacrimation (61.1%) and rhinorrhea (16.7%). Caffeine presented the best therapeutic response in acute treatment. In prophylaxis, lithium, caffeine and indomethacin were effective drugs in 77.8% of the patients. In 56.7% of the patients there was remission with treatment and in 72.7% of them, without recurrence. HH is a rare disease that usually occurs for the first time in older women but may begin in childhood. Lithium and caffeine are effective drugs for pain prophylaxis, but randomized clinical trials are required. Treatments Lithium carbonate 200–600 mg at bedtime is an effective treatment for most patients but for those that can not tolerate Lithium, Verapamil, indomethacin, melatonin or methysergide may be tried. Two patients have also responded to flunarizine 5 mg. It has also been shown that 1–2 cups of coffee or 100–200 mg of caffeine before bed can prevent hypnic headaches. A recent review of 348 cases available in the literature has been recently published. References External links Headaches Treatments A ten-patient study conducted by Pareja et al. found that all patients diagnosed with CPH were responsive to indomethacin and were able to completely control their symptoms. Doses of the drug ranged from 25 mg per day to 150 mg per day with a median dose of 75 mg per 24-hour period. Almost all cases of CPH respond positively and effectively to indometacin, but as much as 25 percent of patients discontinued use of the drug due to adverse side effects, namely complications in the gastrointestinal tract. According to a case study by Milanlioglu et al., 100mg of lamotrigine, an antiepileptic drug, administered twice daily alleviated all painful symptoms. No side effects were noted after two months of treatment. Dosage of lamotrigine was decreased to 50mg a day after the first two months, and no symptoms or side-effects were recorded after a three-month followup. Many experts favor verapamil as the first-line preventive treatment for patients with chronic cluster headache or prolonged bouts. While verapamil compares favorably with lithium in practice, some patients require verapamil doses far in excess of those administered for cardiac disorders. The initial dose range is 40–80 mg twice daily; effective doses may be as high as 960 mg/d. Side effects such as constipation and leg swelling can be problematic. Of paramount concern, however, is the cardiovascular safety of verapamil, particularly Prednisone 1 mg/kg up to Verapamil 160–960 mg/d 60 mg qd, tapering over 21 days Gabapentinb 1200–3600 mg/d Melatoninb 9–12 mg/d aNot available worldwide. bUnproven but of potential benefit. We reported a 36-year-old man, who suffered from cluster headache (CH) associated with hemicrania continua (HC). The continuous, dull or pressure-type headache appeared on the same side of the CH during the third month of a prolonged cluster period, and fluctuated in the severity of pain. This headache was aggravated when the CH was ameliorated by the administration of lithium carbonate. This converse relationship between CH and HC persisted during an on-off trial of the lithium carbonate, and the HC was exacerbated again after the complete cessation of CH. Retrobulbar pain and nasal congestion were present as components of HC similarly to CH, but they subsided gradually and the pressure-type vascular headache over the temporal area predominated later. The continuous headache lasted more than 3 months, and responded significantly to the indomethacin at a dose of 75mg/d. The clinical course of this patient suggests that HC and CH have a common pathomechanism including hyperactivation of the trigemino-vascular reflex, and may be different in the involvement of other central pathway of pain generation. Indomethacin may deserve consideration for the treatment of continuous headache that appears during an atypical course of other primary headaches. Three grown-up males with a long-lasting history of rather uniform, unilateral headache in the ocular-periocular area, in cluster fashion, are examined. Pain paroxysms of short duration (15-60 sec) appear up to 5-30 times per h. The headache is unilateral without side shift. Conjunctival injection appears at the very beginning of the attack and is partly massive, lasting the entire duration of the attack, and fading away at the end of it. Tearing (massive), forehead sweating (subclinical) and rhinorrhea, all on the symptomatic side, accompany the attack. In the youngest patient, the headache became chronic after clustering for six months initially, and after approximately 3 1/2 years it became bilateral. However, even in this patient, a clear unilateral pain preponderance prevails, and the autonomic disturbances are all on the original pain side. Attacks can partly be precipitated by chewing, eating (e.g. citrus fruits), moving the head, etc. The headache is completely refractory to drug therapy, including indomethacin. The authors used lithium carbonate in treatment of 7 patients with Horton's headaches of primarily or secondarily chronic character. In all patients the blood level of lithium was determined and it was found to reach therapeutic levels. Disappearance of attacks was achieved in 3 cases, significant improvement in 2, and in 2 cases treatment was ineffective. The mechanism of lithium action in this disease is discussed. The authors recommend lithium as worthy of use since other drugs are ineffective in this disease or they cannot be used, eg. steroids or indomethacin, in view of frequent coexistence of paptic ulcer. Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome is a very rare disorder characterized by short-lasting neuralgiform unilateral pain affecting the orbital-periorbital area and associated with autonomic phenomena consisting mainly of conjunctival injection, tearing, and rhinorrhea. Treatment of this condition is difficult; many drugs and surgical procedures have been tried with variable results. In the literature, two cases have been described with short-term response to microvascular decompression of the trigeminal root. We present the case of a patient with short-lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome who remains asymptomatic 2 years after microvascular decompression. A 56-year-old woman was referred to our clinic because she had experienced pain in the distribution of the first left trigeminal branch during the previous 2 years. She experienced paroxysms lasting from a few seconds to 1 to 2 minutes superimposed over a dull sensation of pain involving the same territory. The paroxysms had no refractory period and were triggered by touching the eye or the left side of the face, chewing, yawning, washing her hair, and even by light. Although the paroxysms were triggered by light touch or chewing, she was able to talk or touch herself while having the paroxysm. During pain attacks, she experienced tearing and ipsilateral conjunctival injection, eyelid edema and rhinorrhea, as well as intense photophobia. A magnetic resonance imaging scan revealed a vascular structure distorting and compressing the trigeminal root. The patient underwent microvascular decompression of the trigeminal root. At surgery, there was clear compression of the trigeminal root by a superior cerebellar artery loop that was resolved by interposing a Teflon patch. The patient awoke from the operation without pain, and all the accompanying signs and symptoms, such as photophobia, disappeared. The postoperative course was uneventful, and 2 years after treatment, the patient remains asymptomatic. Microvascular decompression could be an alternative therapeutic approach to this rare syndrome. Episodic paroxysmal hemicrania (EPH) is a rare disorder characterized by frequent, daily attacks of short-lived, unilateral headache with accompanying ipsilateral autonomic features. EPH has attack periods which last weeks to months separated by remission intervals lasting months to years, however, a seasonal variation has never been reported in EPH. We report a new case of EPH with a clear seasonal pattern: a 32-year-old woman with a right-sided headache for 17 years. Pain occurred with a seasonal variation, with bouts lasting one month (usually in the first months of the year) and remission periods lasting around 11 months. During these periods she had headache from three to five times per day, lasting from 15 to 30 minutes, without any particular period preference. There were no precipitating or aggravating factors. Tearing and conjunctival injection accompanied ipsilaterally the pain. Previous treatments provided no pain relief. She completely responded to indomethacin 75 mg daily. After three years, the pain recurred with longer attack duration and was just relieved with prednisone. We also propose a new hypothesis: the EPH-cluster headache continuum. Paroxysmal hemicrania is a well-defined clinical condition about which many articles have been published. Attempts have been made to explain the response of this illness to indomethacin, suggesting its possible cervical origin. In some patients it is set off by stimulation of certain trigger zones situated in this region. The exceptional radiation of the pain seen in our patient clearly supports this theory. A 34 year old man with a past history of a similar but briefer episode 5 years previously presented to us. He complained of repeated episodes of stabbing pain with no obvious cause. The pain started at the base of the neck and radiated along the right carotid vessels to the cheek, base of the nose and ipsilateral eye. This was accompanied by injection of the conjunctivae, tears, nasal congestion and nasal discharge. Each episode lasted 15 to 30 minutes and was repeated 20 to 25 times a day without any particular relation to the time of day. The neurological examination, MR and angio-MR were normal. Before being seen by us he had been treated with prednisone and verpamil without effect. Indomethacin at a dose of 100 mg/day controlled the problem completely. We report a case of paroxysmal hemicrania with a spontaneous description of pain starting at the base of the neck and radiating along the carotid vessels. We consider this clinical description to be of interest since it supports the theories of a cervicogenic origin of this type of headache. A 23-year old woman developed headache and papilledema due to benign intracranial hypertension (BIH) while taking lithium carbonate for only seven months because of manic-depressive disease. Having discarded other causes, drug ingestion was the most likely etiology of the syndrome since it was observed that symptoms improved upon lithium withdrawal and worsened when the treatment was restarted. This report shows that BIH may appear as a side-effect of relatively short-term therapy with lithium and, therefore, funduscopic exams should be performed in every patient receiving this drug. The elderly as a whole suffer fewer headaches than the young. For the majority headache will represent a minor annoyance to be endured or treated with any available drug in the medicine chest. For some, migraine headaches or tension-type headaches become entwined with every daily activity. With the advent of modern pharmacology, headache can often be treated successfully. Trigeminal neuralgia is a source of particularly high morbidity among the elderly, but may be treated very satisfactorily with carbamazepine or baclofen. Paroxysmal hemicrania is exquisitely sensitive to indomethacin, while cluster headache patients receive relief from oxygen inhalation, corticosteroids or lithium. Headache may be the signature of the disease which leads to serious morbidity and mortality. The 'sentinel' headache of subarachnoid haemorrhage is evaluated by a physician in 15% of patients who will eventually rupture an intracranial aneurysm. Morning headache with nausea and vomiting may represent increased intracranial pressure caused by a tumour, haematoma or abscess. The elderly patient with a new headache needs emergency evaluation for temporal arteritis and rapid corticosteroid treatment if the diagnosis is confirmed, to prevent blindness. The broad spectrum of headache, at times a benign aggravation, while at others the harbinger of death, makes the careful evaluation of each headache imperative. This article attempts to make the difficult evaluation of head pain a little easier. For twelve years, the subject of this report, a 38-year-old man, presented a clinical condition compatible with the SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) syndrome. He presented a stabbing and intense daily pain located in the left pre-auricular and temporal regions. Each of these intense pain attacks lasted around one minute and presented a frequency of two to eight times per day. The pain was associated with ipsilateral lacrimation, conjunctival injection and rhinorrhea. MRI revealed a pituitary tumor with little suprasellar extent. The subjects serial assays of prolactin, GH, TSH and ACTH were within normal levels. Following transsphenoidal hypophysectomy, with complete removal of the tumor, the subject no more presented pain. The pathological diagnosis was non-secreting adenoma. Fourteen months after the surgery, he remains symptom-free. Lithium is widely used in the prophylaxis of episodic cluster headache without formal evidence of efficacy. Placebo-controlled clinical trials are not easy in conditions characterized by frequent severe pain. In this study, it was assumed that lithium would work quickly if at all, and placebo response would be zero. Strict diagnostic criteria excluded uncertain or atypical cases. Patients were male in so-far untreated episodes expected to last for at least 3 weeks more. In a double-blind, placebo-controlled comparison of matched parallel groups, treatment was either slow-release lithium carbonate, 800 mg/day, or placebo. After 7 days, compliance was estimated by tablet count, blood was taken for lithium assay, efficacy was assessed (attacks stopped or substantially improved) and adverse reactions were recorded. The study was stopped after planned sequential analysis of the 27th patient (13 on lithium, 14 on placebo). Estimated compliance was usually but not always good. Plasma lithium levels were mostly in the range 0.5-0.6 mmol/l on lithium, zero on placebo. Cessation of attacks within 1 week occurred in two patients in each group, substantial improvement in 6/14 (43%) on placebo, 8/13 (62%; NS) on lithium. Only minor adverse events were reported. Lithium treatment was therefore associated with a useful subjective improvement rate but the assumptions made at outset had proved wrong. The trial was stopped because superiority over placebo could not be demonstrated. There were lessons for future trials.\nHere is the question:\nNEUROLOGY: A 40-year-old woman consults for approximately 20 episodes per day of intense left periocular pain lasting 15 minutes, accompanied by intense tearing and rhinorrhea. Her examination and MRI are normal. His treatment of choice would be:\nHere are the potential choices:\n1. Indomethacin.\n2. Lamotrigine.\n3. Verapamil.\n4. Prednisone.\n5. Lithium carbonate.\nThe correct answer is: 1. Indomethacin."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n An 18-year-old black woman with cerebral palsy was admitted for evaluation of an intrathecal baclofen pump site infection. The dermatology service was consulted for treatment suggestions of a presumed diagnosis of chronic tinea capitis. Three courses of oral griseofulvin during the past 2 years failed to resolve the patient's chronic scalp dermatosis. Scalp lesions first began about 2 years earlier after hospitalization for placement of an intrathecal baclofen pump. The patient was unable to care for her scalp due to her cerebral palsy, and her mother interpreted the scalp condition as infectious. No routine shampoo care, scalp care, or topical treatment was performed for more than 1 1/2 years. The mother felt that touching the patient's scalp might cause pain and noted that the majority of her time was spent concentrating on more critical medical issues. Physical examination revealed coalescing hyperkeratotic plaques extending dorsally from the anterior hairline to the occipital scalp with small flecks of keratinous debris throughout the remaining hair (Figure 1). The plate-like plaques were devoid of hair, except at a few fissures where a few tufts of hair emerged. No cervical lymph nodes were appreciated on palpation. Treatment was initiated with compresses consisting of large warm water-soaked towels 4 times daily. Three times a day, a nursing staff applied 5% salicylic acid in olive oil to the scalp under a shower cap for approximately 1 hour. Over the following 2 days, a significant reduction in keratinous debris was appreciated. Within 2 weeks, the bulk of the plaques had been removed (Figure 2). At 6-week follow-up, the underlying scalp showed areas of fibrosis and possible scarring with a few emerging tufts of hair. On the basis of history and response to treatment with salicylic acid and routine scalp care, the patient was diagnosed with an unusually severe case of dermatosis neglecta. Several weeks before coming to Germany the two daughters (aged 3 and 6 years) of a family from Togo had developed desquamating skin changes over the hairy scalp. These had then spread to the trunk and limbs. The 8-weeks-old son also had discrete lesions on the hairy scalp and neck. In all of them these lesions had then spread and begun to itch markedly. When first seen as out-patients the father was free of symptoms, but the other members of the family had multiple, sharply circumscribed, partly confluent, dry and desquamating lesions, about 2-4 cm in diameter, with areas of alopecia and hair breaking off at skin level. In addition there were dry, desquamating, sharply circumscribed, partly hyperpigmented, partly infiltrated plaques, 1-3 cm in diameter, disseminated over the entire body surface, but especially the neck and limbs. Typical micromorphological characteristics for T. soudanese were demonstrated in the outer zones of a primary culture and the organism was also demonstrated in culture on Sabouraud-glucose-agar. Typical colonies on Löwenstein-Jensen medium allowed differentiation from Microsporum ferrugineum. The patients were treated systemically with griseofulvin and locally with ciclopiroxolamine. Marked clinical improvement occurred within 2 months and cultures became negative. But as fungal elements were still demonstrated in native preparations from two of the patients, treatment was continued. Efficacious treatment of tinea needs reliable diagnosis of the pathogen. Human infection with T. soudanese usually results from contact with other humans. If this infection occurs in persons not from Africa there is usually the history of indirect or direct contact with Africans. Increased international migration and tourism is likely to result in more cases of this kind: this pathogen should be considered in the differential diagnosis of tinea of scalp and body. <bBackground:</b Treatment of alopecia areata (AA) involves use of high potency topical corticosteroids under occlusion that, even very effective, can lead to several adverse effects. <bObjective:</b We report 10 cases of patients with AA that, after using high potency topical corticosteroids, have developed tinea versicolor of the neck area. <bMethods:</b Ten patients with AA, aged 18-38 years, were prescribed with clobetasone propionate 0.05% cream under occlusion every other day but, after 3-4 months of treatment, they returned to our facility complaining the appearance of multiple white or red-brown round or oval macules in the neck area. <bResults:</b Diagnosis of pityriasis versicolor was confirmed by direct microscopy examination of skin scrapings in 10% potassion hydroxide (KOH) solution. All patients received systemic antifungal therapy associated with the daily use of ketoconazole shampoo. <bConclusion:</b Tinea versicolor of the neck should be included among a rare but possible side effect of prolonged application of high potency topical steroids on the scalp. These cases reinforce the importance of careful dermatologic examination and recommend preventive measures in patients with alopecia areata that are using these drugs. We report an eight years old boy presenting with a pyogenic granuloma of the scalp, generalized alopecia, descamative plates in the neck, trunk and limbs and nail involvement. Cultures for fungus of all these lesions disclosed Microspore canis. The patient was treated with oral griseofulvin, miconazole and topical tolnaftate. Five years later and after several incomplete treatments, the patient returns with a fistulous mass of 15 x 8 cm in the dorsal area whose culture revealed Microspore canis. The mass was excised and oral ketoconazole was indicated. After three months of follow up, the patient was lost from control. Since the advent of antibiotics, otogenic complications have decreased considerably. However, incomplete antibiotic therapy has altered the clinical course of middle ear disease so as to be more insidious. This paper reports a case of Bezold's abscess associated with cholesteatoma. A 48-year-old man visited our hospital presenting with a 4-day history of right otorrhea and a tender swelling in the right neck. Physical examination showed a febrile patient (38.8 degrees C) with right facial paresis and trismus. A hyperemic, hard and tender swelling was observed in his right neck from the lateral cervical to the mental region. The tympanic membrane was invisible because of granulation and swelling of the posterior wall of the external auditory canal. Intravenous clindamycin and ceftazidime therapy was started immediately. A CT-scan revealed a diffuse shadow with bony destruction in the right mastoid cortex. Extensive abscess formation was also found in the right sternocleidomastoid muscle, in the anterior neck and in the posterior neck. He was diagnosed as having Bezold's abscess associated with cholesteatoma. Radical mastoidectomy and drainage of the neck abscess was performed on the third day under general anesthesia. The mastoid cavity was found to be filled with pus and cholesteatoma debris. A small area of defective bone was found at the mastoid tip, through which there were communications between the mastoid cavity and the abscesses in the neck. Bony destruction was also found in the horizontal and vertical portion of the facial canal. Bacteroides and three kinds of gram-negative rods were cultured from the mastoid cavity.(ABSTRACT TRUNCATED AT 250 WORDS) Tinea capitis is a common and, at times, difficult to treat, fungal infection of the scalp. This article aimed to provide an update on the evaluation, diagnosis, and treatment of tinea capitis. A PubMed search was performed in Clinical Queries using the key term \"tinea capitis\". The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. The search was restricted to English literature. The information retrieved from the above search was used in the compilation of the present article. Patents were searched using the key term \"tinea capitis\" at www.freepatentsonline.com. Tinea capitis is most often caused by Trichophyton tonsurans and Microsporum canis. The peak incidence is between 3 and 7 years of age. Non-inflammatory tinea capitis typically presents as fine scaling with single or multiple scaly patches of circular alopecia (grey patches); diffuse or patchy, fine, white, adherent scaling of the scalp resembling generalized dandruff with subtle hair loss; or single or multiple patches of well-demarcated area (s) of alopecia with fine-scale, studded with broken-off hairs at the scalp surface, resulting in the appearance of \"black dots\". Inflammatory variants of tinea capitis include kerion and favus. Dermoscopy is a highly sensitive tool for the diagnosis of tinea capitis. The diagnosis can be confirmed by direct microscopic examination with a potassium hydroxide wetmount preparation and fungal culture. It is desirable to have mycologic confirmation of tinea capitis before beginning a treatment regimen. Oral antifungal therapy (terbinafine, griseofulvin, itraconazole, and fluconazole) is considered the gold standard for tinea capitis. Recent patents related to the management of tinea capitis are also discussed. Tinea capitis requires systemic antifungal treatment. Although topical antifungal therapies have minimal adverse events, topical antifungal agents alone are not recommended for the treatment of tinea capitis because these agents do not penetrate the root of the hair follicles deep within the dermis. Topical antifungal therapy, however, can be used to reduce transmission of spores and can be used as adjuvant therapy to systemic antifungals. Combined therapy with topical and oral antifungals may increase the cure rate. A 65-year-old man presented with recurrent generalized pruritus and excoriations of many years' duration. He had been treated with antihistamines, topical corticosteroids, and antibiotics for secondary wound infections, but improvement was only temporary. He had also been hospitalized for leg ulcers complicated by cellulitis. Examination revealed multiple oval and linear red papules and nodules measuring 0.5 to 2 cm in diameter. Some of the lesions were eroded and had a central crater and yellowish crust. The patient also had hypopigmented linear scars localized to the posterior scalp, neck, upper back, chest, abdomen, arms, and legs with sparing of the middle and lower back (figures 1 and 2). An ulcer measuring 1.5 x 2 cm that was surrounded by indurated skin was present on the medial aspect of his right ankle. The ulcer was partially covered by yellow exudate. There was no evidence of cellulitis. Liver enzyme, serum creatinine, and thyrotropin levels, as well as a chest roentgenogram, were normal. Wound cultures for bacteria and fungi were nonsignificant. A punch biopsy from a representative lesion showed an abrupt epidermal defect with sparse superficial lymphocytic infiltrate in the dermis. The patient was admitted to the hospital to isolate him from his home environment. He received a 10-day course of systemic cephalexin, topical clobetasol propionate ointment for the affected skin areas, and oral hydroxyzine for pruritus. Ultraviolet light therapy was instituted once daily and was to continue for 2 months. His lesions had improved moderately by the time he was discharged from the hospital. On follow-up 2 weeks later, his lesions were flat and had resulted in hypopigmented scars. Three months later, however, he had persistent, intense pruritus, and new excoriations had developed on his forearms and back. He improved after receiving treatment with oral doxepin hydrochloride. Treatment Oral antifungal medications are the standard of care. Due to the location of the dermatophytes within the hair follicle, treatment with topical antifungals is often unsatisfactory. In patients with tinea pedis or onychomycosis, re-inoculation and recurrence is common. In individuals with recurrent outbreaks, inoculation sources should be identified and treated appropriately. Historical therapies include oral potassium iodide, mildly filtered local X-radiation, and topical applications of Asterol as a fungicide in both tincture and ointment forms. In modern medicine, systemic antifungals, such as griseofulvin, ketoconazole, and itraconazole, are the standard. Therapy extends over at least 4–8 weeks, and treatment continues until all lesions are cleared. Currently, no data about relapse rates or the complications of not treating Majocchi granuloma exist. Treatment Tinea corpora (body), tinea manus (hands), tinea cruris (groin), tinea pedis (foot) and tinea facie (face) can be treated topically. Tinea unguum (nails) usually will require oral treatment with terbinafine, itraconizole, or griseofulvin. Griseofulvin is usually not as effective as terbinafine or itraconizole. A lacquer (Penlac) can be used daily, but is ineffective unless combined with aggressive debridement of the affected nail. Tinea capitis (scalp) must be treated orally, as the medication must be present deep in the hair follicles to eradicate the fungus. Usually griseofulvin is given orally for 2 to 3 months. Clinically dosage up to twice the recommended dose might be used due to relative resistance of some strains of dermatophytes. Shaving the head (if culturally appropriate and with patient's willful consent) 2% ketoconazole or 2% miconazole shampoo or 1 to 1.5% ciclopirox shampoo applied once-to-twice-a-week for 3 to 4 weeks Oral terbinafine 250 mg once daily for 6 weeks Oral itraconazole 100 mg twice-a-day after a meal, with a citrus drink for 1 to 2 weeks Counseling on the maintenance of good scalp hygiene, avoidance of sharing combs, etc. Lymphatic drainage Lymphatic channels from the posterior half of the scalp drain to occipital and posterior auricular nodes. Lymphatic channels from the anterior half drain to the parotid nodes. The lymph eventually reaches the submandibular and deep cervical nodes. Clinical significance Infection The 'danger area of the scalp' is the area of loose connective tissue. This is because pus and blood spread easily within it, and can pass into the cranial cavity along the emissary veins. Therefore, infection can spread from the scalp to the meninges, which could lead to meningitis. A 6-year-old boy was brought to his primary care provider by his mother, who complained of a pruritic rash near his right eye. The eruption was described as a small, erythematous, slightly scaly plaque at the lateral margin of the right eyelid. The child was in good health and took no medications. The diagnosis of eczema was made; the patient was treated with pimecrolimus cream b.i.d. to the affected area. After 2-3 days of treatment, the itching and erythema completely resolved; however, a rough and scaly plaque persisted. After 1-2 weeks of treatment, the itching gradually returned, and the lesion began to increase in size. Multiple, similar lesions appeared several centimeters from the initially affected area. Pimecrolimus was discontinued; topical nystatin/triamcinolone ointment was prescribed. The eruption continued to spread, and the patient was referred to dermatology for further evaluation. The patient presented to the dermatology clinic with multiple annular, scaly papules and plaques with central clearing. Excoriations and mild inflammation were noted around all affected areas (Figure). A potassium hydroxide examination of the lesions revealed numerous hyphae. The nystatin/triamcinolone ointment was discontinued; oral griseofulvin was prescribed. The eruption improved dramatically after 3 weeks and eventually cleared completely after 5 weeks of treatment. Topical 2% ketoconazole cream was applied b.i.d. for the final 2 weeks of treatment. A 68-year-old woman suffered for six weeks from four skin eruptions on her head after returning from Brazil. The skin manifestations resembled furuncles, grew continually in size until they were about 2 cm in diameter and [corrected] she finally developed intermittent sharp pain on her head. On presentation she had a mild lymphadenopathy on her neck but no other systemic complaints. Each skin eruption had a central porus with seropurulent discharge and on examination within the central opening a whitish, tender moving mass could be detected. TREATMENT, COURSE AND DIAGNOSIS: We cautiously infiltrated each skin eruption with lidocaine. Immediately after infiltration a whitish maggot appeared from each nodule and could be easily extracted with a forceps. The maggots were identified as Dermatobia hominis larvae. After extraction a local antiseptic dressing was applied and the wounds healed without complications. Dermatobia hominis is a common cause of myiasis in Central- and South-America and should be taken into account in furuncular skin eruptions of returning travelers. The typical appearance of the skin eruption with a central porus, seropurulent discharge and a whitish, tender moving mass within the nodule is quite characteristic for myiasis. The patients often have [corrected] intermittent sharp pain in the area of the affected skin and report continuing growth of the nodules and a sensation of slight movement within the skin eruption. Extraction is accomplished with a forceps after lidocaine infiltration, alternatively an occlusive dressing could be applied by means of which the larvae can be removed easily from the cavity. A 19-year-old farmer was referred by his general practitioner as an emergency to our otolaryngology department complaining of marked breathlessness of a few hours duration. He gave a three-day history of painful swelling and hair loss in the beard area of the right side of the neck. His upper airway was compromised unless extension of the neck was maintained. Larynx and pharynx were normal. The acute symptoms settled with intravenous antibiotics and hydrocortisone. Culture of skin scrapings revealed a growth of Tricophyton verrucosum. The neck swelling subsided after a course of oral griseofulvin followed by terbinafine. Difficulty in breathing due to fungal infection of the neck has not been previously reported in the English literature. Dear Editor, Folliculitis decalvans (FD) is a rare form of primary neutrophilic cicatricial alopecia. It is a highly distressing disease that affects young and middle-aged adults, with a slight male predominance (1). The most frequent clinical manifestations are follicular pustules and diffuse and perifollicular erythema that heal with centrifugal scarring. Follicular tufting, erosions, and hemorrhagic crusts can also be present, and this alopecia is most often located at the vertex and occipital area. Patients frequently complain about pain, itching, or burning sensations, and the involvement of other body areas is rare (2). The pathogenesis of this disease remains unclear. Staphylococcus aureus and other hair follicle bacteria can often be isolated from the pustules, suggesting the role of a bacterial infection in its etiology. A defect in the host's immune response can also be postulated by reports of familial cases and the appearance of FD in patients with immunity dysfunctions. Other mechanical factors have been suggested, such as structural abnormalities of the follicle or local inflammation (2). Management of this alopecia is difficult and its course is typically chronic and relapsing. The treatment aim is to stop inflammation and further irreversible destruction of hair follicles. Antibiotics remain the first-line therapy, due both to their anti-inflammatory and antimicrobial properties (1). Although topical fusidic acid is widely used as adjuvant treatment, there are few data regarding its oral use. We report a case of folliculitis decalvans successfully treated with oral fusidic acid. Our patient was a 41-year old Cape Verdean woman with a two month history of alopecia with painful, purulent discharge at the vertex of the scalp. The patient was diagnosed with human immunodeficiency virus type 1 (HIV-1) infection 5 years prior and was stable on her regimen of efavirenz, tenofovir, and emtricitabine, with undetectable viral load. She denied application of topical or capillary products. Dermatological examination revealed a patch of cicatricial alopecia with crusts and follicular pustules (Figure 1). Direct microscopic examination and mycological culture showed no fungal element. A diagnosis of folliculitis decalvans was established and the patient was started on oral fusidic acid at a dose of 500 mg three times a day. Betamethasone dipropionate 0.05% and salicylic acid 3% lotion as well as azelaic acid 5% lotion were also applied to the affected area once daily. After two months of treatment, the patient showed clinical improvement, with less erythema and suppuration of the affected scalp. A partial hair regrowth was noted, mainly at the periphery. Subsequently the patient maintained only topical therapy, and no recurrences were observed after 6-months of follow-up. Fusidic acid is useful in the treatment of skin and soft tissue infections, particularly those due to S. aureus, as shown by randomized controlled studies (3). The clinical efficacy of fusidic acid in the treatment of folliculitis decalvans has been reported previously. Bogg was the first to describe this useful effect (4). Sutter also reported good results with fusidic acid used both topically and orally (500 mg three times a day) (5). However, both failed to report the treatment duration or the outcome on discontinuation. Abeck described three patients that responded to a three week oral course of fusidic acid (500 mg three times a day) and to a maintenance treatment with zinc sulfate (4). During the following year, recurrence was observed in only one patient after ending zinc sulfate therapy. Oral antibiotics are frequently used to treat folliculitis decalvans. Tetracyclines and the combination of clindamycin with rifampicin are the most commonly used (2). However, the disease usually progresses when treatment is stopped. Fusidic acid is an anti-staphylococcal drug with few adverse effects. It is highly bioavailable orally, and has a long plasma half-life. Despite years of clinical use in numerous countries, resistance rates remain at low levels to date (6). Since clinical series or cases including ours have shown good results, this drug should not be forgotten when considering treatment options for folliculitis decalvans. A 9-year-old girl presented a large inflammatory cup-shaped scalp lesion with alopecia surrounded by pustules, dander, and suppuration associated with an occipital inflammatory lymphadenopathy for 1 month. Wood's light exam was positive as well as KOH mount showing ectothrix type hair involvement. Hair and pus culture on Sabouraud dextrose agar (SDA) added with chloramphenicol and supplemented with cycloheximide isolated a dermatophyte species identified as <iMicrosporum audouinii</i according to the colonies features. Species identification was confirmed by matrix-assisted laser desorption-ionization-time of flight mass spectrometry (MALDI-TOF MS) and the patient was treated for kerion celsi with terbinafine tablets 125 mg per day associated with a ketoconazole-based shampoo. The evolution was favorable, with hair regrowth after 2 months. Tick-borne lymphadenopathy (TIBOLA) is an infectious disease, mainly caused by species from the spotted fever group rickettsiae and is characterized by enlarged lymph nodes following a tick bite. Among cases of TIBOLA, a case of scalp eschar and neck lymphadenopathy after tick bite (SENLAT) is diagnosed when an eschar is present on the scalp, accompanied by peripheral lymphadenopathy (LAP). Only a few cases of SENLAT caused by Bartonella henselae have been reported. A 58-year-old male sought medical advice while suffering from high fever and diarrhea. Three weeks before the visit, he had been hunting a water deer, and upon bringing the deer home discovered a tick on his scalp area. Symptoms occurred one week after hunting, and a lump was palpated on the right neck area 6 days after the onset of symptoms. Physical examination upon presentation confirmed an eschar-like lesion on the right scalp area, and cervical palpation revealed that the lymph nodes on the right side were non-painful and enlarged at 2.5 × 1.5 cm. Fine needle aspiration of the enlarged lymph nodes was performed, and results of nested PCR for the Bartonella internal transcribed spacer (ITS) confirmed B. henselae as the causative agent. With an isolated case of SENLAT and a confirmation of B. henselae in Korea, it is pertinent to raise awareness to physicians in other Asian countries that B. henselae could be a causative agent for SENLAT. A 48-year-old white woman was admitted to the hospital with low-grade fever, night sweats, fatigue, nonproductive cough with dyspnea, bilateral knee pain, and swelling that progressed slowly over 6 weeks. She was a 30-pack-year smoker, and had received outpatient antibiotic therapy with clarithromycin and then cephalexin without improvement. The admission chest radiograph showed bilateral interstitial infiltrates, and an effusion was seen on knee radiographs. She was treated with levofloxacin, cefepime, and methylprednisolone with some improvement, but fevers persisted up to 104 degrees F/40 degrees C. She also developed multiple painful skin nodules (Figure 1) and an enlarging painful tongue ulcer (Figure 2). Her bilateral knee swelling and pain also worsened, and a bone scan showed increased activity. Skin biopsy showed acute and chronic inflammation with an abscess that contained \"yeast\" (Figure 3). Fungal culture from the skin lesion and joint fluid aspirate grew Blastomyces dermatitidis. Urine antigen and blood antigen enzyme-linked immunoassays for B. dermatitidis were positive. The patient was started on a 6-month course of itraconazole oral solution with slow resolution of her joint inflammation and skin lesions over the next several weeks. We report a familial infection caused by Microsporum canis. The first two patients were a 30-year-old female and her son, a 5-year-old boy, who came in contact with a pet dog at a farm house. The boy then suffered from hair loss for 3 months. There were circular and patchy alopecia with diffuse scaling on his scalp. Meanwhile, his mother also developed patchy erythema and scaling on her face. Several weeks later, the boy's sister, a 4-year-old girl, was noted to have inconspicuous scaly plaques in the center of her scalp. The development of tinea capitis in the two children and tinea corporis in their mother were diagnosed based on the positive KOH examination. Morphologic characteristics and sequencing of the internal transcribed spacers 1 and 2, amplified from primary culture isolates, confirmed that their infections were caused by the zoophilic M. canis. Repetitive sequence-based molecular typing using the DiversiLab system secreted enzymatic activity analysis, and antifungal susceptibility indicated that these isolates might share the same source. The boy and girl were cured by the treatment with oral itraconazole and topical naftifine-ketoconazole cream after washing the hair with 2 % ketoconazole shampoo, and their mother was successfully treated by terbinafine orally in combination with topical application of naftifine-ketoconazole cream. \nHere is the question:\nPEDIATRICS: A 6-year-old boy comes to the clinic accompanied by the monitor of a day care center in our neighborhood because of a painful lump 3 cm in diameter on palpation in the right occipital area of the scalp. He suffers from alopecia in this area and 3 adenomegalies of quite hard consistency in the right posterior cervical region. What would be the most appropriate treatment?\nHere are the potential choices:\n1. Incision and drainage.\n2. Topical Mupirocin.\n3. Griseofulvin orally.\n4. Intravenous cefazolin.\n5. Topical Ketoconazole.\nThe correct answer is: ",
        "gold_answer": "3 Griseofulvin orally.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n An 18-year-old black woman with cerebral palsy was admitted for evaluation of an intrathecal baclofen pump site infection. The dermatology service was consulted for treatment suggestions of a presumed diagnosis of chronic tinea capitis. Three courses of oral griseofulvin during the past 2 years failed to resolve the patient's chronic scalp dermatosis. Scalp lesions first began about 2 years earlier after hospitalization for placement of an intrathecal baclofen pump. The patient was unable to care for her scalp due to her cerebral palsy, and her mother interpreted the scalp condition as infectious. No routine shampoo care, scalp care, or topical treatment was performed for more than 1 1/2 years. The mother felt that touching the patient's scalp might cause pain and noted that the majority of her time was spent concentrating on more critical medical issues. Physical examination revealed coalescing hyperkeratotic plaques extending dorsally from the anterior hairline to the occipital scalp with small flecks of keratinous debris throughout the remaining hair (Figure 1). The plate-like plaques were devoid of hair, except at a few fissures where a few tufts of hair emerged. No cervical lymph nodes were appreciated on palpation. Treatment was initiated with compresses consisting of large warm water-soaked towels 4 times daily. Three times a day, a nursing staff applied 5% salicylic acid in olive oil to the scalp under a shower cap for approximately 1 hour. Over the following 2 days, a significant reduction in keratinous debris was appreciated. Within 2 weeks, the bulk of the plaques had been removed (Figure 2). At 6-week follow-up, the underlying scalp showed areas of fibrosis and possible scarring with a few emerging tufts of hair. On the basis of history and response to treatment with salicylic acid and routine scalp care, the patient was diagnosed with an unusually severe case of dermatosis neglecta. Several weeks before coming to Germany the two daughters (aged 3 and 6 years) of a family from Togo had developed desquamating skin changes over the hairy scalp. These had then spread to the trunk and limbs. The 8-weeks-old son also had discrete lesions on the hairy scalp and neck. In all of them these lesions had then spread and begun to itch markedly. When first seen as out-patients the father was free of symptoms, but the other members of the family had multiple, sharply circumscribed, partly confluent, dry and desquamating lesions, about 2-4 cm in diameter, with areas of alopecia and hair breaking off at skin level. In addition there were dry, desquamating, sharply circumscribed, partly hyperpigmented, partly infiltrated plaques, 1-3 cm in diameter, disseminated over the entire body surface, but especially the neck and limbs. Typical micromorphological characteristics for T. soudanese were demonstrated in the outer zones of a primary culture and the organism was also demonstrated in culture on Sabouraud-glucose-agar. Typical colonies on Löwenstein-Jensen medium allowed differentiation from Microsporum ferrugineum. The patients were treated systemically with griseofulvin and locally with ciclopiroxolamine. Marked clinical improvement occurred within 2 months and cultures became negative. But as fungal elements were still demonstrated in native preparations from two of the patients, treatment was continued. Efficacious treatment of tinea needs reliable diagnosis of the pathogen. Human infection with T. soudanese usually results from contact with other humans. If this infection occurs in persons not from Africa there is usually the history of indirect or direct contact with Africans. Increased international migration and tourism is likely to result in more cases of this kind: this pathogen should be considered in the differential diagnosis of tinea of scalp and body. <bBackground:</b Treatment of alopecia areata (AA) involves use of high potency topical corticosteroids under occlusion that, even very effective, can lead to several adverse effects. <bObjective:</b We report 10 cases of patients with AA that, after using high potency topical corticosteroids, have developed tinea versicolor of the neck area. <bMethods:</b Ten patients with AA, aged 18-38 years, were prescribed with clobetasone propionate 0.05% cream under occlusion every other day but, after 3-4 months of treatment, they returned to our facility complaining the appearance of multiple white or red-brown round or oval macules in the neck area. <bResults:</b Diagnosis of pityriasis versicolor was confirmed by direct microscopy examination of skin scrapings in 10% potassion hydroxide (KOH) solution. All patients received systemic antifungal therapy associated with the daily use of ketoconazole shampoo. <bConclusion:</b Tinea versicolor of the neck should be included among a rare but possible side effect of prolonged application of high potency topical steroids on the scalp. These cases reinforce the importance of careful dermatologic examination and recommend preventive measures in patients with alopecia areata that are using these drugs. We report an eight years old boy presenting with a pyogenic granuloma of the scalp, generalized alopecia, descamative plates in the neck, trunk and limbs and nail involvement. Cultures for fungus of all these lesions disclosed Microspore canis. The patient was treated with oral griseofulvin, miconazole and topical tolnaftate. Five years later and after several incomplete treatments, the patient returns with a fistulous mass of 15 x 8 cm in the dorsal area whose culture revealed Microspore canis. The mass was excised and oral ketoconazole was indicated. After three months of follow up, the patient was lost from control. Since the advent of antibiotics, otogenic complications have decreased considerably. However, incomplete antibiotic therapy has altered the clinical course of middle ear disease so as to be more insidious. This paper reports a case of Bezold's abscess associated with cholesteatoma. A 48-year-old man visited our hospital presenting with a 4-day history of right otorrhea and a tender swelling in the right neck. Physical examination showed a febrile patient (38.8 degrees C) with right facial paresis and trismus. A hyperemic, hard and tender swelling was observed in his right neck from the lateral cervical to the mental region. The tympanic membrane was invisible because of granulation and swelling of the posterior wall of the external auditory canal. Intravenous clindamycin and ceftazidime therapy was started immediately. A CT-scan revealed a diffuse shadow with bony destruction in the right mastoid cortex. Extensive abscess formation was also found in the right sternocleidomastoid muscle, in the anterior neck and in the posterior neck. He was diagnosed as having Bezold's abscess associated with cholesteatoma. Radical mastoidectomy and drainage of the neck abscess was performed on the third day under general anesthesia. The mastoid cavity was found to be filled with pus and cholesteatoma debris. A small area of defective bone was found at the mastoid tip, through which there were communications between the mastoid cavity and the abscesses in the neck. Bony destruction was also found in the horizontal and vertical portion of the facial canal. Bacteroides and three kinds of gram-negative rods were cultured from the mastoid cavity.(ABSTRACT TRUNCATED AT 250 WORDS) Tinea capitis is a common and, at times, difficult to treat, fungal infection of the scalp. This article aimed to provide an update on the evaluation, diagnosis, and treatment of tinea capitis. A PubMed search was performed in Clinical Queries using the key term \"tinea capitis\". The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. The search was restricted to English literature. The information retrieved from the above search was used in the compilation of the present article. Patents were searched using the key term \"tinea capitis\" at www.freepatentsonline.com. Tinea capitis is most often caused by Trichophyton tonsurans and Microsporum canis. The peak incidence is between 3 and 7 years of age. Non-inflammatory tinea capitis typically presents as fine scaling with single or multiple scaly patches of circular alopecia (grey patches); diffuse or patchy, fine, white, adherent scaling of the scalp resembling generalized dandruff with subtle hair loss; or single or multiple patches of well-demarcated area (s) of alopecia with fine-scale, studded with broken-off hairs at the scalp surface, resulting in the appearance of \"black dots\". Inflammatory variants of tinea capitis include kerion and favus. Dermoscopy is a highly sensitive tool for the diagnosis of tinea capitis. The diagnosis can be confirmed by direct microscopic examination with a potassium hydroxide wetmount preparation and fungal culture. It is desirable to have mycologic confirmation of tinea capitis before beginning a treatment regimen. Oral antifungal therapy (terbinafine, griseofulvin, itraconazole, and fluconazole) is considered the gold standard for tinea capitis. Recent patents related to the management of tinea capitis are also discussed. Tinea capitis requires systemic antifungal treatment. Although topical antifungal therapies have minimal adverse events, topical antifungal agents alone are not recommended for the treatment of tinea capitis because these agents do not penetrate the root of the hair follicles deep within the dermis. Topical antifungal therapy, however, can be used to reduce transmission of spores and can be used as adjuvant therapy to systemic antifungals. Combined therapy with topical and oral antifungals may increase the cure rate. A 65-year-old man presented with recurrent generalized pruritus and excoriations of many years' duration. He had been treated with antihistamines, topical corticosteroids, and antibiotics for secondary wound infections, but improvement was only temporary. He had also been hospitalized for leg ulcers complicated by cellulitis. Examination revealed multiple oval and linear red papules and nodules measuring 0.5 to 2 cm in diameter. Some of the lesions were eroded and had a central crater and yellowish crust. The patient also had hypopigmented linear scars localized to the posterior scalp, neck, upper back, chest, abdomen, arms, and legs with sparing of the middle and lower back (figures 1 and 2). An ulcer measuring 1.5 x 2 cm that was surrounded by indurated skin was present on the medial aspect of his right ankle. The ulcer was partially covered by yellow exudate. There was no evidence of cellulitis. Liver enzyme, serum creatinine, and thyrotropin levels, as well as a chest roentgenogram, were normal. Wound cultures for bacteria and fungi were nonsignificant. A punch biopsy from a representative lesion showed an abrupt epidermal defect with sparse superficial lymphocytic infiltrate in the dermis. The patient was admitted to the hospital to isolate him from his home environment. He received a 10-day course of systemic cephalexin, topical clobetasol propionate ointment for the affected skin areas, and oral hydroxyzine for pruritus. Ultraviolet light therapy was instituted once daily and was to continue for 2 months. His lesions had improved moderately by the time he was discharged from the hospital. On follow-up 2 weeks later, his lesions were flat and had resulted in hypopigmented scars. Three months later, however, he had persistent, intense pruritus, and new excoriations had developed on his forearms and back. He improved after receiving treatment with oral doxepin hydrochloride. Treatment Oral antifungal medications are the standard of care. Due to the location of the dermatophytes within the hair follicle, treatment with topical antifungals is often unsatisfactory. In patients with tinea pedis or onychomycosis, re-inoculation and recurrence is common. In individuals with recurrent outbreaks, inoculation sources should be identified and treated appropriately. Historical therapies include oral potassium iodide, mildly filtered local X-radiation, and topical applications of Asterol as a fungicide in both tincture and ointment forms. In modern medicine, systemic antifungals, such as griseofulvin, ketoconazole, and itraconazole, are the standard. Therapy extends over at least 4–8 weeks, and treatment continues until all lesions are cleared. Currently, no data about relapse rates or the complications of not treating Majocchi granuloma exist. Treatment Tinea corpora (body), tinea manus (hands), tinea cruris (groin), tinea pedis (foot) and tinea facie (face) can be treated topically. Tinea unguum (nails) usually will require oral treatment with terbinafine, itraconizole, or griseofulvin. Griseofulvin is usually not as effective as terbinafine or itraconizole. A lacquer (Penlac) can be used daily, but is ineffective unless combined with aggressive debridement of the affected nail. Tinea capitis (scalp) must be treated orally, as the medication must be present deep in the hair follicles to eradicate the fungus. Usually griseofulvin is given orally for 2 to 3 months. Clinically dosage up to twice the recommended dose might be used due to relative resistance of some strains of dermatophytes. Shaving the head (if culturally appropriate and with patient's willful consent) 2% ketoconazole or 2% miconazole shampoo or 1 to 1.5% ciclopirox shampoo applied once-to-twice-a-week for 3 to 4 weeks Oral terbinafine 250 mg once daily for 6 weeks Oral itraconazole 100 mg twice-a-day after a meal, with a citrus drink for 1 to 2 weeks Counseling on the maintenance of good scalp hygiene, avoidance of sharing combs, etc. Lymphatic drainage Lymphatic channels from the posterior half of the scalp drain to occipital and posterior auricular nodes. Lymphatic channels from the anterior half drain to the parotid nodes. The lymph eventually reaches the submandibular and deep cervical nodes. Clinical significance Infection The 'danger area of the scalp' is the area of loose connective tissue. This is because pus and blood spread easily within it, and can pass into the cranial cavity along the emissary veins. Therefore, infection can spread from the scalp to the meninges, which could lead to meningitis. A 6-year-old boy was brought to his primary care provider by his mother, who complained of a pruritic rash near his right eye. The eruption was described as a small, erythematous, slightly scaly plaque at the lateral margin of the right eyelid. The child was in good health and took no medications. The diagnosis of eczema was made; the patient was treated with pimecrolimus cream b.i.d. to the affected area. After 2-3 days of treatment, the itching and erythema completely resolved; however, a rough and scaly plaque persisted. After 1-2 weeks of treatment, the itching gradually returned, and the lesion began to increase in size. Multiple, similar lesions appeared several centimeters from the initially affected area. Pimecrolimus was discontinued; topical nystatin/triamcinolone ointment was prescribed. The eruption continued to spread, and the patient was referred to dermatology for further evaluation. The patient presented to the dermatology clinic with multiple annular, scaly papules and plaques with central clearing. Excoriations and mild inflammation were noted around all affected areas (Figure). A potassium hydroxide examination of the lesions revealed numerous hyphae. The nystatin/triamcinolone ointment was discontinued; oral griseofulvin was prescribed. The eruption improved dramatically after 3 weeks and eventually cleared completely after 5 weeks of treatment. Topical 2% ketoconazole cream was applied b.i.d. for the final 2 weeks of treatment. A 68-year-old woman suffered for six weeks from four skin eruptions on her head after returning from Brazil. The skin manifestations resembled furuncles, grew continually in size until they were about 2 cm in diameter and [corrected] she finally developed intermittent sharp pain on her head. On presentation she had a mild lymphadenopathy on her neck but no other systemic complaints. Each skin eruption had a central porus with seropurulent discharge and on examination within the central opening a whitish, tender moving mass could be detected. TREATMENT, COURSE AND DIAGNOSIS: We cautiously infiltrated each skin eruption with lidocaine. Immediately after infiltration a whitish maggot appeared from each nodule and could be easily extracted with a forceps. The maggots were identified as Dermatobia hominis larvae. After extraction a local antiseptic dressing was applied and the wounds healed without complications. Dermatobia hominis is a common cause of myiasis in Central- and South-America and should be taken into account in furuncular skin eruptions of returning travelers. The typical appearance of the skin eruption with a central porus, seropurulent discharge and a whitish, tender moving mass within the nodule is quite characteristic for myiasis. The patients often have [corrected] intermittent sharp pain in the area of the affected skin and report continuing growth of the nodules and a sensation of slight movement within the skin eruption. Extraction is accomplished with a forceps after lidocaine infiltration, alternatively an occlusive dressing could be applied by means of which the larvae can be removed easily from the cavity. A 19-year-old farmer was referred by his general practitioner as an emergency to our otolaryngology department complaining of marked breathlessness of a few hours duration. He gave a three-day history of painful swelling and hair loss in the beard area of the right side of the neck. His upper airway was compromised unless extension of the neck was maintained. Larynx and pharynx were normal. The acute symptoms settled with intravenous antibiotics and hydrocortisone. Culture of skin scrapings revealed a growth of Tricophyton verrucosum. The neck swelling subsided after a course of oral griseofulvin followed by terbinafine. Difficulty in breathing due to fungal infection of the neck has not been previously reported in the English literature. Dear Editor, Folliculitis decalvans (FD) is a rare form of primary neutrophilic cicatricial alopecia. It is a highly distressing disease that affects young and middle-aged adults, with a slight male predominance (1). The most frequent clinical manifestations are follicular pustules and diffuse and perifollicular erythema that heal with centrifugal scarring. Follicular tufting, erosions, and hemorrhagic crusts can also be present, and this alopecia is most often located at the vertex and occipital area. Patients frequently complain about pain, itching, or burning sensations, and the involvement of other body areas is rare (2). The pathogenesis of this disease remains unclear. Staphylococcus aureus and other hair follicle bacteria can often be isolated from the pustules, suggesting the role of a bacterial infection in its etiology. A defect in the host's immune response can also be postulated by reports of familial cases and the appearance of FD in patients with immunity dysfunctions. Other mechanical factors have been suggested, such as structural abnormalities of the follicle or local inflammation (2). Management of this alopecia is difficult and its course is typically chronic and relapsing. The treatment aim is to stop inflammation and further irreversible destruction of hair follicles. Antibiotics remain the first-line therapy, due both to their anti-inflammatory and antimicrobial properties (1). Although topical fusidic acid is widely used as adjuvant treatment, there are few data regarding its oral use. We report a case of folliculitis decalvans successfully treated with oral fusidic acid. Our patient was a 41-year old Cape Verdean woman with a two month history of alopecia with painful, purulent discharge at the vertex of the scalp. The patient was diagnosed with human immunodeficiency virus type 1 (HIV-1) infection 5 years prior and was stable on her regimen of efavirenz, tenofovir, and emtricitabine, with undetectable viral load. She denied application of topical or capillary products. Dermatological examination revealed a patch of cicatricial alopecia with crusts and follicular pustules (Figure 1). Direct microscopic examination and mycological culture showed no fungal element. A diagnosis of folliculitis decalvans was established and the patient was started on oral fusidic acid at a dose of 500 mg three times a day. Betamethasone dipropionate 0.05% and salicylic acid 3% lotion as well as azelaic acid 5% lotion were also applied to the affected area once daily. After two months of treatment, the patient showed clinical improvement, with less erythema and suppuration of the affected scalp. A partial hair regrowth was noted, mainly at the periphery. Subsequently the patient maintained only topical therapy, and no recurrences were observed after 6-months of follow-up. Fusidic acid is useful in the treatment of skin and soft tissue infections, particularly those due to S. aureus, as shown by randomized controlled studies (3). The clinical efficacy of fusidic acid in the treatment of folliculitis decalvans has been reported previously. Bogg was the first to describe this useful effect (4). Sutter also reported good results with fusidic acid used both topically and orally (500 mg three times a day) (5). However, both failed to report the treatment duration or the outcome on discontinuation. Abeck described three patients that responded to a three week oral course of fusidic acid (500 mg three times a day) and to a maintenance treatment with zinc sulfate (4). During the following year, recurrence was observed in only one patient after ending zinc sulfate therapy. Oral antibiotics are frequently used to treat folliculitis decalvans. Tetracyclines and the combination of clindamycin with rifampicin are the most commonly used (2). However, the disease usually progresses when treatment is stopped. Fusidic acid is an anti-staphylococcal drug with few adverse effects. It is highly bioavailable orally, and has a long plasma half-life. Despite years of clinical use in numerous countries, resistance rates remain at low levels to date (6). Since clinical series or cases including ours have shown good results, this drug should not be forgotten when considering treatment options for folliculitis decalvans. A 9-year-old girl presented a large inflammatory cup-shaped scalp lesion with alopecia surrounded by pustules, dander, and suppuration associated with an occipital inflammatory lymphadenopathy for 1 month. Wood's light exam was positive as well as KOH mount showing ectothrix type hair involvement. Hair and pus culture on Sabouraud dextrose agar (SDA) added with chloramphenicol and supplemented with cycloheximide isolated a dermatophyte species identified as <iMicrosporum audouinii</i according to the colonies features. Species identification was confirmed by matrix-assisted laser desorption-ionization-time of flight mass spectrometry (MALDI-TOF MS) and the patient was treated for kerion celsi with terbinafine tablets 125 mg per day associated with a ketoconazole-based shampoo. The evolution was favorable, with hair regrowth after 2 months. Tick-borne lymphadenopathy (TIBOLA) is an infectious disease, mainly caused by species from the spotted fever group rickettsiae and is characterized by enlarged lymph nodes following a tick bite. Among cases of TIBOLA, a case of scalp eschar and neck lymphadenopathy after tick bite (SENLAT) is diagnosed when an eschar is present on the scalp, accompanied by peripheral lymphadenopathy (LAP). Only a few cases of SENLAT caused by Bartonella henselae have been reported. A 58-year-old male sought medical advice while suffering from high fever and diarrhea. Three weeks before the visit, he had been hunting a water deer, and upon bringing the deer home discovered a tick on his scalp area. Symptoms occurred one week after hunting, and a lump was palpated on the right neck area 6 days after the onset of symptoms. Physical examination upon presentation confirmed an eschar-like lesion on the right scalp area, and cervical palpation revealed that the lymph nodes on the right side were non-painful and enlarged at 2.5 × 1.5 cm. Fine needle aspiration of the enlarged lymph nodes was performed, and results of nested PCR for the Bartonella internal transcribed spacer (ITS) confirmed B. henselae as the causative agent. With an isolated case of SENLAT and a confirmation of B. henselae in Korea, it is pertinent to raise awareness to physicians in other Asian countries that B. henselae could be a causative agent for SENLAT. A 48-year-old white woman was admitted to the hospital with low-grade fever, night sweats, fatigue, nonproductive cough with dyspnea, bilateral knee pain, and swelling that progressed slowly over 6 weeks. She was a 30-pack-year smoker, and had received outpatient antibiotic therapy with clarithromycin and then cephalexin without improvement. The admission chest radiograph showed bilateral interstitial infiltrates, and an effusion was seen on knee radiographs. She was treated with levofloxacin, cefepime, and methylprednisolone with some improvement, but fevers persisted up to 104 degrees F/40 degrees C. She also developed multiple painful skin nodules (Figure 1) and an enlarging painful tongue ulcer (Figure 2). Her bilateral knee swelling and pain also worsened, and a bone scan showed increased activity. Skin biopsy showed acute and chronic inflammation with an abscess that contained \"yeast\" (Figure 3). Fungal culture from the skin lesion and joint fluid aspirate grew Blastomyces dermatitidis. Urine antigen and blood antigen enzyme-linked immunoassays for B. dermatitidis were positive. The patient was started on a 6-month course of itraconazole oral solution with slow resolution of her joint inflammation and skin lesions over the next several weeks. We report a familial infection caused by Microsporum canis. The first two patients were a 30-year-old female and her son, a 5-year-old boy, who came in contact with a pet dog at a farm house. The boy then suffered from hair loss for 3 months. There were circular and patchy alopecia with diffuse scaling on his scalp. Meanwhile, his mother also developed patchy erythema and scaling on her face. Several weeks later, the boy's sister, a 4-year-old girl, was noted to have inconspicuous scaly plaques in the center of her scalp. The development of tinea capitis in the two children and tinea corporis in their mother were diagnosed based on the positive KOH examination. Morphologic characteristics and sequencing of the internal transcribed spacers 1 and 2, amplified from primary culture isolates, confirmed that their infections were caused by the zoophilic M. canis. Repetitive sequence-based molecular typing using the DiversiLab system secreted enzymatic activity analysis, and antifungal susceptibility indicated that these isolates might share the same source. The boy and girl were cured by the treatment with oral itraconazole and topical naftifine-ketoconazole cream after washing the hair with 2 % ketoconazole shampoo, and their mother was successfully treated by terbinafine orally in combination with topical application of naftifine-ketoconazole cream. \nHere is the question:\nPEDIATRICS: A 6-year-old boy comes to the clinic accompanied by the monitor of a day care center in our neighborhood because of a painful lump 3 cm in diameter on palpation in the right occipital area of the scalp. He suffers from alopecia in this area and 3 adenomegalies of quite hard consistency in the right posterior cervical region. What would be the most appropriate treatment?\nHere are the potential choices:\n1. Incision and drainage.\n2. Topical Mupirocin.\n3. Griseofulvin orally.\n4. Intravenous cefazolin.\n5. Topical Ketoconazole.\nThe correct answer is: 3. Griseofulvin orally."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A careful neurologic examination is an essential first step in the evaluation. In most cases, patients with an abnormal examination or a history of recent-onset headache should be evaluated by a computed tomography (CT) or magnetic resonance imaging (MRI) study. As an initial screening procedure for intracranial pathology in this setting, CT and MRI methods appear to be equally sensitive. In some circumstances, a lumbar puncture (LP) is also required, unless a benign etiology can be otherwise established. A general evaluation of acute headache might include cranial arteries by palpation; cervical spine by Pain induced by bending, lifting, cough Pain associated with local tenderness, e.g., region of temporal artery the effect of passive movement of the head and by imaging; the investigation of cardiovascular and renal status by blood pressure monitoring and urine examination; and eyes by funduscopy, intraocular pressure measurement, and refraction. One recommended diagnostic approach is as follows. If any urgent red flags are present such as visual loss, new seizures, new weakness, new confusion, further workup with imaging and possibly a lumbar puncture should be done (see red flags section for more details). If the headache is sudden onset (thunderclap headache), a computed tomography test to look for a brain bleed (subarachnoid hemorrhage) should be done. If the CT scan does not show a bleed, a lumbar puncture should be done to look for blood in the CSF, as the CT scan can be falsely negative and subarachnoid hemorrhages can be fatal. If there are signs of infection such as fever, rash, or stiff neck, a lumbar puncture to look for meningitis should be considered. If there is jaw claudication and scalp tenderness in an older person, a temporal artery biopsy to look for temporal arteritis should be performed and immediate treatment should be started. Neuroimaging A 75-year-old Caucasian woman presented with sudden-onset multifocal scotomas in her right eye's central vision for 1 day. There were subtle white intraretinal foveal lesions that correlated with patchy inner retinal hyperreflectivity on optical coherence tomography, suggestive of paracentral acute middle maculopathy. Initial cerebrovascular work-up was negative. Review of systems was positive for lethargy and jaw claudication. The sedimentation rate and c-reactive protein were elevated, but platelet count was normal. The patient was started on 60 mg oral prednisone daily and underwent bilateral temporal artery that confirmed the diagnosis of giant cell arteritis. The purpose is to report a patient with primary open-angle glaucoma that developed sudden painless unilateral vision loss, a sequential ophthalmoscopic appearance with features of both central retinal artery and later central retinal vein occlusion, and objective visual system dysfunction in the form of a relative afferent pupil defect, who spontaneously recovered vision along with complete resolution of the pupillary defect over several weeks. A 50-year-old woman with a long-standing history of glaucoma presented with acute, painless vision loss in one eye, a pallid retina with a cherry red macula, diffuse retinal hemorrhages, and a relative afferent pupil defect. Spectral domain optical coherence tomography and fluorescein angiography were essentially normal with neither retinal edema nor retinal ischemia to account for the visual dysfunction. Over the course of 2 months, the patient regained vision and the relative afferent pupil defect, typically a permanent manifestation of retinal destruction, resolved. Not all retinal vaso-occlusive phenomena can be completely attributed to a central retinal vein or artery occlusion. In the patient presented, there was no objective diagnostic testing that revealed a cause for the patient's vision loss or relative afferent pupillary defect. This combined with the complete recovery of vision and resolution of the relative afferent pupillary defect underscores a lack of comprehensive understanding of retinal vaso-occlusive disease. A 71-year-old man visited our clinic with a 3-day history of severe throbbing headache and 1-day history of horizontal diplopia. He had had jaw claudication and pain in the neck and shoulder several days previously. His right eye was slightly esotropic and did not move laterally. There was no blepharoptosis, proptosis, lid edema, or conjunctival injection. The pupils were unremarkable. The remainder of the cranial nerve functions was intact. There was no limb weakness or sensory impairment. Superficial temporal arteries were swollen and tender on both sides. Laboratory examination showed elevated CRP level and high erythrocyte sedimentation rate. Cranial MR images were unremarkable. The cerebrospinal fluid was acellular with 45 mg/dl of protein. A diagnosis of temporal arteritis was made. Treatment with 50 mg of prednisolone brought about prompt disappearance of the headache. Right ocular movement fully recovered in 10 days. Temporal artery biopsy findings and response to corticosteroid were consistent with temporal arteritis. The motility pattern of the right eye was consistent with complete abducens nerve palsy, which is a rare manifestation of temporal arteritis. Although temporal arteritis is a rare cause of ophthalmoplegia in the elderly patients, swift diagnosis and treatment is necessary to avoid blindness. Leber hereditary optic neuropathy (LHON) is an inherited mitochondrial disease characterized by painless vision loss affecting both eyes. The disease usually develops in both eyes within weeks to months of onset. We report a case of LHON who presented with unilateral vision loss in childhood with an interval of more than 30 years between vision loss in the two eyes. A 43-year-old man presented with a 1-month history of vision loss in his right eye. At 9 years of age, his visual acuity in the left eye declined, and he had been treated with glaucoma eyedrops bilaterally at his eye clinic. At his first visit to our hospital, his BCVA was 0.15 in the right eye and 0.1 in the left eye, and critical flicker frequency was 16 Hz in the right eye and 15 Hz in the left eye, and he was negative for a relative afferent pupillary defect. The Goldman visual field showed central scotoma in both eyes. Fundus examination revealed slight redness of the right optic disc with meandering retinal small vessels, and the left optic disc had a slight pallor. Fluorescein angiography could not be performed because of liver dysfunction. OCT showed prominent bilateral thinning of the RNFL and retinal ganglion cell layer. Enhancement of the optic nerve was not apparent on orbital gadolinium-enhanced magnetic resonance imaging. Hematologic analysis revealed macrocytic anemia and low levels of vitamin B12 and folate. His mother had a presumptive diagnosis of LHON but did not receive genetic testing. A male cousin also had severe vision loss. Based on the likely family history of LHON, we performed genetic testing, which revealed the 11778 mitochondrial point mutation associated with this condition. We report a case of LHON with 34 years interval in vision loss in the fellow eye. LHON may develop in the second eye decades after its onset in the first. Detailed medical interviews and scrutiny, such as examination of family history, are warranted in consideration of LHON. If a 20-year-old female develops headaches after drinking red wine, think migraine. Associated symptoms/signs: Significant findings include fever or rash (consider meningitis or other infectious causes), jaw claudication (specific for temporal arteritis), or constitutional symptoms such as weight loss (associated with neoplastic, inflammatory, or infectious conditions). Photophobia, nausea, and vomiting are associated with migraine, aneurysmal SAH, and meningitis, but neck stiffness is more likely to accompany the latter two. Neurologic sequelae: Look for diplopia, mental status changes or associated symptoms (numbness, weakness, dizziness, ataxia, visual disturbances), papilledema, or pupillary abnormalities (partial CN III palsy or Horner’s syndrome). Patient risk factors: High-risk patients are > 50 years of age, immunocompromised, or with preexisting malignancy. If SAH is suspected, obtain a head CT without contrast. If CT is , LP is mandatory. Obtain a CBC. Optic neuritis is a common cause of subacute unilateral vision loss, occurring in 1-5 per 100,000 persons per year. It is more common in Caucasians, women, and those from countries with northern latitudes. Those aged 20-49 years are at greatest risk. The condition arises due to inflammation of the optic nerve. Inflammation may occur due to systemic inflammatory disorders, most commonly multiple sclerosis. A 21-year-old African-American male presented to our emergency department with a complaint of painful unilateral vision loss. On examination he was found to have a relative afferent pupillary defect and red desaturation. A bedside ultrasound suggested pseudopapilledema suggestive of optic neuritis. He was admitted to Neurology for confirmation of and treatment for optic neuritis. Magnetic resonance imaging confirmed optic neuritis. The patient was treated with i.v. steroids and discharged after improvement in visual function. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Optic neuritis is a clinical diagnosis. The subtle historical components and examination findings make it a diagnostic challenge for the busy emergency physician. Early diagnosis may improve visual outcomes. Discovery of pseudopapilledema on bedside ultrasound may be seen in optic neuritis, and is another finding that emergency physicians may assess for in patient presenting with unilateral vision loss. Giant cell arteritis (GCA) is a polysymptomatic disease which constitutes an ophthalmic emergency because early recognition and management can prevent blindness. There is conflicting information in the literature on the validity, sensitivity, and specificity of various systemic symptoms and signs of GCA. This paper presents a review of our prospective studies on the subject, and our findings are particularly relevant to dentists. We investigated 363 patients in a prospective study. Positive temporal artery biopsy was seen in 106 patients and negative in 257 referred for diagnosis of GCA. Systemic symptoms and signs of GCA and erythrocyte sedimentation rate (Westergren-ESR) and C-reactive protein (CRP) levels were compared in these two groups of patients. The odds of having a positive temporal artery biopsy (i.e., GCA) were 9.1 times greater with jaw claudication (pain in masticatory muscles on eating), 3.4 times with neck pain, 3.2 times with CRP &gt; 2.45 mg/dL, 2.0 times with ESR 47.107 mm/hr, 2.7 times with ESR &gt; 107 mm/hr, and 2.0 times when the patients were aged &gt; or = 75 years. Other signs and symptoms did not show a significant association with a positive biopsy. Our study showed that \"normal\" ESR values do not rule out GCA but that CRP is a more useful test than ESR. Since jaw claudication is one of the most important symptoms of GCA, dentists should keep this possibility in mind when older patients come complaining of jaw pain while eating. To report the case and multimodal imaging findings of a healthy young woman who developed paracentral acute middle maculopathy (PAMM) 9 weeks after COVID-19 disease. Case report. Ultra-widefield fundus photography, macular spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), and OCT-angiography (OCT-A) were performed. A 36-year-old woman who developed PAMM 9 weeks after SARS-CoV-2 infection. A 36-year-old woman went to the emergency department (ED) with sudden, painless, left eye (LE) vision loss. The only relevant past medical history was COVID-19 disease 9 weeks before. Best corrected visual acuity (BCVA) was 20/200, a LE relative afferent pupillary defect (RAPD) was present and superficial hemorrhages throughout the macular area and peripheral retina were found. Nearly four hours after admission, LE BCVA recovered to 20/20 without RAPD. Five days after presentation in the ED, the patient returned with recurrent LE vision loss, with spontaneous recovery within 12 hours. Macular SD-OCT revealed hyperreflectivity of the inner plexiform and inner nuclear layers and the diagnosis of PAMM was established. The patient started oral acetylsalicylic acid and oral prednisolone. The patient did not report any new episodes of vision loss and there was a progressive resolution of abnormal fundus findings. SARS-CoV-2 infection increases the risk of vascular thrombotic events with possible involvement of the retinal circulation, and PAMM may present as a possible complication. Ophthalmologists should be able to recognize it promptly through multimodal imaging findings. In anterior ischemic optic neuropathy (AION), it is important not to miss the diagnosis of giant cell arteritis (GCA) because this requires immediate steroid treatment to prevent involvement of the second eye and possible blindness. A missed diagnosis also might lead to fatal systemic complications. Observational case report. A 79-year-old woman noticed decreased visual and visual field loss in the right eye. At presentation, right visual acuity was 10/20 (ETDRS chart 2000). There was a right relative afferent pupillary defect of 0.6 log units. Asked for symptoms of GCA she complained about temporal and occipital headache, jaw claudication combined with malaise, and myalgia of the upper limbs. Laboratory tests showed normal inflammatory markers. Repeated tests confirmed ESR and CRP to be within the normal range. GCA being suspected, ultrasound of the superficial temporal arteries and temporal artery biopsy were performed unilaterally on the right side. Histology showed a chronic inflammatory cell infiltrate consistent with active GCA. The patient was treated with high-dose corticosteroids (250 mg methylprednisolone, three times/day, initially) and symptoms rapidly resolved, but visual loss remained unchanged. The case presented here proves that GCA with typical related visual loss (AION) is possible even when both ESR and CRP are in the normal range. Therefore, in the presence of typical symptoms, the clinician must not rely solely on laboratory testing, but start steroid therapy immediately and order a temporal artery biopsy. Cancer should be suspected if there is previous history of it, unexplained weight loss, or unremitting pain. Spinal epidural abscess is more common among those with diabetes mellitus or immunocompromised or who had spinal surgery, injection or catheter; it typically causes fever, leukocytosis and increased erythrocyte sedimentation rate. If cancer or spinal epidural abscess are suspected, urgent magnetic resonance imaging is recommended for confirmation. Proximal diabetic neuropathy typically affects middle aged and older people with well-controlled type-2 diabetes mellitus; onset is sudden causing pain usually in multiple dermatomes quickly followed by weakness. Diagnosis typically involves electromyography and lumbar puncture. Shingles is more common among the elderly and immunocompromised; usually (but not always) pain is followed by appearance of a rash with small blisters along a single dermatome. Acute Lyme radiculopathy may follow a history of outdoor activities during warmer Giant cell arteritis (GCA) is often diagnosed very late, variable \"facets\" of the disease exist render the diagnosis more difficult. Follow-up observations of five very old patients are reported in whom diagnosis was made too late, resulting in blindness of both eyes. Five patients (age 76-84 years, 4 women, one man) with GCA became blind in both eyes because diagnosis had been delayed (two patients) or onset of therapy was too late (three patients). In two patients who also had arterial hypertension, the symptom \"headache\" had been misleading. Symptoms of accompanying general diseases masked the real diagnosis, particularly in the second patient who had renal insufficiency, coronary artery disease, and unilateral obstruction of the internal carotid artery. Symptoms that failed to lead to the correct diagnosis were: muscle or chewing pain (three patients), circumscribed numbness around the mouth (second patient), and persistent headache despite normalization of blood pressure. Normal findings from cranial CTAs (two patients) led to the wrong reassurance of the patient. Swelling of the optic disk (two patients) was misdiagnosed by ophthalmologists, as was a retinal branch arterial occlusion (first patient). Three patients, afraid of possible side effects caused by glucocorticoids, took ineffective alternative medications. Poor vigilance led to blindness of the fifth patient with long-standing polymyalgia rheumatica. Targeted examinations at the onset of symptoms are necessary. GCA-symptoms were mis-constructed by additional diseases that disguised the correct diagnosis. The danger of bilateral blindness is particularly great in patients of great age. A 70-year-old woman presented with new onset of left eye and facial pain. Ophthalmic and neurological examinations, magnetic resonance imaging brain, erythrocyte sedimentation rate, and C-reactive protein were unrevealing. A few days later, she developed vision loss in her left eye. Examination revealed decreased visual acuity with a relative afferent pupillary defect in the left eye and a diffuse mild swelling of the left optic nerve head. Repeat magnetic resonance imaging showed T2 hyperintensity and enhancement of the intraorbital optic nerve and surrounding tissues with no other intracranial abnormalities. Serum studies showed elevated myelin oligodendrocyte glycoprotein IgG titer. She was treated with IV methylprednisolone 1000 mg daily for 3 days and was discharged on prolonged prednisone taper with return of vision to baseline. We report a 62-year-old man who developed coma and died in a fulminant course. The patient was well until May 1, 1996 when he noted chillness, tenderness in his shoulders, and he went to bed without having his lunch and dinner. In the early morning of May 2, his families found him unresponsive and snoring; he was brought into the ER of our hospital. He had histories of hypertension, gout, and hyperlipidemia since 42 years of the age. On admission, his blood pressure was 120/70, heart rate 102 and regular, and body temperature 36.3 degrees C. His respiration was regular and he was not cyanotic. Low pitch rhonchi was heard in his right lower lung field. Otherwise general physical examination was unremarkable. Neurologic examination revealed that he was somnolent and he was only able to respond to simple questions such as opening eyes and grasping the examiner's hand, but he was unable to respond verbally. The optic discs were flat; the right pupil was slightly larger than the left, but both reacted to light. He showed ptosis on the left side, conjugate deviation of eyes to the left, and right facial paresis. The oculocephalic response and the corneal reflex were present. His right extremities were paralyzed and did not respond to pain Deep tendon reflexes were exaggerated on the right side and the plantar response was extensor on the right. No meningeal signs were present. Laboratory examination revealed the following abnormalities; WBC 18,400/ml, GOT 131 IU/l GPT 50 IU/l, CK616 IU/l, BUN 30 mg/dl, Cr 2.1 mg/ dl, glucose 339 mg/dl, and CRP 27.4 mg/dl. ECG showed sinus tachycardia and ST elevation in II, III and a VF leads and abnormal q waves in I, V5, and V6 leads. Chest X-ray revealed cardiac enlargement but the lung fields were clear. Cranial CT scan revealed low density areas in the left middle cerebral and left posterior cerebral artery territories. The patient was treated with intravenous glycerol infusion and other supportive measures. At 2: 10 AM on May 3, he developed sudden hypotension and cardiopulmonary arrest. He was pronounced dead at 3:45 AM. The patient was discussed in a neurological CPC, and the chief discussant arrived at the conclusion that the patient had acute myocardial infarction involving the inferior and the true posterior walls and left internal carotid embolism from a mural thrombus. Post mortem examination revealed occlusion of the circumflex branch of the left coronary artery due to atherom plaque rupture and myocardial infarction involving the posterior and the lateral wall with a rupture in the postero-lateral wall. Marked atheromatous changes were seen in the left internal carotid, the middle cerebral and the basilar arteries; the left internal carotid and the middle cerebral arteries were almost occluded by thrombi and blood coagulate. The territories of the left middle cerebral and the occipital arteries were infarcted; but the left thalamic area was spared. The neuropathologist concluded that the infarction was thrombotic origin not an embolic one as the atherosclerotic changes were severe. Cardiac rupture appeared to be the cause of terminal sudden hypotension and cardiopulmonary arrest. It appears likely that a vegetation which had been attached to the aortic valve induced thromboembolic occlusion of the left internal carotid artery which had already been markedly sclerotic by atherosclerosis. It is also possible that the vegetations in the aortic valve came from mural thrombi at the site of acute myocardial infarction, as no bacteria were found in those vegetations. Leber hereditary optic neuropathy (LHON) is an optic neuropathy of mitochondrial inheritance. Childhood-onset disease is relatively rare and there are limited data on this important patient subgroup. We present 3 particular presentations of LHON. Patient 1 was an 8-year-old boy admitted to the emergency department reporting a progressive bilateral visual loss and intermittent headaches. Neuro-ophthalmological examination revealed a bilateral pseudopapilledema. Lumbar puncture identified intracranial hypertension and the brain and orbits magnetic resonance imaging showed T2 hyperintensity in the posterior region of the left optic nerve and the optic chiasm. Patient 2 was a 12-year-old boy admitted to the emergency department reporting painless, progressive central vision loss in the right eye. Fundus examination revealed a hyperemic disc and vascular network papillary and peripapillary vascular microdilations. Three months later, the left eye presented visual loss. Patient 3 was a 6-year-old female child referred to the neuro-ophthalmology specialist due to painless central visual loss in both eyes. Her BCVA was 1/10 and counting fingers in right and left eye, respectively, and fundus examination revealed a pallor optic disc in the temporal sector. The phenotype of childhood-onset disease may present itself distinct from classical adult-onset LHON. The absence of classical clinical features could lead to initial misdiagnosis. There should exist a high index of suspicion in children presenting unexplained subnormal vision in order to avoid potential diagnostic delays. A 48-year-old woman was referred to the First Dept. of Int. Med., Nagasaki Univ. Sch. Med., in August, 1979, with a six-month history of recurrent episodes of right-sided painful ophthalmoplegia and diplopia. An epidode affected the right eye, lasted one to two weeks, and relapsed every month. On examination she had a complete ptosis on the right side and pain on the right eye. All extraocular muscle supplied by the 3rd nerve were paralysed. The pupils were equal in size both sides, reacting to light completely. Visual acuity was normal except myopia. All the other cranial nerves and the remainder of central nervous system was normal. Results of thyroid function tests and of lumbar puncture were normal. The glucose tolerance test showed a mild diabetic pattern. Blood and CSF cultures for bacteria, fungi, and acid-fast bacillus were negative. The skull, brain CT scan, and carotid angiogram were within normal limits. A tentative diagnosis of Tolosa-Hunt syndrome was made after an unproductive search for a cause for this woman's painful ophthalmoplegia and unsuccessful treatment of ophthalmoplegia with antibiotics or diet therapy for mild hyperglycemia. The patient was given prednisolone 30 mg daily orally when she had the 9th attack of painful ophthalmoplegia Pain, ptosis, and diplopia disappeared in 5 days and she did not show any recurrence of symptoms over the next 7 months. Defective light perception in one eye causes an asymmetrical pupillary constriction reflex called the afferent pupillary defect (APD). Arteritic PION A-PION most commonly affects Caucasian women, with an average age of 73. At onset vision loss is unilateral, but without treatment it rapidly progresses to involve both eyes. Vision loss is usually severe, ranging from counting fingers to no light perception. Associated symptoms are jaw pain exacerbated by chewing, scalp tenderness, shoulder and hip pain, headache and fatigue. Perioperative PION Vision loss is usually apparent upon waking from general anesthesia. Signs observable to a bystander include long surgery duration and facial swelling. Vision loss is usually bilateral and severe, ranging from counting fingers to no light perception. Cause A 71-year-old male presented with a history of sudden partial visual loss in the right eye with an inferior visual field defect over the past 3-4 days. He had no history of headache or of facial pain. Clinical examination confirmed that vision on the right side was reduced to 6/18 and on the left to 6/12. The right eye showed a relative afferent pupillary defect. There was no other abnormality of the anterior segment of either eye. The right retina showed a pale swollen optic disc and a provisional diagnosis of anterior ischaemic optic neuropathy (AION) was made. An urgent erythrocyte sedimentation rate (ESR) was ordered and the patient was asked to return to the eye clinic in one month. However, 16 days later--when it was first recognised that his ESR was elevated to 75 mm in the first hour--the patient was recalled immediately in order to commence systemic steroid treatment; but regrettably, by this time, his right eye had become totally blind. In this case, although the attending doctor made a correct clinical diagnosis on presentation, he failed to act upon the result of the blood test. These diagnostic criteria include: Inflammatory back pain:Chronic, inflammatory back pain is defined when at least four out of five of the following parameters are present: (1) Age of onset below 40 years old, (2) insidious onset, (3) improvement with exercise, (4) no improvement with rest, and (5) pain at night (with improvement upon getting up) Past history of inflammation in the joints, heels, or tendon-bone attachments Family history for axial spondyloarthritis or other associated rheumatic/autoimmune conditions Positive for the biomarker HLA-B27 Good response to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) Signs of elevated inflammation (C-reactive protein and erythrocyte sedimentation rate) Manifestation of psoriasis, inflammatory bowel disease, or inflammation of the eye (uveitis) If these criteria still do not give a compelling diagnosis magnetic resonance imaging (MRI) may be useful. MRI can show inflammation of the sacroiliac joint. Imaging Recurrent unbearable, paroxysmal, unilateral facial pain in the distribution of one or more branches of the trigeminal nerve often provoked by sensory stimuli is typical for idiopathic trigeminal neuralgia. The less frequent localization in the area of ophthalmic branch (5%) is particularly controversial and should be distinguished from pathological lesions in the brainstem and middle and posterior cranial fossa and from diseases of the orbit and eye. This case study presents a 79-year-old woman with typical clinical features of 1st division trigeminalgia without any neurological loss and with normal results of laryngological, ophthalmological, and stomatological examinations as well as neuroimaging CT, and MR /MRA evaluation. Only the evoked potential blink and masseter reflexes demonstrated the pathological values in the early phase of illness. After 1 year of pharmacological treatment no improvement was achieved and the pain became neuropathic and paresis of 3rd, 4th and 6th nerves developed, as observed in Tolose-Hunt syndrome. MRI of the orbit revealed a pathological mass in its apex with a connection to the superior orbital fissure. However, treatment with steroids was completely ineffective. Surgical resection of the tumor (leiomyosarcoma) only partially reversed oculomotor palsy and diminished aching. In differential diagnosis of idiopathic and symptomatic trigeminalgia, early MR and MRA imaging is the most essential and sometimes may be the best single test to evaluate lesions even in distant areas of the nervous system branches. Nonspecific orbital inflammation (NSOI) is a rare idiopathic ocular pathology characterized by unilateral, painful orbital swelling without identifiable infectious or systemic disorders, which can be complicated by optic nerve compromise. A 50-year-old man presented to the Emergency Department with recurring, progressive painless left eye swelling, decreased visual acuity, and binocular diplopia in the absence of trauma, infection, or known malignancy. His physical examination was notable for left-sided decreased visual acuity, an afferent pupillary defect, severe left eye proptosis and chemosis, and restricted extraocular movements; his dilatated funduscopic examination was notable for ipsilateral retinal folds within the macula, concerning for a disruption between the sclera and the retina. Ocular examination of the right eye was unremarkable. Laboratory data were unrevealing. Gadolinium-enhanced magnetic resonance imaging showed marked thickening of the left extraocular muscles associated with proptosis, dense inflammatory infiltration of the orbital fat, and characteristics consistent with perineuritis. The patient was diagnosed with NSOI with optic neuritis and admitted for systemic steroid therapy; he was discharged on hospital day 2 after receiving high-dose intravenous (i.v.) methylprednisolone with significant improvement. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: NSOI is a rare and idiopathic ocular emergency, with clinical mimicry resembling a broad spectrum of systemic diseases such as malignancy, autoimmune diseases, endocrine disorders, and infection. Initial work-up for new-onset ocular proptosis should include comprehensive laboratory testing and gadolinium-enhanced magnetic resonance imaging. Timely evaluation by an ophthalmologist is crucial to assess for optic nerve involvement. Signs of optic nerve compromise include decreased visual acuity, afferent pupillary defect, or decreased color saturation. Patients with optic nerve compromise require admission for aggressive anti-inflammatory therapy with i.v. steroids in an attempt to reduce risk of long-term visual sequelae. Our case demonstrates a severe presentation of this disorder and exhibits remarkable visual recovery after 48 h of systemic i.v. steroid treatment.\nHere is the question:\nNEUROLOGY: A 70-year-old woman with a history of anorexia, weight loss, discomfort in the muscles and proximal joints and pain in the temporomandibular region who comes to the emergency department for unilateral loss of vision (hand movement), sudden and painless onset (afferent pupillary defect).what test would you request first for diagnostic purposes?\nHere are the potential choices:\n1. Lumbar puncture.\n2. C Reactive Protein.\n3. Magnetic resonance angiography.\n4. Carotid ultrasound.\nThe correct answer is: ",
        "gold_answer": "2 C Reactive Protein.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A careful neurologic examination is an essential first step in the evaluation. In most cases, patients with an abnormal examination or a history of recent-onset headache should be evaluated by a computed tomography (CT) or magnetic resonance imaging (MRI) study. As an initial screening procedure for intracranial pathology in this setting, CT and MRI methods appear to be equally sensitive. In some circumstances, a lumbar puncture (LP) is also required, unless a benign etiology can be otherwise established. A general evaluation of acute headache might include cranial arteries by palpation; cervical spine by Pain induced by bending, lifting, cough Pain associated with local tenderness, e.g., region of temporal artery the effect of passive movement of the head and by imaging; the investigation of cardiovascular and renal status by blood pressure monitoring and urine examination; and eyes by funduscopy, intraocular pressure measurement, and refraction. One recommended diagnostic approach is as follows. If any urgent red flags are present such as visual loss, new seizures, new weakness, new confusion, further workup with imaging and possibly a lumbar puncture should be done (see red flags section for more details). If the headache is sudden onset (thunderclap headache), a computed tomography test to look for a brain bleed (subarachnoid hemorrhage) should be done. If the CT scan does not show a bleed, a lumbar puncture should be done to look for blood in the CSF, as the CT scan can be falsely negative and subarachnoid hemorrhages can be fatal. If there are signs of infection such as fever, rash, or stiff neck, a lumbar puncture to look for meningitis should be considered. If there is jaw claudication and scalp tenderness in an older person, a temporal artery biopsy to look for temporal arteritis should be performed and immediate treatment should be started. Neuroimaging A 75-year-old Caucasian woman presented with sudden-onset multifocal scotomas in her right eye's central vision for 1 day. There were subtle white intraretinal foveal lesions that correlated with patchy inner retinal hyperreflectivity on optical coherence tomography, suggestive of paracentral acute middle maculopathy. Initial cerebrovascular work-up was negative. Review of systems was positive for lethargy and jaw claudication. The sedimentation rate and c-reactive protein were elevated, but platelet count was normal. The patient was started on 60 mg oral prednisone daily and underwent bilateral temporal artery that confirmed the diagnosis of giant cell arteritis. The purpose is to report a patient with primary open-angle glaucoma that developed sudden painless unilateral vision loss, a sequential ophthalmoscopic appearance with features of both central retinal artery and later central retinal vein occlusion, and objective visual system dysfunction in the form of a relative afferent pupil defect, who spontaneously recovered vision along with complete resolution of the pupillary defect over several weeks. A 50-year-old woman with a long-standing history of glaucoma presented with acute, painless vision loss in one eye, a pallid retina with a cherry red macula, diffuse retinal hemorrhages, and a relative afferent pupil defect. Spectral domain optical coherence tomography and fluorescein angiography were essentially normal with neither retinal edema nor retinal ischemia to account for the visual dysfunction. Over the course of 2 months, the patient regained vision and the relative afferent pupil defect, typically a permanent manifestation of retinal destruction, resolved. Not all retinal vaso-occlusive phenomena can be completely attributed to a central retinal vein or artery occlusion. In the patient presented, there was no objective diagnostic testing that revealed a cause for the patient's vision loss or relative afferent pupillary defect. This combined with the complete recovery of vision and resolution of the relative afferent pupillary defect underscores a lack of comprehensive understanding of retinal vaso-occlusive disease. A 71-year-old man visited our clinic with a 3-day history of severe throbbing headache and 1-day history of horizontal diplopia. He had had jaw claudication and pain in the neck and shoulder several days previously. His right eye was slightly esotropic and did not move laterally. There was no blepharoptosis, proptosis, lid edema, or conjunctival injection. The pupils were unremarkable. The remainder of the cranial nerve functions was intact. There was no limb weakness or sensory impairment. Superficial temporal arteries were swollen and tender on both sides. Laboratory examination showed elevated CRP level and high erythrocyte sedimentation rate. Cranial MR images were unremarkable. The cerebrospinal fluid was acellular with 45 mg/dl of protein. A diagnosis of temporal arteritis was made. Treatment with 50 mg of prednisolone brought about prompt disappearance of the headache. Right ocular movement fully recovered in 10 days. Temporal artery biopsy findings and response to corticosteroid were consistent with temporal arteritis. The motility pattern of the right eye was consistent with complete abducens nerve palsy, which is a rare manifestation of temporal arteritis. Although temporal arteritis is a rare cause of ophthalmoplegia in the elderly patients, swift diagnosis and treatment is necessary to avoid blindness. Leber hereditary optic neuropathy (LHON) is an inherited mitochondrial disease characterized by painless vision loss affecting both eyes. The disease usually develops in both eyes within weeks to months of onset. We report a case of LHON who presented with unilateral vision loss in childhood with an interval of more than 30 years between vision loss in the two eyes. A 43-year-old man presented with a 1-month history of vision loss in his right eye. At 9 years of age, his visual acuity in the left eye declined, and he had been treated with glaucoma eyedrops bilaterally at his eye clinic. At his first visit to our hospital, his BCVA was 0.15 in the right eye and 0.1 in the left eye, and critical flicker frequency was 16 Hz in the right eye and 15 Hz in the left eye, and he was negative for a relative afferent pupillary defect. The Goldman visual field showed central scotoma in both eyes. Fundus examination revealed slight redness of the right optic disc with meandering retinal small vessels, and the left optic disc had a slight pallor. Fluorescein angiography could not be performed because of liver dysfunction. OCT showed prominent bilateral thinning of the RNFL and retinal ganglion cell layer. Enhancement of the optic nerve was not apparent on orbital gadolinium-enhanced magnetic resonance imaging. Hematologic analysis revealed macrocytic anemia and low levels of vitamin B12 and folate. His mother had a presumptive diagnosis of LHON but did not receive genetic testing. A male cousin also had severe vision loss. Based on the likely family history of LHON, we performed genetic testing, which revealed the 11778 mitochondrial point mutation associated with this condition. We report a case of LHON with 34 years interval in vision loss in the fellow eye. LHON may develop in the second eye decades after its onset in the first. Detailed medical interviews and scrutiny, such as examination of family history, are warranted in consideration of LHON. If a 20-year-old female develops headaches after drinking red wine, think migraine. Associated symptoms/signs: Significant findings include fever or rash (consider meningitis or other infectious causes), jaw claudication (specific for temporal arteritis), or constitutional symptoms such as weight loss (associated with neoplastic, inflammatory, or infectious conditions). Photophobia, nausea, and vomiting are associated with migraine, aneurysmal SAH, and meningitis, but neck stiffness is more likely to accompany the latter two. Neurologic sequelae: Look for diplopia, mental status changes or associated symptoms (numbness, weakness, dizziness, ataxia, visual disturbances), papilledema, or pupillary abnormalities (partial CN III palsy or Horner’s syndrome). Patient risk factors: High-risk patients are > 50 years of age, immunocompromised, or with preexisting malignancy. If SAH is suspected, obtain a head CT without contrast. If CT is , LP is mandatory. Obtain a CBC. Optic neuritis is a common cause of subacute unilateral vision loss, occurring in 1-5 per 100,000 persons per year. It is more common in Caucasians, women, and those from countries with northern latitudes. Those aged 20-49 years are at greatest risk. The condition arises due to inflammation of the optic nerve. Inflammation may occur due to systemic inflammatory disorders, most commonly multiple sclerosis. A 21-year-old African-American male presented to our emergency department with a complaint of painful unilateral vision loss. On examination he was found to have a relative afferent pupillary defect and red desaturation. A bedside ultrasound suggested pseudopapilledema suggestive of optic neuritis. He was admitted to Neurology for confirmation of and treatment for optic neuritis. Magnetic resonance imaging confirmed optic neuritis. The patient was treated with i.v. steroids and discharged after improvement in visual function. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Optic neuritis is a clinical diagnosis. The subtle historical components and examination findings make it a diagnostic challenge for the busy emergency physician. Early diagnosis may improve visual outcomes. Discovery of pseudopapilledema on bedside ultrasound may be seen in optic neuritis, and is another finding that emergency physicians may assess for in patient presenting with unilateral vision loss. Giant cell arteritis (GCA) is a polysymptomatic disease which constitutes an ophthalmic emergency because early recognition and management can prevent blindness. There is conflicting information in the literature on the validity, sensitivity, and specificity of various systemic symptoms and signs of GCA. This paper presents a review of our prospective studies on the subject, and our findings are particularly relevant to dentists. We investigated 363 patients in a prospective study. Positive temporal artery biopsy was seen in 106 patients and negative in 257 referred for diagnosis of GCA. Systemic symptoms and signs of GCA and erythrocyte sedimentation rate (Westergren-ESR) and C-reactive protein (CRP) levels were compared in these two groups of patients. The odds of having a positive temporal artery biopsy (i.e., GCA) were 9.1 times greater with jaw claudication (pain in masticatory muscles on eating), 3.4 times with neck pain, 3.2 times with CRP &gt; 2.45 mg/dL, 2.0 times with ESR 47.107 mm/hr, 2.7 times with ESR &gt; 107 mm/hr, and 2.0 times when the patients were aged &gt; or = 75 years. Other signs and symptoms did not show a significant association with a positive biopsy. Our study showed that \"normal\" ESR values do not rule out GCA but that CRP is a more useful test than ESR. Since jaw claudication is one of the most important symptoms of GCA, dentists should keep this possibility in mind when older patients come complaining of jaw pain while eating. To report the case and multimodal imaging findings of a healthy young woman who developed paracentral acute middle maculopathy (PAMM) 9 weeks after COVID-19 disease. Case report. Ultra-widefield fundus photography, macular spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), and OCT-angiography (OCT-A) were performed. A 36-year-old woman who developed PAMM 9 weeks after SARS-CoV-2 infection. A 36-year-old woman went to the emergency department (ED) with sudden, painless, left eye (LE) vision loss. The only relevant past medical history was COVID-19 disease 9 weeks before. Best corrected visual acuity (BCVA) was 20/200, a LE relative afferent pupillary defect (RAPD) was present and superficial hemorrhages throughout the macular area and peripheral retina were found. Nearly four hours after admission, LE BCVA recovered to 20/20 without RAPD. Five days after presentation in the ED, the patient returned with recurrent LE vision loss, with spontaneous recovery within 12 hours. Macular SD-OCT revealed hyperreflectivity of the inner plexiform and inner nuclear layers and the diagnosis of PAMM was established. The patient started oral acetylsalicylic acid and oral prednisolone. The patient did not report any new episodes of vision loss and there was a progressive resolution of abnormal fundus findings. SARS-CoV-2 infection increases the risk of vascular thrombotic events with possible involvement of the retinal circulation, and PAMM may present as a possible complication. Ophthalmologists should be able to recognize it promptly through multimodal imaging findings. In anterior ischemic optic neuropathy (AION), it is important not to miss the diagnosis of giant cell arteritis (GCA) because this requires immediate steroid treatment to prevent involvement of the second eye and possible blindness. A missed diagnosis also might lead to fatal systemic complications. Observational case report. A 79-year-old woman noticed decreased visual and visual field loss in the right eye. At presentation, right visual acuity was 10/20 (ETDRS chart 2000). There was a right relative afferent pupillary defect of 0.6 log units. Asked for symptoms of GCA she complained about temporal and occipital headache, jaw claudication combined with malaise, and myalgia of the upper limbs. Laboratory tests showed normal inflammatory markers. Repeated tests confirmed ESR and CRP to be within the normal range. GCA being suspected, ultrasound of the superficial temporal arteries and temporal artery biopsy were performed unilaterally on the right side. Histology showed a chronic inflammatory cell infiltrate consistent with active GCA. The patient was treated with high-dose corticosteroids (250 mg methylprednisolone, three times/day, initially) and symptoms rapidly resolved, but visual loss remained unchanged. The case presented here proves that GCA with typical related visual loss (AION) is possible even when both ESR and CRP are in the normal range. Therefore, in the presence of typical symptoms, the clinician must not rely solely on laboratory testing, but start steroid therapy immediately and order a temporal artery biopsy. Cancer should be suspected if there is previous history of it, unexplained weight loss, or unremitting pain. Spinal epidural abscess is more common among those with diabetes mellitus or immunocompromised or who had spinal surgery, injection or catheter; it typically causes fever, leukocytosis and increased erythrocyte sedimentation rate. If cancer or spinal epidural abscess are suspected, urgent magnetic resonance imaging is recommended for confirmation. Proximal diabetic neuropathy typically affects middle aged and older people with well-controlled type-2 diabetes mellitus; onset is sudden causing pain usually in multiple dermatomes quickly followed by weakness. Diagnosis typically involves electromyography and lumbar puncture. Shingles is more common among the elderly and immunocompromised; usually (but not always) pain is followed by appearance of a rash with small blisters along a single dermatome. Acute Lyme radiculopathy may follow a history of outdoor activities during warmer Giant cell arteritis (GCA) is often diagnosed very late, variable \"facets\" of the disease exist render the diagnosis more difficult. Follow-up observations of five very old patients are reported in whom diagnosis was made too late, resulting in blindness of both eyes. Five patients (age 76-84 years, 4 women, one man) with GCA became blind in both eyes because diagnosis had been delayed (two patients) or onset of therapy was too late (three patients). In two patients who also had arterial hypertension, the symptom \"headache\" had been misleading. Symptoms of accompanying general diseases masked the real diagnosis, particularly in the second patient who had renal insufficiency, coronary artery disease, and unilateral obstruction of the internal carotid artery. Symptoms that failed to lead to the correct diagnosis were: muscle or chewing pain (three patients), circumscribed numbness around the mouth (second patient), and persistent headache despite normalization of blood pressure. Normal findings from cranial CTAs (two patients) led to the wrong reassurance of the patient. Swelling of the optic disk (two patients) was misdiagnosed by ophthalmologists, as was a retinal branch arterial occlusion (first patient). Three patients, afraid of possible side effects caused by glucocorticoids, took ineffective alternative medications. Poor vigilance led to blindness of the fifth patient with long-standing polymyalgia rheumatica. Targeted examinations at the onset of symptoms are necessary. GCA-symptoms were mis-constructed by additional diseases that disguised the correct diagnosis. The danger of bilateral blindness is particularly great in patients of great age. A 70-year-old woman presented with new onset of left eye and facial pain. Ophthalmic and neurological examinations, magnetic resonance imaging brain, erythrocyte sedimentation rate, and C-reactive protein were unrevealing. A few days later, she developed vision loss in her left eye. Examination revealed decreased visual acuity with a relative afferent pupillary defect in the left eye and a diffuse mild swelling of the left optic nerve head. Repeat magnetic resonance imaging showed T2 hyperintensity and enhancement of the intraorbital optic nerve and surrounding tissues with no other intracranial abnormalities. Serum studies showed elevated myelin oligodendrocyte glycoprotein IgG titer. She was treated with IV methylprednisolone 1000 mg daily for 3 days and was discharged on prolonged prednisone taper with return of vision to baseline. We report a 62-year-old man who developed coma and died in a fulminant course. The patient was well until May 1, 1996 when he noted chillness, tenderness in his shoulders, and he went to bed without having his lunch and dinner. In the early morning of May 2, his families found him unresponsive and snoring; he was brought into the ER of our hospital. He had histories of hypertension, gout, and hyperlipidemia since 42 years of the age. On admission, his blood pressure was 120/70, heart rate 102 and regular, and body temperature 36.3 degrees C. His respiration was regular and he was not cyanotic. Low pitch rhonchi was heard in his right lower lung field. Otherwise general physical examination was unremarkable. Neurologic examination revealed that he was somnolent and he was only able to respond to simple questions such as opening eyes and grasping the examiner's hand, but he was unable to respond verbally. The optic discs were flat; the right pupil was slightly larger than the left, but both reacted to light. He showed ptosis on the left side, conjugate deviation of eyes to the left, and right facial paresis. The oculocephalic response and the corneal reflex were present. His right extremities were paralyzed and did not respond to pain Deep tendon reflexes were exaggerated on the right side and the plantar response was extensor on the right. No meningeal signs were present. Laboratory examination revealed the following abnormalities; WBC 18,400/ml, GOT 131 IU/l GPT 50 IU/l, CK616 IU/l, BUN 30 mg/dl, Cr 2.1 mg/ dl, glucose 339 mg/dl, and CRP 27.4 mg/dl. ECG showed sinus tachycardia and ST elevation in II, III and a VF leads and abnormal q waves in I, V5, and V6 leads. Chest X-ray revealed cardiac enlargement but the lung fields were clear. Cranial CT scan revealed low density areas in the left middle cerebral and left posterior cerebral artery territories. The patient was treated with intravenous glycerol infusion and other supportive measures. At 2: 10 AM on May 3, he developed sudden hypotension and cardiopulmonary arrest. He was pronounced dead at 3:45 AM. The patient was discussed in a neurological CPC, and the chief discussant arrived at the conclusion that the patient had acute myocardial infarction involving the inferior and the true posterior walls and left internal carotid embolism from a mural thrombus. Post mortem examination revealed occlusion of the circumflex branch of the left coronary artery due to atherom plaque rupture and myocardial infarction involving the posterior and the lateral wall with a rupture in the postero-lateral wall. Marked atheromatous changes were seen in the left internal carotid, the middle cerebral and the basilar arteries; the left internal carotid and the middle cerebral arteries were almost occluded by thrombi and blood coagulate. The territories of the left middle cerebral and the occipital arteries were infarcted; but the left thalamic area was spared. The neuropathologist concluded that the infarction was thrombotic origin not an embolic one as the atherosclerotic changes were severe. Cardiac rupture appeared to be the cause of terminal sudden hypotension and cardiopulmonary arrest. It appears likely that a vegetation which had been attached to the aortic valve induced thromboembolic occlusion of the left internal carotid artery which had already been markedly sclerotic by atherosclerosis. It is also possible that the vegetations in the aortic valve came from mural thrombi at the site of acute myocardial infarction, as no bacteria were found in those vegetations. Leber hereditary optic neuropathy (LHON) is an optic neuropathy of mitochondrial inheritance. Childhood-onset disease is relatively rare and there are limited data on this important patient subgroup. We present 3 particular presentations of LHON. Patient 1 was an 8-year-old boy admitted to the emergency department reporting a progressive bilateral visual loss and intermittent headaches. Neuro-ophthalmological examination revealed a bilateral pseudopapilledema. Lumbar puncture identified intracranial hypertension and the brain and orbits magnetic resonance imaging showed T2 hyperintensity in the posterior region of the left optic nerve and the optic chiasm. Patient 2 was a 12-year-old boy admitted to the emergency department reporting painless, progressive central vision loss in the right eye. Fundus examination revealed a hyperemic disc and vascular network papillary and peripapillary vascular microdilations. Three months later, the left eye presented visual loss. Patient 3 was a 6-year-old female child referred to the neuro-ophthalmology specialist due to painless central visual loss in both eyes. Her BCVA was 1/10 and counting fingers in right and left eye, respectively, and fundus examination revealed a pallor optic disc in the temporal sector. The phenotype of childhood-onset disease may present itself distinct from classical adult-onset LHON. The absence of classical clinical features could lead to initial misdiagnosis. There should exist a high index of suspicion in children presenting unexplained subnormal vision in order to avoid potential diagnostic delays. A 48-year-old woman was referred to the First Dept. of Int. Med., Nagasaki Univ. Sch. Med., in August, 1979, with a six-month history of recurrent episodes of right-sided painful ophthalmoplegia and diplopia. An epidode affected the right eye, lasted one to two weeks, and relapsed every month. On examination she had a complete ptosis on the right side and pain on the right eye. All extraocular muscle supplied by the 3rd nerve were paralysed. The pupils were equal in size both sides, reacting to light completely. Visual acuity was normal except myopia. All the other cranial nerves and the remainder of central nervous system was normal. Results of thyroid function tests and of lumbar puncture were normal. The glucose tolerance test showed a mild diabetic pattern. Blood and CSF cultures for bacteria, fungi, and acid-fast bacillus were negative. The skull, brain CT scan, and carotid angiogram were within normal limits. A tentative diagnosis of Tolosa-Hunt syndrome was made after an unproductive search for a cause for this woman's painful ophthalmoplegia and unsuccessful treatment of ophthalmoplegia with antibiotics or diet therapy for mild hyperglycemia. The patient was given prednisolone 30 mg daily orally when she had the 9th attack of painful ophthalmoplegia Pain, ptosis, and diplopia disappeared in 5 days and she did not show any recurrence of symptoms over the next 7 months. Defective light perception in one eye causes an asymmetrical pupillary constriction reflex called the afferent pupillary defect (APD). Arteritic PION A-PION most commonly affects Caucasian women, with an average age of 73. At onset vision loss is unilateral, but without treatment it rapidly progresses to involve both eyes. Vision loss is usually severe, ranging from counting fingers to no light perception. Associated symptoms are jaw pain exacerbated by chewing, scalp tenderness, shoulder and hip pain, headache and fatigue. Perioperative PION Vision loss is usually apparent upon waking from general anesthesia. Signs observable to a bystander include long surgery duration and facial swelling. Vision loss is usually bilateral and severe, ranging from counting fingers to no light perception. Cause A 71-year-old male presented with a history of sudden partial visual loss in the right eye with an inferior visual field defect over the past 3-4 days. He had no history of headache or of facial pain. Clinical examination confirmed that vision on the right side was reduced to 6/18 and on the left to 6/12. The right eye showed a relative afferent pupillary defect. There was no other abnormality of the anterior segment of either eye. The right retina showed a pale swollen optic disc and a provisional diagnosis of anterior ischaemic optic neuropathy (AION) was made. An urgent erythrocyte sedimentation rate (ESR) was ordered and the patient was asked to return to the eye clinic in one month. However, 16 days later--when it was first recognised that his ESR was elevated to 75 mm in the first hour--the patient was recalled immediately in order to commence systemic steroid treatment; but regrettably, by this time, his right eye had become totally blind. In this case, although the attending doctor made a correct clinical diagnosis on presentation, he failed to act upon the result of the blood test. These diagnostic criteria include: Inflammatory back pain:Chronic, inflammatory back pain is defined when at least four out of five of the following parameters are present: (1) Age of onset below 40 years old, (2) insidious onset, (3) improvement with exercise, (4) no improvement with rest, and (5) pain at night (with improvement upon getting up) Past history of inflammation in the joints, heels, or tendon-bone attachments Family history for axial spondyloarthritis or other associated rheumatic/autoimmune conditions Positive for the biomarker HLA-B27 Good response to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) Signs of elevated inflammation (C-reactive protein and erythrocyte sedimentation rate) Manifestation of psoriasis, inflammatory bowel disease, or inflammation of the eye (uveitis) If these criteria still do not give a compelling diagnosis magnetic resonance imaging (MRI) may be useful. MRI can show inflammation of the sacroiliac joint. Imaging Recurrent unbearable, paroxysmal, unilateral facial pain in the distribution of one or more branches of the trigeminal nerve often provoked by sensory stimuli is typical for idiopathic trigeminal neuralgia. The less frequent localization in the area of ophthalmic branch (5%) is particularly controversial and should be distinguished from pathological lesions in the brainstem and middle and posterior cranial fossa and from diseases of the orbit and eye. This case study presents a 79-year-old woman with typical clinical features of 1st division trigeminalgia without any neurological loss and with normal results of laryngological, ophthalmological, and stomatological examinations as well as neuroimaging CT, and MR /MRA evaluation. Only the evoked potential blink and masseter reflexes demonstrated the pathological values in the early phase of illness. After 1 year of pharmacological treatment no improvement was achieved and the pain became neuropathic and paresis of 3rd, 4th and 6th nerves developed, as observed in Tolose-Hunt syndrome. MRI of the orbit revealed a pathological mass in its apex with a connection to the superior orbital fissure. However, treatment with steroids was completely ineffective. Surgical resection of the tumor (leiomyosarcoma) only partially reversed oculomotor palsy and diminished aching. In differential diagnosis of idiopathic and symptomatic trigeminalgia, early MR and MRA imaging is the most essential and sometimes may be the best single test to evaluate lesions even in distant areas of the nervous system branches. Nonspecific orbital inflammation (NSOI) is a rare idiopathic ocular pathology characterized by unilateral, painful orbital swelling without identifiable infectious or systemic disorders, which can be complicated by optic nerve compromise. A 50-year-old man presented to the Emergency Department with recurring, progressive painless left eye swelling, decreased visual acuity, and binocular diplopia in the absence of trauma, infection, or known malignancy. His physical examination was notable for left-sided decreased visual acuity, an afferent pupillary defect, severe left eye proptosis and chemosis, and restricted extraocular movements; his dilatated funduscopic examination was notable for ipsilateral retinal folds within the macula, concerning for a disruption between the sclera and the retina. Ocular examination of the right eye was unremarkable. Laboratory data were unrevealing. Gadolinium-enhanced magnetic resonance imaging showed marked thickening of the left extraocular muscles associated with proptosis, dense inflammatory infiltration of the orbital fat, and characteristics consistent with perineuritis. The patient was diagnosed with NSOI with optic neuritis and admitted for systemic steroid therapy; he was discharged on hospital day 2 after receiving high-dose intravenous (i.v.) methylprednisolone with significant improvement. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: NSOI is a rare and idiopathic ocular emergency, with clinical mimicry resembling a broad spectrum of systemic diseases such as malignancy, autoimmune diseases, endocrine disorders, and infection. Initial work-up for new-onset ocular proptosis should include comprehensive laboratory testing and gadolinium-enhanced magnetic resonance imaging. Timely evaluation by an ophthalmologist is crucial to assess for optic nerve involvement. Signs of optic nerve compromise include decreased visual acuity, afferent pupillary defect, or decreased color saturation. Patients with optic nerve compromise require admission for aggressive anti-inflammatory therapy with i.v. steroids in an attempt to reduce risk of long-term visual sequelae. Our case demonstrates a severe presentation of this disorder and exhibits remarkable visual recovery after 48 h of systemic i.v. steroid treatment.\nHere is the question:\nNEUROLOGY: A 70-year-old woman with a history of anorexia, weight loss, discomfort in the muscles and proximal joints and pain in the temporomandibular region who comes to the emergency department for unilateral loss of vision (hand movement), sudden and painless onset (afferent pupillary defect).what test would you request first for diagnostic purposes?\nHere are the potential choices:\n1. Lumbar puncture.\n2. C Reactive Protein.\n3. Magnetic resonance angiography.\n4. Carotid ultrasound.\nThe correct answer is: 2. C Reactive Protein."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Other means used in diagnosis of vertiginous epilepsy include: Electroencephalography (EEG) Magnetic resonance imaging (MRI) Positron emission tomography (PET) Neuropsychological testing The EEG measures electrical activity in the brain, allowing a physician to identify any unusual patterns. While EEGs are good for identifying abnormal brain activity is it not helpful in localizing where the seizure originates because they spread so quickly across the brain. MRIs are used to look for masses or lesions in the temporal lobe of the brain, indicating possible tumors or cancer as the cause of the seizures. When using a PET scan, a physician is looking to detect abnormal blood flow and glucose metabolism in the brain, which is visible between seizures, to indicate the region of origin. Management The most definitive test to distinguish epilepsy from PNES is long term video-EEG monitoring, with the aim of capturing one or two episodes on both video recording and EEG simultaneously (some clinicians may use suggestion to attempt to trigger an episode). Additional clinical criteria are usually considered in addition to video-EEG monitoring when diagnosing PNES. By recording the event in question on video and EEG simultaneously, a clear diagnosis can usually be obtained. Laboratory testing can detect rising blood levels of serum prolactin if samples are taken in the right time window after most tonic-clonic or complex partial epileptic seizures. However, due to false positives and variability in results, this test is relied upon less frequently. The pathogenesis of PED has also been linked to mutations in the GLUT1 glucose transporter which can result in transient energy deficits in the basal ganglia. Diagnosis Diagnosis is similar, but slightly different for each type of PD. Some types are more understood than others, and therefore have more criteria for diagnosis. PKD The guidelines for diagnosing PKD were reviewed and confirmed by Unterberger and Trinka. PKD consists of unexpected forms of involuntary movements of the body. The patient is usually diagnosed sometime before their 20s, and is more likely diagnosed during childhood than early adulthood. Almost all PKD's are idiopathic, but there have been examples of autosomal dominant inheritance as well. Physical examination and brain imaging examinations show normal results, and an EEG shows no specific abnormalities as well. However, the negative synchronous EEG results can be used to prove that PKD is not a sort of reflex epilepsy, but a different disease. To confirm diagnosis, awake and asleep EEG and magnetic resonance imaging (MRI) are performed. MRI is used to detect focal brain lesions. Ruling out other diagnoses Certain diagnoses must be ruled out before diagnosing LGS. These diagnoses are: Doose syndrome Dravet syndrome pseudo-Lennox Gastaut syndrome (atypical benign partial epilepsy) LGS is more easily distinguished from Doose syndrome by seizure type after the syndrome has progressed. Doose syndrome has more myoclonic seizures and LGS has more tonic seizures. The Doose syndromes is less likely to have cognitive disabilities. Pseudo-Lennox–Gastaut syndrome can be distinguished from LGS because pseudo-LGS has different spike-and-wave patterns on EEG. Treatment There are several treatment options, including medications, surgery, and diet. Medications In most patients with LGS, the treatment does not end seizure recurrence. There exist various morphological and biochemical changes closely associated with electrophysiological phenomena which cause epileptic seizures in the brains of epilepsy patients. Recent developments in investigation methods, not only electrophysiological(EEG and MEG), but also neuroimaging involving morphological imaging(CT and conventional MRI) and functional imaging(SPECT, PET, functional MRI and MRS) is able to demonstrate these changes. SPECT and PET can particularly clarify the changes of cerebral blood flow and glucose metabolism between interictal and ictal periods. In our experience of 423 patients who underwent epilepsy surgery for intractable seizures, these interventions provide important information to identify the epileptogenic foci. However, in practice, discordance in the results of these presurgical evaluations is recognized, and invasive intracranial recordings are needed in such cases. These problems in diagnosis were shown especially in patients with mesial temporal sclerosis and focal cortical dysplasia. To detect an epileptogenic focus more clearly, a combination of morphological and functional findings, new functional imaging such as neurotransmitter receptor imaging, EEG-triggered or neuropharmacological functional MRI, as well as, statistical parametric analysis may be needed. Diagnosis Diagnosis of PME is based on the individual’s signs and symptoms as well as failure to respond to antiepileptic drugs and therapy. Further diagnosis support includes EEG results, genetic testing, enzyme testing, and skin and muscle biopsies. Gaucher’s disease can be diagnosed through enzyme testing as it is a metabolic disease. Lafora’s disease can be diagnosed using skin biopsies. While Action myoclonus renal failure (AMRF) syndrome can only be diagnosed using genetic test. Using EEG’s as a form of diagnosis can prove difficult as patients differ in their neurophysiology. In Lafora’s disease EEGs can show slowing background activity or focal discharges as well as epileptiform discharges. In ULD EEGs show generalized epileptiform discharges and in MERRF patients show background slowing. Therefore, diagnosis is best made using a combination of different tools like signs and symptoms, age of onset, EEG, gene testing, enzyme measurements, and biopsy of skin and muscle. For adults, the testing of electrolyte, blood glucose and calcium levels is important to rule out problems with these as causes. An electrocardiogram can rule out problems with the rhythm of the heart. A lumbar puncture may be useful to diagnose a central nervous system infection but is not routinely needed. In children additional tests may be required such as urine biochemistry and blood testing looking for metabolic disorders. Together with EEG and neuroimaging, genetic testing is becoming one of the most important diagnostic technique for epilepsy, as a diagnosis might be achieved in a relevant proportion of cases with severe epilepsies, both in children and adults. For those with negative genetic testing, in some it might be important to repeat or re-analyze previous genetic studies after 2–3 years. Diagnosis The diagnosis of epilepsy is typically made based on observation of the seizure onset and the underlying cause. An electroencephalogram (EEG) to look for abnormal patterns of brain waves and neuroimaging (CT scan or MRI) to look at the structure of the brain are also usually part of the initial investigations. While figuring out a specific epileptic syndrome is often attempted, it is not always possible. Video and EEG monitoring may be useful in difficult cases. Definition Epilepsy is a disorder of the brain defined by any of the following conditions: {| cellpadding=5 style=\"border:1px solid #ccc\" |- bgcolor=\"#fafafa\" | At least two unprovoked (or reflex) seizures occurring more than 24 hours apart One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years Diagnosis of an epilepsy syndrome |} The goal of this study was to estimate the frequency of psychogenic pseudosyncope in patients with \"syncope of unknown origin.\" Twenty to thirty percent of patients referred to epilepsy centers for refractory seizures have psychogenic seizures. With syncope, about 20-30% of the cases remain unexplained after a complete evaluation, but, unlike in seizures, a psychogenic etiology is not usually investigated. We prospectively evaluated patients referred to our epilepsy center for evaluation of recurrent syncope-like episodes, that is, limp, motionless fainting. All patients had a negative syncope workup. We performed EEG-video monitoring with activation by suggestion (\"induction\"), similar to what is used for diagnosis of psychogenic seizures. Activation was performed with patients standing or sitting up. The diagnosis of psychogenic pseudosyncope required: (1) an activation procedure that triggered the habitual event; (2) a clinical event of loss of postural tone and limp, motionless unresponsiveness with eyes closed; (3) normal EEG before, during, and after the clinical event, that is, no epileptiform abnormalities, a normal alpha rhythm during unresponsiveness, and no suppression of background or slowing as is typically seen in syncope. Ten patients were recruited over an 18-month period. Habitual syncope-like episodes were triggered in 9 of 10 (90%) patients, and all 9 were shown to have psychogenic pseudosyncope (eyes closed, motionless, unresponsive with normal EEG including normal alpha rhythm). In one patient, no episode was triggered, so a diagnosis could not be made. Among the 9 patients for whom episodes were recorded, age ranged from 21 to 60 (mean=36). Five were women. Duration of symptoms ranged from 6 months to 15 years (mean=4.2 years). Event frequency ranged from four per day to two per month. Prior evaluations for syncope included ECG in all patients, two-dimensional echocardiogram in three, Holter monitoring in two, and tilt-table test in five. Four patients had undergone cardiac catheterization, and one had received a pacemaker. Neurologic tests included CT of the head in seven and MRI of the brain in eight. Many patients with \"syncope of unknown origin\" may have psychogenic pseudosyncope, but most such patients do not undergo EEG-video monitoring, which is the only way to demonstrate a psychogenic etiology. Psychogenic pseudosyncope is not simply a diagnosis of exclusion, and can be firmly diagnosed. As is usually recommended for seizure-like events, patients with syncope-like events and a negative evaluation should undergo EEG-video monitoring with induction, specifically looking for a possible psychogenic etiology. EEGs were recorded in 22 patients with medically refractory complex partial epilepsy undergoing presurgical evaluation and 11 age-matched controls while subjected to moderate levels of hypoglycemia to determine if changes activated were predictive of underlying pathology. Five patients had fasting EEGs showing focal abnormalities not seen in the non-fasting state. With hypoglycemia, EEG tracings in normal individuals showed diffuse background slowing, whereas 7 of 22 patients developed focal temporal changes, including focal spike and focal slow wave activation. The development of focal changes correlated well with clinical data concerning underlying focal pathology; focal abnormalities were not evoked in patients with multifocal disease. Hypoglycemic activation of the EEG may be a useful technique for predicting the presence of pathology in patients considered for anterior temporal lobectomy. Kamiyah Morgan is a 6 year old little girl who suffers from a very unusual set of fainting episodes that will leave her unresponsive and immobile, and they can happen up to 300 times a day. When she experiences a fainting episode she will become completely paralyzed affecting everything in her body including her lungs, her mother states that every day that passes her ability to breathe diminishes. Kamiyah’s mother said that these fainting episodes started when she was about 8 months old as she would be crawling and suddenly tip over and go limp. At first their pediatric physician said the episodes looked like she was having a seizure, but after running an EEG there was no seizure being detected during the episodes. They then tried testing with MRI for any brain tumors or malignancies but again there was nothing. They were then referred over to the NIH or the National Institute of Health where their entire purpose is to be able to research and hopefully diagnose very strange cases. Diagnosis To be diagnosed with PTE, a person must have a history of head trauma and no history of seizures prior to the injury. Witnessing a seizure is the most effective way to diagnose PTE. Electroencephalography (EEG) is a tool used to diagnose a seizure disorder, but a large portion of people with PTE may not have the abnormal \"epileptiform\" EEG findings indicative of epilepsy. In one study, about a fifth of people who had normal EEGs three months after an injury later developed PTE. However, while EEG is not useful for predicting who will develop PTE, it can be useful to localize the epileptic focus, to determine severity, and to predict whether a person will suffer more seizures if they stop taking antiepileptic medications. Magnetic resonance imaging (MRI) is performed in people with PTE, and CT scanning can be used to detect brain lesions if MRI is unavailable. However, it is frequently not possible to detect the epileptic focus using neuroimaging. We have experienced 10 cases of insulinoma during the last 10 years from 1977 to 1986. All cases had strong hypoglycemic symptoms such as disturbance of consciousness, and insulinoma still tended to be misdiagnosed as epilepsy. The diagnosis of insulinoma was easily available from serum IRI (immunoreactive insulin)/plasma glucose ratio in all of the ten cases. As preoperative procedures for the diagnosis of localization, arteriography, computed tomography and portal blood sampling were positive in 6 of 8, 4 of 6 and 2 of 2 patients, respectively. At operation, all insulinomas could be identified by digital palpation. We performed simple excision of the tumor in 6 patients and distal pancreatectomy in 4 patients. The tumors were solitary and benign in all patients, ranging in size from 1.0 cm to 4.5 cm. Three cases were presented as case reports. In these cases, portal blood sampling and/or intraoperative monitoring of plasma glucose and serum IRI were performed. Portal blood sampling was effective even for a case which was negative in image diagnostic procedures. Furthermore, simultaneous monitoring of plasma glucose and serum IRI by quick radioimmunoassay seemed to be a good guide to the completeness of resection of insulin producing tumors. Epilepsy monitoring is typically done to distinguish epileptic seizures from other types of spells, such as psychogenic non-epileptic seizures, syncope (fainting), sub-cortical movement disorders and migraine variants, to characterize seizures for the purposes of treatment, and to localize the region of brain from which a seizure originates for work-up of possible seizure surgery. Hospitals use an EEG monitor to help diagnose a seizure. They use that information to help with the treatment process as well as discovering risks. \"Many professionals have stated the importance of EEG’s when it comes to suspected seizures, for diagnosis and evaluation\". Doctors will be able to use the EEG monitoring system to help look at some treatment options as well as some risk factors. As technology advances, researchers are finding new monitors that are more accurate in regards to seizures. \"Advanced techniques with continuous EEG and simplified technique with aEEG allows clinicians to detect more We performed interictal 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET) studies in 57 patients with complex partial epilepsy (CPE), not controlled by medical treatment and considered for surgical resection of their epileptic focus. A precise localization of the epileptic focus was obtained in 37 of these patients with a combination of subdural and depth electrodes. We visually inspected the metabolic images; we also measured glucose consumption in a number of brain regions and compared the values with those obtained in 17 normal controls. Eighty-two percent of the 57 patients had an area of glucose hypometabolism on the 18FDG-PET images. Six patients had a frontal epileptic focus, 3 of them had a frontal lobe hypometabolism. Twenty-six patients had a unilateral temporal lobe focus and all of them displayed a temporal lobe hypometabolism. The asymmetry was more pronounced in the lateral temporal cortex (-20%) than in the mesial part of the temporal lobe (-9.6%). In each cortical brain region on the side of the epileptic focus (except the sensorimotor cortex), glucose consumption rate was lower than in the contralateral region or than in controls. No differences could be found between patients with a seizure onset restricted to the hippocampus and patients with a seizure onset involving the hippocampus and the adjacent neocortex. Divergent metabolic patterns were obtained in 5 patients with bilateral temporal seizure foci. Combined with other non invasive techniques (EEG, neuroradiology), PET contributes increasingly to the selection of patients with CPE who could benefit from surgical treatment.(ABSTRACT TRUNCATED AT 250 WORDS) Although insulinoma constitutes almost 90% of neuroendocrine tumors localized in the pancreas, it is a rare disease. Quite commonly prior to the diagnosis there is a history of several years and misdiagnosis as neurological or cardiological disease is not infrequent. Patient, 22 years old, since 7 years experiencing multiple incidents of neuroglycopenia with concurrent hyperadrenergic reaction. Consciousness disturbances and muscle tremor together with feeling of hunger and tachycardia occurred mainly in the morning hours, or after physical exercise, and subsided after glucose intake. Increase in body weight, typical for insulinoma, was also observed. The patient was hospitalized twice in Pediatric Department and although hypoglycemia was observed, no additional testing was performed to exclude insulinoma; reported symptoms and abnormalities in EEG recording after provocation resulted in diagnosis and treatment of epilepsy. During hospitalization in the Department of Endocrinology fasting test was performed, which revealed inadequately high insulin level with glucose level of 41 mg% and signs of neuroglycopenia. The image of pancreas was normal in the acquired abdominal ultrasound and in CT a tumor was found in the tail of pancreas. The patient underwent laparoscopic operation and the clinical diagnosis was confirmed by histopathology. Antiepileptic drugs were discontinued. Total remission of symptoms was achieved. The presented case demonstrates the difficulties in correct interpretation of reported symptoms, while the results of biochemical tests and imaging studies point precisely to the diagnosis. Focal neurological signs resulting from multiple episodes of hypoglycemia may lead to misdiagnosis and treatment of epilepsia. Four patients with a well-established diagnosis of tuberous sclerosis and grand mal type epileptic seizures as their principal clinical symptom were examined by conventional surface electroencephalography (EEG), X-ray computed tomography, and positron emission tomography (PET) using the [18F]-2-fluoro-2-deoxyglucose method. The interictal EEG showed various abnormalities of poor localizing value, but no focal epileptic discharges. X-ray computed tomography demonstrated subependymal calcifications in all cases, although cortical lesions were found only twice. However, in the PET images of each patient one or two localized cortical foci with a metabolic rate for glucose more than 40% lower than in the respective contralateral region were clearly delineated. It may be assumed that those hypometabolic areas represent the epileptogenic cortical tubers, which are characteristic of the disease but usually cannot be detected in vivo by other methods. In adults, testing electrolytes, blood glucose and calcium levels is important to rule these out as causes, as is an electrocardiogram. A lumbar puncture may be useful to diagnose a central nervous system infection but is not routinely needed. Routine antiseizure medical levels in the blood are not required in adults or children. In children additional tests may be required. A high blood prolactin level within the first 20 minutes following a seizure may be useful to confirm an epileptic seizure as opposed to psychogenic non-epileptic seizure. Serum prolactin level is less useful for detecting partial seizures. If it is normal an epileptic seizure is still possible and a serum prolactin does not separate epileptic seizures from syncope. It is not recommended as a routine part of diagnosis epilepsy. Epilepsy Macropsia may present itself as a symptom of both frontal lobe epilepsy and temporal lobe epilepsy, which may actually help in the diagnosis of those diseases. Children who experience nocturnal hallucinations accompanied by macropsia may seek medical care for panic attack disorders and instead are diagnosed with forms of epilepsy. Epilepsy patients may have no memory of the seizure, but can remember the hallucinations and aura which proceed the attack. Electroencephalography, or EEG imaging, can then be utilized while the patient experiences the episode. It may be subsequently concluded that the EEG is congruent with temporal or frontal lobe seizure. Anxiety and headaches accompany the episodes of visual distortion associated with epilepsy. While Valproic acid has been used to treat this type of seizure, anti-seizure medications appropriate for focal-onset seizures, like oxcarbazapine, have also been used successfully in the treatment of epilepsy-related macropsia. Four patients with primary generalized or true petit mal epilepsy were studied with positron emission tomography using [18F]fluorodeoxyglucose (FDG). FDG studies were carried out during 10 minutes of hyperventilation before and again after medical control of spontaneous absences. Before seizures were controlled all 4 patients demonstrated frequent bilaterally synchronous three-per-second spike-and-wave discharges associated with altered consciousness. After spontaneous seizures were controlled, hyperventilation produced only electroencephalographic slowing without clinical symptoms in 3; the fourth patient had absences less frequently. Patterns of local cerebral metabolic rate for glucose (CMRGlc) were normal and identical for ictal and interictal scans; there was, however, a 2.5- to 3.5-fold diffuse ictal increase in global CMRGlc evident when ictal studies were compared with hyperventilation control studies in which no seizures occurred. The CMRGlc was similar in the two scans obtained from the patient who had absences during both studies. No anatomical substrate of petit mal epilepsy was identified. The CMRGlc in these patients during petit mal absences was higher than that recorded in other patients during partial or generalized convulsive seizures. This difference may reflect the fact that petit mal absences are not associated with postictal depression. For the diagnosis it is necessary to perform an EEG during the headache that shows epilepsy-compatible discharges coinciding with the onset and cessation of the headache. The so-called hemicrania epileptica is a variant of EH characterized by the fact that head pain and EEG paroxysms are located on the same side. MRI is necessary to establish the cause, which, as in all focal epilepsies, can be varied: malformations/dysplasia, neoplasms, encephalopathies, traumatic brain injury, vasculopathies. Therapy. It depends on the etiology. During the headache, like most seizures, i.v. benzodiazepines are usually effective. Antiepileptic drugs can be used as preventive. 2. Ictal non-epileptic headache. Rare cases are reported. It is a condition that can be differentiated with certainty from the previous one if the headache episode is also present outside the seizure, that is, before and/or after, without specific EEG abnormalities. References External links Interictal positron computed tomography (PCT) with 18F-fluorodeoxyglucose was performed on 50 patients with partial seizures disorders. Electroencephalographic (EEG) monitoring was carried out during the metabolic studies using scalp and sphenoidal electrodes in 33 patients and stereotaxically implanted depth electrodes in 17. Four patients in this series had focal abnormalities on x-ray computed tomographic scans, but these were at the site of the presumed epileptogenic lesion in only 2. One or more discrete zones of hypometabolism were identified in 35 patients, and only 1 patient appeared to show focal interictal hypermetabolism. No quantitative relationship could be demonstrated between the degree of focal hypometabolism and either the frequency of interictal EEG spikes of the presence of focal nonepileptiform EEG changes. It was concluded that metabolic and electrophysiological techniques measure different aspects of cerebral dysfunction in seizure disorders. Although interictal PCT in patients with partial epilepsy usually demonstrates zones of hypometabolism this finding, per se, does not reveal the epileptic nature of the abnormality. Other methods to diagnose Unverricht–Lundborg disease are currently being explored. While electroencephalogram (EEG) is useful in identifying or diagnosing other forms of epilepsy, the location of seizures in ULD is currently known to be generalized across the entire brain. Without a specific region to pinpoint, it is difficult to accurately distinguish an EEG reading from an individual with ULD from an individual with another type of epilepsy characterized by generalized brain seizures. However, with recent research linking ULD brain damage to the hippocampus, the usefulness of EEG as a diagnostic tool may increase. Magnetic Resonance Imaging (MRI) is also often used during diagnosis of patients with epilepsy. While MRIs taken during the onset of the disease are generally similar to those of individuals without ULD, MRIs taken once the disease has progressed show characteristic damage This study reports on the clinical, electrophysiologic, and neuroradiologic aspects of patients with epilepsy secondary to neonatal hypoglycemia. Fifteen patients with epilepsy and/or posterior cerebral lesions, and neonatal hypoglycemia were studied in the epilepsy clinic between February 1990 and March 2003. The mean age was 12 years. The different types of neonatal hypoglycemia were as follows: four patients had transitional-adaptive, seven classic transient, two secondary-associated, and two severe recurrent hypoglycemia. As to epilepsy, we recognized a larger group of 12 patients characterized by focal seizures and posterior abnormalities on the electroencephalogram, the majority of whom had a good outcome, and a second group of two patients presenting electroclinical features of encephalopathy with refractory seizures. All patients except two manifested parieto-occipital lesions on neuroradiologic images. Neurologic examination was normal in one patient. Six patients had microcephaly; eight manifested visual disturbances. Fourteen patients were mentally retarded. One had a pervasive developmental disorder. This study indicates neonatal hypoglycemia may cause posterior cerebral lesions, abnormal findings at neurologic examination, and symptomatic epilepsy, most frequently occipital lobe epilepsy, usually with a good prognosis, and occasionally epileptic encephalopathy with refractory seizures. MRI studies are essential to define the characteristics of cerebral lesions after neonatal hypoglycemia. Using the 2-[F-18]fluorodeoxyglucose method, 213 positron emission tomographic (PET) studies of local brain glucose metabolism (CMRglu) were performed in 124 patients with various forms of epilepsy. Interictal PET scans of primary epileptics typically showed some global metabolic depression and decreased functional activity of insular, basal and anterior temporal cortex. Epilepsia partialis continua Kozevnikov was characterized by hypo- or hyper-metabolism of perirolandic cortex. Tuberous sclerosis was distinguished by neocortical foci of significantly decreased glucose consumption. Even in the interictal resting state, with regard to sensitivity (greater than 90%) and accuracy of focus localization. PET was superior to other diagnostic methods in typical temporal lobe epilepsy. Averaging 23% below normal CMRglu, the majority of hypometabolic foci were found in mesial temporal structures. Improved distinction between the epileptogenic area and the surrounding tissue showing comparatively normal functional responsiveness, was achieved by psychophysical activation using emotional speech or continuous visual recognition during PET scanning. In patients who had undergone total cerebral hemispherectomy because of uncontrolled epilepsy, remarkable recruitment of association areas was observed on both motor and speech activation. Continuous partial epilepsy (CPE) is characterized by isolated, subintrant clonus focalized to a limited territory with critical focal electroencephalography in a concordant territory. CPE is observed in various cortical lesions but also in disorders of metabolism and notably decompensated diabetes mellitus. We report a case of CPE without focal lesion at MRI which revealed hyperglycaemia without ketosis. The 54-year old female patient was hospitalised for C.P.E.. Early CT and later MRI gave normal results. Biochemistry showed hyperglycaemia without kenoturia, acidosis or hyperosmolality. Insulin therapy rapidly brought glycaemia down to its normal level and the clonsism disappeared. Five months later, the patient had no other seizure and the EEG was normal. Epileptic seizures are frequent in hyperglycaemia without ketosis (25% of the cases) where they are mainly partial and motor (75 to 86% of the cases), rarely associated with a focal lesion (15% of the cases with CT scan). They are rare in patients with ketoacidosis. This apparent protective effect of ketoacidosis may be attributed to an increase of GABA bioavailability consecutive to acidosis. CPE is resistant to antiepileptic treatments. In CPE induced by hyperglycaemia without ketosis normalization of blood glucose level with insulin therapy is concomitant with a rapid cure of epilepsy. Thus glycaemia should be measured in all patients presenting with CPE, the aim being to diagnose hyperglycaemia without ketosis rapidly to avoid hyperosmolality and to prescribe an adequate treatment based exclusively on insulin and rehydration. This 71 years old women without any history of epilepsy had diabetes mellitus. She was admitted for repetitive giratory seizures in relation with non-ketotic hyperglycaemia. The EEG showed right centro-parietal paroxysmal slow activity. Symptomatology disappeared within 48 hours after insulin therapy. One month later, she presented with a left hemiplegia in relation with a right sylvian infraction. The role of focal transitory ischaemia in connection with hyperglycaemia is discussed. EEG is most often used to diagnose epilepsy, which causes abnormalities in EEG readings. It is also used to diagnose sleep disorders, depth of anesthesia, coma, encephalopathies, and brain death. EEG used to be a first-line method of diagnosis for tumors, stroke and other focal brain disorders, but this use has decreased with the advent of high-resolution anatomical imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT). Despite limited spatial resolution, EEG continues to be a valuable tool for research and diagnosis. It is one of the few mobile techniques available and offers millisecond-range temporal resolution which is not possible with CT, PET or MRI.\nHere is the question:\nNEUROLOGY AND NEUROSURGERY: In a patient diagnosed with epilepsy who presents with episodes of unresponsiveness to external stimuli, irregular movements of all four limbs, closed eyes, crying and pelvic movements, lasting five to twenty seconds and unresponsive to treatment with antiepileptic drugs, which complementary study is most likely to clarify the diagnosis?\nHere are the potential choices:\n1. Video-EEG monitoring for diagnosis of pseudocrisis (psychogenic seizures).\n2. Holter ECG for diagnosis of arrhythmic heart disease.\n3. Routine EEG to diagnose the type of epilepsy (generalized or foc).\n4. Brain MRI to detect epileptogenic lesions (cortical dysplasia, tumor, medial temporal sclerosis).\n5. Determine capillary blood glucose for diagnosis of hypoglycemia.\nThe correct answer is: ",
        "gold_answer": "1 Video-EEG monitoring for diagnosis of pseudocrisis (psychogenic seizures).",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Other means used in diagnosis of vertiginous epilepsy include: Electroencephalography (EEG) Magnetic resonance imaging (MRI) Positron emission tomography (PET) Neuropsychological testing The EEG measures electrical activity in the brain, allowing a physician to identify any unusual patterns. While EEGs are good for identifying abnormal brain activity is it not helpful in localizing where the seizure originates because they spread so quickly across the brain. MRIs are used to look for masses or lesions in the temporal lobe of the brain, indicating possible tumors or cancer as the cause of the seizures. When using a PET scan, a physician is looking to detect abnormal blood flow and glucose metabolism in the brain, which is visible between seizures, to indicate the region of origin. Management The most definitive test to distinguish epilepsy from PNES is long term video-EEG monitoring, with the aim of capturing one or two episodes on both video recording and EEG simultaneously (some clinicians may use suggestion to attempt to trigger an episode). Additional clinical criteria are usually considered in addition to video-EEG monitoring when diagnosing PNES. By recording the event in question on video and EEG simultaneously, a clear diagnosis can usually be obtained. Laboratory testing can detect rising blood levels of serum prolactin if samples are taken in the right time window after most tonic-clonic or complex partial epileptic seizures. However, due to false positives and variability in results, this test is relied upon less frequently. The pathogenesis of PED has also been linked to mutations in the GLUT1 glucose transporter which can result in transient energy deficits in the basal ganglia. Diagnosis Diagnosis is similar, but slightly different for each type of PD. Some types are more understood than others, and therefore have more criteria for diagnosis. PKD The guidelines for diagnosing PKD were reviewed and confirmed by Unterberger and Trinka. PKD consists of unexpected forms of involuntary movements of the body. The patient is usually diagnosed sometime before their 20s, and is more likely diagnosed during childhood than early adulthood. Almost all PKD's are idiopathic, but there have been examples of autosomal dominant inheritance as well. Physical examination and brain imaging examinations show normal results, and an EEG shows no specific abnormalities as well. However, the negative synchronous EEG results can be used to prove that PKD is not a sort of reflex epilepsy, but a different disease. To confirm diagnosis, awake and asleep EEG and magnetic resonance imaging (MRI) are performed. MRI is used to detect focal brain lesions. Ruling out other diagnoses Certain diagnoses must be ruled out before diagnosing LGS. These diagnoses are: Doose syndrome Dravet syndrome pseudo-Lennox Gastaut syndrome (atypical benign partial epilepsy) LGS is more easily distinguished from Doose syndrome by seizure type after the syndrome has progressed. Doose syndrome has more myoclonic seizures and LGS has more tonic seizures. The Doose syndromes is less likely to have cognitive disabilities. Pseudo-Lennox–Gastaut syndrome can be distinguished from LGS because pseudo-LGS has different spike-and-wave patterns on EEG. Treatment There are several treatment options, including medications, surgery, and diet. Medications In most patients with LGS, the treatment does not end seizure recurrence. There exist various morphological and biochemical changes closely associated with electrophysiological phenomena which cause epileptic seizures in the brains of epilepsy patients. Recent developments in investigation methods, not only electrophysiological(EEG and MEG), but also neuroimaging involving morphological imaging(CT and conventional MRI) and functional imaging(SPECT, PET, functional MRI and MRS) is able to demonstrate these changes. SPECT and PET can particularly clarify the changes of cerebral blood flow and glucose metabolism between interictal and ictal periods. In our experience of 423 patients who underwent epilepsy surgery for intractable seizures, these interventions provide important information to identify the epileptogenic foci. However, in practice, discordance in the results of these presurgical evaluations is recognized, and invasive intracranial recordings are needed in such cases. These problems in diagnosis were shown especially in patients with mesial temporal sclerosis and focal cortical dysplasia. To detect an epileptogenic focus more clearly, a combination of morphological and functional findings, new functional imaging such as neurotransmitter receptor imaging, EEG-triggered or neuropharmacological functional MRI, as well as, statistical parametric analysis may be needed. Diagnosis Diagnosis of PME is based on the individual’s signs and symptoms as well as failure to respond to antiepileptic drugs and therapy. Further diagnosis support includes EEG results, genetic testing, enzyme testing, and skin and muscle biopsies. Gaucher’s disease can be diagnosed through enzyme testing as it is a metabolic disease. Lafora’s disease can be diagnosed using skin biopsies. While Action myoclonus renal failure (AMRF) syndrome can only be diagnosed using genetic test. Using EEG’s as a form of diagnosis can prove difficult as patients differ in their neurophysiology. In Lafora’s disease EEGs can show slowing background activity or focal discharges as well as epileptiform discharges. In ULD EEGs show generalized epileptiform discharges and in MERRF patients show background slowing. Therefore, diagnosis is best made using a combination of different tools like signs and symptoms, age of onset, EEG, gene testing, enzyme measurements, and biopsy of skin and muscle. For adults, the testing of electrolyte, blood glucose and calcium levels is important to rule out problems with these as causes. An electrocardiogram can rule out problems with the rhythm of the heart. A lumbar puncture may be useful to diagnose a central nervous system infection but is not routinely needed. In children additional tests may be required such as urine biochemistry and blood testing looking for metabolic disorders. Together with EEG and neuroimaging, genetic testing is becoming one of the most important diagnostic technique for epilepsy, as a diagnosis might be achieved in a relevant proportion of cases with severe epilepsies, both in children and adults. For those with negative genetic testing, in some it might be important to repeat or re-analyze previous genetic studies after 2–3 years. Diagnosis The diagnosis of epilepsy is typically made based on observation of the seizure onset and the underlying cause. An electroencephalogram (EEG) to look for abnormal patterns of brain waves and neuroimaging (CT scan or MRI) to look at the structure of the brain are also usually part of the initial investigations. While figuring out a specific epileptic syndrome is often attempted, it is not always possible. Video and EEG monitoring may be useful in difficult cases. Definition Epilepsy is a disorder of the brain defined by any of the following conditions: {| cellpadding=5 style=\"border:1px solid #ccc\" |- bgcolor=\"#fafafa\" | At least two unprovoked (or reflex) seizures occurring more than 24 hours apart One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years Diagnosis of an epilepsy syndrome |} The goal of this study was to estimate the frequency of psychogenic pseudosyncope in patients with \"syncope of unknown origin.\" Twenty to thirty percent of patients referred to epilepsy centers for refractory seizures have psychogenic seizures. With syncope, about 20-30% of the cases remain unexplained after a complete evaluation, but, unlike in seizures, a psychogenic etiology is not usually investigated. We prospectively evaluated patients referred to our epilepsy center for evaluation of recurrent syncope-like episodes, that is, limp, motionless fainting. All patients had a negative syncope workup. We performed EEG-video monitoring with activation by suggestion (\"induction\"), similar to what is used for diagnosis of psychogenic seizures. Activation was performed with patients standing or sitting up. The diagnosis of psychogenic pseudosyncope required: (1) an activation procedure that triggered the habitual event; (2) a clinical event of loss of postural tone and limp, motionless unresponsiveness with eyes closed; (3) normal EEG before, during, and after the clinical event, that is, no epileptiform abnormalities, a normal alpha rhythm during unresponsiveness, and no suppression of background or slowing as is typically seen in syncope. Ten patients were recruited over an 18-month period. Habitual syncope-like episodes were triggered in 9 of 10 (90%) patients, and all 9 were shown to have psychogenic pseudosyncope (eyes closed, motionless, unresponsive with normal EEG including normal alpha rhythm). In one patient, no episode was triggered, so a diagnosis could not be made. Among the 9 patients for whom episodes were recorded, age ranged from 21 to 60 (mean=36). Five were women. Duration of symptoms ranged from 6 months to 15 years (mean=4.2 years). Event frequency ranged from four per day to two per month. Prior evaluations for syncope included ECG in all patients, two-dimensional echocardiogram in three, Holter monitoring in two, and tilt-table test in five. Four patients had undergone cardiac catheterization, and one had received a pacemaker. Neurologic tests included CT of the head in seven and MRI of the brain in eight. Many patients with \"syncope of unknown origin\" may have psychogenic pseudosyncope, but most such patients do not undergo EEG-video monitoring, which is the only way to demonstrate a psychogenic etiology. Psychogenic pseudosyncope is not simply a diagnosis of exclusion, and can be firmly diagnosed. As is usually recommended for seizure-like events, patients with syncope-like events and a negative evaluation should undergo EEG-video monitoring with induction, specifically looking for a possible psychogenic etiology. EEGs were recorded in 22 patients with medically refractory complex partial epilepsy undergoing presurgical evaluation and 11 age-matched controls while subjected to moderate levels of hypoglycemia to determine if changes activated were predictive of underlying pathology. Five patients had fasting EEGs showing focal abnormalities not seen in the non-fasting state. With hypoglycemia, EEG tracings in normal individuals showed diffuse background slowing, whereas 7 of 22 patients developed focal temporal changes, including focal spike and focal slow wave activation. The development of focal changes correlated well with clinical data concerning underlying focal pathology; focal abnormalities were not evoked in patients with multifocal disease. Hypoglycemic activation of the EEG may be a useful technique for predicting the presence of pathology in patients considered for anterior temporal lobectomy. Kamiyah Morgan is a 6 year old little girl who suffers from a very unusual set of fainting episodes that will leave her unresponsive and immobile, and they can happen up to 300 times a day. When she experiences a fainting episode she will become completely paralyzed affecting everything in her body including her lungs, her mother states that every day that passes her ability to breathe diminishes. Kamiyah’s mother said that these fainting episodes started when she was about 8 months old as she would be crawling and suddenly tip over and go limp. At first their pediatric physician said the episodes looked like she was having a seizure, but after running an EEG there was no seizure being detected during the episodes. They then tried testing with MRI for any brain tumors or malignancies but again there was nothing. They were then referred over to the NIH or the National Institute of Health where their entire purpose is to be able to research and hopefully diagnose very strange cases. Diagnosis To be diagnosed with PTE, a person must have a history of head trauma and no history of seizures prior to the injury. Witnessing a seizure is the most effective way to diagnose PTE. Electroencephalography (EEG) is a tool used to diagnose a seizure disorder, but a large portion of people with PTE may not have the abnormal \"epileptiform\" EEG findings indicative of epilepsy. In one study, about a fifth of people who had normal EEGs three months after an injury later developed PTE. However, while EEG is not useful for predicting who will develop PTE, it can be useful to localize the epileptic focus, to determine severity, and to predict whether a person will suffer more seizures if they stop taking antiepileptic medications. Magnetic resonance imaging (MRI) is performed in people with PTE, and CT scanning can be used to detect brain lesions if MRI is unavailable. However, it is frequently not possible to detect the epileptic focus using neuroimaging. We have experienced 10 cases of insulinoma during the last 10 years from 1977 to 1986. All cases had strong hypoglycemic symptoms such as disturbance of consciousness, and insulinoma still tended to be misdiagnosed as epilepsy. The diagnosis of insulinoma was easily available from serum IRI (immunoreactive insulin)/plasma glucose ratio in all of the ten cases. As preoperative procedures for the diagnosis of localization, arteriography, computed tomography and portal blood sampling were positive in 6 of 8, 4 of 6 and 2 of 2 patients, respectively. At operation, all insulinomas could be identified by digital palpation. We performed simple excision of the tumor in 6 patients and distal pancreatectomy in 4 patients. The tumors were solitary and benign in all patients, ranging in size from 1.0 cm to 4.5 cm. Three cases were presented as case reports. In these cases, portal blood sampling and/or intraoperative monitoring of plasma glucose and serum IRI were performed. Portal blood sampling was effective even for a case which was negative in image diagnostic procedures. Furthermore, simultaneous monitoring of plasma glucose and serum IRI by quick radioimmunoassay seemed to be a good guide to the completeness of resection of insulin producing tumors. Epilepsy monitoring is typically done to distinguish epileptic seizures from other types of spells, such as psychogenic non-epileptic seizures, syncope (fainting), sub-cortical movement disorders and migraine variants, to characterize seizures for the purposes of treatment, and to localize the region of brain from which a seizure originates for work-up of possible seizure surgery. Hospitals use an EEG monitor to help diagnose a seizure. They use that information to help with the treatment process as well as discovering risks. \"Many professionals have stated the importance of EEG’s when it comes to suspected seizures, for diagnosis and evaluation\". Doctors will be able to use the EEG monitoring system to help look at some treatment options as well as some risk factors. As technology advances, researchers are finding new monitors that are more accurate in regards to seizures. \"Advanced techniques with continuous EEG and simplified technique with aEEG allows clinicians to detect more We performed interictal 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET) studies in 57 patients with complex partial epilepsy (CPE), not controlled by medical treatment and considered for surgical resection of their epileptic focus. A precise localization of the epileptic focus was obtained in 37 of these patients with a combination of subdural and depth electrodes. We visually inspected the metabolic images; we also measured glucose consumption in a number of brain regions and compared the values with those obtained in 17 normal controls. Eighty-two percent of the 57 patients had an area of glucose hypometabolism on the 18FDG-PET images. Six patients had a frontal epileptic focus, 3 of them had a frontal lobe hypometabolism. Twenty-six patients had a unilateral temporal lobe focus and all of them displayed a temporal lobe hypometabolism. The asymmetry was more pronounced in the lateral temporal cortex (-20%) than in the mesial part of the temporal lobe (-9.6%). In each cortical brain region on the side of the epileptic focus (except the sensorimotor cortex), glucose consumption rate was lower than in the contralateral region or than in controls. No differences could be found between patients with a seizure onset restricted to the hippocampus and patients with a seizure onset involving the hippocampus and the adjacent neocortex. Divergent metabolic patterns were obtained in 5 patients with bilateral temporal seizure foci. Combined with other non invasive techniques (EEG, neuroradiology), PET contributes increasingly to the selection of patients with CPE who could benefit from surgical treatment.(ABSTRACT TRUNCATED AT 250 WORDS) Although insulinoma constitutes almost 90% of neuroendocrine tumors localized in the pancreas, it is a rare disease. Quite commonly prior to the diagnosis there is a history of several years and misdiagnosis as neurological or cardiological disease is not infrequent. Patient, 22 years old, since 7 years experiencing multiple incidents of neuroglycopenia with concurrent hyperadrenergic reaction. Consciousness disturbances and muscle tremor together with feeling of hunger and tachycardia occurred mainly in the morning hours, or after physical exercise, and subsided after glucose intake. Increase in body weight, typical for insulinoma, was also observed. The patient was hospitalized twice in Pediatric Department and although hypoglycemia was observed, no additional testing was performed to exclude insulinoma; reported symptoms and abnormalities in EEG recording after provocation resulted in diagnosis and treatment of epilepsy. During hospitalization in the Department of Endocrinology fasting test was performed, which revealed inadequately high insulin level with glucose level of 41 mg% and signs of neuroglycopenia. The image of pancreas was normal in the acquired abdominal ultrasound and in CT a tumor was found in the tail of pancreas. The patient underwent laparoscopic operation and the clinical diagnosis was confirmed by histopathology. Antiepileptic drugs were discontinued. Total remission of symptoms was achieved. The presented case demonstrates the difficulties in correct interpretation of reported symptoms, while the results of biochemical tests and imaging studies point precisely to the diagnosis. Focal neurological signs resulting from multiple episodes of hypoglycemia may lead to misdiagnosis and treatment of epilepsia. Four patients with a well-established diagnosis of tuberous sclerosis and grand mal type epileptic seizures as their principal clinical symptom were examined by conventional surface electroencephalography (EEG), X-ray computed tomography, and positron emission tomography (PET) using the [18F]-2-fluoro-2-deoxyglucose method. The interictal EEG showed various abnormalities of poor localizing value, but no focal epileptic discharges. X-ray computed tomography demonstrated subependymal calcifications in all cases, although cortical lesions were found only twice. However, in the PET images of each patient one or two localized cortical foci with a metabolic rate for glucose more than 40% lower than in the respective contralateral region were clearly delineated. It may be assumed that those hypometabolic areas represent the epileptogenic cortical tubers, which are characteristic of the disease but usually cannot be detected in vivo by other methods. In adults, testing electrolytes, blood glucose and calcium levels is important to rule these out as causes, as is an electrocardiogram. A lumbar puncture may be useful to diagnose a central nervous system infection but is not routinely needed. Routine antiseizure medical levels in the blood are not required in adults or children. In children additional tests may be required. A high blood prolactin level within the first 20 minutes following a seizure may be useful to confirm an epileptic seizure as opposed to psychogenic non-epileptic seizure. Serum prolactin level is less useful for detecting partial seizures. If it is normal an epileptic seizure is still possible and a serum prolactin does not separate epileptic seizures from syncope. It is not recommended as a routine part of diagnosis epilepsy. Epilepsy Macropsia may present itself as a symptom of both frontal lobe epilepsy and temporal lobe epilepsy, which may actually help in the diagnosis of those diseases. Children who experience nocturnal hallucinations accompanied by macropsia may seek medical care for panic attack disorders and instead are diagnosed with forms of epilepsy. Epilepsy patients may have no memory of the seizure, but can remember the hallucinations and aura which proceed the attack. Electroencephalography, or EEG imaging, can then be utilized while the patient experiences the episode. It may be subsequently concluded that the EEG is congruent with temporal or frontal lobe seizure. Anxiety and headaches accompany the episodes of visual distortion associated with epilepsy. While Valproic acid has been used to treat this type of seizure, anti-seizure medications appropriate for focal-onset seizures, like oxcarbazapine, have also been used successfully in the treatment of epilepsy-related macropsia. Four patients with primary generalized or true petit mal epilepsy were studied with positron emission tomography using [18F]fluorodeoxyglucose (FDG). FDG studies were carried out during 10 minutes of hyperventilation before and again after medical control of spontaneous absences. Before seizures were controlled all 4 patients demonstrated frequent bilaterally synchronous three-per-second spike-and-wave discharges associated with altered consciousness. After spontaneous seizures were controlled, hyperventilation produced only electroencephalographic slowing without clinical symptoms in 3; the fourth patient had absences less frequently. Patterns of local cerebral metabolic rate for glucose (CMRGlc) were normal and identical for ictal and interictal scans; there was, however, a 2.5- to 3.5-fold diffuse ictal increase in global CMRGlc evident when ictal studies were compared with hyperventilation control studies in which no seizures occurred. The CMRGlc was similar in the two scans obtained from the patient who had absences during both studies. No anatomical substrate of petit mal epilepsy was identified. The CMRGlc in these patients during petit mal absences was higher than that recorded in other patients during partial or generalized convulsive seizures. This difference may reflect the fact that petit mal absences are not associated with postictal depression. For the diagnosis it is necessary to perform an EEG during the headache that shows epilepsy-compatible discharges coinciding with the onset and cessation of the headache. The so-called hemicrania epileptica is a variant of EH characterized by the fact that head pain and EEG paroxysms are located on the same side. MRI is necessary to establish the cause, which, as in all focal epilepsies, can be varied: malformations/dysplasia, neoplasms, encephalopathies, traumatic brain injury, vasculopathies. Therapy. It depends on the etiology. During the headache, like most seizures, i.v. benzodiazepines are usually effective. Antiepileptic drugs can be used as preventive. 2. Ictal non-epileptic headache. Rare cases are reported. It is a condition that can be differentiated with certainty from the previous one if the headache episode is also present outside the seizure, that is, before and/or after, without specific EEG abnormalities. References External links Interictal positron computed tomography (PCT) with 18F-fluorodeoxyglucose was performed on 50 patients with partial seizures disorders. Electroencephalographic (EEG) monitoring was carried out during the metabolic studies using scalp and sphenoidal electrodes in 33 patients and stereotaxically implanted depth electrodes in 17. Four patients in this series had focal abnormalities on x-ray computed tomographic scans, but these were at the site of the presumed epileptogenic lesion in only 2. One or more discrete zones of hypometabolism were identified in 35 patients, and only 1 patient appeared to show focal interictal hypermetabolism. No quantitative relationship could be demonstrated between the degree of focal hypometabolism and either the frequency of interictal EEG spikes of the presence of focal nonepileptiform EEG changes. It was concluded that metabolic and electrophysiological techniques measure different aspects of cerebral dysfunction in seizure disorders. Although interictal PCT in patients with partial epilepsy usually demonstrates zones of hypometabolism this finding, per se, does not reveal the epileptic nature of the abnormality. Other methods to diagnose Unverricht–Lundborg disease are currently being explored. While electroencephalogram (EEG) is useful in identifying or diagnosing other forms of epilepsy, the location of seizures in ULD is currently known to be generalized across the entire brain. Without a specific region to pinpoint, it is difficult to accurately distinguish an EEG reading from an individual with ULD from an individual with another type of epilepsy characterized by generalized brain seizures. However, with recent research linking ULD brain damage to the hippocampus, the usefulness of EEG as a diagnostic tool may increase. Magnetic Resonance Imaging (MRI) is also often used during diagnosis of patients with epilepsy. While MRIs taken during the onset of the disease are generally similar to those of individuals without ULD, MRIs taken once the disease has progressed show characteristic damage This study reports on the clinical, electrophysiologic, and neuroradiologic aspects of patients with epilepsy secondary to neonatal hypoglycemia. Fifteen patients with epilepsy and/or posterior cerebral lesions, and neonatal hypoglycemia were studied in the epilepsy clinic between February 1990 and March 2003. The mean age was 12 years. The different types of neonatal hypoglycemia were as follows: four patients had transitional-adaptive, seven classic transient, two secondary-associated, and two severe recurrent hypoglycemia. As to epilepsy, we recognized a larger group of 12 patients characterized by focal seizures and posterior abnormalities on the electroencephalogram, the majority of whom had a good outcome, and a second group of two patients presenting electroclinical features of encephalopathy with refractory seizures. All patients except two manifested parieto-occipital lesions on neuroradiologic images. Neurologic examination was normal in one patient. Six patients had microcephaly; eight manifested visual disturbances. Fourteen patients were mentally retarded. One had a pervasive developmental disorder. This study indicates neonatal hypoglycemia may cause posterior cerebral lesions, abnormal findings at neurologic examination, and symptomatic epilepsy, most frequently occipital lobe epilepsy, usually with a good prognosis, and occasionally epileptic encephalopathy with refractory seizures. MRI studies are essential to define the characteristics of cerebral lesions after neonatal hypoglycemia. Using the 2-[F-18]fluorodeoxyglucose method, 213 positron emission tomographic (PET) studies of local brain glucose metabolism (CMRglu) were performed in 124 patients with various forms of epilepsy. Interictal PET scans of primary epileptics typically showed some global metabolic depression and decreased functional activity of insular, basal and anterior temporal cortex. Epilepsia partialis continua Kozevnikov was characterized by hypo- or hyper-metabolism of perirolandic cortex. Tuberous sclerosis was distinguished by neocortical foci of significantly decreased glucose consumption. Even in the interictal resting state, with regard to sensitivity (greater than 90%) and accuracy of focus localization. PET was superior to other diagnostic methods in typical temporal lobe epilepsy. Averaging 23% below normal CMRglu, the majority of hypometabolic foci were found in mesial temporal structures. Improved distinction between the epileptogenic area and the surrounding tissue showing comparatively normal functional responsiveness, was achieved by psychophysical activation using emotional speech or continuous visual recognition during PET scanning. In patients who had undergone total cerebral hemispherectomy because of uncontrolled epilepsy, remarkable recruitment of association areas was observed on both motor and speech activation. Continuous partial epilepsy (CPE) is characterized by isolated, subintrant clonus focalized to a limited territory with critical focal electroencephalography in a concordant territory. CPE is observed in various cortical lesions but also in disorders of metabolism and notably decompensated diabetes mellitus. We report a case of CPE without focal lesion at MRI which revealed hyperglycaemia without ketosis. The 54-year old female patient was hospitalised for C.P.E.. Early CT and later MRI gave normal results. Biochemistry showed hyperglycaemia without kenoturia, acidosis or hyperosmolality. Insulin therapy rapidly brought glycaemia down to its normal level and the clonsism disappeared. Five months later, the patient had no other seizure and the EEG was normal. Epileptic seizures are frequent in hyperglycaemia without ketosis (25% of the cases) where they are mainly partial and motor (75 to 86% of the cases), rarely associated with a focal lesion (15% of the cases with CT scan). They are rare in patients with ketoacidosis. This apparent protective effect of ketoacidosis may be attributed to an increase of GABA bioavailability consecutive to acidosis. CPE is resistant to antiepileptic treatments. In CPE induced by hyperglycaemia without ketosis normalization of blood glucose level with insulin therapy is concomitant with a rapid cure of epilepsy. Thus glycaemia should be measured in all patients presenting with CPE, the aim being to diagnose hyperglycaemia without ketosis rapidly to avoid hyperosmolality and to prescribe an adequate treatment based exclusively on insulin and rehydration. This 71 years old women without any history of epilepsy had diabetes mellitus. She was admitted for repetitive giratory seizures in relation with non-ketotic hyperglycaemia. The EEG showed right centro-parietal paroxysmal slow activity. Symptomatology disappeared within 48 hours after insulin therapy. One month later, she presented with a left hemiplegia in relation with a right sylvian infraction. The role of focal transitory ischaemia in connection with hyperglycaemia is discussed. EEG is most often used to diagnose epilepsy, which causes abnormalities in EEG readings. It is also used to diagnose sleep disorders, depth of anesthesia, coma, encephalopathies, and brain death. EEG used to be a first-line method of diagnosis for tumors, stroke and other focal brain disorders, but this use has decreased with the advent of high-resolution anatomical imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT). Despite limited spatial resolution, EEG continues to be a valuable tool for research and diagnosis. It is one of the few mobile techniques available and offers millisecond-range temporal resolution which is not possible with CT, PET or MRI.\nHere is the question:\nNEUROLOGY AND NEUROSURGERY: In a patient diagnosed with epilepsy who presents with episodes of unresponsiveness to external stimuli, irregular movements of all four limbs, closed eyes, crying and pelvic movements, lasting five to twenty seconds and unresponsive to treatment with antiepileptic drugs, which complementary study is most likely to clarify the diagnosis?\nHere are the potential choices:\n1. Video-EEG monitoring for diagnosis of pseudocrisis (psychogenic seizures).\n2. Holter ECG for diagnosis of arrhythmic heart disease.\n3. Routine EEG to diagnose the type of epilepsy (generalized or foc).\n4. Brain MRI to detect epileptogenic lesions (cortical dysplasia, tumor, medial temporal sclerosis).\n5. Determine capillary blood glucose for diagnosis of hypoglycemia.\nThe correct answer is: 1. Video-EEG monitoring for diagnosis of pseudocrisis (psychogenic seizures)."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The Wiskott-Aldrich syndrome is a primary immunodeficiency characterized by congenital microthrombocytopenia, eczema and recurrent infections. This paper reports the case of a 3-year-6-month male patient, whose maternal uncle died at the age of 3 months due to fulminant sepsis from a pulmonary infection. The patient was a product of the first pregnancy, he was born at 27 weeks' gestation and weighed 1,400 g. As a neonate he was hospitalized during the first 2 months of life because of a low gastrointestinal bleeding, thrombocytopenia and severe infections. In the next 4 months and before coming to our hospital the infant was hospitalized 54 times. On admission he presented disseminated dermatosis, enlarged neck lymph nodes and psychomotor retardation. Laboratory studies revealed hemoglobin 8.1 g/dL, platelets 31,000/uL, mean platelet volume 5.6 fL, IgM 39.3 mg/dL, IgA 67 mg/dL, IgG 1,380 mg/dL. On several occasions he received globular packages and platelet concentrates. The infusion of immunoglobulin G was started every 21 days. Bone marrow transplantation was delayed due to the complications that merited 13 hospitalizations and severe thrombocytopenia, low gastrointestinal bleeding, septic arthritis, infectious gastroenteritis, chronic suppurative otitis media and severe folliculitis. At the age of 4 years BMT of cord was performed, and 26 days after transplantation he presented septic shock and died. The prognosis of bone marrow transplantation in Wiskott-Aldrich syndrome and in other primary immunodeficiencies depends on the promptness of its performance at early stages in life. It is important that the first contact physicians be aware of the primary immunodeficiency signs and symptoms. Primary immunodeficiency diseases are not common in children. The possibility of an immunological defect should be considered in any individual with repeated infections. A definite diagnosis for immodeficiency is sometimes difficult to achieve because of overlapping clinical manifestations. Immunoglobulin subclass deficiency is an immunological deficiency disease with which, one or more IgG subclasses are deficient. T cell immunity is normal. Patients may develop recurrent bacterial and respiratory infections or could remain asymptomatic. The authors report a case of immunoglobulin G subclass deficiency presenting initially as transient hypogammaglobulinemia of infancy. A 2 month-old boy presented to Siriraj Hospital with a history of chronic protracted diarrhea, disseminated scabies and sepsis. On presentation, he had generalized scaly and maculopapular rash with no palpable lymph nodes. CBC revealed WBC 22,100 cells/cm3 with PMN 42 per cent, lymphocytes 38 per cent, Eosinophils 4 per cent, Basophil 2 per cent and platelets 254,000/cm3. The immunoglobulin levels were as follows: IgG 181 mg/dl, IgA &lt; 6.6 mg/dl, IgM 26.3 mg/dl. Lymphocyte enumerations revealed CD4 of 2,433 cells/cm3 (N 1,460-5,160); CD8 4,682 cells/cm3 (N 650-2,450); CD19 1,588 cell/cm3 (N 500-1,500); CD16 230 cell/cm3 (N 573 +/- 264). The initial diagnosis was X-linked agammaglobulinemia vs common variable immunodeficiency disease. His diarrhea and five courses of sepsis responded well to antibiotics administration and courses of intravenous immunoglobulin (IVIG) replacement. His through IgG became normal at 2 years of age (after 12 months of IVIG). IVIG was stopped and the diagnosis was changed to transient hypogammaglobulinemia of infancy (THI). Nevertheless, during his 4 month follow-up he developed recurrent sinopulmonary infections (i.e, otitis media and pneumonia). Repeated immunoglobulin profile showed IgG 1,200 mg/dl, IgA 135 mg/dl, IgM 26 mg/dl, IgG subclass were IgG, 1,030 mg/dl (N 280-830), IgG2 30 mg/dl (N 40-2,400), IgG3 22 mg/dl (N 6-130), IgG4 3 mg/dl (N 3-120). A diagnosis of IgG2 subclass deficiency presenting early as transient hypogammaglobulinemia of infancy was then made. Treatment with monthly IVIG was reinitiated and the patient is currently doing well. The authors present a case of IgG subclass deficiency presenting as transient hypogammaglbulinemia of infancy. Follow-up of the immune profile and clinical manifestation is necessary for a definite diagnosis. X-linked hyper-IgM syndrome (XHIM) is a rare primary immunodeficiency disorder caused by mutations of the gene encoding the CD40 ligand (CD40L). It is characterized by recurrent infections with markedly decreased serum IgG, IgA and IgE levels but normal or elevated IgM levels. We report the clinical manifestations and complete immune studies in the first family with molecularly proven XHIM in Taiwan. A 5-month-old boy presented with rapidly progressive pneumonia which responded poorly to antibiotics. High levels of IgM and very low levels of IgG, IgA, and IgE were noted in his plasma specimen: IgM, 128 mg/dl; IgG, 18 mg/dl; IgA, 4 mg/dl); IgE, 1 IU/ml. Whole blood flow cytometry when he was 21 months old showed that only a small percentage (0.48%) of his in vitro-activated CD4+ T cells expressed CD40L. When he was 3 years old, repeated flow cytometry showed essentially the same result (0.4%), compared with his father's CD40L expression of over 85%. The patient's mother had moderately decreased CD40L expression (74.4%). Hyper-IgM syndrome was confirmed by CD40L mutation analysis in the boy, which revealed a Lys 96 stop (nucleotide A307T) in exon 2 of CD40L, with a truncated protein resulting in the loss of the entire TNF domain. His mother was a carrier and apparently the individual in whom the mutation originated. Eleven other family members, including the patient's father, sister, and grandmother, and the mother's sisters and their children, all had normal results on CD40L mutation analysis. The patient has remained without significant bacterial infection on a regimen of monthly IVIG infusion and oral trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) prophylaxis, although he has had recurrent oral ulcers and neutropenia. Bone marrow transplantation is planned. Wiskott-Aldrich syndrome (WAS) is an X-linked syndrome consisting of eczema, recurrent pyogenic infection, and thrombocytopenia with decreased platelet volume. Immunologic studies reveal normal immunoglobulin G (IgG), decreased IgM, elevated IgA and IgE levels, and decreased T-cell function. Patients with WAS often have increased susceptibility to lymphoproliferative disorders (LPDs). We report a 3-year-old boy who had persistent thrombocytopenia with bleeding, recurrent infections, and chronic eczema with frequent skin infections since birth. A blood smear revealed small platelets (50% of normal size). Immunologic studies showed normal IgG (1880 mg/dL), decreased IgM (76 mg/dL) and increased IgA (228 mg/dL) and IgE (14,282 IU/mL) levels. The relative proportions of immune cells were CD2 52.2%, CD3 41.1%, CD4 23.4%, CD8 16.8%, CD19 8.0%, CD57 7.7% and active T cells 14.6%. T-cell dysfunction was detected on the multitest for cell-mediated immunity. The WAS diagnosis was confirmed by mutation analysis which demonstrated a 4-base pair deletion in WAS protein gene exon 1. His thrombocytopenia was uncontrolled despite intravenous immunoglobulin infusions, so splenectomy was performed. The platelet count then rose to about 60,000 to 80,000/microL. However, about 2 weeks after splenectomy, he developed generalized lymphadenopathy and lymphoma was misdiagnosed based on lymph node biopsy at another hospital where he was admitted for urgent care. However, our analysis of his lymph node pathology led to the diagnosis of atypical LPD (ALPD). The lymphadenopathy regressed spontaneously 1 month later without chemotherapy. Early and correct diagnosis of WAS complicated with ALPD is important to avoid unnecessary chemotherapy. Bruton's agammaglobulinemia is a primary immunodeficiency with a disease onset during the first months of age, when the maternal serum immunoglobulin levels decrease. It is characterized by recurrent infections and agammaglobulinemia. We report the case of a 6-year-old male patient with third-degree consanguinity, product of a third pregnancy and complete immunization scheme. He had a history of oral candidiasis at the age of 3 months, chicken pox at the age of 7 months, and two episodes of complicated bronchopneumonia at the age of 1 year and 6 years. He was admitted to the hospital because of fever and cough. Examination of the chest showed rales and right basilar hypoventilation, and a blood cell count revealed leukocytosis and neutrophilia. The diagnosis of pneumonia was made. He was treated with IV antibiotics. Serum immunoglobulins were reported to be low (IgM 55 mg/dL, IgA 0.9 mg/dL, and IgG 199 mg/dL). With these findings the clinical diagnosis of X-linked agammaglobulinemia (ALX) was concluded. A molecular test was performed fining a BTK gene confirming the diagnosis of Bruton's disease. Therapy with intravenous IgG was started every 21 days. During his evolution, he presented three episodes of rhinosinusitis, one of suppurative otitis media, and four events of pneumonia that required 37 days of hospitalization. After hospital discharge, the patient was free of infections and he returned to his daily activities. In cases of recurrent and severe respiratory infections in children, we must consider primary immunodeficiency disease in the differential diagnosis, mainly antibiotic deficiency. Early diagnosis and treatment improves the survival and quality of life in these patients. Two hundred and eight children with recurrent pneumonia were studied over a 5-year period. Among these patients we found 10 cases with primary immunodeficiency disease: 6 cases of IgA deficiency, 1 case of X-linked agammaglobulinemia, 1 case of common variable immunodeficiency, 1 case of hyper IgM syndrome, and 1 case of Wiskott-Aldrich syndrome. This study describes the clinical features of these cases and assesses the usefulness of our immunodeficiency screening protocol. In this group 6 were males; the mean age at first episode of pneumonia was 3 years (range 3 months to 18 years), and the age of diagnosis ranged between 10 months and 19 years. The average number of episodes of pneumonia in each patient was 5 (range 2 to 12), and the number of hospitalizations ranged up to 13. The etiologic agents isolated from this recurrent pneumonia were S. pneumoniae, Moraxella, adenovirus, respiratory syncytial virus, and influenza B virus. Intravenous immunoglobulin was used in four cases. Two patients had chronic pulmonary damage with bronchiectasis and interstitial pneumonia. Only one patient died (Wiskott-Aldrich syndrome) during the follow-up from an intracranial hemorrhage. We found that the screening protocol applied to patients with recurrent pneumonia is a useful tool for ruling out the primary immunodeficiency disorders. Concentrations of IgD and IgE were measured in sera from 165 patients with well-defined immunodeficiency in an effort to find information possibly relevant to the roles of antibodies of these classes in host defense. Values for both immunoglobulins were generally quite low in patients who had marked deficiencies of all three major immunoglobulins, although occasional normal or high normal values for IgD were seen in hypogammaglobulinemic patients. Group mean IgD concentrations were also depressed in patients with Wiskott-Aldrich syndrome and in those with selective IgA deficiency; IgE concentrations were depressed in patients with X-linked immunodeficiency with hyper-IgM and in those with ataxia telangiectasia. IgD and IgE were both significantly elevated in patients with extreme hyperimmunoglobulinemia E and undue susceptibility to infection and in a patient with the Nezelof syndrome; none of these patients had histories suggestive of atopy. In addition, the mean IgE concentration was significantly elevated in patients with selective IgA deficiency, many of whom were atopic, and in those with the Wiskott-Aldrich syndrome. The highest IgD concentration (163 mg/100 ml) was found in serum from a boy with variable immunodeficiency who had a lifelong history of severe recurrent pharyngeal infections, primarily streptococcal in etiology. Recurrent staphylococcal infection was a feature common to many but not all patients with elevated serum IgE concentration. These data may prove useful in the future delineation of biologic roles for antibodies in these two immunoglobulin classes. Hyper IgM with low IgG and IgA is a rare humoral immunodeficiency. We presently report 12 new observations which have been clinically and immunologically studied. On one occasion the syndrome was found to be associated with congenital rubella. Since 10/12 children were male, X-linked inheritance is suggested which has been confirmed in 2 cases. In most cases (9/12), the first infections occurred within the first year of life. The syndrome is causing upper and lower respiratory tract infections due to bacteria, as well as gut infections. Lymphoid organ hyperplasia has been noted in 11/12 patients. Polyclonal hyper IgM serum contrasts with low or absent IgG, IgA and IgE. In some instances, some IgM antibody response was detected. A dysfunction of cellular immunity was not detected. Autoimmunity was detected in 3 patients. Finally, transient neutropenia occurred in 50% of the patients. Intravenous immunoglobulin G substitution treatment resulted in a significant reduction in the occurrence of infections as well as in normalization of growth rate. Immunoglobulin infusion also frequently induced correction of hyper IgM and neutropenia. The hyper-IgM syndrome (HIM) is a rare primary immunodeficiency disorder caused by defects in the CD40 ligand (CD40L)/CD40-signaling pathway. It is characterized by recurrent infections with markedly decreased IgG, IgA and IgE levels but normal or elevated serum IgM levels. A 5-month-old boy presented with rapidly progressive pneumonia which responded poorly to antibiotics. High levels of IgM and very low levels of IgG, IgE and IgA were noted in his plasma specimen (IgM, 128 mg/dl; IgG, 18 mg/dl; IgE, 1 IU/ml; IgA, 4 mg/dl). The relative proportions of immune cells were CD3 24.6%, CD4 10.3%, CD8 2.2%, CD19 30.2%, CD57 1.0% and active T cells 1.1%. After IVIG treatment, the pneumonia improved. Repeat assessment at the age of 15 months showed IgM decreased to the normal range (32 mg/dl). Whole blood flow cytometry assay for CD40L expression confirmed the diagnosis of hyper-lgM syndrome when he was 21 months old. Only a small percentage (0.48%) of the patient's in vitro activated CD4+ T cells expressed CD40L, compared with 33.54% from a healthy control. The patient's father, mother and sister all had a normal CD40L expression activation patterns (43.52%, 40.78%, 34.11%, respectively). On a regimen of monthly IVIG infusion and oral trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) prophylaxis, the patient has had no recurrent infections. X-linked agammaglobulinemia (XLA), caused by mutations in Bruton's tyrosine kinase (BTK), is a common form of inherited antibody deficiency. There were very few case reports of this disease that were diagnosed only based on clinical findings in China. The purpose of this study was to evaluate the clinical features of 8 Chinese cases with XLA with BTK defect which were confirmed by flow cytometry and/or gene analysis. Based on clinical findings, 8 suspected XLA patients were confirmed by detecting the expression of BTK by flow cytometry and/or gene analysis of BTK. The history and thorough physical examination and routine immunological evaluation of 8 cases were collected and reviewed. The age of onset of all the 8 male patients were from 3 months to 3 years. The mean age at diagnosis was 6 years. Recurrent upper respiratory infection and pneumonia with fever were seen in all the patients. Nasopharynx infection was mainly contributed to upper respiratory infection. Very few or no otitis (1/8) and sinusitis (0/8) were involved. Polyarthritis without evidence of infection was common (3/8). Chronic diarrhea was documented during the first 2 years after the onset of the disease in 2 cases. Two of the patients suffered from meningitis one time each. Skin infection was not serious in two patients. Osteomyelitis occurred in one case, which occurred secondary to a trauma. One case had poliomyelitis-like disease that was considered to be related to polio vaccine. Only two cases had unconfirmed maternal family history of XLA. The prominent signs at diagnosis were dystrophia, growth and developmental retardation and markedly decreased or absent tonsils and lymph nodes. Concentration of all classes of serum immunoglobulins (Igs) and the number of B cells in the peripheral circulation were dramatically decreased. The ratio of CD4/CD8 in most of the patients (6/8) was markedly inverse. The age at diagnosis of this reported group was older. Clinical symptoms displayed recurrent upper respiratory infection (nasopharynx infection but rare or no otitis or sinusitis) and pneumonia; polyarthritis was common. There were no confirmed family history of XLA. Most of the patients showed inverse ratios of CD4/CD8, the reason and potential significance are unclear. Signs and symptoms WAS occurs most often in males due to its X-linked recessive pattern of inheritance, affecting between 1 to 10 males per million. The first signs are usually petechiae and bruising, resulting from a low platelet count (i.e. thrombocytopenia). Spontaneous nose bleeds and bloody diarrhea are also common and eczema typically develops within the first month of life. Recurrent bacterial infections typically develop by three months of age. The majority of children with WAS develop at least one autoimmune disorder, and cancers (mainly lymphoma and leukemia) develop in up to a third of patients. Immunoglobulin M (IgM) levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated. In addition to thrombocytopenia, WAS patients have abnormally small platelets (i.e. microthrombocytes) and ~30% also have elevated eosinophil counts (i.e. eosinophilia). Diagnosis The diagnosis can be made on the basis of clinical findings, the peripheral blood smear, and low immunoglobulin levels. Typically, IgM levels are low, IgA levels are elevated, and IgE levels may be elevated; paraproteins are occasionally observed. Skin immunologic testing (allergy testing) may reveal hyposensitivity. Individuals with Wiskott–Aldrich syndrome however are at higher risk for severe food allergies. Not all patients have a positive family history of the disorder; new mutations do occur. Often, leukemia may be suspected on the basis of low platelets and infections, and bone marrow biopsy may be performed. Decreased levels of WASp are typically observed. The current gold standard for diagnosis is DNA sequence analysis, which can detect WAS and the related disorders XLT and XLN in 95% of patients and carriers. Normal numbers of B cells with decreased IgG and IgA and increased IgM: Hyper-IgM syndromes Normal numbers of B cells with isotype or light chain deficiencies: heavy chain deletions, kappa chain deficiency, isolated IgG subclass deficiency, IgA with IgG subclass deficiency, selective immunoglobulin A deficiency Specific antibody deficiency to specific antigens with normal B cell and normal Ig concentrations Transient hypogammaglobulinemia of infancy (THI) The Wiskott-Aldrich Syndrome (WAS) is a rare X-linked immunohematological disorder characterized by eczema, profound thrombocytopenia, and progressive immunodeficiency. Severe hemorrhage, overwhelming sepsis, or lymphoreticular malignancy usually cause death in childhood. Recently, bone marrow transplantation (BMT) has been curative in some well-established cases, but there is no general agreement about the place of BMT in infants with WAS before the development of significant immunological abnormalities. We describe the successful use of early histocompatible BMT in a 10-month-old infant in whom WAS was diagnosed on the basis of eczema, thrombocytopenia, small platelets, and raised serum immunoglobulin A (Ig) and IgE, but before the development of immunodeficiency as evidenced clinically by recurrent infections, or immunologically by low serum IgM or consistently abnormal lymphocyte responses to mitogens. After an unstable period for several weeks posttransplantation when he developed marked hepatomegaly and severe interstitial pneumonitis, he made a good recovery. His eczema and thrombocytopenia resolved and he has shown no clinical or laboratory evidence of immunodeficiency. It is now over 2 years since his BMT. Because of the poor prognosis of WAS, where a histocompatible donor is available, BMT at the earliest opportunity, despite the inherent risks of such a procedure, may be the best option for an infant with WAS. To investigate the clinical and immunological laboratory features, gene mutations, treatment and prognosis in children with Wiskott-Aldrich syndrome (WAS). The clinical, laboratory characteristics, treatment and prognosis of 132 children with WAS, who visited Children's Hospital of Chongqing Medical University from April 2000 to June 2015, were analyzed retrospectively. All patients were male. The median age of disease onset was 15 days and the median age at diagnosis was 10 months. Of the 132 cases, 112 had classic WAS, 20 had X-linked thrombocytopenia (XLT). The median platelet count was 23×10(9)/L. All cases had the clinical characteristics of WAS including bleeding, eczema, and being susceptible to infection. The initial symptoms include hemorrhage (75.0%) and eczema (16.7%). Twenty-one cases had autoimmune diseases and one patient had leukemia. WAS protein (WASP) expression in 115 cases were measured by flow cytometry, 88 cases were negative, in 12 cases WASP decreased, in 5 cases it was normal, 10 cases had bimodal distribution. Eighty-one kinds of mutations were found in 122 families, including eight kinds of hot-spot mutations, which were 290 C&gt; N / 291G&gt; N (R86C / H / L), 665 C&gt; T (R211X), 155 C&gt; T (R41X), 168 C&gt; T (T45 M), IVS1+ 1 g&gt; t/ a, IVS6 + 5 g&gt; a, IVS8 + 1 g&gt; a and IVS8 + 1to + 6del gtga. Meantime, 29 kinds of novel mutations were found, which were 321T&gt;C, 415C&gt;A, 471C&gt;T, 102-105delC, 521 del C, 1330 del A, IVS2-2 a&gt;c, 168 C&gt;A/1412 C&gt; T, exon1-2 del/1412 C&gt;T, and so on. The proportion of CD3(+) T cells (31.3%), helper T cells (37.3%) and cytotoxic T cells (38.6%) in the peripheral blood declined. The serum levels of IgG (51.1%), IgA (43.3%) and IgE (40.0%) increased, IgM (25.6%) decreased. Of the 132 cases, 72 remain survived, of whom 36 cases received hematopoietic stem cell transplantation (HSCT), 14 patients with classic WAS received intravenous immunoglobulin (IVIG) therapy. With regular IVIG therapy, the frequency of infections was reduced and the patients' symptoms were improved. The clinical characteristics of Wiskott-Aldrich syndrome were early age of onset, microthrombocytopenia, eczema and recurrent infections. The proportion of T lymphocyte declined, the serum levels of IgG, IgA, and IgE increased, and level of IgM decreased in a part of patients. The detection of WAS gene mutation and WAS protein detection was the key diagnostic methods. Regular IVIG can gain more time for children who will receive HSCT and improve their quality of life. The most important differential diagnosis includes the following: X-linked agammaglobulinemia characterizes by recurrent bacterial infections in boys, and genetic studies may reveal the presence of Bruton tyrosine kinase (BTK) mutations. Transient hypogammaglobulinemia of newborns presents in newborns above the age of 4 months and characterizes by recurrent pneumonia, meningitis, otitis media, and other problems that resemble Bruton disease. It is a physiological defect in the immune system caused by maternal IgG disappearance and corrected soon but requires treatment. In super-IgM syndrome, recurrent bacterial infections occur, but the cause of this illness is a mutation in the gene encoding for CD40 on T lymphocytes that causes a failure in T and B lymphocyte cooperation. Common variable immunodeficiency presents with recurrent bacterial infections, including sinopulmonary problems but later in life (second-fourth decade), and the diagnosis is made once all causes of immunodeficiency have been ruled out. [6] [7] [21] [33] of primary immunodeficiency (PID). These different forms can affect different parts of the immune system, including immunoglobulin production. Primary immunodeficiencies usually have a delay of several years between initial clinical presentation and diagnosis. Some primary immune deficiencies include ataxia-telangiectasia (A-T), autosomal recessive agammaglobulinemia (ARA), common variable immunodeficiency (CVID), hyper-IgM syndromes, IgG subclass deficiency, isolated non-IgG immunoglobulin deficiencies, severe combined immunodeficiency (SCID), specific antibody deficiency (SAD), Wiskott-Aldrich syndrome, or X-linked agammaglobulinemia. CVID is the most common form of primary immunodeficiency. SCID is considered a medical emergency and suspected cases require immediate specialist center referral for diagnosis and treatment. It is more often that hypogammaglobulinemia develops as a result of another condition, which are called secondary or acquired immune deficiencies. These Signs and symptoms Affects males 50% of the time if mother is a carrier for the gene. Children are generally asymptomatic until 6–9 months of age when maternal IgG decreases. Present with recurrent infections with Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, hepatitis virus, and enterovirus CNS infections. Examination shows lymphoid hypoplasia (tonsils and adenoids, no splenomegaly or lymphadenopathy). There is significant decrease in all immunoglobulins. Genetics Most antibodies are gamma globulins. Antibodies are made mainly by plasma cells, which are daughter cells of the B cell line. The Btk enzyme plays an essential role in the maturation of B cells in the bone marrow, and when mutated, immature pro-B lymphocytes are unable to develop into pre-B lymphocytes, which normally develop into mature (naive) B cells that leave the bone marrow into the blood stream.\nHere is the question:\nGENETICS AND IMMUNOLOGY: 2-year-old boy. His personal history includes 3 episodes of acute otitis media, 1 meningococcal meningitis and 2 pneumonias (one middle lobe and one left upper lobe). She has been admitted on 3 occasions for thrombopenic purpura (on three occasions antiplatelet antibodies were negative and bone marrow showed normal megakaryocytes). Several males of the maternal family had died in childhood due to infectious processes. Physical examination showed lesions typical of atopic dermatitis. The immunological study showed a slight decrease in T-lymphocyte subpopulations; elevated IgA and IgE; decreased IgM and IgG at the lower limit of normal. What is the most likely diagnosis?\nHere are the potential choices:\n1. Wiskott-Aldrich syndrome.\n2. Hyper IgE syndrome.\n3. Transient hypogammaglobulinemia of childhood.\n4. X-linked severe combined immunodeficiency.\n5. Common variable immunodeficiency.\nThe correct answer is: ",
        "gold_answer": "4 X-linked severe combined immunodeficiency.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The Wiskott-Aldrich syndrome is a primary immunodeficiency characterized by congenital microthrombocytopenia, eczema and recurrent infections. This paper reports the case of a 3-year-6-month male patient, whose maternal uncle died at the age of 3 months due to fulminant sepsis from a pulmonary infection. The patient was a product of the first pregnancy, he was born at 27 weeks' gestation and weighed 1,400 g. As a neonate he was hospitalized during the first 2 months of life because of a low gastrointestinal bleeding, thrombocytopenia and severe infections. In the next 4 months and before coming to our hospital the infant was hospitalized 54 times. On admission he presented disseminated dermatosis, enlarged neck lymph nodes and psychomotor retardation. Laboratory studies revealed hemoglobin 8.1 g/dL, platelets 31,000/uL, mean platelet volume 5.6 fL, IgM 39.3 mg/dL, IgA 67 mg/dL, IgG 1,380 mg/dL. On several occasions he received globular packages and platelet concentrates. The infusion of immunoglobulin G was started every 21 days. Bone marrow transplantation was delayed due to the complications that merited 13 hospitalizations and severe thrombocytopenia, low gastrointestinal bleeding, septic arthritis, infectious gastroenteritis, chronic suppurative otitis media and severe folliculitis. At the age of 4 years BMT of cord was performed, and 26 days after transplantation he presented septic shock and died. The prognosis of bone marrow transplantation in Wiskott-Aldrich syndrome and in other primary immunodeficiencies depends on the promptness of its performance at early stages in life. It is important that the first contact physicians be aware of the primary immunodeficiency signs and symptoms. Primary immunodeficiency diseases are not common in children. The possibility of an immunological defect should be considered in any individual with repeated infections. A definite diagnosis for immodeficiency is sometimes difficult to achieve because of overlapping clinical manifestations. Immunoglobulin subclass deficiency is an immunological deficiency disease with which, one or more IgG subclasses are deficient. T cell immunity is normal. Patients may develop recurrent bacterial and respiratory infections or could remain asymptomatic. The authors report a case of immunoglobulin G subclass deficiency presenting initially as transient hypogammaglobulinemia of infancy. A 2 month-old boy presented to Siriraj Hospital with a history of chronic protracted diarrhea, disseminated scabies and sepsis. On presentation, he had generalized scaly and maculopapular rash with no palpable lymph nodes. CBC revealed WBC 22,100 cells/cm3 with PMN 42 per cent, lymphocytes 38 per cent, Eosinophils 4 per cent, Basophil 2 per cent and platelets 254,000/cm3. The immunoglobulin levels were as follows: IgG 181 mg/dl, IgA &lt; 6.6 mg/dl, IgM 26.3 mg/dl. Lymphocyte enumerations revealed CD4 of 2,433 cells/cm3 (N 1,460-5,160); CD8 4,682 cells/cm3 (N 650-2,450); CD19 1,588 cell/cm3 (N 500-1,500); CD16 230 cell/cm3 (N 573 +/- 264). The initial diagnosis was X-linked agammaglobulinemia vs common variable immunodeficiency disease. His diarrhea and five courses of sepsis responded well to antibiotics administration and courses of intravenous immunoglobulin (IVIG) replacement. His through IgG became normal at 2 years of age (after 12 months of IVIG). IVIG was stopped and the diagnosis was changed to transient hypogammaglobulinemia of infancy (THI). Nevertheless, during his 4 month follow-up he developed recurrent sinopulmonary infections (i.e, otitis media and pneumonia). Repeated immunoglobulin profile showed IgG 1,200 mg/dl, IgA 135 mg/dl, IgM 26 mg/dl, IgG subclass were IgG, 1,030 mg/dl (N 280-830), IgG2 30 mg/dl (N 40-2,400), IgG3 22 mg/dl (N 6-130), IgG4 3 mg/dl (N 3-120). A diagnosis of IgG2 subclass deficiency presenting early as transient hypogammaglobulinemia of infancy was then made. Treatment with monthly IVIG was reinitiated and the patient is currently doing well. The authors present a case of IgG subclass deficiency presenting as transient hypogammaglbulinemia of infancy. Follow-up of the immune profile and clinical manifestation is necessary for a definite diagnosis. X-linked hyper-IgM syndrome (XHIM) is a rare primary immunodeficiency disorder caused by mutations of the gene encoding the CD40 ligand (CD40L). It is characterized by recurrent infections with markedly decreased serum IgG, IgA and IgE levels but normal or elevated IgM levels. We report the clinical manifestations and complete immune studies in the first family with molecularly proven XHIM in Taiwan. A 5-month-old boy presented with rapidly progressive pneumonia which responded poorly to antibiotics. High levels of IgM and very low levels of IgG, IgA, and IgE were noted in his plasma specimen: IgM, 128 mg/dl; IgG, 18 mg/dl; IgA, 4 mg/dl); IgE, 1 IU/ml. Whole blood flow cytometry when he was 21 months old showed that only a small percentage (0.48%) of his in vitro-activated CD4+ T cells expressed CD40L. When he was 3 years old, repeated flow cytometry showed essentially the same result (0.4%), compared with his father's CD40L expression of over 85%. The patient's mother had moderately decreased CD40L expression (74.4%). Hyper-IgM syndrome was confirmed by CD40L mutation analysis in the boy, which revealed a Lys 96 stop (nucleotide A307T) in exon 2 of CD40L, with a truncated protein resulting in the loss of the entire TNF domain. His mother was a carrier and apparently the individual in whom the mutation originated. Eleven other family members, including the patient's father, sister, and grandmother, and the mother's sisters and their children, all had normal results on CD40L mutation analysis. The patient has remained without significant bacterial infection on a regimen of monthly IVIG infusion and oral trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) prophylaxis, although he has had recurrent oral ulcers and neutropenia. Bone marrow transplantation is planned. Wiskott-Aldrich syndrome (WAS) is an X-linked syndrome consisting of eczema, recurrent pyogenic infection, and thrombocytopenia with decreased platelet volume. Immunologic studies reveal normal immunoglobulin G (IgG), decreased IgM, elevated IgA and IgE levels, and decreased T-cell function. Patients with WAS often have increased susceptibility to lymphoproliferative disorders (LPDs). We report a 3-year-old boy who had persistent thrombocytopenia with bleeding, recurrent infections, and chronic eczema with frequent skin infections since birth. A blood smear revealed small platelets (50% of normal size). Immunologic studies showed normal IgG (1880 mg/dL), decreased IgM (76 mg/dL) and increased IgA (228 mg/dL) and IgE (14,282 IU/mL) levels. The relative proportions of immune cells were CD2 52.2%, CD3 41.1%, CD4 23.4%, CD8 16.8%, CD19 8.0%, CD57 7.7% and active T cells 14.6%. T-cell dysfunction was detected on the multitest for cell-mediated immunity. The WAS diagnosis was confirmed by mutation analysis which demonstrated a 4-base pair deletion in WAS protein gene exon 1. His thrombocytopenia was uncontrolled despite intravenous immunoglobulin infusions, so splenectomy was performed. The platelet count then rose to about 60,000 to 80,000/microL. However, about 2 weeks after splenectomy, he developed generalized lymphadenopathy and lymphoma was misdiagnosed based on lymph node biopsy at another hospital where he was admitted for urgent care. However, our analysis of his lymph node pathology led to the diagnosis of atypical LPD (ALPD). The lymphadenopathy regressed spontaneously 1 month later without chemotherapy. Early and correct diagnosis of WAS complicated with ALPD is important to avoid unnecessary chemotherapy. Bruton's agammaglobulinemia is a primary immunodeficiency with a disease onset during the first months of age, when the maternal serum immunoglobulin levels decrease. It is characterized by recurrent infections and agammaglobulinemia. We report the case of a 6-year-old male patient with third-degree consanguinity, product of a third pregnancy and complete immunization scheme. He had a history of oral candidiasis at the age of 3 months, chicken pox at the age of 7 months, and two episodes of complicated bronchopneumonia at the age of 1 year and 6 years. He was admitted to the hospital because of fever and cough. Examination of the chest showed rales and right basilar hypoventilation, and a blood cell count revealed leukocytosis and neutrophilia. The diagnosis of pneumonia was made. He was treated with IV antibiotics. Serum immunoglobulins were reported to be low (IgM 55 mg/dL, IgA 0.9 mg/dL, and IgG 199 mg/dL). With these findings the clinical diagnosis of X-linked agammaglobulinemia (ALX) was concluded. A molecular test was performed fining a BTK gene confirming the diagnosis of Bruton's disease. Therapy with intravenous IgG was started every 21 days. During his evolution, he presented three episodes of rhinosinusitis, one of suppurative otitis media, and four events of pneumonia that required 37 days of hospitalization. After hospital discharge, the patient was free of infections and he returned to his daily activities. In cases of recurrent and severe respiratory infections in children, we must consider primary immunodeficiency disease in the differential diagnosis, mainly antibiotic deficiency. Early diagnosis and treatment improves the survival and quality of life in these patients. Two hundred and eight children with recurrent pneumonia were studied over a 5-year period. Among these patients we found 10 cases with primary immunodeficiency disease: 6 cases of IgA deficiency, 1 case of X-linked agammaglobulinemia, 1 case of common variable immunodeficiency, 1 case of hyper IgM syndrome, and 1 case of Wiskott-Aldrich syndrome. This study describes the clinical features of these cases and assesses the usefulness of our immunodeficiency screening protocol. In this group 6 were males; the mean age at first episode of pneumonia was 3 years (range 3 months to 18 years), and the age of diagnosis ranged between 10 months and 19 years. The average number of episodes of pneumonia in each patient was 5 (range 2 to 12), and the number of hospitalizations ranged up to 13. The etiologic agents isolated from this recurrent pneumonia were S. pneumoniae, Moraxella, adenovirus, respiratory syncytial virus, and influenza B virus. Intravenous immunoglobulin was used in four cases. Two patients had chronic pulmonary damage with bronchiectasis and interstitial pneumonia. Only one patient died (Wiskott-Aldrich syndrome) during the follow-up from an intracranial hemorrhage. We found that the screening protocol applied to patients with recurrent pneumonia is a useful tool for ruling out the primary immunodeficiency disorders. Concentrations of IgD and IgE were measured in sera from 165 patients with well-defined immunodeficiency in an effort to find information possibly relevant to the roles of antibodies of these classes in host defense. Values for both immunoglobulins were generally quite low in patients who had marked deficiencies of all three major immunoglobulins, although occasional normal or high normal values for IgD were seen in hypogammaglobulinemic patients. Group mean IgD concentrations were also depressed in patients with Wiskott-Aldrich syndrome and in those with selective IgA deficiency; IgE concentrations were depressed in patients with X-linked immunodeficiency with hyper-IgM and in those with ataxia telangiectasia. IgD and IgE were both significantly elevated in patients with extreme hyperimmunoglobulinemia E and undue susceptibility to infection and in a patient with the Nezelof syndrome; none of these patients had histories suggestive of atopy. In addition, the mean IgE concentration was significantly elevated in patients with selective IgA deficiency, many of whom were atopic, and in those with the Wiskott-Aldrich syndrome. The highest IgD concentration (163 mg/100 ml) was found in serum from a boy with variable immunodeficiency who had a lifelong history of severe recurrent pharyngeal infections, primarily streptococcal in etiology. Recurrent staphylococcal infection was a feature common to many but not all patients with elevated serum IgE concentration. These data may prove useful in the future delineation of biologic roles for antibodies in these two immunoglobulin classes. Hyper IgM with low IgG and IgA is a rare humoral immunodeficiency. We presently report 12 new observations which have been clinically and immunologically studied. On one occasion the syndrome was found to be associated with congenital rubella. Since 10/12 children were male, X-linked inheritance is suggested which has been confirmed in 2 cases. In most cases (9/12), the first infections occurred within the first year of life. The syndrome is causing upper and lower respiratory tract infections due to bacteria, as well as gut infections. Lymphoid organ hyperplasia has been noted in 11/12 patients. Polyclonal hyper IgM serum contrasts with low or absent IgG, IgA and IgE. In some instances, some IgM antibody response was detected. A dysfunction of cellular immunity was not detected. Autoimmunity was detected in 3 patients. Finally, transient neutropenia occurred in 50% of the patients. Intravenous immunoglobulin G substitution treatment resulted in a significant reduction in the occurrence of infections as well as in normalization of growth rate. Immunoglobulin infusion also frequently induced correction of hyper IgM and neutropenia. The hyper-IgM syndrome (HIM) is a rare primary immunodeficiency disorder caused by defects in the CD40 ligand (CD40L)/CD40-signaling pathway. It is characterized by recurrent infections with markedly decreased IgG, IgA and IgE levels but normal or elevated serum IgM levels. A 5-month-old boy presented with rapidly progressive pneumonia which responded poorly to antibiotics. High levels of IgM and very low levels of IgG, IgE and IgA were noted in his plasma specimen (IgM, 128 mg/dl; IgG, 18 mg/dl; IgE, 1 IU/ml; IgA, 4 mg/dl). The relative proportions of immune cells were CD3 24.6%, CD4 10.3%, CD8 2.2%, CD19 30.2%, CD57 1.0% and active T cells 1.1%. After IVIG treatment, the pneumonia improved. Repeat assessment at the age of 15 months showed IgM decreased to the normal range (32 mg/dl). Whole blood flow cytometry assay for CD40L expression confirmed the diagnosis of hyper-lgM syndrome when he was 21 months old. Only a small percentage (0.48%) of the patient's in vitro activated CD4+ T cells expressed CD40L, compared with 33.54% from a healthy control. The patient's father, mother and sister all had a normal CD40L expression activation patterns (43.52%, 40.78%, 34.11%, respectively). On a regimen of monthly IVIG infusion and oral trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) prophylaxis, the patient has had no recurrent infections. X-linked agammaglobulinemia (XLA), caused by mutations in Bruton's tyrosine kinase (BTK), is a common form of inherited antibody deficiency. There were very few case reports of this disease that were diagnosed only based on clinical findings in China. The purpose of this study was to evaluate the clinical features of 8 Chinese cases with XLA with BTK defect which were confirmed by flow cytometry and/or gene analysis. Based on clinical findings, 8 suspected XLA patients were confirmed by detecting the expression of BTK by flow cytometry and/or gene analysis of BTK. The history and thorough physical examination and routine immunological evaluation of 8 cases were collected and reviewed. The age of onset of all the 8 male patients were from 3 months to 3 years. The mean age at diagnosis was 6 years. Recurrent upper respiratory infection and pneumonia with fever were seen in all the patients. Nasopharynx infection was mainly contributed to upper respiratory infection. Very few or no otitis (1/8) and sinusitis (0/8) were involved. Polyarthritis without evidence of infection was common (3/8). Chronic diarrhea was documented during the first 2 years after the onset of the disease in 2 cases. Two of the patients suffered from meningitis one time each. Skin infection was not serious in two patients. Osteomyelitis occurred in one case, which occurred secondary to a trauma. One case had poliomyelitis-like disease that was considered to be related to polio vaccine. Only two cases had unconfirmed maternal family history of XLA. The prominent signs at diagnosis were dystrophia, growth and developmental retardation and markedly decreased or absent tonsils and lymph nodes. Concentration of all classes of serum immunoglobulins (Igs) and the number of B cells in the peripheral circulation were dramatically decreased. The ratio of CD4/CD8 in most of the patients (6/8) was markedly inverse. The age at diagnosis of this reported group was older. Clinical symptoms displayed recurrent upper respiratory infection (nasopharynx infection but rare or no otitis or sinusitis) and pneumonia; polyarthritis was common. There were no confirmed family history of XLA. Most of the patients showed inverse ratios of CD4/CD8, the reason and potential significance are unclear. Signs and symptoms WAS occurs most often in males due to its X-linked recessive pattern of inheritance, affecting between 1 to 10 males per million. The first signs are usually petechiae and bruising, resulting from a low platelet count (i.e. thrombocytopenia). Spontaneous nose bleeds and bloody diarrhea are also common and eczema typically develops within the first month of life. Recurrent bacterial infections typically develop by three months of age. The majority of children with WAS develop at least one autoimmune disorder, and cancers (mainly lymphoma and leukemia) develop in up to a third of patients. Immunoglobulin M (IgM) levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated. In addition to thrombocytopenia, WAS patients have abnormally small platelets (i.e. microthrombocytes) and ~30% also have elevated eosinophil counts (i.e. eosinophilia). Diagnosis The diagnosis can be made on the basis of clinical findings, the peripheral blood smear, and low immunoglobulin levels. Typically, IgM levels are low, IgA levels are elevated, and IgE levels may be elevated; paraproteins are occasionally observed. Skin immunologic testing (allergy testing) may reveal hyposensitivity. Individuals with Wiskott–Aldrich syndrome however are at higher risk for severe food allergies. Not all patients have a positive family history of the disorder; new mutations do occur. Often, leukemia may be suspected on the basis of low platelets and infections, and bone marrow biopsy may be performed. Decreased levels of WASp are typically observed. The current gold standard for diagnosis is DNA sequence analysis, which can detect WAS and the related disorders XLT and XLN in 95% of patients and carriers. Normal numbers of B cells with decreased IgG and IgA and increased IgM: Hyper-IgM syndromes Normal numbers of B cells with isotype or light chain deficiencies: heavy chain deletions, kappa chain deficiency, isolated IgG subclass deficiency, IgA with IgG subclass deficiency, selective immunoglobulin A deficiency Specific antibody deficiency to specific antigens with normal B cell and normal Ig concentrations Transient hypogammaglobulinemia of infancy (THI) The Wiskott-Aldrich Syndrome (WAS) is a rare X-linked immunohematological disorder characterized by eczema, profound thrombocytopenia, and progressive immunodeficiency. Severe hemorrhage, overwhelming sepsis, or lymphoreticular malignancy usually cause death in childhood. Recently, bone marrow transplantation (BMT) has been curative in some well-established cases, but there is no general agreement about the place of BMT in infants with WAS before the development of significant immunological abnormalities. We describe the successful use of early histocompatible BMT in a 10-month-old infant in whom WAS was diagnosed on the basis of eczema, thrombocytopenia, small platelets, and raised serum immunoglobulin A (Ig) and IgE, but before the development of immunodeficiency as evidenced clinically by recurrent infections, or immunologically by low serum IgM or consistently abnormal lymphocyte responses to mitogens. After an unstable period for several weeks posttransplantation when he developed marked hepatomegaly and severe interstitial pneumonitis, he made a good recovery. His eczema and thrombocytopenia resolved and he has shown no clinical or laboratory evidence of immunodeficiency. It is now over 2 years since his BMT. Because of the poor prognosis of WAS, where a histocompatible donor is available, BMT at the earliest opportunity, despite the inherent risks of such a procedure, may be the best option for an infant with WAS. To investigate the clinical and immunological laboratory features, gene mutations, treatment and prognosis in children with Wiskott-Aldrich syndrome (WAS). The clinical, laboratory characteristics, treatment and prognosis of 132 children with WAS, who visited Children's Hospital of Chongqing Medical University from April 2000 to June 2015, were analyzed retrospectively. All patients were male. The median age of disease onset was 15 days and the median age at diagnosis was 10 months. Of the 132 cases, 112 had classic WAS, 20 had X-linked thrombocytopenia (XLT). The median platelet count was 23×10(9)/L. All cases had the clinical characteristics of WAS including bleeding, eczema, and being susceptible to infection. The initial symptoms include hemorrhage (75.0%) and eczema (16.7%). Twenty-one cases had autoimmune diseases and one patient had leukemia. WAS protein (WASP) expression in 115 cases were measured by flow cytometry, 88 cases were negative, in 12 cases WASP decreased, in 5 cases it was normal, 10 cases had bimodal distribution. Eighty-one kinds of mutations were found in 122 families, including eight kinds of hot-spot mutations, which were 290 C&gt; N / 291G&gt; N (R86C / H / L), 665 C&gt; T (R211X), 155 C&gt; T (R41X), 168 C&gt; T (T45 M), IVS1+ 1 g&gt; t/ a, IVS6 + 5 g&gt; a, IVS8 + 1 g&gt; a and IVS8 + 1to + 6del gtga. Meantime, 29 kinds of novel mutations were found, which were 321T&gt;C, 415C&gt;A, 471C&gt;T, 102-105delC, 521 del C, 1330 del A, IVS2-2 a&gt;c, 168 C&gt;A/1412 C&gt; T, exon1-2 del/1412 C&gt;T, and so on. The proportion of CD3(+) T cells (31.3%), helper T cells (37.3%) and cytotoxic T cells (38.6%) in the peripheral blood declined. The serum levels of IgG (51.1%), IgA (43.3%) and IgE (40.0%) increased, IgM (25.6%) decreased. Of the 132 cases, 72 remain survived, of whom 36 cases received hematopoietic stem cell transplantation (HSCT), 14 patients with classic WAS received intravenous immunoglobulin (IVIG) therapy. With regular IVIG therapy, the frequency of infections was reduced and the patients' symptoms were improved. The clinical characteristics of Wiskott-Aldrich syndrome were early age of onset, microthrombocytopenia, eczema and recurrent infections. The proportion of T lymphocyte declined, the serum levels of IgG, IgA, and IgE increased, and level of IgM decreased in a part of patients. The detection of WAS gene mutation and WAS protein detection was the key diagnostic methods. Regular IVIG can gain more time for children who will receive HSCT and improve their quality of life. The most important differential diagnosis includes the following: X-linked agammaglobulinemia characterizes by recurrent bacterial infections in boys, and genetic studies may reveal the presence of Bruton tyrosine kinase (BTK) mutations. Transient hypogammaglobulinemia of newborns presents in newborns above the age of 4 months and characterizes by recurrent pneumonia, meningitis, otitis media, and other problems that resemble Bruton disease. It is a physiological defect in the immune system caused by maternal IgG disappearance and corrected soon but requires treatment. In super-IgM syndrome, recurrent bacterial infections occur, but the cause of this illness is a mutation in the gene encoding for CD40 on T lymphocytes that causes a failure in T and B lymphocyte cooperation. Common variable immunodeficiency presents with recurrent bacterial infections, including sinopulmonary problems but later in life (second-fourth decade), and the diagnosis is made once all causes of immunodeficiency have been ruled out. [6] [7] [21] [33] of primary immunodeficiency (PID). These different forms can affect different parts of the immune system, including immunoglobulin production. Primary immunodeficiencies usually have a delay of several years between initial clinical presentation and diagnosis. Some primary immune deficiencies include ataxia-telangiectasia (A-T), autosomal recessive agammaglobulinemia (ARA), common variable immunodeficiency (CVID), hyper-IgM syndromes, IgG subclass deficiency, isolated non-IgG immunoglobulin deficiencies, severe combined immunodeficiency (SCID), specific antibody deficiency (SAD), Wiskott-Aldrich syndrome, or X-linked agammaglobulinemia. CVID is the most common form of primary immunodeficiency. SCID is considered a medical emergency and suspected cases require immediate specialist center referral for diagnosis and treatment. It is more often that hypogammaglobulinemia develops as a result of another condition, which are called secondary or acquired immune deficiencies. These Signs and symptoms Affects males 50% of the time if mother is a carrier for the gene. Children are generally asymptomatic until 6–9 months of age when maternal IgG decreases. Present with recurrent infections with Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, hepatitis virus, and enterovirus CNS infections. Examination shows lymphoid hypoplasia (tonsils and adenoids, no splenomegaly or lymphadenopathy). There is significant decrease in all immunoglobulins. Genetics Most antibodies are gamma globulins. Antibodies are made mainly by plasma cells, which are daughter cells of the B cell line. The Btk enzyme plays an essential role in the maturation of B cells in the bone marrow, and when mutated, immature pro-B lymphocytes are unable to develop into pre-B lymphocytes, which normally develop into mature (naive) B cells that leave the bone marrow into the blood stream.\nHere is the question:\nGENETICS AND IMMUNOLOGY: 2-year-old boy. His personal history includes 3 episodes of acute otitis media, 1 meningococcal meningitis and 2 pneumonias (one middle lobe and one left upper lobe). She has been admitted on 3 occasions for thrombopenic purpura (on three occasions antiplatelet antibodies were negative and bone marrow showed normal megakaryocytes). Several males of the maternal family had died in childhood due to infectious processes. Physical examination showed lesions typical of atopic dermatitis. The immunological study showed a slight decrease in T-lymphocyte subpopulations; elevated IgA and IgE; decreased IgM and IgG at the lower limit of normal. What is the most likely diagnosis?\nHere are the potential choices:\n1. Wiskott-Aldrich syndrome.\n2. Hyper IgE syndrome.\n3. Transient hypogammaglobulinemia of childhood.\n4. X-linked severe combined immunodeficiency.\n5. Common variable immunodeficiency.\nThe correct answer is: 1. Wiskott-Aldrich syndrome."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n an injection of 1% lidocaine solution around this structure should attenuate this reflexive response.The most common delayed complication following carotid endarterectomy remains myocardial infarction. The possibility of a postoperative myocardial infarction should be considered as a cause of labile blood pressure and arrhythmias in high-risk patients.Thyroid and Parathyroid Glands. Surgery of the thyroid and parathyroid glands can result in hypocalcemia in the immedi-ate postoperative period. Manifestations include ECG changes (shortened P-R interval), muscle spasm (tetany, Chvostek’s sign, and Trousseau’s sign), paresthesias, and laryngospasm. Treatment includes calcium gluconate infusion and, if tetany ensues, chemical paralysis with intubation. Maintenance treat-ment is thyroid hormone replacement (after thyroidectomy) in addition to calcium carbonate and vitamin D.Recurrent laryngeal nerve (RLN) injury occurs in less than 5% of patients. Of those with injury, approximately 10% Since 1983 we have been involved in the diagnostic work-up and emergency treatment of a female patient now 48 years old who has a mitochondrial myopathy resembling Luft's disease. The syndrome was first described in 1959, and in more detail in 1962, by Luft and et al., who reported a picture of hypermetabolism with high temperature, extreme sweating, tachycardia, dyspnoea at rest, polydipsia, polyphagia and irritability but normal thyroid function. In 1971 and 1976 Haydar and Di Mauro presented a second case and proposed treatment with chloramphenicol. Our patient has the third case of the syndrome reported so far: her case was initially published in 1987. CASE REPORT. Since her 17th year of life the patient had suffered from episodes of fever, tachycardia and sweating. At the age of 32 these attacks worsened, leading to unconsciousness and apnoea. The patient then had to be intubated, ventilated and sometimes resuscitated. The diagnosis of MH susceptibility and Luft's disease was made on biochemical grounds after the first muscle biopsy in 1983. Therapy with chloramphenicol failed. Therapy with beta blockers, vitamin C and K or E, coenzyme Q10 and a high-caloric diet was started in 1985. The patient was registered with an emergency service, which flew her to our ICU whenever she had a severe crisis. For milder episodes she was supplied with an oxygen breathing mask at home. Myalgia increased with the episodes starting in 1988, and the patient needed dantrolene infusions and analgesics at home. To facilitate venepuncture a Port-A-Cath system was implanted in 1987, which had to be removed four times due to infection and sepsis. A muscle biopsy was taken in Rotterdam, which revealed differences in mitochondrial function from the biochemical findings recorded in 1983 and not in keeping with Luft's disease. Unfortunately, the patient was not able to undergo further metabolic investigations or therapeutic trials. ANAESTHESIA. The patient received three local and six general anaesthetics in our clinic. The muscle biopsies, two in 1983 and one in 1985, were performed under local infiltration with procaine and were uneventful. The general anaesthetics were carried out without MH trigger substances following pretreatment with dantrolene for the following surgical procedures: the repair of an extensive arterio-venous fistula between the brachiocephalicus trunk and the right jugular and subclavian vein, revision of the sternum cerclage, implantations and explanations of infectious Port-A-Cath systems. We used etomidate, propofol and fentanyl or alfentanil with nitrous oxide and oxygen for induction and maintenance of anaesthesia. Muscle relaxation was induced with vecuronium or atracurium. All cardiovascular, respiratory, metabolic and temperature measurements stayed in normal ranges. After the extensive vascular repair (av fistula) the patient had to be mechanically ventilated for some hours until normal body temperature was restored. At the end of all other periods of anaesthesia she was extubated in the operating theatre. In five cases the postoperative period was uneventful. Only once she developed a crisis with hyperthermia, tachycardia, sweating and dyspnoea. INTENSIVE CARE. From 1985 to 1992 the patient was treated in our ICU 21 times. On 11 occasions she was already intubated and being ventilated by the emergency service on arrival. Extubation was usually possible within 2-20 h. During the crisis, heart rate was about 160-190 per minute and temperature above 40 degrees C. Serum values of CK, glucose, BUN, electrolytes, lactate and thyroid hormones were always in the normal ranges. Blood gas controls showed a constant respiratory alkalosis, arterial pCO2 values decreasing to 20 mm Hg or less. In addition to mechanical ventilation, treatment consisted in dantrolene infusions and droperidol injections, supplemented from 1989 onward with piritramide injections because of the increased severity of myalgia. In 1991 we gave propofol by Several studies clarified the role of different interventions such as vitamine D replacement, denosumab treatment, and vertebroplasty in the prevention and management of falls and fractures. A trial tested the effectiveness of pharmaceutical assistance at the time of discharge, emphasizing the potential benefits for the patients and the health care system. Syncopal episodes frequently lead to hospital admission. A retrospective study evaluated the diagnostic yield of different tests and emphasized the importance to actively seek orthostatic hypotension in older patients. Finally, advances remain modest in the field of dementias. Post-infarction ventricular septal defect (VSD) is a rare but potentially lethal complication of acute myocardial infarction. Medical management is usually futile, so definitive surgery remains the treatment of choice but the risk surgery is very high and the optimal timing for surgery is still under debate. A 55-year-old man with no previous medical history attended the emergency-room for 12 h evolution of oppressive chest pain and strong anginal pain 7 days ago. On physical examination, blood pressure was 96/70 mmHg, pansystolic murmur over left sternal border without pulmonary crackles. An electrocardiogram revealed sinus rhythm 110 bpm, elevation ST and Q in inferior-posterior leads. Transthoracic echocardiogram showed inferoposterior akinesia, posterior-basal septal rupture (2 cm × 2 cm) with left-right shunt. Suspecting VSD in inferior-posterior acute myocardial infarction evolved, we performed emergency coronarography with 3-vessels disease and complete subacute occlusion of the mid segment of the right coronary artery. Left ventriculography demonstrated shunting of contrast from the left ventricule to the right ventricule. He was rejected for heart transplantation because of his age. Considering the high surgical risk to early surgery and his hemodynamic and clinical stability, delayed surgical treatment is decided, and 4 days after admission the patient suffered hemodynamic instability so venoarterial extracorporeal membrane oxygenation system (ECMO) is implanted as a bridge to reparative surgery. The 9th day after admission double bypass, interventricular defect repair with pericardial two-patch exclusion technique, and ECMO decannulation were performed. The patient's postoperative course was free of complications and was discharged 10 days post VSD repair surgery. Follow-up 3-month later revealed the patient to be in good functional status and good image outcome with intact interventricular septal patch without shunt. ECMO as a bridge to reparative surgery in postinfarction VSD is an adequate option to stabilize patients until surgery. An 86-year-old woman with low cardiac function was scheduled to undergo hip fracture surgery. Preoperative electrocardiogram showed complete left bundle brunch block, first degree atrioventricular block, left axis deviation and bigeminy. However, her electrocardiogram had changed to complete atrioventricular block on arrival at operating theater. ACC/AHA guideline on perioperative cardiovascular evaluation and care for non cardiac surgery indicates the assessment of both the urgency of the surgery and cardiac complications. Because complete atrioventricular block is classified to \"active cardiac conditions\", we decided to postpone the surgery for more detailed evaluation and treatment of cardiac conditions. In spite of the discontinuation of digoxin and carvegilol, complete atrioventricular block continued for a week, and the permanent pacemaker was inserted. The surgery was performed 2 weeks following the insertion of the pacemaker without any problems under combined general and lumbar epidural anesthesia. Treatment Medical therapy of aneurysm of the aortic sinus includes blood pressure control through the use of drugs, such as beta blockers. Another approach is surgical repair. The determination to perform surgery is usually based upon the diameter of the aortic root (with 5 centimeters being a rule of thumb - a normal size is 2-3 centimeters) and the rate of increase in its size (as determined through repeated echocardiography). An alternative to surgical repair or a ruptured aneurysm is percutaneous closure. In this technique, a wire is introduced via a small incision in the groin and advanced through the vascular system to the aneurysm. A closure device is advanced along the wire before being expanded to straddle the site of rupture. Hypercalcemia is not a rare event and can lead to severe consequences. Its main etiologies are primary hyperparathyroidism and neoplasic conditions. The iatrogenic etiology by vitamin D intoxication is more rarely found. A 76-year-old finish woman comes to the emergency room for chest pain. Her medical history is impossible to specify due to the language barrier and initial confusion. She has severe hypercalcaemia (4.14mmol/L), renal insufficiency, cardiac arrhythmia later complicated by an ischemic cardiac episode. Clinic and biologic examinations initially guided the research towards a hematological and neoplasic pathology. The iatrogenic etiology will be permitted by the contribution of details on its medical history and treatment learnt secondly. She was treated for post-surgical hypoparathyroidism by dihydrotachysterol, a vitamin D derivative. The cessation of substitution, treatment with hydration and biphosphonates allowed the rapid correction of hypercalcemia. Dihydrotachysterol intoxication is a rare etiology of hypercalcemia. Because of the longer half-life of this molecule, the risk of hypercalcemia seems to be greater than with other vitamin D derivatives. This molecule, withdrawn from the French market in 1982, is not detected by the dosage of 25 and 1.25 OH vitamin D. We report an original case of intoxication by dihydrotachysterol. The risk of hypercalcemia encountered with this molecule must be known. The close medical follow-up recommended in case of hypoparathyroidism seems to be particularly necessary in case of supplementation by this molecule. Amantadine hydrochloride is an antiviral medication used as therapy for parkinsonism and as a cognitive enhancer. We report 2 cases of massive, acute ingestion of amantadine hydrochloride confirmed with serial serum levels. A 47-year-old woman presented to the emergency department (ED) 30 minutes after ingesting 10 g of amantadine (150 mg/kg) by her report. Initial ECG revealed a sinus rhythm with rate of 93 bpm, and a QRS of 84 msec. While in the ED, the patient sustained a pulseless cardiac arrest and the monitor revealed ventricular tachycardia. She was successfully defibrillated. Postdefibrillation ECG showed a sinus rhythm (rate = 82 bpm), QRS of 236 msec, and QTc of 567 msec. The serum potassium was 1.0 mEq/L (1.0 mmol/L). The patient was given 300 ml (300 cc) 3% sodium chloride IV over 10 minutes. Ten minutes after completion of the hypertonic saline infusion, the patient's ECG abnormalities resolved and the QRS was 88 msec. Her potassium was repleted over the next 11 hours postpresentation, and she also received an IV bolus of 4 g of magnesium sulfate immediately after the cardiac arrest. No further hypotension, dysrhythmia, conduction delay, or ectopy was noted during the patient's hospital stay. The second case involved a 33-year-old female patient who presented 1 hour after ingesting 100 tablets of amantadine hydrochloride (100 mg/tab). Initial ECG revealed sinus tachycardia with a QRS of 113 msec, an R wave in lead aVR of 4-5 mm and a QTc of 526 msec. Her serum potassium was 3.0 mEq/L (3.0 mmol/L), her serum calcium was 9.4 mg/dl (2.35 mmol/L), and serum magnesium was 2.1 mg/dl (0.86 mmol/L) on labs drawn at initial presentation. The patient was intubated for airway protection, and her potassium was repleted and corrected over the next 9 hours. Her ECG abnormalities improved 8 hours after initial presentation and normalized at approximately 14 hours postingestion. The patient was discharged home 11 days after her ingestion. Acute amantadine toxicity manifests with life-threatening cardiotoxicity. Concurrent, often profound, hypokalemia may complicate the administration of sodium bicarbonate in the management of cardiac dysrhythmias. 130 young and middle age patients of both sexes with chronic form of coronary heart disease: functional class II-III stable exertional angina pectoris including functional class I-III chronic cardiac insufficiency were studied. In protocol 1 cured 70 patients (48 (68.6%) males and 22 (31.4%) females) 32-59 years of age (medium age was 48.4 +/- 3.25 years) with coronary heart disease. In protocol 2 (with prescription of calcium-D3) cured 60 patients (40 (66.7%) males and 20 (33.3%) females) 34-58 years of age (medium age was 47.8 +/- 3.12 years) with coronary heart disease. The groups were comparable on key parameters of disease. All patients had alimentary calcium deficit and (or) risk factors of osteoporosis, instrumental signs (X-ray filming and densitometry) of initial or evident osteoporosis. Correction of alimentary calcium deficit was realized by prescription of 1-3 tablets of calcium- Ds in different food intakes. Positive dynamics in decrease of functional class of angina pectoris and nitroglycerin requirement in both groups was noticed. Negative influence of calcium- D3 on studied indices of coronary heart disease severity was absent. The thirst and dry mouth in patients, who took furosemide, in group 1 were noticed against the background of body weight decrease (p &lt; 0.05) and increase of diuresis. Decrease of the therapy antiarrhythmic action (p &lt; 0.05) in patients, who took hydrochlorothiazide, was noticed too. It leaded to needs of furosemide and hydrochlorothiatide dose correction in protocol 1. In whole use of calcium- D3 together with anti-ischemic drugs in patients with chronic forms of coronary heart disease did not impair clinical course of angina pectoris and did not decrease efficiency of coronary heart disease therapy. Most hip fractures are treated surgically by implanting a prosthesis. Surgical treatment outweighs the risks of nonsurgical treatment which requires extensive bedrest. Prolonged immobilization increases risk of thromboembolism, pneumonia, deconditioning, and decubitus ulcers. Regardless, the surgery is a major stress, particularly in the elderly. Pain is also significant, and can also result in immobilization, so patients are encouraged to become mobile as soon as possible, often with the assistance of physical therapy. Skeletal traction pending surgery is not supported by the evidence. Regional nerve blocks are useful for pain management in hip fractures. Peripheral nerve blocks may reduce pain on movement and acute confusional state, may improve time to first mobilisation, and may reduce the risk of postoperative lower respiratory tract infection. Surgery can be performed under general anaesthesia or with neuraxial techniques – choice is based on surgical and patient factors, as 1. Hypo- and hypercalcemia can be explained as derangements of the calcium homeostasis. Hypocalcemic tetany usually alarming the patient tremendously is, at least in adults, rarely life-threatening. Hypercalcemia leads in 30% of the cases to clinical symptoms which may inadvertedly pass into a state of hypercalcemic crisis. This latter requires an often difficult emergency treatment. 2. Hypocalcemic tetany may be reversed by administering calcium i.v. or, in severe cases, by a calcium infusion. Only rarely are magnesium supplements necessary to let the tetany disappear. Vitamin D or dihydrotachysterol (DHT) do not correct hypocalcemia immediately, since their effects may be delayed up to 15-25 days. In order to normalize the serum calcium permanently, vitamin D or DHT treatment should be instituted as rarely as possible. 3. Initially, hypercalcemic crisis is best treated by forced intravenous fluid administration with normal saline (and furosemide) in combination with high doses of prednisone. Fluid-, sodium- and potassium balances ought to be checked during this type of treatment. A first evaluation of the effectiveness of these measures is recommended after 24 hours: treatment is continued in patients who respond favorably, while subjects who do not show a significant decrease of the serum calcium may either be given a phosphate infusion or mithramycine as a bolus. Calcitonin appears to be useful only to start treatment before institution of a phosphate infusion. A patient with a giant ovarian tumor weighing about 7 kg was successfully removed by operation. However, her ECG demonstrated ischemic changes after the operation. We report a case of ischemic heart disease due to persistent diuresis after giant ovarian tumor resection. A 75-year-old, 56.5 kg, 143.5 cm woman was admitted to our hospital for ovarian tumor resection. The preoperative ECG showed normal sinus rhythm and no ischemic changes. Both general anesthesia and epidural anesthesia were planed. An epidural catheter was inserted at T12-L1. Anesthesia was induced with propofol 100 mg, fentanyl 100 microg and vecuronium 8 mg under 100% oxygen inhalation. General anesthesia was maintained with sevoflurane while epidural anesthesia was achieved using 0.375% ropivacaine 6 ml. During the operation, blood pressure was 90-110/70-80 mmHg, with SaO2, 100% and heart rate, 70-80 beats x min(-1). The content of tumor was suctioned for 30 minutes. Surgery was successfully finished without any other incidence. After extubation, her ECG changed to atrial fibrillation from normal sinus rhythm and showed ST-T depression. And then her systolic blood pressure became 80 mmHg or below, but we found continued diuresis at about 10 ml x kg(-1) x hr(-1) for over 2 hr. The total of 7 unit vasopressin was intermittently given for vasoconstriction and antidiuresis. Her hemodynamic was immediately restored, and ECG turned to normal ST-T. The patient had uneventful postoperative recovery. 2017 highlights benefits of prevention. Better control of cardiovascular risk reduces the incidence of dementia and monthly high-dose vitamin D the incidence of respiratory infections in nursing home. Pre-operative geriatric assessment lowers by 20% the rate of delirium after hip-fracture surgery and complications in vascular surgery. Deleterious effects are also reported. High-dose vitamin D triples the rate of falls in supplemented residents and doesn't improve gait speed in sedentary men. Widely used in cardiovascular prevention, antithrombotic therapy is associated with an astonishing risk of subdural bleeding that further increases with the number of drugs combined together. Finally, the non-pharmacological management of behavioral and psychotic symptoms in advanced dementia, although effective, doesn't reduce the associated burden for proxies. Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome (ACS), seen mostly in young females. The rarity and limited knowledge of the disease make its management challenging. Prompt diagnosis of the condition is extremely important to decrease both long- and short-term complications. Treatment options depend on hemodynamic stability and the location of the dissection- with more distal lesions treated more conservatively as opposed to proximal lesions which are treated with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). The following are the two cases with different presentation, management and outcomes. Our first patient was a 35-year-old woman with no medical history who presented with acute, anginal pain, diaphoresis and palpitations. She was hemodynamically stable on presentation, with work-up significant for electrocardiogram (ECG) with sinus bradycardia, ST elevation in leads V1-V6, and elevated troponin level of 4 ng/ml. There was no evidence of a pulmonary embolism on computed tomography (CT) of the chest. A coronary angiogram showed 100% dissection of the proximal to mid-left anterior descending (LAD) artery. Attempts to place a stent in the proximal to mid LAD were unsuccessful as the true lumen of the LAD was not accessible. The patient became hemodynamically unstable, and an emergent CABG was done, restoring blood flow. The patient recovered during her hospital stay and was discharged with dual antiplatelet therapy (DAPT), beta-blockers, and atorvastatin. The second patient was a 28-year-old woman, with a history of hypertension who presented with anginal chest pain. Workup showed ECG with minimal ST elevations in anteroseptal leads, with elevated troponin level to 0.71 ng/ml. Coronary angiogram showed 40-50% stenosis of the mid LAD with an aneurysmal segment. An echocardiogram showed no evidence of wall motion abnormalities, and she had a normal left ventricular ejection fraction (LVEF). She was discharged home the next day, on medical management. After two days, she returned to the hospital with similar complaints, with work-up significant for ECG with non-specific ST-T abnormality, and troponin level which peaked at 2.22 ng/ml. She was started on a heparin drip, and a repeat left heart catheterization revealed type 2 dissection of the mid to distal LAD, with intravascular ultrasound showing a fractional flow reserve of 0.76. She was discharged home on DAPT, beta-blocker, calcium channel blocker (CCB), and atorvastatin, with close cardiology follow up. These two cases highlight the importance of keeping in mind the possibility of SCAD, especially when relatively healthy young women present with anginal symptoms. Early diagnosis of the condition and prompt management are extremely important to ensure favourable outcomes. The two cases also describe the coronary angiogram findings in SCAD, and the different strategies employed in the management of this condition. 729 consecutive patients underwent thyroidectomy in 1988 in the same institution, including 477 (68%) bilateral resections and 242 (33%) total thyroidectomies. An effort was made to see and save all 4 parathyroids and their blood supply. Early post-operative hypoparathyroidism was defined at day 5, by serum calcium less than 8 mg/dl. and serum phosphate less than 4 mg/dl or by serum calcium only if greater than 7.5 mg/dl. Patients afflicted with early hypoparathyroidism were given calcium tablets without any vit D for 1 year at most. Follow-up, checking serum Ca, P and i PIH was done on a 3 months basis during 1 year. Permanent hypoparathyroidism was defined by persistence of the above-mentioned criteria after 1 year, and eventually vit D was started. 27 patients (5.6% our of 477 bilateral thyroid resections) experienced early post-op hypoparathyroidism. Inciting factors were previous thyroid surgery (4), radioiodine treatment (2), modified neck dissection (2), sternal split with mediastinal node clearance (1), visualization of 1 parathyroid gland only (3 redo cases) and autotransplantation of more than 1 parathyroid (1 case). 1 patient was lost for follow-up. 25 others recovered a normal parathyroid function. 1 is permanently hypoparathyroid (1 redo case with other risk factors). Painstaking parathyroid dissection allows a 0% rate of permanent hypoparathyroidism after primary surgery, if vit D is not given in the early post-operative period. We suggest that avoidance of early vit D prescription in cases of early post-operative hypoparathyroidism, leading to mild sustained hypocalcemia, stimulates the spared parathyroid glands (including a possible 5th) and therefore allows full recovery of the parathyroid function.\nHere is the question:\nANESTHESIOLOGY AND CRITICAL CARE: We are consulted to assess an 83-year-old woman admitted to the Trauma service for a hip fracture 6 hours ago. She has AP of hypertension, LBP, moderate dementia and lives in a nursing home. Her usual treatment is thiazide, atorvastatin, donepezil, Calcium and vitamin D. EF: Confused patient, pulse 90 bpm, respiratory rate 20 rpm, T art 170/88, jugular venous pressure normal. The CBC and chest X-ray are normal and the ECG shows sinus rhythm without ischemic alterations. Which of the following is the most correct therapeutic approach?\nHere are the potential choices:\n1. Delay surgery until the confusional picture has disappeared.\n2. Delay surgery and perform an echocardiogram.\n3. Delay surgery until good blood pressure control.\n4. Start a beta-blocker and initiate surgery.\n5. Perform closed osteosynthesis, avoiding in any case the implantation of prosthesis.\nThe correct answer is: ",
        "gold_answer": "4 Start a beta-blocker and initiate surgery.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n an injection of 1% lidocaine solution around this structure should attenuate this reflexive response.The most common delayed complication following carotid endarterectomy remains myocardial infarction. The possibility of a postoperative myocardial infarction should be considered as a cause of labile blood pressure and arrhythmias in high-risk patients.Thyroid and Parathyroid Glands. Surgery of the thyroid and parathyroid glands can result in hypocalcemia in the immedi-ate postoperative period. Manifestations include ECG changes (shortened P-R interval), muscle spasm (tetany, Chvostek’s sign, and Trousseau’s sign), paresthesias, and laryngospasm. Treatment includes calcium gluconate infusion and, if tetany ensues, chemical paralysis with intubation. Maintenance treat-ment is thyroid hormone replacement (after thyroidectomy) in addition to calcium carbonate and vitamin D.Recurrent laryngeal nerve (RLN) injury occurs in less than 5% of patients. Of those with injury, approximately 10% Since 1983 we have been involved in the diagnostic work-up and emergency treatment of a female patient now 48 years old who has a mitochondrial myopathy resembling Luft's disease. The syndrome was first described in 1959, and in more detail in 1962, by Luft and et al., who reported a picture of hypermetabolism with high temperature, extreme sweating, tachycardia, dyspnoea at rest, polydipsia, polyphagia and irritability but normal thyroid function. In 1971 and 1976 Haydar and Di Mauro presented a second case and proposed treatment with chloramphenicol. Our patient has the third case of the syndrome reported so far: her case was initially published in 1987. CASE REPORT. Since her 17th year of life the patient had suffered from episodes of fever, tachycardia and sweating. At the age of 32 these attacks worsened, leading to unconsciousness and apnoea. The patient then had to be intubated, ventilated and sometimes resuscitated. The diagnosis of MH susceptibility and Luft's disease was made on biochemical grounds after the first muscle biopsy in 1983. Therapy with chloramphenicol failed. Therapy with beta blockers, vitamin C and K or E, coenzyme Q10 and a high-caloric diet was started in 1985. The patient was registered with an emergency service, which flew her to our ICU whenever she had a severe crisis. For milder episodes she was supplied with an oxygen breathing mask at home. Myalgia increased with the episodes starting in 1988, and the patient needed dantrolene infusions and analgesics at home. To facilitate venepuncture a Port-A-Cath system was implanted in 1987, which had to be removed four times due to infection and sepsis. A muscle biopsy was taken in Rotterdam, which revealed differences in mitochondrial function from the biochemical findings recorded in 1983 and not in keeping with Luft's disease. Unfortunately, the patient was not able to undergo further metabolic investigations or therapeutic trials. ANAESTHESIA. The patient received three local and six general anaesthetics in our clinic. The muscle biopsies, two in 1983 and one in 1985, were performed under local infiltration with procaine and were uneventful. The general anaesthetics were carried out without MH trigger substances following pretreatment with dantrolene for the following surgical procedures: the repair of an extensive arterio-venous fistula between the brachiocephalicus trunk and the right jugular and subclavian vein, revision of the sternum cerclage, implantations and explanations of infectious Port-A-Cath systems. We used etomidate, propofol and fentanyl or alfentanil with nitrous oxide and oxygen for induction and maintenance of anaesthesia. Muscle relaxation was induced with vecuronium or atracurium. All cardiovascular, respiratory, metabolic and temperature measurements stayed in normal ranges. After the extensive vascular repair (av fistula) the patient had to be mechanically ventilated for some hours until normal body temperature was restored. At the end of all other periods of anaesthesia she was extubated in the operating theatre. In five cases the postoperative period was uneventful. Only once she developed a crisis with hyperthermia, tachycardia, sweating and dyspnoea. INTENSIVE CARE. From 1985 to 1992 the patient was treated in our ICU 21 times. On 11 occasions she was already intubated and being ventilated by the emergency service on arrival. Extubation was usually possible within 2-20 h. During the crisis, heart rate was about 160-190 per minute and temperature above 40 degrees C. Serum values of CK, glucose, BUN, electrolytes, lactate and thyroid hormones were always in the normal ranges. Blood gas controls showed a constant respiratory alkalosis, arterial pCO2 values decreasing to 20 mm Hg or less. In addition to mechanical ventilation, treatment consisted in dantrolene infusions and droperidol injections, supplemented from 1989 onward with piritramide injections because of the increased severity of myalgia. In 1991 we gave propofol by Several studies clarified the role of different interventions such as vitamine D replacement, denosumab treatment, and vertebroplasty in the prevention and management of falls and fractures. A trial tested the effectiveness of pharmaceutical assistance at the time of discharge, emphasizing the potential benefits for the patients and the health care system. Syncopal episodes frequently lead to hospital admission. A retrospective study evaluated the diagnostic yield of different tests and emphasized the importance to actively seek orthostatic hypotension in older patients. Finally, advances remain modest in the field of dementias. Post-infarction ventricular septal defect (VSD) is a rare but potentially lethal complication of acute myocardial infarction. Medical management is usually futile, so definitive surgery remains the treatment of choice but the risk surgery is very high and the optimal timing for surgery is still under debate. A 55-year-old man with no previous medical history attended the emergency-room for 12 h evolution of oppressive chest pain and strong anginal pain 7 days ago. On physical examination, blood pressure was 96/70 mmHg, pansystolic murmur over left sternal border without pulmonary crackles. An electrocardiogram revealed sinus rhythm 110 bpm, elevation ST and Q in inferior-posterior leads. Transthoracic echocardiogram showed inferoposterior akinesia, posterior-basal septal rupture (2 cm × 2 cm) with left-right shunt. Suspecting VSD in inferior-posterior acute myocardial infarction evolved, we performed emergency coronarography with 3-vessels disease and complete subacute occlusion of the mid segment of the right coronary artery. Left ventriculography demonstrated shunting of contrast from the left ventricule to the right ventricule. He was rejected for heart transplantation because of his age. Considering the high surgical risk to early surgery and his hemodynamic and clinical stability, delayed surgical treatment is decided, and 4 days after admission the patient suffered hemodynamic instability so venoarterial extracorporeal membrane oxygenation system (ECMO) is implanted as a bridge to reparative surgery. The 9th day after admission double bypass, interventricular defect repair with pericardial two-patch exclusion technique, and ECMO decannulation were performed. The patient's postoperative course was free of complications and was discharged 10 days post VSD repair surgery. Follow-up 3-month later revealed the patient to be in good functional status and good image outcome with intact interventricular septal patch without shunt. ECMO as a bridge to reparative surgery in postinfarction VSD is an adequate option to stabilize patients until surgery. An 86-year-old woman with low cardiac function was scheduled to undergo hip fracture surgery. Preoperative electrocardiogram showed complete left bundle brunch block, first degree atrioventricular block, left axis deviation and bigeminy. However, her electrocardiogram had changed to complete atrioventricular block on arrival at operating theater. ACC/AHA guideline on perioperative cardiovascular evaluation and care for non cardiac surgery indicates the assessment of both the urgency of the surgery and cardiac complications. Because complete atrioventricular block is classified to \"active cardiac conditions\", we decided to postpone the surgery for more detailed evaluation and treatment of cardiac conditions. In spite of the discontinuation of digoxin and carvegilol, complete atrioventricular block continued for a week, and the permanent pacemaker was inserted. The surgery was performed 2 weeks following the insertion of the pacemaker without any problems under combined general and lumbar epidural anesthesia. Treatment Medical therapy of aneurysm of the aortic sinus includes blood pressure control through the use of drugs, such as beta blockers. Another approach is surgical repair. The determination to perform surgery is usually based upon the diameter of the aortic root (with 5 centimeters being a rule of thumb - a normal size is 2-3 centimeters) and the rate of increase in its size (as determined through repeated echocardiography). An alternative to surgical repair or a ruptured aneurysm is percutaneous closure. In this technique, a wire is introduced via a small incision in the groin and advanced through the vascular system to the aneurysm. A closure device is advanced along the wire before being expanded to straddle the site of rupture. Hypercalcemia is not a rare event and can lead to severe consequences. Its main etiologies are primary hyperparathyroidism and neoplasic conditions. The iatrogenic etiology by vitamin D intoxication is more rarely found. A 76-year-old finish woman comes to the emergency room for chest pain. Her medical history is impossible to specify due to the language barrier and initial confusion. She has severe hypercalcaemia (4.14mmol/L), renal insufficiency, cardiac arrhythmia later complicated by an ischemic cardiac episode. Clinic and biologic examinations initially guided the research towards a hematological and neoplasic pathology. The iatrogenic etiology will be permitted by the contribution of details on its medical history and treatment learnt secondly. She was treated for post-surgical hypoparathyroidism by dihydrotachysterol, a vitamin D derivative. The cessation of substitution, treatment with hydration and biphosphonates allowed the rapid correction of hypercalcemia. Dihydrotachysterol intoxication is a rare etiology of hypercalcemia. Because of the longer half-life of this molecule, the risk of hypercalcemia seems to be greater than with other vitamin D derivatives. This molecule, withdrawn from the French market in 1982, is not detected by the dosage of 25 and 1.25 OH vitamin D. We report an original case of intoxication by dihydrotachysterol. The risk of hypercalcemia encountered with this molecule must be known. The close medical follow-up recommended in case of hypoparathyroidism seems to be particularly necessary in case of supplementation by this molecule. Amantadine hydrochloride is an antiviral medication used as therapy for parkinsonism and as a cognitive enhancer. We report 2 cases of massive, acute ingestion of amantadine hydrochloride confirmed with serial serum levels. A 47-year-old woman presented to the emergency department (ED) 30 minutes after ingesting 10 g of amantadine (150 mg/kg) by her report. Initial ECG revealed a sinus rhythm with rate of 93 bpm, and a QRS of 84 msec. While in the ED, the patient sustained a pulseless cardiac arrest and the monitor revealed ventricular tachycardia. She was successfully defibrillated. Postdefibrillation ECG showed a sinus rhythm (rate = 82 bpm), QRS of 236 msec, and QTc of 567 msec. The serum potassium was 1.0 mEq/L (1.0 mmol/L). The patient was given 300 ml (300 cc) 3% sodium chloride IV over 10 minutes. Ten minutes after completion of the hypertonic saline infusion, the patient's ECG abnormalities resolved and the QRS was 88 msec. Her potassium was repleted over the next 11 hours postpresentation, and she also received an IV bolus of 4 g of magnesium sulfate immediately after the cardiac arrest. No further hypotension, dysrhythmia, conduction delay, or ectopy was noted during the patient's hospital stay. The second case involved a 33-year-old female patient who presented 1 hour after ingesting 100 tablets of amantadine hydrochloride (100 mg/tab). Initial ECG revealed sinus tachycardia with a QRS of 113 msec, an R wave in lead aVR of 4-5 mm and a QTc of 526 msec. Her serum potassium was 3.0 mEq/L (3.0 mmol/L), her serum calcium was 9.4 mg/dl (2.35 mmol/L), and serum magnesium was 2.1 mg/dl (0.86 mmol/L) on labs drawn at initial presentation. The patient was intubated for airway protection, and her potassium was repleted and corrected over the next 9 hours. Her ECG abnormalities improved 8 hours after initial presentation and normalized at approximately 14 hours postingestion. The patient was discharged home 11 days after her ingestion. Acute amantadine toxicity manifests with life-threatening cardiotoxicity. Concurrent, often profound, hypokalemia may complicate the administration of sodium bicarbonate in the management of cardiac dysrhythmias. 130 young and middle age patients of both sexes with chronic form of coronary heart disease: functional class II-III stable exertional angina pectoris including functional class I-III chronic cardiac insufficiency were studied. In protocol 1 cured 70 patients (48 (68.6%) males and 22 (31.4%) females) 32-59 years of age (medium age was 48.4 +/- 3.25 years) with coronary heart disease. In protocol 2 (with prescription of calcium-D3) cured 60 patients (40 (66.7%) males and 20 (33.3%) females) 34-58 years of age (medium age was 47.8 +/- 3.12 years) with coronary heart disease. The groups were comparable on key parameters of disease. All patients had alimentary calcium deficit and (or) risk factors of osteoporosis, instrumental signs (X-ray filming and densitometry) of initial or evident osteoporosis. Correction of alimentary calcium deficit was realized by prescription of 1-3 tablets of calcium- Ds in different food intakes. Positive dynamics in decrease of functional class of angina pectoris and nitroglycerin requirement in both groups was noticed. Negative influence of calcium- D3 on studied indices of coronary heart disease severity was absent. The thirst and dry mouth in patients, who took furosemide, in group 1 were noticed against the background of body weight decrease (p &lt; 0.05) and increase of diuresis. Decrease of the therapy antiarrhythmic action (p &lt; 0.05) in patients, who took hydrochlorothiazide, was noticed too. It leaded to needs of furosemide and hydrochlorothiatide dose correction in protocol 1. In whole use of calcium- D3 together with anti-ischemic drugs in patients with chronic forms of coronary heart disease did not impair clinical course of angina pectoris and did not decrease efficiency of coronary heart disease therapy. Most hip fractures are treated surgically by implanting a prosthesis. Surgical treatment outweighs the risks of nonsurgical treatment which requires extensive bedrest. Prolonged immobilization increases risk of thromboembolism, pneumonia, deconditioning, and decubitus ulcers. Regardless, the surgery is a major stress, particularly in the elderly. Pain is also significant, and can also result in immobilization, so patients are encouraged to become mobile as soon as possible, often with the assistance of physical therapy. Skeletal traction pending surgery is not supported by the evidence. Regional nerve blocks are useful for pain management in hip fractures. Peripheral nerve blocks may reduce pain on movement and acute confusional state, may improve time to first mobilisation, and may reduce the risk of postoperative lower respiratory tract infection. Surgery can be performed under general anaesthesia or with neuraxial techniques – choice is based on surgical and patient factors, as 1. Hypo- and hypercalcemia can be explained as derangements of the calcium homeostasis. Hypocalcemic tetany usually alarming the patient tremendously is, at least in adults, rarely life-threatening. Hypercalcemia leads in 30% of the cases to clinical symptoms which may inadvertedly pass into a state of hypercalcemic crisis. This latter requires an often difficult emergency treatment. 2. Hypocalcemic tetany may be reversed by administering calcium i.v. or, in severe cases, by a calcium infusion. Only rarely are magnesium supplements necessary to let the tetany disappear. Vitamin D or dihydrotachysterol (DHT) do not correct hypocalcemia immediately, since their effects may be delayed up to 15-25 days. In order to normalize the serum calcium permanently, vitamin D or DHT treatment should be instituted as rarely as possible. 3. Initially, hypercalcemic crisis is best treated by forced intravenous fluid administration with normal saline (and furosemide) in combination with high doses of prednisone. Fluid-, sodium- and potassium balances ought to be checked during this type of treatment. A first evaluation of the effectiveness of these measures is recommended after 24 hours: treatment is continued in patients who respond favorably, while subjects who do not show a significant decrease of the serum calcium may either be given a phosphate infusion or mithramycine as a bolus. Calcitonin appears to be useful only to start treatment before institution of a phosphate infusion. A patient with a giant ovarian tumor weighing about 7 kg was successfully removed by operation. However, her ECG demonstrated ischemic changes after the operation. We report a case of ischemic heart disease due to persistent diuresis after giant ovarian tumor resection. A 75-year-old, 56.5 kg, 143.5 cm woman was admitted to our hospital for ovarian tumor resection. The preoperative ECG showed normal sinus rhythm and no ischemic changes. Both general anesthesia and epidural anesthesia were planed. An epidural catheter was inserted at T12-L1. Anesthesia was induced with propofol 100 mg, fentanyl 100 microg and vecuronium 8 mg under 100% oxygen inhalation. General anesthesia was maintained with sevoflurane while epidural anesthesia was achieved using 0.375% ropivacaine 6 ml. During the operation, blood pressure was 90-110/70-80 mmHg, with SaO2, 100% and heart rate, 70-80 beats x min(-1). The content of tumor was suctioned for 30 minutes. Surgery was successfully finished without any other incidence. After extubation, her ECG changed to atrial fibrillation from normal sinus rhythm and showed ST-T depression. And then her systolic blood pressure became 80 mmHg or below, but we found continued diuresis at about 10 ml x kg(-1) x hr(-1) for over 2 hr. The total of 7 unit vasopressin was intermittently given for vasoconstriction and antidiuresis. Her hemodynamic was immediately restored, and ECG turned to normal ST-T. The patient had uneventful postoperative recovery. 2017 highlights benefits of prevention. Better control of cardiovascular risk reduces the incidence of dementia and monthly high-dose vitamin D the incidence of respiratory infections in nursing home. Pre-operative geriatric assessment lowers by 20% the rate of delirium after hip-fracture surgery and complications in vascular surgery. Deleterious effects are also reported. High-dose vitamin D triples the rate of falls in supplemented residents and doesn't improve gait speed in sedentary men. Widely used in cardiovascular prevention, antithrombotic therapy is associated with an astonishing risk of subdural bleeding that further increases with the number of drugs combined together. Finally, the non-pharmacological management of behavioral and psychotic symptoms in advanced dementia, although effective, doesn't reduce the associated burden for proxies. Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome (ACS), seen mostly in young females. The rarity and limited knowledge of the disease make its management challenging. Prompt diagnosis of the condition is extremely important to decrease both long- and short-term complications. Treatment options depend on hemodynamic stability and the location of the dissection- with more distal lesions treated more conservatively as opposed to proximal lesions which are treated with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). The following are the two cases with different presentation, management and outcomes. Our first patient was a 35-year-old woman with no medical history who presented with acute, anginal pain, diaphoresis and palpitations. She was hemodynamically stable on presentation, with work-up significant for electrocardiogram (ECG) with sinus bradycardia, ST elevation in leads V1-V6, and elevated troponin level of 4 ng/ml. There was no evidence of a pulmonary embolism on computed tomography (CT) of the chest. A coronary angiogram showed 100% dissection of the proximal to mid-left anterior descending (LAD) artery. Attempts to place a stent in the proximal to mid LAD were unsuccessful as the true lumen of the LAD was not accessible. The patient became hemodynamically unstable, and an emergent CABG was done, restoring blood flow. The patient recovered during her hospital stay and was discharged with dual antiplatelet therapy (DAPT), beta-blockers, and atorvastatin. The second patient was a 28-year-old woman, with a history of hypertension who presented with anginal chest pain. Workup showed ECG with minimal ST elevations in anteroseptal leads, with elevated troponin level to 0.71 ng/ml. Coronary angiogram showed 40-50% stenosis of the mid LAD with an aneurysmal segment. An echocardiogram showed no evidence of wall motion abnormalities, and she had a normal left ventricular ejection fraction (LVEF). She was discharged home the next day, on medical management. After two days, she returned to the hospital with similar complaints, with work-up significant for ECG with non-specific ST-T abnormality, and troponin level which peaked at 2.22 ng/ml. She was started on a heparin drip, and a repeat left heart catheterization revealed type 2 dissection of the mid to distal LAD, with intravascular ultrasound showing a fractional flow reserve of 0.76. She was discharged home on DAPT, beta-blocker, calcium channel blocker (CCB), and atorvastatin, with close cardiology follow up. These two cases highlight the importance of keeping in mind the possibility of SCAD, especially when relatively healthy young women present with anginal symptoms. Early diagnosis of the condition and prompt management are extremely important to ensure favourable outcomes. The two cases also describe the coronary angiogram findings in SCAD, and the different strategies employed in the management of this condition. 729 consecutive patients underwent thyroidectomy in 1988 in the same institution, including 477 (68%) bilateral resections and 242 (33%) total thyroidectomies. An effort was made to see and save all 4 parathyroids and their blood supply. Early post-operative hypoparathyroidism was defined at day 5, by serum calcium less than 8 mg/dl. and serum phosphate less than 4 mg/dl or by serum calcium only if greater than 7.5 mg/dl. Patients afflicted with early hypoparathyroidism were given calcium tablets without any vit D for 1 year at most. Follow-up, checking serum Ca, P and i PIH was done on a 3 months basis during 1 year. Permanent hypoparathyroidism was defined by persistence of the above-mentioned criteria after 1 year, and eventually vit D was started. 27 patients (5.6% our of 477 bilateral thyroid resections) experienced early post-op hypoparathyroidism. Inciting factors were previous thyroid surgery (4), radioiodine treatment (2), modified neck dissection (2), sternal split with mediastinal node clearance (1), visualization of 1 parathyroid gland only (3 redo cases) and autotransplantation of more than 1 parathyroid (1 case). 1 patient was lost for follow-up. 25 others recovered a normal parathyroid function. 1 is permanently hypoparathyroid (1 redo case with other risk factors). Painstaking parathyroid dissection allows a 0% rate of permanent hypoparathyroidism after primary surgery, if vit D is not given in the early post-operative period. We suggest that avoidance of early vit D prescription in cases of early post-operative hypoparathyroidism, leading to mild sustained hypocalcemia, stimulates the spared parathyroid glands (including a possible 5th) and therefore allows full recovery of the parathyroid function.\nHere is the question:\nANESTHESIOLOGY AND CRITICAL CARE: We are consulted to assess an 83-year-old woman admitted to the Trauma service for a hip fracture 6 hours ago. She has AP of hypertension, LBP, moderate dementia and lives in a nursing home. Her usual treatment is thiazide, atorvastatin, donepezil, Calcium and vitamin D. EF: Confused patient, pulse 90 bpm, respiratory rate 20 rpm, T art 170/88, jugular venous pressure normal. The CBC and chest X-ray are normal and the ECG shows sinus rhythm without ischemic alterations. Which of the following is the most correct therapeutic approach?\nHere are the potential choices:\n1. Delay surgery until the confusional picture has disappeared.\n2. Delay surgery and perform an echocardiogram.\n3. Delay surgery until good blood pressure control.\n4. Start a beta-blocker and initiate surgery.\n5. Perform closed osteosynthesis, avoiding in any case the implantation of prosthesis.\nThe correct answer is: 4. Start a beta-blocker and initiate surgery."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Because approximately 1 in 10 women with a breast lump or abnormal mammography result will have breast cancer, a series of decisions must be taken by a primary care practitioner to exclude or establish a diagnosis of breast cancer among these women. To determine the most accurate and least invasive means to evaluate an abnormal mammography result and a palpable breast abnormality. MEDLINE search (January 1966 to March 2003) for articles and reviews describing the accuracy of clinical examination, biopsy procedures, and radiographic examination for patients with abnormal mammography results or palpable breast abnormalities. The authors reviewed abstracts and selected articles that provided relevant primary data. Studies were included if 1) mammography, fine-needle aspiration biopsy, or core-needle biopsy was performed before a definitive diagnosis was obtained; 2) the study sample included 100 or more women; and 3) breast cancer status was determined from histopathology review of excisional biopsy specimens, from linkage with a state cancer registry or the Surveillance, Epidemiology, and End Results program, or from clinical follow-up of 95% or more of the study sample. One investigator abstracted results. Methods were evaluated for major potential biases, but methodologic scoring was not performed. Likelihood ratios for first screening mammography were 0.1 for the Breast Imaging Reporting and Data System (BI-RADS) assessment category \"negative or benign finding,\" 1.2 for \"probably benign finding,\" 7 for \"need additional imaging evaluation,\" 125 for \"suspicious abnormality,\" and 2200 for \"highly suggestive of malignancy.\" For fine-needle aspiration biopsy of a palpable lump performed by formally trained physicians, the likelihood ratio was infinity for an assessment of \"malignant,\" 2.6 for \"atypical/suspicious,\" and 0.02 for \"benign.\" When diagnostic mammography was used to evaluate a palpable lump or nonpalpable breast abnormality, the positive likelihood ratios were 5.6 and 9.4, and the negative likelihood ratios were 0.15 and 0.19, respectively. Women whose screening mammography results are interpreted as \"suspicious abnormality\" or \"highly suggestive of malignancy\" have a high risk for breast cancer and should undergo core-needle biopsy or needle localization with surgical biopsy. Women whose screening mammography results are interpreted as \"need additional imaging evaluation\" have a moderate risk for breast cancer and should undergo diagnostic mammography or ultrasonography to decide whether a nonpalpable breast lesion should be biopsied. Women whose screening mammography results are interpreted as \"probably benign finding\" have a low risk for breast cancer and can undergo follow-up mammography in 6 months. Either fine-needle aspiration biopsy or ultrasonography is recommended as the first diagnostic test of a palpable breast abnormality to distinguish simple cysts from solid masses. Fine-needle aspiration biopsy also allows characterization of a solid mass. Diagnostic mammography does not help determine whether a palpable breast mass should be biopsied and should not affect the decision to perform a biopsy. The importance of these missed cancers is not clear, particularly if the woman is getting yearly mammograms. Research on a closely related situation has shown that small cancers that are not acted upon immediately, but are observed over periods of several years, will have good outcomes. A group of 3,184 women had mammograms that were formally classified as \"probably benign\". This classification is for patients who are not clearly normal but have some area of minor concern. This results not in the patient being biopsied, but rather in having early follow up mammography every six months for three years to determine whether there has been any change in status. Of these 3,184 women, 17 (0.5%) did have cancers. Most importantly, when the diagnosis was finally made, they were all still stage 0 or 1, the earliest stages. Five years after treatment, none of these 17 women had evidence of re-occurrence. Thus, small early cancers, even though not acted on immediately, were still reliably Mammography Mammography is a common screening method, since it is relatively fast and widely available in developed countries. Mammography is a type of radiography used on the breasts. It is typically used for two purposes: to aid in the diagnosis of a woman who is experiencing symptoms or has been called back for follow-up views (called diagnostic mammography), and for medical screening of apparently healthy women (called screening mammography). Mammography is not very useful in finding breast tumors in dense breast tissue characteristic of women under 40 years. In women over 50 without dense breasts, breast cancers detected by screening mammography are usually smaller and less aggressive than those detected by patients or doctors as a breast lump. This is because the most aggressive breast cancers are found in dense breast tissue, which mammograms perform poorly on. Histologically proven benign breast disease increases a woman's relative risk for subsequent cancer development. Yet follow-up guidelines for mammogram and clinical breast examination after a benign breast biopsy are lacking. Our objective was to determine if increased surveillance is indicated following a benign breast biopsy. Following institutional review board approval, a retrospective database review was conducted of prospectively gathered patients who had a benign breast biopsy (core or excisional) for an abnormality detected on mammogram, ultrasound, or clinical breast examination. Follow-up, for all subjects, was a clinical breast examination and mammogram or ultrasound at 6 months, 1 year, and 2 years after benign breast biopsy by a breast surgeon. End points were the need for additional biopsies or cancer detection. Statistical analysis was performed using chi-squared analysis. From January 2000 to July 2003, 156 patients age 18-86 years had a benign breast biopsy. During the 2 year follow-up, 20 patients (13%) required a subsequent biopsy. No significant difference was observed in mean age, race, menarche, menopause, parity, age at first live birth, use of oral contraceptives, history of prior biopsy, or the pathology of the initial lesion between those who needed a subsequent biopsy and those who did not. Seven excisional biopsies were performed (one at 6 months, four at 1 year, and two at 2 years follow-up) for growth of the benign breast biopsy lesion, and pathology remained concordant with the original diagnosis. Thirteen biopsies were done for new findings on mammogram or ultrasound. Three of these (1.9%) yielded a cancer diagnosis (one at 6 months, one at 1 year, and one at 2 years follow-up). No new lesions were identified on follow-up by clinical breast examination alone. Increased surveillance following a benign breast biopsy is necessary because of the increased need for subsequent biopsy or risk of cancer development. This should include imaging (mammography or ultrasound) and a clinical breast examination 6 months, 1 year, and 2 years after a benign breast biopsy. The final assessment includes the BI-RADS 0 to 6 categorization. A category assessment of BI-RADS 0 refers to an incomplete evaluation with further imaging required including additional mammographic views including spot compression or magnification and or ultrasound. BI-RADS 1 refers to a negative examination, meaning that there are no masses, suspicious calcifications or areas of architectural distortion. There can be no description of a finding in the report if it is categorized as a BI-RADS 1.  BI-RADS 2 is consistent with benign findings. Benign findings include secretory calcifications, simple cysts, fat-containing lesions, calcified fibroadenomas, implants and intramammary lymph nodes. BI-RADS 3 is probably benign and should have shortened interval follow-up to determine stability. The risk of malignancy is below 2%. There are very strict classifications to qualify a finding in the BI-RADS 3 category: a non-palpable, circumscribed mass on a baseline mammogram; a focal asymmetry, which becomes less dense on spot compression images, or a solitary group of punctate calcifications. Any findings other than this cannot be placed in the category 3. BI-RADS 4 is a suspicious abnormality, which can represent the chance of being malignant (in percent). The BI-RADS category 4 is subdivided into a, b, and c. The subcategory of (a) has a low probability of malignancy with a 2% to 10% chance of malignancy. The subcategory of (b) has an intermediate change of malignancy ranging from 10% to 50%. The subcategory of (c) has a high probability of malignancy ranging from 50% to 95%. BI-RADS 5 is highly suggestive of malignancy more than 95%. If something is placed in this classification and the pathology comes back as benign, the recommendation is still surgical consultation, because the pathology is discordant with the radiographic findings. The last category that was recently added is the BI-RADS 6, used for pathology proven malignancy. The accidental harm from screening mammography has been underestimated. Women who have mammograms end up with increased surgeries, chemotherapy, radiotherapy and other potentially procedures resulting from the over-detection of harmless lumps. Many women will experience important psychological distress for many months because of false positive findings. Half of suspicious findings will not become dangerous or will disappear over time. Consequently, the value of routine mammography in women at low or average risk is controversial. With unnecessary treatment of ten women for every one woman whose life was prolonged, the authors concluded that routine mammography may do more harm than good. If 1,000 women in their 50s are screened every year for ten years, the following outcomes are considered typical in the developed world: To provide information and recommendations to facilitate decision-making when a mammographic abnormality is detected by screening. References identified by use of MEDLINE, AIDSLINE, CANCERLIT and reference lists of review articles to December 1996. Where experimental evidence is lacking, recommendations are based on expert opinion. The evidence is graded accordingly in \"levels\" (page S2). Exclusion or confirmation of the presence of cancer with minimum intervention and delay. When an abnormality is detected on screening mammography, clinical evaluation and thorough radiologic work-up are needed to determine its significance. Clinical evaluation should include a history and a thorough examination of the breast, axilla and supraclavicular areas. In the radiologic work-up, diagnostic mammograms should be obtained with additional views, spot compression and magnification views as appropriate. Current mammograms should be compared with previous mammograms whenever possible. The mammographic report should include a precise description of the abnormal features visualized and an estimate of the level of suspicion of cancer they imply. Whenever there is any doubt in the interpretation of mammograms, the interpretation of 2 experienced readers should be obtained. (The following radiologic classification into 4 categories is suggested: 1--benign, not due to cancer; 2--low risk, probability of cancer under 2%; 3--intermediate risk, probability of cancer 2% to 10%; 4--high risk, probability of cancer over 10%.) Ultrasonography can be used to clarify the nature of noncalcified nodular lesions. Management decisions require close communication between the woman and her physicians. Throughout, a clinician in charge should be identified who will coordinate and transmit all decisions. Management will depend on the estimated level of risk Category 1 abnormalities require no further investigation. Category 2 abnormalities may be followed up by periodic mammographic and clinical examinations. Follow-up examination of category 2 abnormalities should be carried out at approximately 6 and 12 months. If the abnormality is stable, examination should be repeated annually for 2 to 3 years thereafter. The rationale of follow-up should be explained, and women should be made aware that it is not possible to provide complete assurance that an abnormality is benign. Category 3 abnormalities usually require image-guided fine-needle or core biopsy. Every image-guided needle biopsy should be accompanied by a full report. Category 4 abnormalities should usually be excised. This may be preceded by image-guided needle biopsy. When surgical biopsy is carried out, the margins of the resected specimen must be free of tumour. The intact pathology specimen should be examined radiographically to confirm that all mammographic abnormalities have been removed. The patient should be kept fully informed as to the reason for each test and the meaning of its results. The process, from initial detection of the mammographic abnormality to the final management decision, should be completed as rapidly as possible. Guidelines were reviewed and revised by the Writing Committee, expert primary reviewers, secondary reviewers selected from all regions of Canada and by the Steering Committee. The final document reflects a consensus of all these contributors. From 1976 to 1978 11, 197 women were examined clinically and mammographically. Biopsy material from 1,673 breasts were examined microscopically. In 536 cases, or almost every third case (32%), a carcinoma of the breast was detected. The cancer was bilateral in 19 cases and the total number of women was therefore 517. A clinically occult tumour was only found in 7.7% (40 of 517) of the cases. 5% of these patients were high risk patients and 2.7% preventive examinations. 5 women with occult carcinoma of the breast were under age 40 and 14 under age 50. Benign changes of the glandular tissue were found in 59.5% of the cases. Marked proliferative changes were found in 4.6% of the cases and carcinoma in situ was found in 3.8% of the patients. In the age group 45--54 benign and proliferative changes of the parenchyma occured almost twice as often as cancers. The ratio between benign and malignant findings was 1:1 in the age group 55--59 and was less than 1:2 in the age group over 70. A sophistication of the mammograhic technique must be obtained. A thorough microscopic examination of tissue from subcutaneous mastectomies and tissue obtained at the time of reduction mammoplasties showed occasionally unexpected malignant tissue in an unexpected location. Especially these cases are suitable for later comparison to the mammographies. We examined a 34-year-old premenopausal woman who had noticed a left-breast lump a month previously. She had no past history of malignancies but had a family history of breast and ovarian cancers. Her mother had suffered from ovarian cancer when aged 47 years and had died of the disease at age 52. The younger two of the patient's four aunts had developed breast cancer when they were 37 and 48 years old. A physical examination showed an ill-defined mass, 1.5 cm in diameter, located in the upper outer quadrant of the patient's left breast. Mammography revealed diffuse microcalcification in both breasts but ultrasonography revealed an irregular tumorous lesion only in the left breast. Aspiration breast cytology revealed adenocarcinoma of the left breast. Modified radical mastectomy of the left breast and excision of a biopsy specimen from the right breast were carried out simultaneously. Histopathologically the left-breast tumor was an atypical medullary carcinoma with cartilaginous metaplasia, of histological grade 3, and the right-breast specimen showed fibrocystic changes with atypical ductal hyperplasia. Estrogen receptors were positive, but progesterone receptor was not detected on the tumor cells, which were immunopositive for nuclear p53 although c-erbB-2 overexpression was not observed. A nonsense germline mutation of the BRCA1 gene (exon5) was detected. The patient has been well since the operation (10 months). These findings may provide useful information about the carcinogenesis and biological behavior of BRCA1-associated breast cancers. In this study, we aimed to determine the need for biopsy in patients referred from other clinics for the performance of biopsy with the suspicion of breast cancer. 112 patients were included in the study. It was decided that their biopsies be performed following examinations in other clinics and they presented to the breast radiology unit of our hospital for a second opinion. The demographic characteristics, diagnostic studies completed in the other centers, properties of lesions, decision made as a result of examinations and BI-RADS (Breast Imaging Reporting and Data Systems) categorizations were recorded on the registration forms of the study patients. In addition, the quality of examinations, reasons of repeat tests, additional tests features and the last decision of our clinic were documented. The obtained data were analyzed in terms of re-examination, additional tests and change in the biopsy decision. Changes in the biopsy decisions for patients were specifically inquired. The biopsy decisions were cancelled in our breast radiology unit for 63 out of 112 patients (56.3%) whose biopsy decisions were made at an external institute. For 42 patients, examinations made by the other clinics were deemed adequate, yet there was no need for biopsy in 22 of them. The biopsy decisions were cancelled for 27 out of 47 patients (57.4%) with repeat examination and 18 out of 28 patients (64.3%) with additional tests because of the insufficient test quality. Incorrect, inadequate breast screening and false positivity were higher at inexperienced institutes. The patient was a 41-year-old, premenopausal woman with a chief complaint of well-circumscribed palpable, right breast mass without nipple discharge. Although she noticed the lump 3 months previously, the size of the tumor (1.1 × 0.9 cm(2)) had been stable. The patient's mother suffered from gastric cancer. Her previous history of the triple different malignancies was as follows: (1) left osteosarcoma [amputation of left lower leg at 15 years old (y/o)]. After the operation, she was treated with various kinds of anticancer drugs including a total of 45 g ifosphamide and 342 g methotrexate; (2) tongue cancer (right radical neck resection; 23 y/o); and (3) thyroid cancer (right lobectomy; 40 y/o). There was no evidence of recurrence of these malignancies at the present consultation. At the time of tongue cancer operation, chromosome abnormality was investigated, but the results were normal. Physical examination showed a well-delimited, elastic-firm, mobile tumor in the central outer right breast. Regional lymph nodes were not palpable. Mammography showed a focal asymmetry in the right upper breast on the mediolateral oblique view. Ultrasonography revealed a hypoechoic mass with irregular margins. Distant metastases could not be detected by whole-body computed tomography scan. The histology of the Mammotome(®) (vacuum-assisted core needle biopsy) specimen revealed that this tumor was low-grade ductal carcinoma in situ (DCIS). She underwent breast-conserving surgery with sentinel lymph node biopsy. On permanent histopathological examination, the diagnosis of the tumor was intracystic papilloma with low-grade DCIS. Surgical margin was negative, and sentinel lymph node metastases could not be observed. Estrogen and progesterone receptor (ER/PR) were strongly positive, but human epidermal growth factor receptor-2 (HER-2) overexpression was not tested because the lesion was DCIS. She has received no adjuvant therapy and is currently disease free 3 months after surgery. BI-RADS Assessment Categories are: 0: Incomplete 1: Negative 2: Benign 3: Probably benign 4: Suspicious 5: Highly suggestive of malignancy 6: Known biopsy – proven malignancy An incomplete (BI-RADS 0) classification warrants either an effort to ascertain prior imaging for comparison or to call the patient back for additional views and/or higher quality films. A BI-RADS classification of 4 or 5 warrants biopsy to further evaluate the offending lesion. Some experts believe that the single BI-RADS 4 classification does not adequately communicate the risk of cancer to doctors and recommend a subclassification scheme: 4A: low suspicion for malignancy, about > 2% to ≤ 10% likelihood of malignancy 4B: intermediate suspicion of malignancy, about > 10% to ≤ 50% likelihood of malignancy 4C: moderate concern, but not classic for malignancy, about > 50% to < 95% likelihood of malignancy The aim of this study was to determine the features that make interval cancers apparent on the preceding screening mammogram and determine whether changes in the ways of performing the interval cancer review will affect the true interval cancer rate. This study was approved by the clinical governance committee. Mammograms of women diagnosed with an interval cancer were included in the study if they had been allocated to either the \"suspicious signs\" group or \"subtle signs\" group, during the historic interval cancer review. Three radiologists, individually and blinded to the site of interval cancer, reviewed the mammograms and documented the presence, site, characteristics and classification of any abnormality. Findings were compared with the appearances of the abnormality at the site of subsequent cancer development by a different breast radiologist. The chi-squared test was used in the analysis of the results, seeking associations between recall concordance and cancer mammographic or histological characteristics. 111/590 interval cancers fulfilled the study inclusion criteria. In 17% of the cases none of the readers identified the relevant abnormality on the screening mammogram. 1/3 readers identified the relevant lesion in 22% of the cases, 2/3 readers in 28% of cases and all 3 readers in 33% of cases. The commonest unanimously recalled abnormality was microcalcification and the most challenging mammographic abnormality to detect was asymmetric density. We did not find any statistically significant association between recall concordance and time to interval cancer, position of lesion in the breast, breast density or cancer grade. Even the simple step of performing an independent blinded review of interval cancers reduces the rate of interval cancers classified as missed by up to 39%. The triple test score (TTS) is a diagnostic tool for examining potentially cancerous breasts. Diagnostic accuracy of the triple test score is nearly 100%. Scoring includes using the procedures of physical examination, mammography and needle biopsy. If the results of a TTS are greater than five, an excisional biopsy is indicated. Scoring To obtain the triple test score, a number from 1 through 3 is assigned to each one of the procedures. A score of 1 is assigned to a benign test result, 2 applies to a suspicious test result, and 3 applies to a malignant result. The sum of the scores of all three procedures is the triple test score. A score of 3 to 4 is most likely benign, whereas a score of greater than 6 is possibly malignant. References Breast cancer New evaluation of breast ultrasound based upon review of new literature comparing ultrasound and mammography. Description and discussion of the published trials regarding breast imaging methods. Breast ultrasound is the preferable method in the case of a symptomatic patient (after clinical examination). In the case of a patient without symptoms (screening), breast ultrasound is ascribed a higher sensitivity for detecting breast cancer in women with dense breast tissue, women under the age of 50 and high-risk women. Mammographically occult cancers can be detected by sonography in 10 to 40 % of the cases depending on the patient's breast density and age. The mean size of cancers detected only by ultrasound is not significantly different to that only detected by mammography. The prevalence of breast cancers detected by ultrasound is approximately equal to the one detected by mammography, regarding the total number of examined patients. Breast ultrasound should be the preferred imaging procedure in the case of a palpable lump, leading to a definitive diagnosis itself or with an additional consecutive core needle biopsy. For women without symptoms, breast sonography should be mandatory and complementary to mammography in the case of breast density grade II (BI-RADS) or more. Application of breast ultrasound as a primary method or an alternative to mammography has not yet been evaluated sufficiently. It seems advisable in the case of women with dense breast tissue grade III and IV, women under the age of 50 and high-risk women. The implementation of breast ultrasound in this manner has to be checked by future trials. The consequences of a false-positive screening test result also need to be considered. For example, when 1000 screening mammograms are taken, only 2 to 4 new cases of cancer will be identified; this number is slightly higher (6 to 10 prevalent cancers per 1000 mammograms) for initial screen-ing mammograms.106 However, as many as 10% of screening mammograms may be potentially suggestive of an abnormal-ity, which requires further imaging (i.e., a 10% recall rate). Of those women with abnormal mammogram findings, only 5% to 10% will be determined to have a breast cancer. Among women for whom biopsy specimen is recommended, 25% to 40% will have a breast cancer. A false-positive screening result is likely to induce significant emotional distress in patients, leads to unnecessary biopsy specimens, and has cost implications for the health care system.American Cancer Society guidelines for the early detec-tion of cancer are listed in Table 10-9.96 These guidelines are updated periodically to To retrospectively correlate high-risk proliferative breast lesions (radial scar, atypical lobular hyperplasia, lobular carcinoma in situ and papillary lesions) diagnosed on core biopsy with the definitive histopathological diagnosis obtained after surgical excision or with the follow-up, in order to assess the role of core biopsy in such lesions. To discuss the management of the patient after a core biopsy diagnosis of high-risk proliferative breast lesion. We evaluated 74 out of 1776 core biopsies consecutively performed on 67 patients. The histopathologic findings were as follows: 11 radial scars (RS), 3 atypical lobular hyperplasias (ALH), 3 lobular carcinomas in situ (LCIS), 57 benign papillary lesions. All patients underwent bilateral mammography, whole-breast ultrasound with a linear-array broadband transducer, and core biopsy with a 14 Gauge needle and a mean number of samples of 5 (range 4-7). Sixty-two of 67 patients, for a total of 69/74 lesions, underwent surgical biopsy despite benign histopathologic findings, mostly because of highly suspicious imaging for malignancy (BIRADS 4-5), whereas 5 patients refused surgery and have been followed up for a least 18 months and are still being followed up (2 with RS, 1 with ADH and 2 with papillary lesions). Among the core biopsied lesions with a diagnosis of RS (n = 11) pathology revealed one ductal carcinoma in situ (DCIS) (this case was characterized by granular microcalcifications on mammography and by a mass with irregular margins on ultrasound). Also in the group of ADH (n = 3) pathology revealed one DCIS (lesion not visible on mammography but depicted as a suspicious mass on US). In the group of LCIS (n = 3) pathologists found an invasive lobular carcinoma (ILC). Among the benign papillary lesions (n = 57) histopathologic analysis of the surgical specimen revealed 7 malignant lesions (4 papillary carcinomas and 3 DCIS), whose mammographic and ultrasound findings were indistinguishable from benign lesions. Altogether there were 10 false negative results (underestimation) out of 74 core biopsies with a diagnosis of high-risk proliferative breast lesions. The high rate of histological underestimation after core biopsy (10/74) (13.5%) demands a very careful management of patents with a core biopsy diagnosis of high-risk proliferative breast lesions, especially in the case of RS, lobular neoplasia and papillary lesions. However, the high imaging suspicion for malignancy prompts surgery. It is possible to assume that, when there is a low imaging suspicion for malignancy, when enough tissue has been sampled for pathology and no atypia is found within the lesions, surgery is not mandatory but a very careful follow-up is recommended. We must underline that there is no agreement regarding the quantity of tissue to sample. Vacuum-assisted biopsy may lead to better results, although there is as yet no proof that it can actually replace surgery in this group of lesions, since it seems only to reduce but not abolish the histological underestimation. The History of mammography began in 1913, when a Berliner surgeon, A. Salomon realized a roentgeno-histological study on 3,000 mastectomies. This work is the basis of mammography. Until 1938, few articles were published but were of little help to mammography. From 1947 to 1970, the second period brought the results of roentgenologic and clinical correlation. R. Leborgne was the first accountable for the wide development of this method. Since 1951, many American and European radiologists brought their contribution. Ch. Gros is the best known. He gave this technique an acknowledgment throughout the world for the diagnosis of breast diseases. Since 1970, the third period emphasizes the value of mammography as a technique for detection of breast cancer. Some \"Screening working groups\" are being set up. The problem is mainly economical. Often women are quite distressed to be called back for a diagnostic mammogram. Most of these recalls will be false positive results. Of every 1,000 U.S. women who are screened, about 7% will be called back for a diagnostic session (although some studies estimate the number to be closer to 10% to 15%). About 10 of these individuals will be referred for a biopsy; the remaining 60 cases are found to be of benign cause. Of the 10 referred for biopsy, about 3.5 will have cancer and 6.5 will not. Of the 3.5 who have cancer, about 2 will have an early stage cancer that will be cured after treatment. If suspicious signs are identified in the image, then the woman is usually recalled for a second mammogram, sometimes after waiting six months to see whether the spot is growing, or a biopsy of the breast. Most of these will prove to be false positives, resulting in sometimes debilitating anxiety over nothing. Most women recalled will undergo additional imaging only, without any further intervention. Recall rates are higher in the U.S. than in the UK. Effectiveness On balance, screening mammography in older women increases medical treatment and saves a small number of lives. Usually, it has no effect on the outcome of any breast cancer that it detects. Screening targeted towards women with above-average risk produces more benefit than screening of women at average or low risk for breast cancer.\nHere is the question:\nONCOLOGY: A 40-year-old woman consults because she has noticed a lump in the superoexternal quadrant of the right breast for the past month. She provides a mammography report describing a BIRADS 3 lesion. What is the best course of action?\nHere are the potential choices:\n1. Reassure him, since an imaging test has already been done and malignancy has been ruled out.\n2. This classification probably implies surgery since the probability of cancer is greater than 10%. He explains it to you and refers you preferentially to the Breast Unit.\n3. This is a probably benign finding, since there is less than a 2% chance of cancer. He explains that it requires follow-up every 6-12 months until 24 months or a biopsy.\n4. The findings are of low suspicion of cancer (between 2 and 10 %) but a biopsy is necessary.\nThe correct answer is: ",
        "gold_answer": "3 This is a probably benign finding, since there is less than a 2% chance of cancer. He explains that it requires follow-up every 6-12 months until 24 months or a biopsy.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Because approximately 1 in 10 women with a breast lump or abnormal mammography result will have breast cancer, a series of decisions must be taken by a primary care practitioner to exclude or establish a diagnosis of breast cancer among these women. To determine the most accurate and least invasive means to evaluate an abnormal mammography result and a palpable breast abnormality. MEDLINE search (January 1966 to March 2003) for articles and reviews describing the accuracy of clinical examination, biopsy procedures, and radiographic examination for patients with abnormal mammography results or palpable breast abnormalities. The authors reviewed abstracts and selected articles that provided relevant primary data. Studies were included if 1) mammography, fine-needle aspiration biopsy, or core-needle biopsy was performed before a definitive diagnosis was obtained; 2) the study sample included 100 or more women; and 3) breast cancer status was determined from histopathology review of excisional biopsy specimens, from linkage with a state cancer registry or the Surveillance, Epidemiology, and End Results program, or from clinical follow-up of 95% or more of the study sample. One investigator abstracted results. Methods were evaluated for major potential biases, but methodologic scoring was not performed. Likelihood ratios for first screening mammography were 0.1 for the Breast Imaging Reporting and Data System (BI-RADS) assessment category \"negative or benign finding,\" 1.2 for \"probably benign finding,\" 7 for \"need additional imaging evaluation,\" 125 for \"suspicious abnormality,\" and 2200 for \"highly suggestive of malignancy.\" For fine-needle aspiration biopsy of a palpable lump performed by formally trained physicians, the likelihood ratio was infinity for an assessment of \"malignant,\" 2.6 for \"atypical/suspicious,\" and 0.02 for \"benign.\" When diagnostic mammography was used to evaluate a palpable lump or nonpalpable breast abnormality, the positive likelihood ratios were 5.6 and 9.4, and the negative likelihood ratios were 0.15 and 0.19, respectively. Women whose screening mammography results are interpreted as \"suspicious abnormality\" or \"highly suggestive of malignancy\" have a high risk for breast cancer and should undergo core-needle biopsy or needle localization with surgical biopsy. Women whose screening mammography results are interpreted as \"need additional imaging evaluation\" have a moderate risk for breast cancer and should undergo diagnostic mammography or ultrasonography to decide whether a nonpalpable breast lesion should be biopsied. Women whose screening mammography results are interpreted as \"probably benign finding\" have a low risk for breast cancer and can undergo follow-up mammography in 6 months. Either fine-needle aspiration biopsy or ultrasonography is recommended as the first diagnostic test of a palpable breast abnormality to distinguish simple cysts from solid masses. Fine-needle aspiration biopsy also allows characterization of a solid mass. Diagnostic mammography does not help determine whether a palpable breast mass should be biopsied and should not affect the decision to perform a biopsy. The importance of these missed cancers is not clear, particularly if the woman is getting yearly mammograms. Research on a closely related situation has shown that small cancers that are not acted upon immediately, but are observed over periods of several years, will have good outcomes. A group of 3,184 women had mammograms that were formally classified as \"probably benign\". This classification is for patients who are not clearly normal but have some area of minor concern. This results not in the patient being biopsied, but rather in having early follow up mammography every six months for three years to determine whether there has been any change in status. Of these 3,184 women, 17 (0.5%) did have cancers. Most importantly, when the diagnosis was finally made, they were all still stage 0 or 1, the earliest stages. Five years after treatment, none of these 17 women had evidence of re-occurrence. Thus, small early cancers, even though not acted on immediately, were still reliably Mammography Mammography is a common screening method, since it is relatively fast and widely available in developed countries. Mammography is a type of radiography used on the breasts. It is typically used for two purposes: to aid in the diagnosis of a woman who is experiencing symptoms or has been called back for follow-up views (called diagnostic mammography), and for medical screening of apparently healthy women (called screening mammography). Mammography is not very useful in finding breast tumors in dense breast tissue characteristic of women under 40 years. In women over 50 without dense breasts, breast cancers detected by screening mammography are usually smaller and less aggressive than those detected by patients or doctors as a breast lump. This is because the most aggressive breast cancers are found in dense breast tissue, which mammograms perform poorly on. Histologically proven benign breast disease increases a woman's relative risk for subsequent cancer development. Yet follow-up guidelines for mammogram and clinical breast examination after a benign breast biopsy are lacking. Our objective was to determine if increased surveillance is indicated following a benign breast biopsy. Following institutional review board approval, a retrospective database review was conducted of prospectively gathered patients who had a benign breast biopsy (core or excisional) for an abnormality detected on mammogram, ultrasound, or clinical breast examination. Follow-up, for all subjects, was a clinical breast examination and mammogram or ultrasound at 6 months, 1 year, and 2 years after benign breast biopsy by a breast surgeon. End points were the need for additional biopsies or cancer detection. Statistical analysis was performed using chi-squared analysis. From January 2000 to July 2003, 156 patients age 18-86 years had a benign breast biopsy. During the 2 year follow-up, 20 patients (13%) required a subsequent biopsy. No significant difference was observed in mean age, race, menarche, menopause, parity, age at first live birth, use of oral contraceptives, history of prior biopsy, or the pathology of the initial lesion between those who needed a subsequent biopsy and those who did not. Seven excisional biopsies were performed (one at 6 months, four at 1 year, and two at 2 years follow-up) for growth of the benign breast biopsy lesion, and pathology remained concordant with the original diagnosis. Thirteen biopsies were done for new findings on mammogram or ultrasound. Three of these (1.9%) yielded a cancer diagnosis (one at 6 months, one at 1 year, and one at 2 years follow-up). No new lesions were identified on follow-up by clinical breast examination alone. Increased surveillance following a benign breast biopsy is necessary because of the increased need for subsequent biopsy or risk of cancer development. This should include imaging (mammography or ultrasound) and a clinical breast examination 6 months, 1 year, and 2 years after a benign breast biopsy. The final assessment includes the BI-RADS 0 to 6 categorization. A category assessment of BI-RADS 0 refers to an incomplete evaluation with further imaging required including additional mammographic views including spot compression or magnification and or ultrasound. BI-RADS 1 refers to a negative examination, meaning that there are no masses, suspicious calcifications or areas of architectural distortion. There can be no description of a finding in the report if it is categorized as a BI-RADS 1.  BI-RADS 2 is consistent with benign findings. Benign findings include secretory calcifications, simple cysts, fat-containing lesions, calcified fibroadenomas, implants and intramammary lymph nodes. BI-RADS 3 is probably benign and should have shortened interval follow-up to determine stability. The risk of malignancy is below 2%. There are very strict classifications to qualify a finding in the BI-RADS 3 category: a non-palpable, circumscribed mass on a baseline mammogram; a focal asymmetry, which becomes less dense on spot compression images, or a solitary group of punctate calcifications. Any findings other than this cannot be placed in the category 3. BI-RADS 4 is a suspicious abnormality, which can represent the chance of being malignant (in percent). The BI-RADS category 4 is subdivided into a, b, and c. The subcategory of (a) has a low probability of malignancy with a 2% to 10% chance of malignancy. The subcategory of (b) has an intermediate change of malignancy ranging from 10% to 50%. The subcategory of (c) has a high probability of malignancy ranging from 50% to 95%. BI-RADS 5 is highly suggestive of malignancy more than 95%. If something is placed in this classification and the pathology comes back as benign, the recommendation is still surgical consultation, because the pathology is discordant with the radiographic findings. The last category that was recently added is the BI-RADS 6, used for pathology proven malignancy. The accidental harm from screening mammography has been underestimated. Women who have mammograms end up with increased surgeries, chemotherapy, radiotherapy and other potentially procedures resulting from the over-detection of harmless lumps. Many women will experience important psychological distress for many months because of false positive findings. Half of suspicious findings will not become dangerous or will disappear over time. Consequently, the value of routine mammography in women at low or average risk is controversial. With unnecessary treatment of ten women for every one woman whose life was prolonged, the authors concluded that routine mammography may do more harm than good. If 1,000 women in their 50s are screened every year for ten years, the following outcomes are considered typical in the developed world: To provide information and recommendations to facilitate decision-making when a mammographic abnormality is detected by screening. References identified by use of MEDLINE, AIDSLINE, CANCERLIT and reference lists of review articles to December 1996. Where experimental evidence is lacking, recommendations are based on expert opinion. The evidence is graded accordingly in \"levels\" (page S2). Exclusion or confirmation of the presence of cancer with minimum intervention and delay. When an abnormality is detected on screening mammography, clinical evaluation and thorough radiologic work-up are needed to determine its significance. Clinical evaluation should include a history and a thorough examination of the breast, axilla and supraclavicular areas. In the radiologic work-up, diagnostic mammograms should be obtained with additional views, spot compression and magnification views as appropriate. Current mammograms should be compared with previous mammograms whenever possible. The mammographic report should include a precise description of the abnormal features visualized and an estimate of the level of suspicion of cancer they imply. Whenever there is any doubt in the interpretation of mammograms, the interpretation of 2 experienced readers should be obtained. (The following radiologic classification into 4 categories is suggested: 1--benign, not due to cancer; 2--low risk, probability of cancer under 2%; 3--intermediate risk, probability of cancer 2% to 10%; 4--high risk, probability of cancer over 10%.) Ultrasonography can be used to clarify the nature of noncalcified nodular lesions. Management decisions require close communication between the woman and her physicians. Throughout, a clinician in charge should be identified who will coordinate and transmit all decisions. Management will depend on the estimated level of risk Category 1 abnormalities require no further investigation. Category 2 abnormalities may be followed up by periodic mammographic and clinical examinations. Follow-up examination of category 2 abnormalities should be carried out at approximately 6 and 12 months. If the abnormality is stable, examination should be repeated annually for 2 to 3 years thereafter. The rationale of follow-up should be explained, and women should be made aware that it is not possible to provide complete assurance that an abnormality is benign. Category 3 abnormalities usually require image-guided fine-needle or core biopsy. Every image-guided needle biopsy should be accompanied by a full report. Category 4 abnormalities should usually be excised. This may be preceded by image-guided needle biopsy. When surgical biopsy is carried out, the margins of the resected specimen must be free of tumour. The intact pathology specimen should be examined radiographically to confirm that all mammographic abnormalities have been removed. The patient should be kept fully informed as to the reason for each test and the meaning of its results. The process, from initial detection of the mammographic abnormality to the final management decision, should be completed as rapidly as possible. Guidelines were reviewed and revised by the Writing Committee, expert primary reviewers, secondary reviewers selected from all regions of Canada and by the Steering Committee. The final document reflects a consensus of all these contributors. From 1976 to 1978 11, 197 women were examined clinically and mammographically. Biopsy material from 1,673 breasts were examined microscopically. In 536 cases, or almost every third case (32%), a carcinoma of the breast was detected. The cancer was bilateral in 19 cases and the total number of women was therefore 517. A clinically occult tumour was only found in 7.7% (40 of 517) of the cases. 5% of these patients were high risk patients and 2.7% preventive examinations. 5 women with occult carcinoma of the breast were under age 40 and 14 under age 50. Benign changes of the glandular tissue were found in 59.5% of the cases. Marked proliferative changes were found in 4.6% of the cases and carcinoma in situ was found in 3.8% of the patients. In the age group 45--54 benign and proliferative changes of the parenchyma occured almost twice as often as cancers. The ratio between benign and malignant findings was 1:1 in the age group 55--59 and was less than 1:2 in the age group over 70. A sophistication of the mammograhic technique must be obtained. A thorough microscopic examination of tissue from subcutaneous mastectomies and tissue obtained at the time of reduction mammoplasties showed occasionally unexpected malignant tissue in an unexpected location. Especially these cases are suitable for later comparison to the mammographies. We examined a 34-year-old premenopausal woman who had noticed a left-breast lump a month previously. She had no past history of malignancies but had a family history of breast and ovarian cancers. Her mother had suffered from ovarian cancer when aged 47 years and had died of the disease at age 52. The younger two of the patient's four aunts had developed breast cancer when they were 37 and 48 years old. A physical examination showed an ill-defined mass, 1.5 cm in diameter, located in the upper outer quadrant of the patient's left breast. Mammography revealed diffuse microcalcification in both breasts but ultrasonography revealed an irregular tumorous lesion only in the left breast. Aspiration breast cytology revealed adenocarcinoma of the left breast. Modified radical mastectomy of the left breast and excision of a biopsy specimen from the right breast were carried out simultaneously. Histopathologically the left-breast tumor was an atypical medullary carcinoma with cartilaginous metaplasia, of histological grade 3, and the right-breast specimen showed fibrocystic changes with atypical ductal hyperplasia. Estrogen receptors were positive, but progesterone receptor was not detected on the tumor cells, which were immunopositive for nuclear p53 although c-erbB-2 overexpression was not observed. A nonsense germline mutation of the BRCA1 gene (exon5) was detected. The patient has been well since the operation (10 months). These findings may provide useful information about the carcinogenesis and biological behavior of BRCA1-associated breast cancers. In this study, we aimed to determine the need for biopsy in patients referred from other clinics for the performance of biopsy with the suspicion of breast cancer. 112 patients were included in the study. It was decided that their biopsies be performed following examinations in other clinics and they presented to the breast radiology unit of our hospital for a second opinion. The demographic characteristics, diagnostic studies completed in the other centers, properties of lesions, decision made as a result of examinations and BI-RADS (Breast Imaging Reporting and Data Systems) categorizations were recorded on the registration forms of the study patients. In addition, the quality of examinations, reasons of repeat tests, additional tests features and the last decision of our clinic were documented. The obtained data were analyzed in terms of re-examination, additional tests and change in the biopsy decision. Changes in the biopsy decisions for patients were specifically inquired. The biopsy decisions were cancelled in our breast radiology unit for 63 out of 112 patients (56.3%) whose biopsy decisions were made at an external institute. For 42 patients, examinations made by the other clinics were deemed adequate, yet there was no need for biopsy in 22 of them. The biopsy decisions were cancelled for 27 out of 47 patients (57.4%) with repeat examination and 18 out of 28 patients (64.3%) with additional tests because of the insufficient test quality. Incorrect, inadequate breast screening and false positivity were higher at inexperienced institutes. The patient was a 41-year-old, premenopausal woman with a chief complaint of well-circumscribed palpable, right breast mass without nipple discharge. Although she noticed the lump 3 months previously, the size of the tumor (1.1 × 0.9 cm(2)) had been stable. The patient's mother suffered from gastric cancer. Her previous history of the triple different malignancies was as follows: (1) left osteosarcoma [amputation of left lower leg at 15 years old (y/o)]. After the operation, she was treated with various kinds of anticancer drugs including a total of 45 g ifosphamide and 342 g methotrexate; (2) tongue cancer (right radical neck resection; 23 y/o); and (3) thyroid cancer (right lobectomy; 40 y/o). There was no evidence of recurrence of these malignancies at the present consultation. At the time of tongue cancer operation, chromosome abnormality was investigated, but the results were normal. Physical examination showed a well-delimited, elastic-firm, mobile tumor in the central outer right breast. Regional lymph nodes were not palpable. Mammography showed a focal asymmetry in the right upper breast on the mediolateral oblique view. Ultrasonography revealed a hypoechoic mass with irregular margins. Distant metastases could not be detected by whole-body computed tomography scan. The histology of the Mammotome(®) (vacuum-assisted core needle biopsy) specimen revealed that this tumor was low-grade ductal carcinoma in situ (DCIS). She underwent breast-conserving surgery with sentinel lymph node biopsy. On permanent histopathological examination, the diagnosis of the tumor was intracystic papilloma with low-grade DCIS. Surgical margin was negative, and sentinel lymph node metastases could not be observed. Estrogen and progesterone receptor (ER/PR) were strongly positive, but human epidermal growth factor receptor-2 (HER-2) overexpression was not tested because the lesion was DCIS. She has received no adjuvant therapy and is currently disease free 3 months after surgery. BI-RADS Assessment Categories are: 0: Incomplete 1: Negative 2: Benign 3: Probably benign 4: Suspicious 5: Highly suggestive of malignancy 6: Known biopsy – proven malignancy An incomplete (BI-RADS 0) classification warrants either an effort to ascertain prior imaging for comparison or to call the patient back for additional views and/or higher quality films. A BI-RADS classification of 4 or 5 warrants biopsy to further evaluate the offending lesion. Some experts believe that the single BI-RADS 4 classification does not adequately communicate the risk of cancer to doctors and recommend a subclassification scheme: 4A: low suspicion for malignancy, about > 2% to ≤ 10% likelihood of malignancy 4B: intermediate suspicion of malignancy, about > 10% to ≤ 50% likelihood of malignancy 4C: moderate concern, but not classic for malignancy, about > 50% to < 95% likelihood of malignancy The aim of this study was to determine the features that make interval cancers apparent on the preceding screening mammogram and determine whether changes in the ways of performing the interval cancer review will affect the true interval cancer rate. This study was approved by the clinical governance committee. Mammograms of women diagnosed with an interval cancer were included in the study if they had been allocated to either the \"suspicious signs\" group or \"subtle signs\" group, during the historic interval cancer review. Three radiologists, individually and blinded to the site of interval cancer, reviewed the mammograms and documented the presence, site, characteristics and classification of any abnormality. Findings were compared with the appearances of the abnormality at the site of subsequent cancer development by a different breast radiologist. The chi-squared test was used in the analysis of the results, seeking associations between recall concordance and cancer mammographic or histological characteristics. 111/590 interval cancers fulfilled the study inclusion criteria. In 17% of the cases none of the readers identified the relevant abnormality on the screening mammogram. 1/3 readers identified the relevant lesion in 22% of the cases, 2/3 readers in 28% of cases and all 3 readers in 33% of cases. The commonest unanimously recalled abnormality was microcalcification and the most challenging mammographic abnormality to detect was asymmetric density. We did not find any statistically significant association between recall concordance and time to interval cancer, position of lesion in the breast, breast density or cancer grade. Even the simple step of performing an independent blinded review of interval cancers reduces the rate of interval cancers classified as missed by up to 39%. The triple test score (TTS) is a diagnostic tool for examining potentially cancerous breasts. Diagnostic accuracy of the triple test score is nearly 100%. Scoring includes using the procedures of physical examination, mammography and needle biopsy. If the results of a TTS are greater than five, an excisional biopsy is indicated. Scoring To obtain the triple test score, a number from 1 through 3 is assigned to each one of the procedures. A score of 1 is assigned to a benign test result, 2 applies to a suspicious test result, and 3 applies to a malignant result. The sum of the scores of all three procedures is the triple test score. A score of 3 to 4 is most likely benign, whereas a score of greater than 6 is possibly malignant. References Breast cancer New evaluation of breast ultrasound based upon review of new literature comparing ultrasound and mammography. Description and discussion of the published trials regarding breast imaging methods. Breast ultrasound is the preferable method in the case of a symptomatic patient (after clinical examination). In the case of a patient without symptoms (screening), breast ultrasound is ascribed a higher sensitivity for detecting breast cancer in women with dense breast tissue, women under the age of 50 and high-risk women. Mammographically occult cancers can be detected by sonography in 10 to 40 % of the cases depending on the patient's breast density and age. The mean size of cancers detected only by ultrasound is not significantly different to that only detected by mammography. The prevalence of breast cancers detected by ultrasound is approximately equal to the one detected by mammography, regarding the total number of examined patients. Breast ultrasound should be the preferred imaging procedure in the case of a palpable lump, leading to a definitive diagnosis itself or with an additional consecutive core needle biopsy. For women without symptoms, breast sonography should be mandatory and complementary to mammography in the case of breast density grade II (BI-RADS) or more. Application of breast ultrasound as a primary method or an alternative to mammography has not yet been evaluated sufficiently. It seems advisable in the case of women with dense breast tissue grade III and IV, women under the age of 50 and high-risk women. The implementation of breast ultrasound in this manner has to be checked by future trials. The consequences of a false-positive screening test result also need to be considered. For example, when 1000 screening mammograms are taken, only 2 to 4 new cases of cancer will be identified; this number is slightly higher (6 to 10 prevalent cancers per 1000 mammograms) for initial screen-ing mammograms.106 However, as many as 10% of screening mammograms may be potentially suggestive of an abnormal-ity, which requires further imaging (i.e., a 10% recall rate). Of those women with abnormal mammogram findings, only 5% to 10% will be determined to have a breast cancer. Among women for whom biopsy specimen is recommended, 25% to 40% will have a breast cancer. A false-positive screening result is likely to induce significant emotional distress in patients, leads to unnecessary biopsy specimens, and has cost implications for the health care system.American Cancer Society guidelines for the early detec-tion of cancer are listed in Table 10-9.96 These guidelines are updated periodically to To retrospectively correlate high-risk proliferative breast lesions (radial scar, atypical lobular hyperplasia, lobular carcinoma in situ and papillary lesions) diagnosed on core biopsy with the definitive histopathological diagnosis obtained after surgical excision or with the follow-up, in order to assess the role of core biopsy in such lesions. To discuss the management of the patient after a core biopsy diagnosis of high-risk proliferative breast lesion. We evaluated 74 out of 1776 core biopsies consecutively performed on 67 patients. The histopathologic findings were as follows: 11 radial scars (RS), 3 atypical lobular hyperplasias (ALH), 3 lobular carcinomas in situ (LCIS), 57 benign papillary lesions. All patients underwent bilateral mammography, whole-breast ultrasound with a linear-array broadband transducer, and core biopsy with a 14 Gauge needle and a mean number of samples of 5 (range 4-7). Sixty-two of 67 patients, for a total of 69/74 lesions, underwent surgical biopsy despite benign histopathologic findings, mostly because of highly suspicious imaging for malignancy (BIRADS 4-5), whereas 5 patients refused surgery and have been followed up for a least 18 months and are still being followed up (2 with RS, 1 with ADH and 2 with papillary lesions). Among the core biopsied lesions with a diagnosis of RS (n = 11) pathology revealed one ductal carcinoma in situ (DCIS) (this case was characterized by granular microcalcifications on mammography and by a mass with irregular margins on ultrasound). Also in the group of ADH (n = 3) pathology revealed one DCIS (lesion not visible on mammography but depicted as a suspicious mass on US). In the group of LCIS (n = 3) pathologists found an invasive lobular carcinoma (ILC). Among the benign papillary lesions (n = 57) histopathologic analysis of the surgical specimen revealed 7 malignant lesions (4 papillary carcinomas and 3 DCIS), whose mammographic and ultrasound findings were indistinguishable from benign lesions. Altogether there were 10 false negative results (underestimation) out of 74 core biopsies with a diagnosis of high-risk proliferative breast lesions. The high rate of histological underestimation after core biopsy (10/74) (13.5%) demands a very careful management of patents with a core biopsy diagnosis of high-risk proliferative breast lesions, especially in the case of RS, lobular neoplasia and papillary lesions. However, the high imaging suspicion for malignancy prompts surgery. It is possible to assume that, when there is a low imaging suspicion for malignancy, when enough tissue has been sampled for pathology and no atypia is found within the lesions, surgery is not mandatory but a very careful follow-up is recommended. We must underline that there is no agreement regarding the quantity of tissue to sample. Vacuum-assisted biopsy may lead to better results, although there is as yet no proof that it can actually replace surgery in this group of lesions, since it seems only to reduce but not abolish the histological underestimation. The History of mammography began in 1913, when a Berliner surgeon, A. Salomon realized a roentgeno-histological study on 3,000 mastectomies. This work is the basis of mammography. Until 1938, few articles were published but were of little help to mammography. From 1947 to 1970, the second period brought the results of roentgenologic and clinical correlation. R. Leborgne was the first accountable for the wide development of this method. Since 1951, many American and European radiologists brought their contribution. Ch. Gros is the best known. He gave this technique an acknowledgment throughout the world for the diagnosis of breast diseases. Since 1970, the third period emphasizes the value of mammography as a technique for detection of breast cancer. Some \"Screening working groups\" are being set up. The problem is mainly economical. Often women are quite distressed to be called back for a diagnostic mammogram. Most of these recalls will be false positive results. Of every 1,000 U.S. women who are screened, about 7% will be called back for a diagnostic session (although some studies estimate the number to be closer to 10% to 15%). About 10 of these individuals will be referred for a biopsy; the remaining 60 cases are found to be of benign cause. Of the 10 referred for biopsy, about 3.5 will have cancer and 6.5 will not. Of the 3.5 who have cancer, about 2 will have an early stage cancer that will be cured after treatment. If suspicious signs are identified in the image, then the woman is usually recalled for a second mammogram, sometimes after waiting six months to see whether the spot is growing, or a biopsy of the breast. Most of these will prove to be false positives, resulting in sometimes debilitating anxiety over nothing. Most women recalled will undergo additional imaging only, without any further intervention. Recall rates are higher in the U.S. than in the UK. Effectiveness On balance, screening mammography in older women increases medical treatment and saves a small number of lives. Usually, it has no effect on the outcome of any breast cancer that it detects. Screening targeted towards women with above-average risk produces more benefit than screening of women at average or low risk for breast cancer.\nHere is the question:\nONCOLOGY: A 40-year-old woman consults because she has noticed a lump in the superoexternal quadrant of the right breast for the past month. She provides a mammography report describing a BIRADS 3 lesion. What is the best course of action?\nHere are the potential choices:\n1. Reassure him, since an imaging test has already been done and malignancy has been ruled out.\n2. This classification probably implies surgery since the probability of cancer is greater than 10%. He explains it to you and refers you preferentially to the Breast Unit.\n3. This is a probably benign finding, since there is less than a 2% chance of cancer. He explains that it requires follow-up every 6-12 months until 24 months or a biopsy.\n4. The findings are of low suspicion of cancer (between 2 and 10 %) but a biopsy is necessary.\nThe correct answer is: 3. This is a probably benign finding, since there is less than a 2% chance of cancer. He explains that it requires follow-up every 6-12 months until 24 months or a biopsy."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Bacteria can cause lung cavities in one of two ways; they can either enter the lung through the trachea (windpipe), or they can enter through the bloodstream as septic pulmonary emboli (infected blood clots). Community-acquired pneumonia is an uncommon cause of lung cavities, but cavitary pneumonia is occasionally seen with Streptococcus pneumoniae or Haemophilus influenzae infection. However, since these two species of bacteria are such common causes of pneumonia, they may cause a significant fraction of all cavitary pneumonias. The most common bacterial causes of lung cavities are Streptococcus species and Klebsiella pneumoniae. Less commonly, the bacteria Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter, Escherichia coli, and Legionella can cause cavitation. Nocardia is a bacterium that can cause pulmonary nocardiosis and lung cavities in people who are immunocompromised (have weak immune systems), including organ transplant recipients who are on immunosuppressants, Causative organisms The most common pathogens responsible for NP are Streptococcus pneumonia, Staphylococcus aureus, Klebsiella pneumoniae. Other pathogens which are less likely to cause NP are bacteria like Haemophilus influenzae, Streptococcus anginosus group, Pseudomonas aeruginosa, Mycoplasma pneumoniae, Acinetobacter baumannii, Streptococcus pyogenes, Stenotrophomonas maltophilia, anaerobes like Fusobacterium nucleatum and Bacteroides fragilis; fungi like Aspergillus sp. and Histoplasma capsulatum; viruses like Influenza and Adenovirus. Necrotizing pneumonia (NP), also known as cavitary pneumonia or cavitatory necrosis, is a rare but severe complication of lung parenchymal infection. In necrotizing pneumonia, there is a substantial liquefaction following death of the lung tissue, which may lead to gangrene formation in the lung. In most cases patients with NP have fever, cough and bad breath, and those with more indolent infections have weight loss. Often patients clinically present with acute respiratory failure. The most common pathogens responsible for NP are Streptococcus pneumonia, Staphylococcus aureus, Klebsiella pneumoniae. Diagnosis is usually done by chest imaging, e.g. chest X-ray, CT scan. Among these CT scan is the most sensitive test which shows loss of lung architecture and multiple small thin walled cavities. Often cultures from bronchoalveolar lavage and blood may be done for identification of the causative organism(s). Causes In some studies, the bacteria found in patients with HCAP were more similar to HAP than to CAP; compared to CAP, they could have higher rates of Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa, and less Streptococcus pneumoniae and Haemophilus influenzae. In European and Asian studies, the etiology of HCAP was similar to that of CAP, and rates of multi drug resistant pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa were not as high as seen in North American studies. It is well known that nursing home residents have high rates of colonization with MRSA. However, not all studies have found high rates of S. aureus and gram-negative bacteria. One factor responsible for these differences is the reliance on sputum samples and the strictness of the criteria to discriminate A. fumigatus (the most common species) infections are primary pulmonary infections and can potentially become a rapidly necrotizing pneumonia with a potential to disseminate. The organism can be differentiated from other common mold infections based on the fact that it takes on a mold form both in the environment and in the host (unlike Candida albicans which is a dimorphic mold in the environment and a yeast in the body). Aspergillosis Aspergillosis is the group of diseases caused by Aspergillus. The most common species among paranasal sinus infections associated with aspergillosis is A. fumigatus. The symptoms include fever, cough, chest pain, or breathlessness, which also occur in many other illnesses, so diagnosis can be difficult. Usually, only patients with already weakened immune systems or who suffer other lung conditions are susceptible. Opportunistic pneumonia People with weakened immune defense, such as HIV/AIDS patients, are highly susceptible to opportunistic infections affecting the lungs. Most common pathogens are Pneumocystis jiroveci, Mycobacterium avium-intracellulare complex, Streptococcus pneumoniae, Haemophilus species. Less frequent pathogens are Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, cytomegalovirus (CMV), and Toxoplasma gondii. Chemotherapy-induced immunodeficiency may lead to severe lung infections. Pathogens commonly associated with lung infectioins are bacteria (like Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Nocardia species), viruses (eg, respiratory syncytial virus, parainfluenza virus, influenza virus A and influenza B, and cytomegalovirus), and fungi (eg, Aspergillus, Fusarium, and Mucorales species, and Pneumocystis jirovecii). Bacteria such as S. aureus , P. aeruginosa , Stenotrophomonas maltophilia , and Burkholderia cepacia complex, are the most common pathogens involved in pulmonary infections immediately after solid organ transplantation, especially heart and lung. ESKAPE pathogens ( Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) especially cause pulmonary infections after lung transplant. Due to the immunosuppression, infections from other opportunistic pathogens such as Cytomegalovirus (CMV) can also occur after solid organ transplantation. In the early phase following hematopoietic stem cell transplantation (HSCT), the majority of pulmonary infections are due to bacteria, for example, S. pneumoniae , Klebsiella , Gram-negative bacilli, and S. aureus . Up to three weeks following HSCT, which is the neutropenic phase, fungi, especially Aspergillus spp. are a common cause of infections, while CMV infections can occur up to three months following HSCT. Pneumocystis pneumonia (PCP) is uncommon after HSCT except in the setting of graft-vs-host disease. [2] [3] Following allogeneic cell transplantation, pulmonary infections due to Fusarium species can also occur, which are seen exclusively in the severely immunocompromised. [4] Bacteria have been the most commonly isolated pathogens, although viral and fungal pathogens are potentially found in immunocompromised hosts (patients on chronic immunosuppressed medications, solid organ and bone marrow transplant recipients). In general, the distribution of microbial pathogens varies among institutions, partly because of differences in patient population and local patterns of anti microbial resistance in hospitals and critical care units' Common bacterial pathogens include aerobic GNB, such as Pseudomonas aeruginosa, Acinetobacter baumanii, Klebsiella pneumoniae, Escherichia coli as well as gram-positive organisms such as Staphylococcus aureus. In patients with an early onset pneumonia (within 5 days of hospitalization), they are usually due to anti microbial-sensitive bacteria such as Enterobacter spp, E. coli, Klebsiella spp, Proteus spp, Serratia mare scans, community pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, and methicillin-sensitive S. Due to their poor immune response, patients with HIV and those with immunosuppression for other causes, such as malignancy, autoimmune disease, or iatrogenic due to underlying condition or organ transplant patients, require prophylaxis for numerous pathogens. These pathogens include: Aspergillus species Candida albicans Clostridium difficile Coccidioides immitis Cryptococcus neoformans Cytomegalovirus Histoplasma capsulatum Legionella pneumophila Microsporidium Mycobacterium avium complex Mycobacterium tuberculosis Pseudomonas aeruginosa Salmonella Staphylococcus aureus Streptococcus pneumoniae Streptococcus pyogenes Toxoplasma gondii [2] [3] [5] A total of 32 patients with mycoses other than cavity-formed aspergilloma were reviewed. The main pathogenic fungi were Aspergillus in 14, Candida in 8, Cryptococcus in 4, Trichosporon in 4 and Mucor in 2. Coinfection by two species was detected in 3 cases: Trichosporon and Aspergillus in 2 and Aspergillus and Candida in 1. The underlying diseases were hematologic malignancies in all cases except 1 case of lung cancer. The hematologic malignancies were mostly leukemias of various types. Cryptococcosis developed in patients given long-term corticosteroid treatment but not in leukemic patients. All cases of aspergillosis, candidiasis and mucormycosis were due to nosocomial infection. On the other hand, 3 of 4 cases of cryptococcosis or trichosporonosis were attributable to community-acquired infection. Two of 4 trichosporonosis cases were considered to have been acquired during 2-day home stays. The diagnosis of pulmonary mycosis was made pathologically in 18 and clinically in 14 cases. Of the latter, 6 cases had an air-crescent sign on chest X-ray films and 8 cases were culture-positive. Extrapulmonary involvement was seen in all 16 cases of candidiasis, cryptococcosis and trichosporonosis but not in 10 of 14 aspergillosis cases. Severe granulocytopenia was present in all cases except 4 cases of cryptococcosis and 3 cases of aspergillosis. Chest X-ray findings of aspergillosis were of two types: one was an air-crescent sign which was noted in the recovery phase from leukopenia and the other was gradually enlarging consolidation which was bound by the interlobar fissure and progressed to lobar penumonia. A diffuse granular shadow was not characteristic of any fungus species.(ABSTRACT TRUNCATED AT 250 WORDS) Imaging modalities for evaluation of pneumonia include: Chest X-ray (CXR). This is the first-line imaging of choice in the evaluation of a suspected case of pneumonia. Posteroanterior (PA) and lateral radiographs should be obtained. However, CXR may be normal for up to 72 hours in immunocompromised patients despite having symptoms. Computed tomography (CT) of the chest should be obtained in patients with high suspicion of pneumonia and normal findings on CXR. In neutropenic patients, CXR will have minimal or no abnormalities and so performing a CT scan is highly recommended. Other investigations for specific etiologies include: Urine antigen testing for pneumococcus and Legionella ELISA and PCR for viruses such as Herpes Simplex Virus (HSV), Influenza A and B, and Cytomegalovirus (CMV) Serum antigen testing for Cryptococcus and Aspergillus Beta-D-glucan testing if a fungal pathogen is suspected. [2] [8] [17] [20] Types Bacterial pneumonia: The majority of cases related to various rod shaped gram-negative organisms (52%) and Staphylococcus aureus (19%), usually of the MRSA type. Others are Haemophilus spp. (5%). In the ICU results were S. aureus (17.4%), Pseudomonas aeruginosa (17.4%), Klebsiella pneumoniae and Enterobacter spp. (18.1%), and Haemophilus influenzae (4.9%). Viral pneumonia: influenza and respiratory syncytial virus and, in the immunocompromised host, cytomegalovirus – cause 10–20% of infections. Ventilator-associated pneumonia Recurrent pneumonia is typical, predominately due to S. aureus , and less frequently due to Streptococcus pneumoniae, and Haemophilus. It can get complicated with the development of recurrent lung abscesses, bronchiectasis, and pneumatoceles. These pneumatoceles can get colonized with Aspergillus and Pseudomonas . Superinfection with Pneumocystis carinii [5] was also reported. Neutrophil-specific granule deficiency ( previously known as lactoferrin deficiency) is a rare congenital immunodeficiency characterized by an increased risk for pyogenic infections due to defective production of specific granules and gelatinase granules in patient neutrophils. Symptoms and signs Atypical infections are the key clinical manifestation of SGD. Within the first few years of life, patients will experience repeated pyogenic infections by species such as Staphylococcus aureus, Pseudomonas aeruginosa or other Enterobacteriaceae, and Candida albicans. Cutaneous ulcers or abscesses and pneumonia and chronic lung disease are common. Patients may also develop sepsis, mastoiditis, otitis media, and lymphadenopathy. Infants may present with vomiting, diarrhea, and failure to thrive. Studying the proven and probable invasive pulmonary aspergillosis (IPA) cases of some hospitals in Shanghai to provide evidence for the improvement of IPA clinical diagnosis and therapy. Forty-nine IPA cases were retrospectively analyzed for demography data, host factors, underlying conditions, chest CT, microorganism and histopathology examination, as well as therapy and clinical outcome. Of 49 subjects including 19 (38.8%) proven and 30 (61.2%) probable IPA, 3 patients (6.1%) had no host factors, 25 patients (51.0%) had IPA associated host factors and underlying conditions, while 21 patients (42.9%) had uncertain fundamental diseases. Chest CT evaluation demonstrated that radiological lesions include nodules in 29 patients, patching in 15, mass in 12, consolidation in 10, cavitation in 34, Halo sign in 19, air bronchogram in 18, crescentic sign in 6, bilateral in 33 and multifocal lesions in 38. The yielding rate of fungus culture in sputum was 26.5% (13/49), and in bronchoalveolar lavage fluid was 66.7% (10/15). Eleven of thirty-six patients (30.6%) had positive results of serum galactomannan antigen tests. Nineteen of twenty-one patients (90.5%) were proven as IPA by lung histologic examinations. Aspergillus fumigatus was the most common pathogen 81.0% (17/21). The responding rate to initial anti-fungus therapy was 50% (21/42). Our study suggests that in IPA patients, bilateral, multifocal and nodular lesion could be the most common radiological characteristic, while Halo and crescentic sign occur occasionally. Invasive technologies are more valuable to IPA diagnosis. Defense against infections PGLYRP2 plays a limited role in host defense against infections. PGLYRP2-deficient mice are more sensitive to Pseudomonas aeruginosa-induced keratitis and Streptococcus pneumoniae-induced pneumonia and sepsis. However, PGLYRP2-deficient mice did not show a changed susceptibility to systemic Escherichia coli, Staphylococcus aureus, and Candida albicans infections or intestinal Salmonella enterica infection, although the latter was accompanied by increased inflammation in the cecum. Although PGLYRP2 is not directly bacteriolytic, it has antibacterial activity against both Gram-positive and Gram-negative bacteria and Chlamydia trachomatis. Maintaining microbiome Mouse PGLYRP2 plays a role in maintaining healthy microbiome, as PGLYRP2-deficient mice have significant changes in the composition of their intestinal microbiome, which affect their sensitivity to colitis. The aim of this study is to determine the aetiology and characteristics of pulmonary cavities that developed in patients recovering from COVID-19 infection. Between 1<supst</sup May 2021 and 30<supst</sup June 2021, we found 9 post COVID-19 patients who developed lung cavities on chest radiograph or CT during the follow-up period. These patients underwent routine blood examination, sputum examination and bronchoscopy to identify the aetiologies for the lung cavities. The duration from the onset of COVID-19 symptoms to the detection of lung cavities ranged from 18 to 82 days. Out of 7 patients, 4 had recovered from severe COVID-19 disease, 2 from moderate and 1 from mild disease. After the diagnostic workup, 5 patients were found to have COVID-19 associated pulmonary aspergillosis (CAPA), 1 patient with mucormycosis and 1 patient with mycobacterium infection. Two patients with CAPA also had bacterial infection; sputum culture from both these patients grew Klebsiella pneumonia. Lung cavities can develop in patients recovering from COVID-19 pneumonia and fungal infection is the most common cause for such cavities. To assess the clinical, radiologic and microbiological features of lung cavitation and HIV infection. Evaluation of the differences related to this disease in the last years. Retrospective review of all patients with lung cavitation and HIV infection admitted at our hospital from January 1989 until December 1994 and prospective study of all patients with the same characteristics during 1995 and 1996. Lung cavitation was defined as any parenchymal lesion, with air content, visible in a simple X-ray and greater than 1 cm of diameter. Criteria for confirmed, probable or possible diagnosis were defined. 78 cases of lung cavitation have been identified in 73 patients. The radiologic patterns included unilobar and multilobular involvement in 31 and 47 cases, respectively. Cavities were multiple and single in 40 and 38 cases respectively. Findings with fine needle aspiration biopsy (FNAB) were diagnostic in 11 out of 14 cases. A clinical diagnosis was performed in all 78 cases, with microbiological results in 69 cases (88.5%): Mycobacterium tuberculosis in 20, Pneumocystis carinii in nine, Pseudomonas aeruginosa in nine, Staphylococcus aureus in eight (5 endocarditis with cavitary septic emboli), Rhodococcus equi in six, P. aeruginosa and S. aureus in three, Salmonella enteritidis in three, Cryptococcus neoformans in two, Aspergillus fumigatus in two and others in 7 cases. Confirmed, probable and possible diagnosis was considered in 54, 15 and 9 cases, respectively. Thirteen episodes of spontaneous pneumothorax were found. The lung cavitation rate is low, compared with the number of admissions related to HIV infection; nevertheless, many of them are in close relationship with HIV infection, and most of them are caused by treatable infections. It is important to know the clinical and radiological characteristics, in order to establish an early diagnosis and an appropriate therapy. Pseudomonas aeruginosa is becoming an important cause of lung cavitation. In our series, spontaneous pneumo-thorax was not related to Pneumocystis carinii pneumonia in 61.5% of cases. The aims of this study were to compare the high-resolution computed tomography (HRCT) findings of pulmonary infections in immunocompromised patients and to assess the usefulness of HRCT in the differential diagnosis of these infections. A total of 345 immunocompromised patients with pulmonary infections were included in this study. The diagnoses of the patients consisted of bacterial pneumonia (123 cases), pneumocystis pneumonia (PCP) (105 cases), fungal pneumonia (80 cases), tuberculosis (15 cases), cytomegalovirus pneumonia (11 cases), and septic embolism (11 cases). Two chest radiologists retrospectively evaluated the computed tomography (CT) images, which consisted of 22 findings including ground-glass attenuation, consolidation, nodules, and thickening of the bronchial wall and interlobular septum. Associations between the CT criteria and infections were investigated using χ<sup2</sup test; multiple logistic regression analyses were conducted to identify the significant indicator for each infection. The area under the curve (AUC) of each model was calculated. Bronchial wall thickening was a significant indicator for bacterial pneumonia (p = 0.002; odds ratio [OR], 2.341; 95% confidence interval [CI], 1.378-3.978). The presence of a mosaic pattern and the absence of nodules were significant indicators for PCP (p &lt; 0.001; OR, 9.808; 95% CI, 4.883-13.699, and p &lt; 0.001; OR, 6.834; 95% CI, 3.438-13.587, respectively). The presence of nodules was a significant indicator for fungal infection (p = 0.005; OR, 2.531; 95% CI, 1.326-4.828). The AUC for PCP was the highest (0.904). HRCT findings are potentially useful for the differential diagnosis of some pulmonary infections in immunocompromised patients. • Differential diagnosis of pulmonary infections in immunocompromised patients could be established with the help of high-resolution computed tomography. • Bronchial wall thickening was a significant indicator for bacterial pneumonia. • The presence of a mosaic pattern and the absence of nodules were significant indicators for pneumocystis pneumonia. Patients with defective humoral immunity are at increased risk of infection from encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae . Those with neutropenia are predisposed to infections from S. aureus , Gram-negative bacilli (including Pseudomonas aeruginosa ), as well as fungi such as Aspergillus spp. Impaired T-cell immunity can lead to a range of infections from: Viruses, such as Cytomegalovirus Intracellular bacteria, for example, Legionella Acid-fast bacteria such as Mycobacteria and Nocardia Fungi, such as Pneumocystis jirovecii , Aspergillus spp., Coccidioides immitis , Cryptococcus spp., Blastomyces dermatitidis , Histoplasma capsulatum , etc [3] Interleukin-1 receptor-associated kinase deficiency is an inherited disorder of the immune system. This immunodeficiency leads to recurrent infections caused by the pyogenic bacteria, for example Streptococcus pneumoniae, Staphylococcus aureus and Pseudomonas aeruginosa, but not by other infectious agents. Most patients with IRAK-4 deficiency suffer from invasive bacterial infections, which can cause sepsis, meningitis or they affect the joints that can lead to inflammation and arthritis. These invasive infections can also cause areas of tissue breakdown and pus production (abscesses) on internal organs. In addition, patients are characterized by infections of the upper respiratory tract, eyes or skin. Although fever is a common reaction to bacterial infections, many people with IRAK-4 deficiency do not at first develop a high fever in response to these infections, even if the infection is severe. Most patients have their first bacterial infection before age 2, and the infections can The purpose of this study was to establish the diagnostic value of central hypointensity (\"hypodense sign\") in lung consolidations or nodules, in severely immunocompromised or neutropenic patients, suspected of having invasive pulmonary aspergillosis (IPA), and to assess its recognition on unenhanced CT scans. Serial CT scans of the lung were retrospectively reviewed in 43 consecutive immunosuppressed patients with IPA, and assessed for the presence of the hypodense sign using standard mediastinal and lung windowing settings, as well as a special, narrower window setting (width 110-140 HU; level 15-40 HU). The temporal relationship between the occurrence of the first CT-finding suspicious of IPA and the appearance of the hypodense sign, as well as between this and the occurrence of the crescent sign, cavitation or reduction in lesion size, was evaluated. Additionally, CT-scans from 89 immunocompromised patients with viral (n=45) or bacterial (n=44) pneumonia, investigated in the same time period at our institution were reviewed, with respect to the presence of the \"hypodense\" sign. Unenhanced CT scans revealed the hypodense sign in 11 neutropenic patients and 2 severely immunocompromised patients, out of a total of 43 patients with IPA evaluated in this study (30.2%). The mean time between the appearance of the first CT-findings of IPA (large nodule or consolidation +/- positive halo sign) and the hypodense sign was 7.8 days, while the time interval between the hypodense sign and the occurrence of crescent sign, cavitation, or decrease of the lesion's size was 8.3 days. The hypodense sign did not occur in any of the patients with viral or bacterial pneumonia, in the control series. We consider the hypodense sign to be a supplementary tool in the diagnosis of IPA. Its sensitivity was low in our series, but the high specificity makes it valuable in predicting IPA, anticipating the occurrence of cavitation or crescent sign, which are considered specific, but late findings of IPA. The hypodense sign is recognizable also on unenhanced CT, when a narrower lung window setting is used. Types Hospital-acquired pneumonia Ventilator-associated pneumonia Urinary tract infection Gastroenteritis Puerperal fever Central line-associated blood stream infection Organisms Staphylococcus aureus Methicillin resistant Staphylococcus aureus Candida albicans Pseudomonas aeruginosa Acinetobacter baumannii' Stenotrophomonas maltophilia Clostridium difficile Escherichia coli Tuberculosis Vancomycin-resistant Enterococcus Legionnaires' disease Cause Transmission In-dwelling catheters have recently been identified with hospital acquired infections. To deal with this complication, procedures are used, called intravascular antimicrobial lock therapy that can reduce infections that are unexposed to blood-borne antibiotics. Introducing antibiotics, including ethanol, into the catheter (without flushing it into the bloodstream) reduces the formation of biofilms. Overwhelming pneumonias remain an important cause of morbidity and mortality. These illnesses may be rapidly fatal; thus, many patients are treated empirically. Although the various etiologic agents cannot be differentiated on the basis of radiographic appearance, epidemiologic information may give a clue to the cause. Community-acquired overwhelming pneumonias are usually due to pyogenic bacteria (especially Streptococcus pneumoniae), mycoplasma, mycobacteria, and fungi. Hospital-acquired pneumonias are usually due to aerobic gram-negative bacilli. If the patient is immunocompromised, Pneumocystis carinii, Candida, and Aspergillus must be considered. Choice of optimal antimicrobial therapy requires that a specific etiology be identified. Gram's stain of sputum is often helpful in the diagnosis of community-acquired pneumonia. Invasive diagnostic techniques such as bronchoscopy and open lung biopsy are often required in nosocomial pneumonias and pneumonias in immunocompromised patients. Bacterial Bacterial keratitis. Bacterial infection of the cornea can follow from an injury or from wearing contact lenses. The bacteria involved are Staphylococcus aureus and for contact lens wearers, Pseudomonas aeruginosa. Pseudomonas aeruginosa contains enzymes that can digest the cornea. Fungal Fungal keratitis, caused by Aspergillus fumigatus and Candida albicans (cf. Fusarium, causing an outbreak of keratitis in 2005–2006 through the possible vector of Bausch & Lomb ReNu with MoistureLoc contact lens solution) Amoebic Acanthamoebic keratitis Amoebic infection of the cornea is a serious corneal infection, often affecting contact lens wearers. It is usually caused by Acanthamoeba. On May 25, 2007, the U.S. Center for Disease Control issued a health advisory due to increased risk of Acanthamoeba keratitis associated with use of Advanced Medical Optics Complete Moisture Plus Multi-Purpose eye solution. Although patients with severe immunodeficiency and hematological malignancies has been considered at highest risk for invasive fungal infection, patients with severe pneumonia due to influenza, and severe acute respiratory syndrome coronavirus (SARS-CoV) are also at a higher risk of developing invasive pulmonary aspergillosis (IPA). Recently, reports of IPA have also emerged among SARS-CoV-2 infected patients admitted to intensive care units (ICUs). Here, we report a fatal case of probable IPA in an acute myeloid leukemia patient co-infected with SARS-CoV-2 and complicated by acute respiratory distress syndrome (ARDS). Probable IPA is supported by multiple pulmonary nodules with ground glass opacities which indicate halo sign and positive serum galactomannan results. Screening studies are needed to evaluate the prevalence of IPA in immunocompromised patients infected with SARS-CoV-2. Consequently, testing for the presence of Aspergillus in lower respiratory secretions and galactomannan in consecutive serum samples of COVID-19 patients with timely and targeted antifungal therapy based on early clinical suspicion of IPA are highly recommended.\nHere is the question:\nINFECTIOUS: An immunodeficient patient who presents a pneumonia with meniscus halo sign or crescentic contour on chest X-ray/CT suggests infection by a microorganism:\nHere are the potential choices:\n1. Staphylococcus aureus.\n2. Streptococcus pneumoniae.\n3. Candida albicans.\n4. Pseudomonas aeruginosa.\n5. Aspergillus fumigatus.\nThe correct answer is: ",
        "gold_answer": "5 Aspergillus fumigatus.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Bacteria can cause lung cavities in one of two ways; they can either enter the lung through the trachea (windpipe), or they can enter through the bloodstream as septic pulmonary emboli (infected blood clots). Community-acquired pneumonia is an uncommon cause of lung cavities, but cavitary pneumonia is occasionally seen with Streptococcus pneumoniae or Haemophilus influenzae infection. However, since these two species of bacteria are such common causes of pneumonia, they may cause a significant fraction of all cavitary pneumonias. The most common bacterial causes of lung cavities are Streptococcus species and Klebsiella pneumoniae. Less commonly, the bacteria Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter, Escherichia coli, and Legionella can cause cavitation. Nocardia is a bacterium that can cause pulmonary nocardiosis and lung cavities in people who are immunocompromised (have weak immune systems), including organ transplant recipients who are on immunosuppressants, Causative organisms The most common pathogens responsible for NP are Streptococcus pneumonia, Staphylococcus aureus, Klebsiella pneumoniae. Other pathogens which are less likely to cause NP are bacteria like Haemophilus influenzae, Streptococcus anginosus group, Pseudomonas aeruginosa, Mycoplasma pneumoniae, Acinetobacter baumannii, Streptococcus pyogenes, Stenotrophomonas maltophilia, anaerobes like Fusobacterium nucleatum and Bacteroides fragilis; fungi like Aspergillus sp. and Histoplasma capsulatum; viruses like Influenza and Adenovirus. Necrotizing pneumonia (NP), also known as cavitary pneumonia or cavitatory necrosis, is a rare but severe complication of lung parenchymal infection. In necrotizing pneumonia, there is a substantial liquefaction following death of the lung tissue, which may lead to gangrene formation in the lung. In most cases patients with NP have fever, cough and bad breath, and those with more indolent infections have weight loss. Often patients clinically present with acute respiratory failure. The most common pathogens responsible for NP are Streptococcus pneumonia, Staphylococcus aureus, Klebsiella pneumoniae. Diagnosis is usually done by chest imaging, e.g. chest X-ray, CT scan. Among these CT scan is the most sensitive test which shows loss of lung architecture and multiple small thin walled cavities. Often cultures from bronchoalveolar lavage and blood may be done for identification of the causative organism(s). Causes In some studies, the bacteria found in patients with HCAP were more similar to HAP than to CAP; compared to CAP, they could have higher rates of Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa, and less Streptococcus pneumoniae and Haemophilus influenzae. In European and Asian studies, the etiology of HCAP was similar to that of CAP, and rates of multi drug resistant pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa were not as high as seen in North American studies. It is well known that nursing home residents have high rates of colonization with MRSA. However, not all studies have found high rates of S. aureus and gram-negative bacteria. One factor responsible for these differences is the reliance on sputum samples and the strictness of the criteria to discriminate A. fumigatus (the most common species) infections are primary pulmonary infections and can potentially become a rapidly necrotizing pneumonia with a potential to disseminate. The organism can be differentiated from other common mold infections based on the fact that it takes on a mold form both in the environment and in the host (unlike Candida albicans which is a dimorphic mold in the environment and a yeast in the body). Aspergillosis Aspergillosis is the group of diseases caused by Aspergillus. The most common species among paranasal sinus infections associated with aspergillosis is A. fumigatus. The symptoms include fever, cough, chest pain, or breathlessness, which also occur in many other illnesses, so diagnosis can be difficult. Usually, only patients with already weakened immune systems or who suffer other lung conditions are susceptible. Opportunistic pneumonia People with weakened immune defense, such as HIV/AIDS patients, are highly susceptible to opportunistic infections affecting the lungs. Most common pathogens are Pneumocystis jiroveci, Mycobacterium avium-intracellulare complex, Streptococcus pneumoniae, Haemophilus species. Less frequent pathogens are Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, cytomegalovirus (CMV), and Toxoplasma gondii. Chemotherapy-induced immunodeficiency may lead to severe lung infections. Pathogens commonly associated with lung infectioins are bacteria (like Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Nocardia species), viruses (eg, respiratory syncytial virus, parainfluenza virus, influenza virus A and influenza B, and cytomegalovirus), and fungi (eg, Aspergillus, Fusarium, and Mucorales species, and Pneumocystis jirovecii). Bacteria such as S. aureus , P. aeruginosa , Stenotrophomonas maltophilia , and Burkholderia cepacia complex, are the most common pathogens involved in pulmonary infections immediately after solid organ transplantation, especially heart and lung. ESKAPE pathogens ( Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) especially cause pulmonary infections after lung transplant. Due to the immunosuppression, infections from other opportunistic pathogens such as Cytomegalovirus (CMV) can also occur after solid organ transplantation. In the early phase following hematopoietic stem cell transplantation (HSCT), the majority of pulmonary infections are due to bacteria, for example, S. pneumoniae , Klebsiella , Gram-negative bacilli, and S. aureus . Up to three weeks following HSCT, which is the neutropenic phase, fungi, especially Aspergillus spp. are a common cause of infections, while CMV infections can occur up to three months following HSCT. Pneumocystis pneumonia (PCP) is uncommon after HSCT except in the setting of graft-vs-host disease. [2] [3] Following allogeneic cell transplantation, pulmonary infections due to Fusarium species can also occur, which are seen exclusively in the severely immunocompromised. [4] Bacteria have been the most commonly isolated pathogens, although viral and fungal pathogens are potentially found in immunocompromised hosts (patients on chronic immunosuppressed medications, solid organ and bone marrow transplant recipients). In general, the distribution of microbial pathogens varies among institutions, partly because of differences in patient population and local patterns of anti microbial resistance in hospitals and critical care units' Common bacterial pathogens include aerobic GNB, such as Pseudomonas aeruginosa, Acinetobacter baumanii, Klebsiella pneumoniae, Escherichia coli as well as gram-positive organisms such as Staphylococcus aureus. In patients with an early onset pneumonia (within 5 days of hospitalization), they are usually due to anti microbial-sensitive bacteria such as Enterobacter spp, E. coli, Klebsiella spp, Proteus spp, Serratia mare scans, community pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, and methicillin-sensitive S. Due to their poor immune response, patients with HIV and those with immunosuppression for other causes, such as malignancy, autoimmune disease, or iatrogenic due to underlying condition or organ transplant patients, require prophylaxis for numerous pathogens. These pathogens include: Aspergillus species Candida albicans Clostridium difficile Coccidioides immitis Cryptococcus neoformans Cytomegalovirus Histoplasma capsulatum Legionella pneumophila Microsporidium Mycobacterium avium complex Mycobacterium tuberculosis Pseudomonas aeruginosa Salmonella Staphylococcus aureus Streptococcus pneumoniae Streptococcus pyogenes Toxoplasma gondii [2] [3] [5] A total of 32 patients with mycoses other than cavity-formed aspergilloma were reviewed. The main pathogenic fungi were Aspergillus in 14, Candida in 8, Cryptococcus in 4, Trichosporon in 4 and Mucor in 2. Coinfection by two species was detected in 3 cases: Trichosporon and Aspergillus in 2 and Aspergillus and Candida in 1. The underlying diseases were hematologic malignancies in all cases except 1 case of lung cancer. The hematologic malignancies were mostly leukemias of various types. Cryptococcosis developed in patients given long-term corticosteroid treatment but not in leukemic patients. All cases of aspergillosis, candidiasis and mucormycosis were due to nosocomial infection. On the other hand, 3 of 4 cases of cryptococcosis or trichosporonosis were attributable to community-acquired infection. Two of 4 trichosporonosis cases were considered to have been acquired during 2-day home stays. The diagnosis of pulmonary mycosis was made pathologically in 18 and clinically in 14 cases. Of the latter, 6 cases had an air-crescent sign on chest X-ray films and 8 cases were culture-positive. Extrapulmonary involvement was seen in all 16 cases of candidiasis, cryptococcosis and trichosporonosis but not in 10 of 14 aspergillosis cases. Severe granulocytopenia was present in all cases except 4 cases of cryptococcosis and 3 cases of aspergillosis. Chest X-ray findings of aspergillosis were of two types: one was an air-crescent sign which was noted in the recovery phase from leukopenia and the other was gradually enlarging consolidation which was bound by the interlobar fissure and progressed to lobar penumonia. A diffuse granular shadow was not characteristic of any fungus species.(ABSTRACT TRUNCATED AT 250 WORDS) Imaging modalities for evaluation of pneumonia include: Chest X-ray (CXR). This is the first-line imaging of choice in the evaluation of a suspected case of pneumonia. Posteroanterior (PA) and lateral radiographs should be obtained. However, CXR may be normal for up to 72 hours in immunocompromised patients despite having symptoms. Computed tomography (CT) of the chest should be obtained in patients with high suspicion of pneumonia and normal findings on CXR. In neutropenic patients, CXR will have minimal or no abnormalities and so performing a CT scan is highly recommended. Other investigations for specific etiologies include: Urine antigen testing for pneumococcus and Legionella ELISA and PCR for viruses such as Herpes Simplex Virus (HSV), Influenza A and B, and Cytomegalovirus (CMV) Serum antigen testing for Cryptococcus and Aspergillus Beta-D-glucan testing if a fungal pathogen is suspected. [2] [8] [17] [20] Types Bacterial pneumonia: The majority of cases related to various rod shaped gram-negative organisms (52%) and Staphylococcus aureus (19%), usually of the MRSA type. Others are Haemophilus spp. (5%). In the ICU results were S. aureus (17.4%), Pseudomonas aeruginosa (17.4%), Klebsiella pneumoniae and Enterobacter spp. (18.1%), and Haemophilus influenzae (4.9%). Viral pneumonia: influenza and respiratory syncytial virus and, in the immunocompromised host, cytomegalovirus – cause 10–20% of infections. Ventilator-associated pneumonia Recurrent pneumonia is typical, predominately due to S. aureus , and less frequently due to Streptococcus pneumoniae, and Haemophilus. It can get complicated with the development of recurrent lung abscesses, bronchiectasis, and pneumatoceles. These pneumatoceles can get colonized with Aspergillus and Pseudomonas . Superinfection with Pneumocystis carinii [5] was also reported. Neutrophil-specific granule deficiency ( previously known as lactoferrin deficiency) is a rare congenital immunodeficiency characterized by an increased risk for pyogenic infections due to defective production of specific granules and gelatinase granules in patient neutrophils. Symptoms and signs Atypical infections are the key clinical manifestation of SGD. Within the first few years of life, patients will experience repeated pyogenic infections by species such as Staphylococcus aureus, Pseudomonas aeruginosa or other Enterobacteriaceae, and Candida albicans. Cutaneous ulcers or abscesses and pneumonia and chronic lung disease are common. Patients may also develop sepsis, mastoiditis, otitis media, and lymphadenopathy. Infants may present with vomiting, diarrhea, and failure to thrive. Studying the proven and probable invasive pulmonary aspergillosis (IPA) cases of some hospitals in Shanghai to provide evidence for the improvement of IPA clinical diagnosis and therapy. Forty-nine IPA cases were retrospectively analyzed for demography data, host factors, underlying conditions, chest CT, microorganism and histopathology examination, as well as therapy and clinical outcome. Of 49 subjects including 19 (38.8%) proven and 30 (61.2%) probable IPA, 3 patients (6.1%) had no host factors, 25 patients (51.0%) had IPA associated host factors and underlying conditions, while 21 patients (42.9%) had uncertain fundamental diseases. Chest CT evaluation demonstrated that radiological lesions include nodules in 29 patients, patching in 15, mass in 12, consolidation in 10, cavitation in 34, Halo sign in 19, air bronchogram in 18, crescentic sign in 6, bilateral in 33 and multifocal lesions in 38. The yielding rate of fungus culture in sputum was 26.5% (13/49), and in bronchoalveolar lavage fluid was 66.7% (10/15). Eleven of thirty-six patients (30.6%) had positive results of serum galactomannan antigen tests. Nineteen of twenty-one patients (90.5%) were proven as IPA by lung histologic examinations. Aspergillus fumigatus was the most common pathogen 81.0% (17/21). The responding rate to initial anti-fungus therapy was 50% (21/42). Our study suggests that in IPA patients, bilateral, multifocal and nodular lesion could be the most common radiological characteristic, while Halo and crescentic sign occur occasionally. Invasive technologies are more valuable to IPA diagnosis. Defense against infections PGLYRP2 plays a limited role in host defense against infections. PGLYRP2-deficient mice are more sensitive to Pseudomonas aeruginosa-induced keratitis and Streptococcus pneumoniae-induced pneumonia and sepsis. However, PGLYRP2-deficient mice did not show a changed susceptibility to systemic Escherichia coli, Staphylococcus aureus, and Candida albicans infections or intestinal Salmonella enterica infection, although the latter was accompanied by increased inflammation in the cecum. Although PGLYRP2 is not directly bacteriolytic, it has antibacterial activity against both Gram-positive and Gram-negative bacteria and Chlamydia trachomatis. Maintaining microbiome Mouse PGLYRP2 plays a role in maintaining healthy microbiome, as PGLYRP2-deficient mice have significant changes in the composition of their intestinal microbiome, which affect their sensitivity to colitis. The aim of this study is to determine the aetiology and characteristics of pulmonary cavities that developed in patients recovering from COVID-19 infection. Between 1<supst</sup May 2021 and 30<supst</sup June 2021, we found 9 post COVID-19 patients who developed lung cavities on chest radiograph or CT during the follow-up period. These patients underwent routine blood examination, sputum examination and bronchoscopy to identify the aetiologies for the lung cavities. The duration from the onset of COVID-19 symptoms to the detection of lung cavities ranged from 18 to 82 days. Out of 7 patients, 4 had recovered from severe COVID-19 disease, 2 from moderate and 1 from mild disease. After the diagnostic workup, 5 patients were found to have COVID-19 associated pulmonary aspergillosis (CAPA), 1 patient with mucormycosis and 1 patient with mycobacterium infection. Two patients with CAPA also had bacterial infection; sputum culture from both these patients grew Klebsiella pneumonia. Lung cavities can develop in patients recovering from COVID-19 pneumonia and fungal infection is the most common cause for such cavities. To assess the clinical, radiologic and microbiological features of lung cavitation and HIV infection. Evaluation of the differences related to this disease in the last years. Retrospective review of all patients with lung cavitation and HIV infection admitted at our hospital from January 1989 until December 1994 and prospective study of all patients with the same characteristics during 1995 and 1996. Lung cavitation was defined as any parenchymal lesion, with air content, visible in a simple X-ray and greater than 1 cm of diameter. Criteria for confirmed, probable or possible diagnosis were defined. 78 cases of lung cavitation have been identified in 73 patients. The radiologic patterns included unilobar and multilobular involvement in 31 and 47 cases, respectively. Cavities were multiple and single in 40 and 38 cases respectively. Findings with fine needle aspiration biopsy (FNAB) were diagnostic in 11 out of 14 cases. A clinical diagnosis was performed in all 78 cases, with microbiological results in 69 cases (88.5%): Mycobacterium tuberculosis in 20, Pneumocystis carinii in nine, Pseudomonas aeruginosa in nine, Staphylococcus aureus in eight (5 endocarditis with cavitary septic emboli), Rhodococcus equi in six, P. aeruginosa and S. aureus in three, Salmonella enteritidis in three, Cryptococcus neoformans in two, Aspergillus fumigatus in two and others in 7 cases. Confirmed, probable and possible diagnosis was considered in 54, 15 and 9 cases, respectively. Thirteen episodes of spontaneous pneumothorax were found. The lung cavitation rate is low, compared with the number of admissions related to HIV infection; nevertheless, many of them are in close relationship with HIV infection, and most of them are caused by treatable infections. It is important to know the clinical and radiological characteristics, in order to establish an early diagnosis and an appropriate therapy. Pseudomonas aeruginosa is becoming an important cause of lung cavitation. In our series, spontaneous pneumo-thorax was not related to Pneumocystis carinii pneumonia in 61.5% of cases. The aims of this study were to compare the high-resolution computed tomography (HRCT) findings of pulmonary infections in immunocompromised patients and to assess the usefulness of HRCT in the differential diagnosis of these infections. A total of 345 immunocompromised patients with pulmonary infections were included in this study. The diagnoses of the patients consisted of bacterial pneumonia (123 cases), pneumocystis pneumonia (PCP) (105 cases), fungal pneumonia (80 cases), tuberculosis (15 cases), cytomegalovirus pneumonia (11 cases), and septic embolism (11 cases). Two chest radiologists retrospectively evaluated the computed tomography (CT) images, which consisted of 22 findings including ground-glass attenuation, consolidation, nodules, and thickening of the bronchial wall and interlobular septum. Associations between the CT criteria and infections were investigated using χ<sup2</sup test; multiple logistic regression analyses were conducted to identify the significant indicator for each infection. The area under the curve (AUC) of each model was calculated. Bronchial wall thickening was a significant indicator for bacterial pneumonia (p = 0.002; odds ratio [OR], 2.341; 95% confidence interval [CI], 1.378-3.978). The presence of a mosaic pattern and the absence of nodules were significant indicators for PCP (p &lt; 0.001; OR, 9.808; 95% CI, 4.883-13.699, and p &lt; 0.001; OR, 6.834; 95% CI, 3.438-13.587, respectively). The presence of nodules was a significant indicator for fungal infection (p = 0.005; OR, 2.531; 95% CI, 1.326-4.828). The AUC for PCP was the highest (0.904). HRCT findings are potentially useful for the differential diagnosis of some pulmonary infections in immunocompromised patients. • Differential diagnosis of pulmonary infections in immunocompromised patients could be established with the help of high-resolution computed tomography. • Bronchial wall thickening was a significant indicator for bacterial pneumonia. • The presence of a mosaic pattern and the absence of nodules were significant indicators for pneumocystis pneumonia. Patients with defective humoral immunity are at increased risk of infection from encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae . Those with neutropenia are predisposed to infections from S. aureus , Gram-negative bacilli (including Pseudomonas aeruginosa ), as well as fungi such as Aspergillus spp. Impaired T-cell immunity can lead to a range of infections from: Viruses, such as Cytomegalovirus Intracellular bacteria, for example, Legionella Acid-fast bacteria such as Mycobacteria and Nocardia Fungi, such as Pneumocystis jirovecii , Aspergillus spp., Coccidioides immitis , Cryptococcus spp., Blastomyces dermatitidis , Histoplasma capsulatum , etc [3] Interleukin-1 receptor-associated kinase deficiency is an inherited disorder of the immune system. This immunodeficiency leads to recurrent infections caused by the pyogenic bacteria, for example Streptococcus pneumoniae, Staphylococcus aureus and Pseudomonas aeruginosa, but not by other infectious agents. Most patients with IRAK-4 deficiency suffer from invasive bacterial infections, which can cause sepsis, meningitis or they affect the joints that can lead to inflammation and arthritis. These invasive infections can also cause areas of tissue breakdown and pus production (abscesses) on internal organs. In addition, patients are characterized by infections of the upper respiratory tract, eyes or skin. Although fever is a common reaction to bacterial infections, many people with IRAK-4 deficiency do not at first develop a high fever in response to these infections, even if the infection is severe. Most patients have their first bacterial infection before age 2, and the infections can The purpose of this study was to establish the diagnostic value of central hypointensity (\"hypodense sign\") in lung consolidations or nodules, in severely immunocompromised or neutropenic patients, suspected of having invasive pulmonary aspergillosis (IPA), and to assess its recognition on unenhanced CT scans. Serial CT scans of the lung were retrospectively reviewed in 43 consecutive immunosuppressed patients with IPA, and assessed for the presence of the hypodense sign using standard mediastinal and lung windowing settings, as well as a special, narrower window setting (width 110-140 HU; level 15-40 HU). The temporal relationship between the occurrence of the first CT-finding suspicious of IPA and the appearance of the hypodense sign, as well as between this and the occurrence of the crescent sign, cavitation or reduction in lesion size, was evaluated. Additionally, CT-scans from 89 immunocompromised patients with viral (n=45) or bacterial (n=44) pneumonia, investigated in the same time period at our institution were reviewed, with respect to the presence of the \"hypodense\" sign. Unenhanced CT scans revealed the hypodense sign in 11 neutropenic patients and 2 severely immunocompromised patients, out of a total of 43 patients with IPA evaluated in this study (30.2%). The mean time between the appearance of the first CT-findings of IPA (large nodule or consolidation +/- positive halo sign) and the hypodense sign was 7.8 days, while the time interval between the hypodense sign and the occurrence of crescent sign, cavitation, or decrease of the lesion's size was 8.3 days. The hypodense sign did not occur in any of the patients with viral or bacterial pneumonia, in the control series. We consider the hypodense sign to be a supplementary tool in the diagnosis of IPA. Its sensitivity was low in our series, but the high specificity makes it valuable in predicting IPA, anticipating the occurrence of cavitation or crescent sign, which are considered specific, but late findings of IPA. The hypodense sign is recognizable also on unenhanced CT, when a narrower lung window setting is used. Types Hospital-acquired pneumonia Ventilator-associated pneumonia Urinary tract infection Gastroenteritis Puerperal fever Central line-associated blood stream infection Organisms Staphylococcus aureus Methicillin resistant Staphylococcus aureus Candida albicans Pseudomonas aeruginosa Acinetobacter baumannii' Stenotrophomonas maltophilia Clostridium difficile Escherichia coli Tuberculosis Vancomycin-resistant Enterococcus Legionnaires' disease Cause Transmission In-dwelling catheters have recently been identified with hospital acquired infections. To deal with this complication, procedures are used, called intravascular antimicrobial lock therapy that can reduce infections that are unexposed to blood-borne antibiotics. Introducing antibiotics, including ethanol, into the catheter (without flushing it into the bloodstream) reduces the formation of biofilms. Overwhelming pneumonias remain an important cause of morbidity and mortality. These illnesses may be rapidly fatal; thus, many patients are treated empirically. Although the various etiologic agents cannot be differentiated on the basis of radiographic appearance, epidemiologic information may give a clue to the cause. Community-acquired overwhelming pneumonias are usually due to pyogenic bacteria (especially Streptococcus pneumoniae), mycoplasma, mycobacteria, and fungi. Hospital-acquired pneumonias are usually due to aerobic gram-negative bacilli. If the patient is immunocompromised, Pneumocystis carinii, Candida, and Aspergillus must be considered. Choice of optimal antimicrobial therapy requires that a specific etiology be identified. Gram's stain of sputum is often helpful in the diagnosis of community-acquired pneumonia. Invasive diagnostic techniques such as bronchoscopy and open lung biopsy are often required in nosocomial pneumonias and pneumonias in immunocompromised patients. Bacterial Bacterial keratitis. Bacterial infection of the cornea can follow from an injury or from wearing contact lenses. The bacteria involved are Staphylococcus aureus and for contact lens wearers, Pseudomonas aeruginosa. Pseudomonas aeruginosa contains enzymes that can digest the cornea. Fungal Fungal keratitis, caused by Aspergillus fumigatus and Candida albicans (cf. Fusarium, causing an outbreak of keratitis in 2005–2006 through the possible vector of Bausch & Lomb ReNu with MoistureLoc contact lens solution) Amoebic Acanthamoebic keratitis Amoebic infection of the cornea is a serious corneal infection, often affecting contact lens wearers. It is usually caused by Acanthamoeba. On May 25, 2007, the U.S. Center for Disease Control issued a health advisory due to increased risk of Acanthamoeba keratitis associated with use of Advanced Medical Optics Complete Moisture Plus Multi-Purpose eye solution. Although patients with severe immunodeficiency and hematological malignancies has been considered at highest risk for invasive fungal infection, patients with severe pneumonia due to influenza, and severe acute respiratory syndrome coronavirus (SARS-CoV) are also at a higher risk of developing invasive pulmonary aspergillosis (IPA). Recently, reports of IPA have also emerged among SARS-CoV-2 infected patients admitted to intensive care units (ICUs). Here, we report a fatal case of probable IPA in an acute myeloid leukemia patient co-infected with SARS-CoV-2 and complicated by acute respiratory distress syndrome (ARDS). Probable IPA is supported by multiple pulmonary nodules with ground glass opacities which indicate halo sign and positive serum galactomannan results. Screening studies are needed to evaluate the prevalence of IPA in immunocompromised patients infected with SARS-CoV-2. Consequently, testing for the presence of Aspergillus in lower respiratory secretions and galactomannan in consecutive serum samples of COVID-19 patients with timely and targeted antifungal therapy based on early clinical suspicion of IPA are highly recommended.\nHere is the question:\nINFECTIOUS: An immunodeficient patient who presents a pneumonia with meniscus halo sign or crescentic contour on chest X-ray/CT suggests infection by a microorganism:\nHere are the potential choices:\n1. Staphylococcus aureus.\n2. Streptococcus pneumoniae.\n3. Candida albicans.\n4. Pseudomonas aeruginosa.\n5. Aspergillus fumigatus.\nThe correct answer is: 5. Aspergillus fumigatus."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Amoxicillin, 500 mg PO q8h × 60 d, likely to be effective if strain is penicillin sensitive Active disease: Ciprofloxacin, 400 mg IV q12h or doxycycline, 100 mg IV q12h plus Clindamycin, 900 mg IV q8h and/or rifampin, 300 mg IV q12h; switch to PO when stable × 60 d total plus Raxibacumab, 40 mg/kg IV over 2.25 h; diphenhydramine to reduce reaction Gentamicin, 2.0 mg/kg IV loading then 1.7 mg/kg q8h IV or Streptomycin, 1.0 g q12h IM or IV Alternatives include doxycycline, 100 mg bid PO or IV; chloramphenicol, 500 mg qid PO or IV Supportive measures; consideration for cidofovir, tecovirimat, antivaccinia immunoglobulin Streptomycin, 1 g IM bid or Gentamicin, 5 mg/kg per day div q8h IV for 14 days or Doxycycline, 100 mg IV bid or Chloramphenicol, 15 mg/kg up to 1 g IV qid or Ciprofloxacin, 400 mg IV bid Ribavirin 30 mg/kg up to 2 g × 1, followed by 16 mg/kg IV up to 1 g q6h for 4 days, followed by 8 mg/ kg IV up to 0.5 g q8h × 6 days For outpatient management, amoxicillin (1 g every 8 h) provides effective treatment for virtually all cases of pneumococcal pneumonia. Neither cephalosporins nor quinolones, which are far more expensive, offer any advantage over amoxicillin. Levofloxacin (500–750 mg/d as a single dose) and moxifloxacin (400 mg/d as a single dose) also are highly likely to be effective in the United States except in patients who come from closed populations where these drugs are used widely or who have themselves been treated recently with a quinolone. Clindamycin (600–1200 mg/d every 6 h) is effective in 90% of cases and azithromycin (500 mg on day 1 followed by 250–500 mg/d) or clarithromycin (500–750 mg/d as a single dose) in 80% of cases. Treatment failure resulting in bacteremic disease due to macrolide-resistant isolates has been amply documented in patients given azithromycin empirically. As noted above, rates of resistance to all these antibiotics are relatively low in some countries and much 7. Volume overexpansion with IV fluid administration is not uncommon and contributes to the development of hyperchloremic acidosis during the later stages of treatment of DKA. Volume overexpansion should be avoided. A 25-year-old man with a 6-year history of HIV-AIDS complicated recently by Pneumocystis jiroveci pneumonia (PCP) was treated with intravenous trimethoprim-sulfamethoxazole (20 mg trimethoprim/kg per day). On day 4 of treatment, the following laboratory data were PART 2 Cardinal Manifestations and Presentation of Diseases H2O AQP-2AQP-3, 4 H2O As a result of the increased prevalence of resistant pneumococci, first-line therapy for persons ≥1 month of age is a combination of vancomycin (adults, 30–60 mg/kg per day; infants and children, 60 mg/kg per day) and cefotaxime (adults, 8–12 g/d in 4–6 divided doses; children, 225–300 mg/kg per day in 1 dose or 2 divided doses) or ceftriaxone (adults, 4 g/d in 1 dose or 2 divided doses; children, 100 mg/kg per day in 1 dose or 2 divided doses). If children are hypersensitive to β-lactam agents (penicillins and cephalosporins), rifampin (adults, 600 mg/d; children, 20 mg/d in 1 dose or 2 divided doses) can be substituted for cefotaxime or ceftriaxone. A repeat lumbar puncture should be considered after 48 h if the organism is not susceptible to penicillin and information on cephalosporin sensitivity is not yet available, if the patient’s clinical condition does not improve or deteriorates, or if dexamethasone has been administered and may be compromising clinical evaluation. When Cefoxitin, 2 g q6h; A combination of metronidazole (500 mg q8–12h) plus cefazolin (1–2 g q8h) or cefuroxime (1.5 g q8h) or ceftriaxone (1–2 g q12–24h) or cefotaxime (1–2 g q6–8h) A carbapenem (imipenem, 1 g q8h; meropenem, 1 g q8h; doripenem, 500 mg q8h); Piperacillin-tazobactam, 3.375 g q6hf; A combination of metronidazole (500 mg q8–12h) plus an antipseudomonal cephalosporin (cefepime, 2 g q8–12h; ceftazidime, 2 g q8h) or an antipseudomonal fluoroquinolone (ciprofloxacin, 400 mg q12h; levofloxacin, 750 mg q24h) — Dexamethasone (0.15 mg/ kg IV q6h for 2–4 d) should be added for patients with suspected or proven pneumococcal meningitis, with the first dose administered 10–20 min before the first dose of antibiotics. If MRSA is a consideration, add vancomycin (15 mg/kg q12hb) or linezolid (600 mg q12h); daptomycin should not be used in patients with pneumonia. If MRSA is a consideration, add vancomycin (15 mg/kg q12hb). 159, 201, and pathogen-specific chapters A 15-year-old boy with T-cell acute lymphoblastic leukemia (ALL) (FAB L1), diagnosed in 1995, received combination chemotherapy consisting of 6 weeks of induction (vincristine, epirubicin, L-asparaginase, prednisolone) and 2 weeks of consolidation (cytosine arabinosides, etoposide). After achieving remission, for further maintenance of remission, he was treated with 14 cycles of intensive chemotherapy consisting of 6-MP, 10 mg/kg orally on the first 4 days, and cyclophosphamide, 1200 mg/m2, vincristine, 1.5 mg/m2, epirubicin, 15 mg/m2, and cytosine arabinoside, 40 mg/m2, intravenously on days 4, 11, 39, and 40, respectively. On day 18 of each cycle, he received intravenous methotrexate (MTX) infusion in a total dose of 150 mg/m2 plus oral leucovorin (30 mg/m2 ) rescue 36 h after starting MTX therapy. In addition, oral trimethoprim-sulfamethoxazole was given regularly to prevent Pneumocystis carinii infection. The patient achieved remission during the first course of treatment, but 8 months later the disease relapsed. He then received four doses of MTX (800 mg intravenously) plus leucovorin rescue in the following 4 months. During the last MTX therapy, small hemorrhagic bullae were found on the lateral side of the right ankle, but subsided after a few days. Due to partial remission of the disease, he was admitted again in January 1999 for high-dose MTX therapy. An initial hemogram on admission revealed hemoglobin 7.2 g/dL, white cell count 15,200/mm3, platelet count 153/mm3, blood creatinine 0.5 mg/dL, and alanine leucine aminotransferase (ALT) 20 U/L. He received 8500 mg of MTX (5000 mg/m2 ) as a continuous intravenous infusion for 24 h. Thirty-six hours after the start of MTX infusion, leucovorin (30 mg, intravenous) rescue was initiated every 6 h for 3 days. Another preventive measure to cover MTX toxicity included aggressive intravenous fluid replacement (4 L/m2 /day) and the addition of 25 meq/L sodium bicarbonate to the intravenous fluid to alkalinize the urine. Concurrent medication included 6-MP (50 mg) once daily and trimethoprim-sulfamethoxazole (120 mg, 600 mg) twice daily every other day. Plasma MTX levels were 52.36 micromol/L 24 h after MTX infusion, 1.87 micromol/L after 48 h, 0.57 micromol/L after 72 h, and 0.41 micromol/L after 96 h. These indicated delayed MTX plasma clearance. The blood creatinine level was mildly elevated from 0.5 mg/dL to 0.7 mg/dL. Thirty-six hours after the administration of MTX, the patient developed an erythematous painful swelling on the right middle finger. The erythema, with subsequent large bulla formation, progressed to all the fingers, toes, palms, and the soles of the feet. Some erythematous to hemorrhagic papules also appeared on the bilateral elbows. Subsequently, diffuse tender erythema with extensive erosions and focal tiny pustules developed on the back, abdomen, proximal extremities, and face (Fig. 1a,b). A positive Nikolsky's sign was also present. A biopsy specimen of the right dorsal hand lesion revealed parakeratosis, detached acanthotic epidermis with scattered necrotic keratinocytes, dyskeratotic cells and nuclear atypia, neutrophilic exocytosis, and many neutrophils in the papillary dermis (Fig. 2). The skin condition deteriorated rapidly. Toxic epidermal necrolysis-like lesions involved 90% of the total body surface on the fifth day after MTX infusion. Mucositis, diarrhea, involuntary tremor, fever, and chills were noted. The patient was then sent to the burn unit for intensive skin care. Ten days after MTX therapy, profound agranulocytosis and thrombocytopenia (white cell count 100/mm3, platelets 14,000/mm3, and hemoglobin 5.6 g/dL) were found. The patient was then started on granulocyte colony stimulation factor (G-CSF, 5 microg/kg/day), but his general condition deteriorated rapidly and he died 6 days later due to septic shock and multiple organ failure. 12 Alternative treatments for mild to moderate PCP include dapsone/ trimethoprim, clindamycin/primaquine, and atovaquone. IV pentami dine is the treatment of choice for severe disease in the patient unable 8 to tolerate TMP/SMX. For patients with a Pao <70 mmHg or with an 6 a–a gradient >35 mmHg, adjunct glucocorticoid therapy should be used in addition to specific antimicrobials. Overall, treatment should be continued for 21 days and followed by secondary prophylaxis. 2 Prophylaxis for PCP is indicated for any HIV-infected individual who 0 has experienced a prior bout of PCP, any patient with a CD4+ T cell count of <200/μL or a CD4 percentage <15, any patient with unex- Cefiderocol is a novel siderophore cephalosporin antibiotic with broad coverage against difficult-to-treat Gram-negative bacteria, including those resistant to carbapenems. Its activity against <iStenotrophomonas maltophilia</i was investigated <iin vitro</i against clinical isolates and in lung infection models using strains either resistant (SR202006) or susceptible (SR201934, SR200614) to trimethoprim-sulfamethoxazole. Cefiderocol demonstrated potent <iin vitro</i activity against all 217 <iS. maltophilia</i clinical isolates tested (MIC<sub50</sub, 0.063 μg/ml; MIC<sub90</sub, 0.25 μg/ml). Cefiderocol also demonstrated low MICs against the trimethoprim-sulfamethoxazole-resistant <iS. maltophilia</i strains (i.e., SR202006; MIC, 0.125 μg/ml). In a neutropenic mouse lung infection model, cefiderocol (30 mg/kg body weight and 100 mg/kg) demonstrated a significant, dose-dependent reduction in the lung viable bacteria cell count compared with untreated controls in <iS. maltophilia</i infection and was the only antibiotic tested to show a similar significant effect in a trimethoprim-sulfamethoxazole-resistant <iS. maltophilia</i infection. In immunocompetent rat lung infection models of <iS. maltophilia</i, humanized dosing of cefiderocol (2 g every 8 h) and meropenem (1 g every 8 h) revealed pharmacokinetic profiles similar to those in human subjects, and the humanized cefiderocol dosing significantly reduced the lung viable bacteria cell count compared with baseline controls, which received no intervention. Together, the results from these studies suggest that cefiderocol could provide an effective alternative treatment option for <iS. maltophilia</i infections in the lower respiratory tract, particularly strains resistant to empirical antibiotics, such as trimethoprim-sulfamethoxazole or minocycline. Daptomycin-nonsusceptible (DNS) Staphylococcus aureus is found in difficult-to-treat infections, and the optimal therapy is unknown. We investigated the activity of high-dose (HD) daptomycin plus trimethoprim-sulfamethoxazole de-escalated to HD daptomycin or trimethoprim-sulfamethoxazole against 4 clinical DNS methicillin-resistant S. aureus (MRSA) isolates in an in vitro pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations (10(9) CFU/g). Simulated regimens included HD daptomycin at 10 mg/kg/day for 14 days, trimethoprim-sulfamethoxazole at 160/800 mg every 12 h for 14 days, HD daptomycin plus trimethoprim-sulfamethoxazole for 14 days, and the combination for 7 days de-escalated to HD daptomycin for 7 days and de-escalated to trimethoprim-sulfamethoxazole for 7 days. Differences in CFU/g (at 168 and 336 h) were evaluated by analysis of variance (ANOVA) with a Tukey's post hoc test. Daptomycin MICs were 4 μg/ml (SA H9749-1, vancomycin-intermediate Staphylococcus aureus; R6212, heteroresistant vancomycin-intermediate Staphylococcus aureus) and 2 μg/ml (R5599 and R5563). Trimethoprim-sulfamethoxazole MICs were ≤0.06/1.19 μg/ml. HD daptomycin plus trimethoprim-sulfamethoxazole displayed rapid bactericidal activity against SA H9749-1 (at 7 h) and R6212 (at 6 h) and bactericidal activity against R5599 (at 72 h) and R5563 (at 36 h). A ≥8 log(10) CFU/g decrease was observed with HD daptomycin plus trimethoprim-sulfamethoxazole against all strains (at 48 to 144 h), which was maintained with de-escalation to HD daptomycin or trimethoprim-sulfamethoxazole at 336 h. The combination for 14 days and the combination for 7 days de-escalated to HD daptomycin or trimethoprim-sulfamethoxazole was significantly better than daptomycin monotherapy (P &lt; 0.05) and trimethoprim-sulfamethoxazole monotherapy (P &lt; 0.05) at 168 and 336 h. Combination therapy followed by de-escalation offers a novel bactericidal therapeutic alternative for high-inoculum, serious DNS MRSA infections. No definitive trials have defined the best therapeutic algorithm for patients in whom TMP-SMX treatment for PCP is failing. If no other treatable infectious or noninfectious processes are detected and pulmonary dysfunction appears to be due to PCP alone, many authorities would switch from TMP-SMX to either IV pentamidine or IV clindamycin plus oral primaquine. Some authorities would add the second drug or drug combination to TMP-SMX rather than switching regimens. If patients are not already receiving them, glucocorticoids should be added to the regimen; the dosage and regimen, which are usually chosen empirically, depend on what glucocorticoid regimen (if any) the patient was receiving when PCP therapy was begun. Pathogenesis H. ducreyi is an opportunistic microorganism that infects its host by way of breaks in the skin or epidermis. Inflammation then takes place as the area of infection is inundated with lymphocytes, macrophages, and granulocytes. This pyogenic inflammation causes regional lymphadenitis in the sexually transmitted disease chancroid. Diagnosis Although antigen detection, serology, and genetic amplification methods are sometimes used to diagnose infections with H. ducreyi and the genetic tests have greater sensitivity, they are not widely available, so cultures are currently considered the \"gold standard\" test. Treatment The first line treatments are one of four options : azithromycin 1 g orally in a single dose, ceftriaxone 250 mg intramuscularly in a single dose, ciprofloxacin 500 mg orally 2 times a day for 3 days, or erythromycin base 500 mg orally 3 times a day for 7 days. See also Sexually transmitted disease References <iPneumocystis jirovecii</i pneumonia (PCP) is a common opportunistic infection causing more than 400000 cases annually worldwide. Although antiretroviral therapy has reduced the burden of PCP in persons with human immunodeficiency virus (HIV), an increasing proportion of cases occur in other immunocompromised populations. In this review, we synthesize the available randomized controlled trial (RCT) evidence base for PCP treatment. We identified 14 RCTs that were conducted 25-35 years ago, principally in 40-year-old men with HIV. Trimethoprim-sulfamethoxazole, at a dose of 15-20 mg/kg per day, is the treatment of choice based on historical practice rather than on quality comparative, dose-finding studies. Treatment duration is similarly based on historical practice and is not evidence based. Corticosteroids have a demonstrated role in hypoxemic patients with HIV but have yet to be studied in RCTs as an adjunctive therapy in non-HIV populations. The echinocandins are potential synergistic treatments in need of further investigation. The dosage regimen of vancomycin, teicoplanin and daptomycin remains controversial for critically ill patients undergoing continuous renal replacement therapy (CRRT). Monte Carlo simulation was applied to identify the optimal regimens of antimicrobial agents in patients with methicillin-resistant <iStaphylococcus aureus</i (MRSA) infections based on the mechanisms of different CRRT modalities on drug clearance. The optimal vancomycin dosage for patients received a CRRT doses ≤ 30 mL/kg/h was 20 mg/kg loading dose followed by 500 mg every 8 h, while 1 g every 12 h was appropriate when 35 mL/kg/h was prescribed. The optimal teicoplanin dosage under a CRRT dose ≤ 25 mL/kg/h was four loading doses of 10 mg/kg every 12 h followed by 10 mg/kg every 48 h, 8 mg/kg every 24 h and 6 mg/kg every 24 h for continuous veno-venous hemofiltration, continuous veno-venous hemodialysis and continuous veno-venous hemodiafiltration, respectively. When the CRRT dose increased to 30-35 mL/kg/h, the teicoplanin dosage should be increased by 30%. The recommended regimen for daptomycin was 6-8 mg/kg every 24 h under a CRRT dose ≤ 25 mL/kg/h, while 8-10 mg/kg every 24 h was optimal under 30-35 mg/kg/h. The CRRT dose has an impact on probability of target attainment and CRRT modality only influences teicoplanin. Culture Results Intensive Phase Continuation Phase Extension of Total Treatment Culture positive HRZE for 2 months, daily or intermit-HR for 4 months, daily or 5 d/wk To 9 months, if 2 months of Z is not completed or culture tent (with dose adjustment) or conversion is prolonged and cavitation is evident on plain radiographa HR for 4 months, intermittent (with dose adjustment) Culture negative HRZE for 2 months 2 months To 6 months, if patient is infected with HIV Extrapulmonary HRZE for 2 months HR for 4–7 months, daily or 5 d/wkb To 9–12 months in TB meningitis. Some recommend 9 months for bone/joint TB. Resistant to H QRZEc or, less often, RZES for 6 months … Prolonged culture conversion, cavitation Resistant to R HZEQc (IAd) for 2 months HEQ(S) for 10–16 months Prolonged culture conversion, delayed response Adults: For adults, the recommended dosage of amoxicillin is 750 to 1750 mg/d, divided into doses and administered every 8 to 12 hours. Pediatric: For pediatric patients 3 months and older, the recommended amoxicillin dosage is 20 to 45 mg/kg/d, divided into doses and administered every 8 to 12 hours. H pylori infection (triple therapy): For the treatment of H pylori infection, the recommended dosing for triple therapy involves administering 1 g of amoxicillin, 500 mg of clarithromycin, and 30 mg of lansoprazole twice daily (every 12 hours) for 14 days. H pylori infection (dual therapy): For dual therapy against H pylori infection, the recommended dosing is 1 g of amoxicillin and 30 mg of lansoprazole, each administered 3 times daily. Of the currently available agents, trimethoprim-sulfamethoxazole (TMP-SMX) appears to be an effective alternative for treatment of TE in resource-poor settings where the preferred combination of pyrimethamine plus sulfadiazine is not available. The daily dose of TMP-SMX (one double-strength tablet) that is recommended as the preferred regimen for prophylaxis of PcP is effective against TE. If patients cannot tolerate TMP-SMX, the recommended alternative is dapsone-pyrimethamine, which likewise is effective against PcP. Atovaquone with or without pyrimethamine also can be considered. Prophylactic monotherapy with dapsone, pyrimethamine, azithromycin, clarithromycin, or aerosolized pentamidine is probably insufficient. AIDS patients who are seronegative for Toxoplasma and are not receiving prophylaxis for PcP should be retested for IgG antibody to Toxoplasma if their CD4+ T cell count drops to <100/µL. If seroconversion has taken place, then the patient should be given prophylaxis as Medical treatment Medical treatment entails low dose antibiotic prophylaxis until resolution of VUR occurs. Antibiotics are administered nightly at half the normal therapeutic dose. The specific antibiotics used differ with the age of the patient and include: Amoxicillin or ampicillin – infants younger than 6 weeks Trimethoprim-sulfamethoxazole (co-trimoxazole) – 6 weeks to 2 months After 2 months the following antibiotics are suitable: Nitrofurantoin {5–7 mg/kg/24hrs} Nalidixic acid Bactrim Trimethoprim Cephalosporins Urine cultures are performed 3 monthly to exclude breakthrough infection. Annual radiological investigations are likewise indicated. Good perineal hygiene, and timed and double voiding are also important aspects of medical treatment. Bladder dysfunction is treated with the administration of anticholinergics. Rhodococcus equi is a facultative intracellular, obligate aerobe, partially acid fast, gram-positive pathogen that causes cavitary pneumonia in animals and immunocompromised humans. We describe 8 cases of R. equi pneumonia in patients with advanced HIV infection (CD4 counts less than 100/mm3), 7 males and 1 female (mean age 30.8 years), observed between 1991 and 1994. A history of exposure to farm animals was found in 4 patients. The most common presenting symptoms were fever, malaise, dyspnea, cough and hemoptysis, chest pain and weight loss. Chest x-rays showed tipical focal area of consolidation throughout the lung (3 upper, 3 lower and 2 middle fields) associated with cavitation in 4 cases. The definitive diagnosis in our hands was delayed only in the first case in which conflicting data resulted from blood culture (Bacillus sp. isolation) and sputum examen (acid-fast bacterium in the Ziehl-Neelsen stain). Final microbiological diagnosis depended on blood cultures (n=5), bronchoalveolar lavage (n=1), sputum (n=1), lung biopsy (n=1). All the patients were treated with prolonged courses of antibiotic therapy (259 days, range 120-340 in 6 dead patients; more than one year and two months respectively in two patients alive). According to microbial susceptibility TMP/SMX, vancomycin, imipenem, rifampin, aminoglycosides, macrolides and quinolons were more frequently used. Resistant R. equi mutants were selected during therapy with TMP/SMX (n=2), rifampin (n=1) and erythromycin (n=1). Five patient underwent pulmonary lobectomy after exclusion of metastatic bacterial lesions. Only 2 patients are alive, one after 365 days of antibiotic therapy and upper lung lobectomy, one after 60 days of antibiotic therapy. Optimal antimicrobial therapy and the role of surgery remain, in our experience, uncertain. Maintenance phase After the 5–7 day loading phase, muscle creatine stores are fully saturated and supplementation only needs to cover the amount of creatine broken down per day. This maintenance dose was originally reported to be around 2–3 g/day (or 0.03 g/kg/day), however, recent studies have suggested 3–5 g/day maintenance dose to maintain saturated muscle creatine. Absorption Endogenous serum or plasma creatine concentrations in healthy adults are normally in a range of 2–12 mg/L. A single 5 gram (5000 mg) oral dose in healthy adults results in a peak plasma creatine level of approximately 120 mg/L at 1–2 hours post-ingestion. Creatine has a fairly short elimination half life, averaging just less than 3 hours, so to maintain an elevated plasma level it would be necessary to take small oral doses every 3–6 hours throughout the day. Clearance It has been shown that once supplementation of creatine stops, muscle creatine stores return to baseline in 4–6 weeks.\nHere is the question:\nINFECTIOUS DISEASES AND MICROBIOLOGY: A 45-year-old man consults for a productive cough, pleuritic pain in the right flank and fever of 48 h of evolution. He has a baseline O2 saturation of 88% and rales in the right base. Chest X-ray shows a right basal consolidation. She has a history of HIV infection well controlled with antiretroviral drugs (CD4 lymphocytes 550 ce/uL and undetectable HIV viral load). Which of the following empirical antimicrobial treatments do you consider most appropriate?\nHere are the potential choices:\n1. Cefiriaxone 2 g and azithromycin 500 mg every 24 hours.\n2. Cefiriaxone 2 g, azithrornicin 500 mg every 24 h and trimethoprim-sulfamethoxazole 5 mg/kg/8 h (based on trimethoprim doses).\n3. Methyl-prednisolone 40 mg/day, cefiriaxone 2 g IV 124 h and trimethoprim-sulfamethoxazole 5 mg/kg/8 h (based on trimethoprim doses).\n4. Meropenem I g/8 h and vancomycin I g/l2 h.\nThe correct answer is: ",
        "gold_answer": "1 Cefiriaxone 2 g and azithromycin 500 mg every 24 hours.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Amoxicillin, 500 mg PO q8h × 60 d, likely to be effective if strain is penicillin sensitive Active disease: Ciprofloxacin, 400 mg IV q12h or doxycycline, 100 mg IV q12h plus Clindamycin, 900 mg IV q8h and/or rifampin, 300 mg IV q12h; switch to PO when stable × 60 d total plus Raxibacumab, 40 mg/kg IV over 2.25 h; diphenhydramine to reduce reaction Gentamicin, 2.0 mg/kg IV loading then 1.7 mg/kg q8h IV or Streptomycin, 1.0 g q12h IM or IV Alternatives include doxycycline, 100 mg bid PO or IV; chloramphenicol, 500 mg qid PO or IV Supportive measures; consideration for cidofovir, tecovirimat, antivaccinia immunoglobulin Streptomycin, 1 g IM bid or Gentamicin, 5 mg/kg per day div q8h IV for 14 days or Doxycycline, 100 mg IV bid or Chloramphenicol, 15 mg/kg up to 1 g IV qid or Ciprofloxacin, 400 mg IV bid Ribavirin 30 mg/kg up to 2 g × 1, followed by 16 mg/kg IV up to 1 g q6h for 4 days, followed by 8 mg/ kg IV up to 0.5 g q8h × 6 days For outpatient management, amoxicillin (1 g every 8 h) provides effective treatment for virtually all cases of pneumococcal pneumonia. Neither cephalosporins nor quinolones, which are far more expensive, offer any advantage over amoxicillin. Levofloxacin (500–750 mg/d as a single dose) and moxifloxacin (400 mg/d as a single dose) also are highly likely to be effective in the United States except in patients who come from closed populations where these drugs are used widely or who have themselves been treated recently with a quinolone. Clindamycin (600–1200 mg/d every 6 h) is effective in 90% of cases and azithromycin (500 mg on day 1 followed by 250–500 mg/d) or clarithromycin (500–750 mg/d as a single dose) in 80% of cases. Treatment failure resulting in bacteremic disease due to macrolide-resistant isolates has been amply documented in patients given azithromycin empirically. As noted above, rates of resistance to all these antibiotics are relatively low in some countries and much 7. Volume overexpansion with IV fluid administration is not uncommon and contributes to the development of hyperchloremic acidosis during the later stages of treatment of DKA. Volume overexpansion should be avoided. A 25-year-old man with a 6-year history of HIV-AIDS complicated recently by Pneumocystis jiroveci pneumonia (PCP) was treated with intravenous trimethoprim-sulfamethoxazole (20 mg trimethoprim/kg per day). On day 4 of treatment, the following laboratory data were PART 2 Cardinal Manifestations and Presentation of Diseases H2O AQP-2AQP-3, 4 H2O As a result of the increased prevalence of resistant pneumococci, first-line therapy for persons ≥1 month of age is a combination of vancomycin (adults, 30–60 mg/kg per day; infants and children, 60 mg/kg per day) and cefotaxime (adults, 8–12 g/d in 4–6 divided doses; children, 225–300 mg/kg per day in 1 dose or 2 divided doses) or ceftriaxone (adults, 4 g/d in 1 dose or 2 divided doses; children, 100 mg/kg per day in 1 dose or 2 divided doses). If children are hypersensitive to β-lactam agents (penicillins and cephalosporins), rifampin (adults, 600 mg/d; children, 20 mg/d in 1 dose or 2 divided doses) can be substituted for cefotaxime or ceftriaxone. A repeat lumbar puncture should be considered after 48 h if the organism is not susceptible to penicillin and information on cephalosporin sensitivity is not yet available, if the patient’s clinical condition does not improve or deteriorates, or if dexamethasone has been administered and may be compromising clinical evaluation. When Cefoxitin, 2 g q6h; A combination of metronidazole (500 mg q8–12h) plus cefazolin (1–2 g q8h) or cefuroxime (1.5 g q8h) or ceftriaxone (1–2 g q12–24h) or cefotaxime (1–2 g q6–8h) A carbapenem (imipenem, 1 g q8h; meropenem, 1 g q8h; doripenem, 500 mg q8h); Piperacillin-tazobactam, 3.375 g q6hf; A combination of metronidazole (500 mg q8–12h) plus an antipseudomonal cephalosporin (cefepime, 2 g q8–12h; ceftazidime, 2 g q8h) or an antipseudomonal fluoroquinolone (ciprofloxacin, 400 mg q12h; levofloxacin, 750 mg q24h) — Dexamethasone (0.15 mg/ kg IV q6h for 2–4 d) should be added for patients with suspected or proven pneumococcal meningitis, with the first dose administered 10–20 min before the first dose of antibiotics. If MRSA is a consideration, add vancomycin (15 mg/kg q12hb) or linezolid (600 mg q12h); daptomycin should not be used in patients with pneumonia. If MRSA is a consideration, add vancomycin (15 mg/kg q12hb). 159, 201, and pathogen-specific chapters A 15-year-old boy with T-cell acute lymphoblastic leukemia (ALL) (FAB L1), diagnosed in 1995, received combination chemotherapy consisting of 6 weeks of induction (vincristine, epirubicin, L-asparaginase, prednisolone) and 2 weeks of consolidation (cytosine arabinosides, etoposide). After achieving remission, for further maintenance of remission, he was treated with 14 cycles of intensive chemotherapy consisting of 6-MP, 10 mg/kg orally on the first 4 days, and cyclophosphamide, 1200 mg/m2, vincristine, 1.5 mg/m2, epirubicin, 15 mg/m2, and cytosine arabinoside, 40 mg/m2, intravenously on days 4, 11, 39, and 40, respectively. On day 18 of each cycle, he received intravenous methotrexate (MTX) infusion in a total dose of 150 mg/m2 plus oral leucovorin (30 mg/m2 ) rescue 36 h after starting MTX therapy. In addition, oral trimethoprim-sulfamethoxazole was given regularly to prevent Pneumocystis carinii infection. The patient achieved remission during the first course of treatment, but 8 months later the disease relapsed. He then received four doses of MTX (800 mg intravenously) plus leucovorin rescue in the following 4 months. During the last MTX therapy, small hemorrhagic bullae were found on the lateral side of the right ankle, but subsided after a few days. Due to partial remission of the disease, he was admitted again in January 1999 for high-dose MTX therapy. An initial hemogram on admission revealed hemoglobin 7.2 g/dL, white cell count 15,200/mm3, platelet count 153/mm3, blood creatinine 0.5 mg/dL, and alanine leucine aminotransferase (ALT) 20 U/L. He received 8500 mg of MTX (5000 mg/m2 ) as a continuous intravenous infusion for 24 h. Thirty-six hours after the start of MTX infusion, leucovorin (30 mg, intravenous) rescue was initiated every 6 h for 3 days. Another preventive measure to cover MTX toxicity included aggressive intravenous fluid replacement (4 L/m2 /day) and the addition of 25 meq/L sodium bicarbonate to the intravenous fluid to alkalinize the urine. Concurrent medication included 6-MP (50 mg) once daily and trimethoprim-sulfamethoxazole (120 mg, 600 mg) twice daily every other day. Plasma MTX levels were 52.36 micromol/L 24 h after MTX infusion, 1.87 micromol/L after 48 h, 0.57 micromol/L after 72 h, and 0.41 micromol/L after 96 h. These indicated delayed MTX plasma clearance. The blood creatinine level was mildly elevated from 0.5 mg/dL to 0.7 mg/dL. Thirty-six hours after the administration of MTX, the patient developed an erythematous painful swelling on the right middle finger. The erythema, with subsequent large bulla formation, progressed to all the fingers, toes, palms, and the soles of the feet. Some erythematous to hemorrhagic papules also appeared on the bilateral elbows. Subsequently, diffuse tender erythema with extensive erosions and focal tiny pustules developed on the back, abdomen, proximal extremities, and face (Fig. 1a,b). A positive Nikolsky's sign was also present. A biopsy specimen of the right dorsal hand lesion revealed parakeratosis, detached acanthotic epidermis with scattered necrotic keratinocytes, dyskeratotic cells and nuclear atypia, neutrophilic exocytosis, and many neutrophils in the papillary dermis (Fig. 2). The skin condition deteriorated rapidly. Toxic epidermal necrolysis-like lesions involved 90% of the total body surface on the fifth day after MTX infusion. Mucositis, diarrhea, involuntary tremor, fever, and chills were noted. The patient was then sent to the burn unit for intensive skin care. Ten days after MTX therapy, profound agranulocytosis and thrombocytopenia (white cell count 100/mm3, platelets 14,000/mm3, and hemoglobin 5.6 g/dL) were found. The patient was then started on granulocyte colony stimulation factor (G-CSF, 5 microg/kg/day), but his general condition deteriorated rapidly and he died 6 days later due to septic shock and multiple organ failure. 12 Alternative treatments for mild to moderate PCP include dapsone/ trimethoprim, clindamycin/primaquine, and atovaquone. IV pentami dine is the treatment of choice for severe disease in the patient unable 8 to tolerate TMP/SMX. For patients with a Pao <70 mmHg or with an 6 a–a gradient >35 mmHg, adjunct glucocorticoid therapy should be used in addition to specific antimicrobials. Overall, treatment should be continued for 21 days and followed by secondary prophylaxis. 2 Prophylaxis for PCP is indicated for any HIV-infected individual who 0 has experienced a prior bout of PCP, any patient with a CD4+ T cell count of <200/μL or a CD4 percentage <15, any patient with unex- Cefiderocol is a novel siderophore cephalosporin antibiotic with broad coverage against difficult-to-treat Gram-negative bacteria, including those resistant to carbapenems. Its activity against <iStenotrophomonas maltophilia</i was investigated <iin vitro</i against clinical isolates and in lung infection models using strains either resistant (SR202006) or susceptible (SR201934, SR200614) to trimethoprim-sulfamethoxazole. Cefiderocol demonstrated potent <iin vitro</i activity against all 217 <iS. maltophilia</i clinical isolates tested (MIC<sub50</sub, 0.063 μg/ml; MIC<sub90</sub, 0.25 μg/ml). Cefiderocol also demonstrated low MICs against the trimethoprim-sulfamethoxazole-resistant <iS. maltophilia</i strains (i.e., SR202006; MIC, 0.125 μg/ml). In a neutropenic mouse lung infection model, cefiderocol (30 mg/kg body weight and 100 mg/kg) demonstrated a significant, dose-dependent reduction in the lung viable bacteria cell count compared with untreated controls in <iS. maltophilia</i infection and was the only antibiotic tested to show a similar significant effect in a trimethoprim-sulfamethoxazole-resistant <iS. maltophilia</i infection. In immunocompetent rat lung infection models of <iS. maltophilia</i, humanized dosing of cefiderocol (2 g every 8 h) and meropenem (1 g every 8 h) revealed pharmacokinetic profiles similar to those in human subjects, and the humanized cefiderocol dosing significantly reduced the lung viable bacteria cell count compared with baseline controls, which received no intervention. Together, the results from these studies suggest that cefiderocol could provide an effective alternative treatment option for <iS. maltophilia</i infections in the lower respiratory tract, particularly strains resistant to empirical antibiotics, such as trimethoprim-sulfamethoxazole or minocycline. Daptomycin-nonsusceptible (DNS) Staphylococcus aureus is found in difficult-to-treat infections, and the optimal therapy is unknown. We investigated the activity of high-dose (HD) daptomycin plus trimethoprim-sulfamethoxazole de-escalated to HD daptomycin or trimethoprim-sulfamethoxazole against 4 clinical DNS methicillin-resistant S. aureus (MRSA) isolates in an in vitro pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations (10(9) CFU/g). Simulated regimens included HD daptomycin at 10 mg/kg/day for 14 days, trimethoprim-sulfamethoxazole at 160/800 mg every 12 h for 14 days, HD daptomycin plus trimethoprim-sulfamethoxazole for 14 days, and the combination for 7 days de-escalated to HD daptomycin for 7 days and de-escalated to trimethoprim-sulfamethoxazole for 7 days. Differences in CFU/g (at 168 and 336 h) were evaluated by analysis of variance (ANOVA) with a Tukey's post hoc test. Daptomycin MICs were 4 μg/ml (SA H9749-1, vancomycin-intermediate Staphylococcus aureus; R6212, heteroresistant vancomycin-intermediate Staphylococcus aureus) and 2 μg/ml (R5599 and R5563). Trimethoprim-sulfamethoxazole MICs were ≤0.06/1.19 μg/ml. HD daptomycin plus trimethoprim-sulfamethoxazole displayed rapid bactericidal activity against SA H9749-1 (at 7 h) and R6212 (at 6 h) and bactericidal activity against R5599 (at 72 h) and R5563 (at 36 h). A ≥8 log(10) CFU/g decrease was observed with HD daptomycin plus trimethoprim-sulfamethoxazole against all strains (at 48 to 144 h), which was maintained with de-escalation to HD daptomycin or trimethoprim-sulfamethoxazole at 336 h. The combination for 14 days and the combination for 7 days de-escalated to HD daptomycin or trimethoprim-sulfamethoxazole was significantly better than daptomycin monotherapy (P &lt; 0.05) and trimethoprim-sulfamethoxazole monotherapy (P &lt; 0.05) at 168 and 336 h. Combination therapy followed by de-escalation offers a novel bactericidal therapeutic alternative for high-inoculum, serious DNS MRSA infections. No definitive trials have defined the best therapeutic algorithm for patients in whom TMP-SMX treatment for PCP is failing. If no other treatable infectious or noninfectious processes are detected and pulmonary dysfunction appears to be due to PCP alone, many authorities would switch from TMP-SMX to either IV pentamidine or IV clindamycin plus oral primaquine. Some authorities would add the second drug or drug combination to TMP-SMX rather than switching regimens. If patients are not already receiving them, glucocorticoids should be added to the regimen; the dosage and regimen, which are usually chosen empirically, depend on what glucocorticoid regimen (if any) the patient was receiving when PCP therapy was begun. Pathogenesis H. ducreyi is an opportunistic microorganism that infects its host by way of breaks in the skin or epidermis. Inflammation then takes place as the area of infection is inundated with lymphocytes, macrophages, and granulocytes. This pyogenic inflammation causes regional lymphadenitis in the sexually transmitted disease chancroid. Diagnosis Although antigen detection, serology, and genetic amplification methods are sometimes used to diagnose infections with H. ducreyi and the genetic tests have greater sensitivity, they are not widely available, so cultures are currently considered the \"gold standard\" test. Treatment The first line treatments are one of four options : azithromycin 1 g orally in a single dose, ceftriaxone 250 mg intramuscularly in a single dose, ciprofloxacin 500 mg orally 2 times a day for 3 days, or erythromycin base 500 mg orally 3 times a day for 7 days. See also Sexually transmitted disease References <iPneumocystis jirovecii</i pneumonia (PCP) is a common opportunistic infection causing more than 400000 cases annually worldwide. Although antiretroviral therapy has reduced the burden of PCP in persons with human immunodeficiency virus (HIV), an increasing proportion of cases occur in other immunocompromised populations. In this review, we synthesize the available randomized controlled trial (RCT) evidence base for PCP treatment. We identified 14 RCTs that were conducted 25-35 years ago, principally in 40-year-old men with HIV. Trimethoprim-sulfamethoxazole, at a dose of 15-20 mg/kg per day, is the treatment of choice based on historical practice rather than on quality comparative, dose-finding studies. Treatment duration is similarly based on historical practice and is not evidence based. Corticosteroids have a demonstrated role in hypoxemic patients with HIV but have yet to be studied in RCTs as an adjunctive therapy in non-HIV populations. The echinocandins are potential synergistic treatments in need of further investigation. The dosage regimen of vancomycin, teicoplanin and daptomycin remains controversial for critically ill patients undergoing continuous renal replacement therapy (CRRT). Monte Carlo simulation was applied to identify the optimal regimens of antimicrobial agents in patients with methicillin-resistant <iStaphylococcus aureus</i (MRSA) infections based on the mechanisms of different CRRT modalities on drug clearance. The optimal vancomycin dosage for patients received a CRRT doses ≤ 30 mL/kg/h was 20 mg/kg loading dose followed by 500 mg every 8 h, while 1 g every 12 h was appropriate when 35 mL/kg/h was prescribed. The optimal teicoplanin dosage under a CRRT dose ≤ 25 mL/kg/h was four loading doses of 10 mg/kg every 12 h followed by 10 mg/kg every 48 h, 8 mg/kg every 24 h and 6 mg/kg every 24 h for continuous veno-venous hemofiltration, continuous veno-venous hemodialysis and continuous veno-venous hemodiafiltration, respectively. When the CRRT dose increased to 30-35 mL/kg/h, the teicoplanin dosage should be increased by 30%. The recommended regimen for daptomycin was 6-8 mg/kg every 24 h under a CRRT dose ≤ 25 mL/kg/h, while 8-10 mg/kg every 24 h was optimal under 30-35 mg/kg/h. The CRRT dose has an impact on probability of target attainment and CRRT modality only influences teicoplanin. Culture Results Intensive Phase Continuation Phase Extension of Total Treatment Culture positive HRZE for 2 months, daily or intermit-HR for 4 months, daily or 5 d/wk To 9 months, if 2 months of Z is not completed or culture tent (with dose adjustment) or conversion is prolonged and cavitation is evident on plain radiographa HR for 4 months, intermittent (with dose adjustment) Culture negative HRZE for 2 months 2 months To 6 months, if patient is infected with HIV Extrapulmonary HRZE for 2 months HR for 4–7 months, daily or 5 d/wkb To 9–12 months in TB meningitis. Some recommend 9 months for bone/joint TB. Resistant to H QRZEc or, less often, RZES for 6 months … Prolonged culture conversion, cavitation Resistant to R HZEQc (IAd) for 2 months HEQ(S) for 10–16 months Prolonged culture conversion, delayed response Adults: For adults, the recommended dosage of amoxicillin is 750 to 1750 mg/d, divided into doses and administered every 8 to 12 hours. Pediatric: For pediatric patients 3 months and older, the recommended amoxicillin dosage is 20 to 45 mg/kg/d, divided into doses and administered every 8 to 12 hours. H pylori infection (triple therapy): For the treatment of H pylori infection, the recommended dosing for triple therapy involves administering 1 g of amoxicillin, 500 mg of clarithromycin, and 30 mg of lansoprazole twice daily (every 12 hours) for 14 days. H pylori infection (dual therapy): For dual therapy against H pylori infection, the recommended dosing is 1 g of amoxicillin and 30 mg of lansoprazole, each administered 3 times daily. Of the currently available agents, trimethoprim-sulfamethoxazole (TMP-SMX) appears to be an effective alternative for treatment of TE in resource-poor settings where the preferred combination of pyrimethamine plus sulfadiazine is not available. The daily dose of TMP-SMX (one double-strength tablet) that is recommended as the preferred regimen for prophylaxis of PcP is effective against TE. If patients cannot tolerate TMP-SMX, the recommended alternative is dapsone-pyrimethamine, which likewise is effective against PcP. Atovaquone with or without pyrimethamine also can be considered. Prophylactic monotherapy with dapsone, pyrimethamine, azithromycin, clarithromycin, or aerosolized pentamidine is probably insufficient. AIDS patients who are seronegative for Toxoplasma and are not receiving prophylaxis for PcP should be retested for IgG antibody to Toxoplasma if their CD4+ T cell count drops to <100/µL. If seroconversion has taken place, then the patient should be given prophylaxis as Medical treatment Medical treatment entails low dose antibiotic prophylaxis until resolution of VUR occurs. Antibiotics are administered nightly at half the normal therapeutic dose. The specific antibiotics used differ with the age of the patient and include: Amoxicillin or ampicillin – infants younger than 6 weeks Trimethoprim-sulfamethoxazole (co-trimoxazole) – 6 weeks to 2 months After 2 months the following antibiotics are suitable: Nitrofurantoin {5–7 mg/kg/24hrs} Nalidixic acid Bactrim Trimethoprim Cephalosporins Urine cultures are performed 3 monthly to exclude breakthrough infection. Annual radiological investigations are likewise indicated. Good perineal hygiene, and timed and double voiding are also important aspects of medical treatment. Bladder dysfunction is treated with the administration of anticholinergics. Rhodococcus equi is a facultative intracellular, obligate aerobe, partially acid fast, gram-positive pathogen that causes cavitary pneumonia in animals and immunocompromised humans. We describe 8 cases of R. equi pneumonia in patients with advanced HIV infection (CD4 counts less than 100/mm3), 7 males and 1 female (mean age 30.8 years), observed between 1991 and 1994. A history of exposure to farm animals was found in 4 patients. The most common presenting symptoms were fever, malaise, dyspnea, cough and hemoptysis, chest pain and weight loss. Chest x-rays showed tipical focal area of consolidation throughout the lung (3 upper, 3 lower and 2 middle fields) associated with cavitation in 4 cases. The definitive diagnosis in our hands was delayed only in the first case in which conflicting data resulted from blood culture (Bacillus sp. isolation) and sputum examen (acid-fast bacterium in the Ziehl-Neelsen stain). Final microbiological diagnosis depended on blood cultures (n=5), bronchoalveolar lavage (n=1), sputum (n=1), lung biopsy (n=1). All the patients were treated with prolonged courses of antibiotic therapy (259 days, range 120-340 in 6 dead patients; more than one year and two months respectively in two patients alive). According to microbial susceptibility TMP/SMX, vancomycin, imipenem, rifampin, aminoglycosides, macrolides and quinolons were more frequently used. Resistant R. equi mutants were selected during therapy with TMP/SMX (n=2), rifampin (n=1) and erythromycin (n=1). Five patient underwent pulmonary lobectomy after exclusion of metastatic bacterial lesions. Only 2 patients are alive, one after 365 days of antibiotic therapy and upper lung lobectomy, one after 60 days of antibiotic therapy. Optimal antimicrobial therapy and the role of surgery remain, in our experience, uncertain. Maintenance phase After the 5–7 day loading phase, muscle creatine stores are fully saturated and supplementation only needs to cover the amount of creatine broken down per day. This maintenance dose was originally reported to be around 2–3 g/day (or 0.03 g/kg/day), however, recent studies have suggested 3–5 g/day maintenance dose to maintain saturated muscle creatine. Absorption Endogenous serum or plasma creatine concentrations in healthy adults are normally in a range of 2–12 mg/L. A single 5 gram (5000 mg) oral dose in healthy adults results in a peak plasma creatine level of approximately 120 mg/L at 1–2 hours post-ingestion. Creatine has a fairly short elimination half life, averaging just less than 3 hours, so to maintain an elevated plasma level it would be necessary to take small oral doses every 3–6 hours throughout the day. Clearance It has been shown that once supplementation of creatine stops, muscle creatine stores return to baseline in 4–6 weeks.\nHere is the question:\nINFECTIOUS DISEASES AND MICROBIOLOGY: A 45-year-old man consults for a productive cough, pleuritic pain in the right flank and fever of 48 h of evolution. He has a baseline O2 saturation of 88% and rales in the right base. Chest X-ray shows a right basal consolidation. She has a history of HIV infection well controlled with antiretroviral drugs (CD4 lymphocytes 550 ce/uL and undetectable HIV viral load). Which of the following empirical antimicrobial treatments do you consider most appropriate?\nHere are the potential choices:\n1. Cefiriaxone 2 g and azithromycin 500 mg every 24 hours.\n2. Cefiriaxone 2 g, azithrornicin 500 mg every 24 h and trimethoprim-sulfamethoxazole 5 mg/kg/8 h (based on trimethoprim doses).\n3. Methyl-prednisolone 40 mg/day, cefiriaxone 2 g IV 124 h and trimethoprim-sulfamethoxazole 5 mg/kg/8 h (based on trimethoprim doses).\n4. Meropenem I g/8 h and vancomycin I g/l2 h.\nThe correct answer is: 3. Methyl-prednisolone 40 mg/day, cefiriaxone 2 g IV 124 h and trimethoprim-sulfamethoxazole 5 mg/kg/8 h (based on trimethoprim doses)."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n To explore methods of treating middle and distal tibia nonunion with the treatment of advanced bone graft combined with locking compression plate. From January 2011 to December 2012, 12 patients with middle and distal tibia nonunion were treated with advanced bone graft combined with locking compression plate. Among patients, there were 8 males and 4 females aged from 20 to 69 with an average of 47 years old. The time from first injuries to bone nonunion was from 9 months to 5 years, avergaed 19 months. Four cases were treated with external fixation, 6 cases were treated with plate fixation, 2 cases of 12 patients occurred broken of plate and nail. Eleven patients were non-infective bone nonunion and 1 patient was infective bone nonunion. Preoperative X-ray and CT showed all patients had sequestration and formation of ossified bone with different degrees. Operative time, blood loss, wound healing were observed, fracture healing time was evaluated by postoperative X-ray. Johner-Wruhs scoring standards was used to evaluate ankle joint function after operation at 10 months. Operative time ranged from 90 to 185 min with an average of (125.00±20.15) min; blood loss ranged from 225 to 750 ml with an average of (415.00±120.00) ml. All patients were followed up from 10 months to 2.5 years with an average of 1.5 years. Postoperative X-ray showed bone union was formed around fracture after operation at 4 months in all patients, 3 cases obtained bone healing within 6 months after operation, 9 cases obtained from 8 to 12 months. No infection, injury of nerve and vessles, and broken of plate and nail were ocurred. According to Johner-Wruhs scoring at 10 months after operation, 10 cases obtained excellent results, 1 good and 1 moderate. Advanced bone graft combined with locking compression plate, which can build fracture multi-point supporting based on full compression of bone nonunion to get effective fixation, is an effective method in treating middle and distal tibia nonunion. To evaluate the limbs shortening and re-lengthening in the treatment of tibial infectious bone defect and chronic osteomyelitis. Between January 2011 and April 2016, 19 cases of tibial infectious bone defect and chronic osteomyelitis were treated with the limbs shortening and re-lengthening technique. There were 13 males and 6 females, aged from 22 to 62 years (mean, 44 years). The causes of injury included traffic accident injury in 16 cases, crush injury in 1 case, and falling from height in 2 cases. One patient was infected after plate internal fixation of closed tibial fracture and 18 patients after external fixation of open tibial fractures (Gustilo type IIIB). The mean previous operation times was 3 times (range, 2-5 times). The time from injury to bone transport operation was 3-11 months (mean, 6.5 months). The bone defect length was 2.0-5.5 cm (mean, 4.3 cm) after debridement. After tibial shortening, limb peripheral blood supply should be checked after release of the tourniquet. Seven wounds were closed directly, 5 were repaired with adjacent skin flap, 5 were repaired with sural neurovascular flap, 1 was repaired with medial head of gastrocnemius muscle flap, and 1 underwent skin grafting. Single arm external fixator or ring type external fixator were used, and completely sawed off between 2 sets of external fixation screws at proximal and distal metaphysis of the tibia. Limb lengthening was performed after 1 week with the speed of 1 mm/d. All patients were followed up 10-36 months with an average of 14 months. Two cases delayed healing of the wound after operation, and the other wounds healed primarily. Natural healing of the opposite end of the bone were found in 18 cases, and 1 case had nonunion in the opposite end of the bone because of incomplete removal of lesion bone. There were 5 cases of slow growth of the callus, and healed smoothly by \"accordion\" technology and injecting red bone marrow in 4 cases, and by bone grafting and internal fixation in 1 case. The time of bone lengthening was 1-3 months, the prolongation index was 1.6-2.7 cm/month (2.20 cm/month). The bone healing time was 7-13 months (mean, 11.1 months). According to tibial stem diagnostic criteria Johner-Wruhs score, 9 cases were excellent, 8 cases were good, 2 cases were fair, with an excellent and good rate of 89.5%. Limbs shortening and re-lengthening is an effective method for the treatment of tibial infectious bone defect and chronic osteomyelitis, with the advantages of improving the immediate alignment of the osteotomy ends, significantly shortening the bone healing time of opposite ends of bone. Tibia fracture is the most common long bone fracture. The fractures of tibia are commonly open fractures due to subcutaneous position of the tibia. The choice of technique for stabilization of open tibia fractures includes - External fixation, unreamed intra-medullary nails [URTN], Reamed intra-medullary nails, ORIF with Plating. To evaluate &amp; compare the results of Unreamed Intra-Medullary Nail Versus Half Pin External Fixator in Grade III [A &amp; B] Open tibia fractures. This prospective clinical study [Randomized chit box] was done on 50 patients presenting to our institute within 24 h of injury. Only those who were skeletally mature with open tibia fracture Grade IIIA &amp; IIIB [Gustilo-Anderson] were included in this study. After initial management, radiological assessment was done. Following this adequate wound debridement, skeletal stabilization with either primary URTN or external fixator was done. Inspection and debridement were repeated at 48-h intervals until the wound was considered clean. 50 cases [25 each group] were compared in terms of - Final Alignment of the Fracture, Presence of Infection/Non-union/Mal-union, Hardware failure, Time to Bone Union, Number of Operative Procedures after index admission. Mean time to full weight bearing was 20.96 weeks in URTN group versus 24.8 weeks in Ex-fix group. 5 in URTN group required further surgery for non-union versus 11 patients in Ex-fix group. There were 6 significant pin track infection. Removal of nail was required in 1 case of deep infection. This study supports the use of the URTN over External fixator in the treatment of severe open tibia fractures. Osteomyelitis with multiresistant bacteria in non-union following fracture treated with osteosynthesis requires complete removal of infected sequestrum and dead bone. For consecutive bone defects, it is frequently necessary to bridge with a fixator external. The treatment is not only challenging due to reduced bone stock but also characterized by decreased bioavailability of antibiotics. We report a two-step-surgery approach to preserve the bone stock using autologous cancellous bone in a bacterial infected non-union for subsequently leg length reconstruction. The 24-year-old male patient from Belarus was admitted to our department with persistent wound secretion and subsequent osteomyelitis of the right femur 3 years after initial surgery, several revisions, and several different antibiotic therapies. Biopsy revealed methicillin-resistant and borderline oxacillin-resistant Staphylococcus aureus. Firstly, the Ilizarov ring fixator was removed and a vigorous debridement was performed by refreshing the pseudarthrosis, removing of sequestrum, and dead bone. Finally, an AO fixator external was applied for 10 weeks combined with appropriate antibiotic treatment followed by 5 weeks antibiotic-free window. The bone defect was stabilized by a long gamma trochanteric nail after removal of the AO fixateurexterne. A wide resection of the fragments was performed and the resected bone tissue was crushed and placed adjacent to the nail. Noteworthy, the biopsies of both re-section sides revealed same germs as detected in initial biopsies. Thus, antibiotics were administered for additional 3 months. Frequent radiographic and clinical controls showed a remodeling of the femur during a period of 3 years and no signs of infection. Subsequently, we restored leg length of 4 cm using a fully implantable motorized lengthening nail. In the end, the patient achieved full weight-bearing with unlimited range of motion in hip and knee. No further germ could be revealed in biopsies. In this case report, we used autologous bone from the infected side, crushed, and placed it adjacent to an intramedullary nail. Crushed bone tissue might improve bioavailability of antibiotics when dealing with multiresistant bacteria in non-union healed fracture side. Furthermore, this approach was able to provide new bone formation in a limb resulting in full weight-bearing. Single-stage approach: This involves surgical debridement of all non-viable tissues and bone ends, multiple cultures to be taken from the nonunion site or canal reaming followed by revision open reduction and internal fixation or exchange nailing. Antibiotic administration is tailored to culture results and sensitivities [24] [25] . When open treatment is essential, autologous bone grafting has been recommended as an adjunct [16] . Staged approach: usually indicated for septic tibial nonunion. This involves steps to control infection followed by definitive surgery. As mentioned above, correlation between cultures of bone and those of wound swabs or wound punctures is poor. Antibiotic treatment should be based on bone culture. If no bone biopsy is performed, empirical therapy chosen in light of the most common infecting agents and the type of clinical syndrome should be given. Wound debridement combined with a 4to 6-week course of antibiotics has been shown to render amputation unnecessary in about two-thirds of patients. According to the 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections, the following management strategies should be considered. If a foot ulcer is clinically infected, prompt empirical antimicrobial therapy may prevent progression to osteomyelitis. When the risk of methicillin-resistant S. aureus is considered high, an agent active against these strains (e.g., vancomycin) should be chosen. If the patient has not recently received antibiotics, the Management of the large gap in long bone fractures is a challenging problem after compound injuries. A novel technique called as Masquelet's technique of \"induced membrane formation\", is used to bridge a gap of more than 5 cm using bone cement as a spacer in first stage and autologous cancellous bone graft to fill the gap in second stage. We present two different and difficult cases with bone defects after open injuries associated with long bone fractures in this paper. First case is a 50-year-old lady with grade IIIa open fracture right distal femur with intra-articular extension and bone loss. She underwent wound debriment, stabilization of the fracture with locking compression plate along with antibiotic cement spacer, which is removed latter and underwent bone grafting. Another is a 15-year-old boy with open grade IIIb fracture tibia and fibula (mid-distal third junction) of right leg, wound debridement and ankle spanning triangular external fixation was applied on same day and after two months, external fixation was removed due to florid infection and plaster of Paris was applied. Instead of the tedious and demanding treatment options like Ilizarov, a new technique described by Masquelet is used here. It uses bone cement as a spacer to fill the cavity to form pseudo-membrane around it and in the second stage autologous cancellous bone graft fills the gap of even more than 5 cm, to achieve union. The membrane also secretes vascular and osteo-inductive factors to stimulate bone regeneration and also prevents resorption of the bone graft and achieves early fracture healing avoiding tedious options like bone transport in external fixator. By this two staged technique, union occurred clinically and radiologically in these two cases. In a follow up study of 47 patients with infected pseudarthrosis of tibia therapy and results are declared. The most important matter in therapy is the osteosyntesis with compression of the pseudarthrosis. In the majority of cases externe stabilisation is used; seldom compression plate or medullary nailing is indicated. Such cases require much experience in the therapy of bone infection, although if the stabilisation with the fibula is tryed. Flush drainage, suction drainage, antibiotic therapy and cancellous bone grafting are necessary for localisation and decreasing of infection and for induction and acceleration of bone union. In some cases amutation can't be prevented. With correct judgement and consequent treatment in the majority of cases bone union will be obtained. Distal radius fractures are one of the most common fractures in the United States. Treatment usually involves internal fixation using a volar Henry approach with placement of a volar locking plate. Optimal treatment becomes less apparent when significant bone loss occurs. No case of an open distal radius fracture treated using a staged Masquelet technique involving proximal tibial autograft is available in the literature. Herein, we describe and discuss a case report of a novel technique to treat a large (5 cm) bone defect for an open distal radius fracture. A 59-year-old man suffered an open, comminuted, and intra-articular distal radius fracture with 5 cm of bone loss. He was treated using a staged Masquelet technique with incorporation of ipsilateral proximal tibial autograft with a bone harvester to obtain cancellous autograft and bone marrow graft. The patient initially underwent emergent I and D, acute carpal tunnel release, and internal and external fixation. A 5 cm bone void was filled with antibiotic cement. Four weeks later, the antibiotic cement was removed, cancellous bone graft and marrow were harvested from the proximal tibia, and the graft was placed within the prior bone void. Fracture site healing was confirmed radiographically and with computer-tomography imaging 3 months later. The patient has demonstrated excellent results 1 year post-operative with 60° of wrist flexion, 40° of wrist extension with mild pain, and full finger range of motion with radiographic union. Internal fixation with placement of a volar locking plate remains the mainstay of treatment for distal radial fractures. However, in more comminuted fractures with bone loss, treatment becomes more challenging. We have presented a unique case utilizing a staged Masquelet technique with incorporation of a proximal tibial autograft to educate readers on an alternative option and technique for autograft donor sites in these more complicated fractures. From 1988 to 1990 a total of 187 fractures of the tibia (92 compound, 95 closed fractures) were treated with a primary osteosynthesis. In 102 fractures an external fixation was performed, 85 internal fixations were divided into 58 intramedullary nails and 27 plates. In a follow-up study the fracture healing was analysed, 90% of the patients were examined about 18 months after the accident. The mean healing time was between 12 weeks (internal fixation) and 16 weeks (external fixateur). After primary Fixateur externe 54 were treated by secondary internal fixation, intramedullary nailing was the method of choice. Contamination rate of the tibia, taken by an intraoperative wound swab before nailing was 30%. Infection occurred in 3.2%, non union and refractures in 1.5% and 1%. Over all 80% excellent and good results were found after consolidation. 10% fair and 10% bad results including three amputations after III degrees compound fractures and three death after polytrauma. In the treatment of Gustilo Type 3B open tibial fractures, it is important to perform soft tissue reconstruction and bone reconstruction simultaneously. Gastrocnemius muscle and soleus muscle flaps are generally used as rotational flaps for the tibia. The distal third of the tibia can often not be covered with the gastrocnemius muscle and soleus muscle flaps. Treatment distal to the distal third of the tibia is difficult because fewer flap options are available. In the present report, we describe our experience with a Gustilo Type 3B open tibial fracture treated by gastrocnemius muscle and soleus muscle flaps, along with an additional proximally based flexor hallucis longus flap, which is a rare procedure. The participant was a 17-year-old male who injured his left tibia in a motorcycle traffic accident. Physical examination revealed a wound of 13 cm × 7 cm extending from the medial lower leg to the posterior aspect, with extensive skin loss. There was no nerve or vascular injury. The tibia was exposed, with detachment of the periosteum. The radiograph revealed a tibial shaft fracture. The AO/OTA classification was 42-A3.3, and it was classified as a Gustilo-Anderson Type 3B fracture. Gastrocnemius muscle and soleus muscle flaps were lifted in the area of the soft-tissue defect and then, placed over the tibia. Despite this, the distal portion of the tibia remained uncovered. Therefore, a flexor hallucis longus flap was lifted and placed over the distal portion of the tibia. On day 7 after the injury, the external fixation device was removed and the tibial shaft was fixated with two Ender nails (4.5 mm in diameter). The clinical course was satisfactory, and the skin graft and flap were successful. Bone union was achieved without infection, and the resulting range of motion was normal. For the treatment of Gustilo-Anderson Type 3B open tibial fractures, early treatment of the soft-tissue defect is vital. We surgically treated a Gustilo-Anderson Type 3B open tibial fracture with gastrocnemius muscle and soleus muscle flaps, along with an additional proximally based flexor hallucis longus flap, which is a rare procedure. In the event of a soft-tissue defect in the distal third of the tibia, the use of a proximally based flexor hallucis longus flap is an effective surgical approach. Soft tissue management and fracture fixation including initial external fixation in Gustilo-Anderson type II and type III open fractures are cornerstones in the treatment but details on timing and type of wound closure, irrigation and debridement, systemic and local antibiotics, antimicrobial-coated implants and the use of Bone Morphogenetic Protein-2 remain controversial. This article looks at current clinical evidence of these items for the management of open fractures. Timing of debridement and wound closure remains critical. Early debridement by an experienced team within 24 h seems adequate while gross contamination, a devascularized limb, a multi-injured patient and compartment syndrome require immediate surgical intervention. Wound closure during the first surgery was shown to result in reduced rates for infections and nonunion. If soft-tissue reconstruction is needed, it should be performed within the first 7 days. Regarding types of irrigation fluid, antiseptic and antibacterial solutions did not prove to be superior to saline. High pressure irrigation has not been demonstrated to be beneficial whereas antibiotic administration as soon as possible has been proven to be favorable. Administration of more than 72 h was not superior to shorter systemic antibiotic intervals. For Gustilo-Anderson type I and II, broad spectrum antibiotic therapy is reasonable. Additional aminoglycosides for broader coverage are recommended in Gustilo-Anderson type III fractures. There is newer literature on the beneficial effects of the use of local antibiotics, e.g. by antibiotic beads. Coating of internal fixation devices is a modern approach to improve infection prophylaxis and gentamicin-coated implants have been demonstrated to be safe in clinical application. Vacuum assisted closure (VAC) could not evidence negative pressure wound therapy to reduce infection risk, improve self-rated disability or quality of life in open fractures, however, enhance treatment costs. Recombinant human bone morphogenetic proteins (rhBMP)-2 showed promising data in Gustilo-Anderson type III open tibial shaft fractures with lower rates of invasive secondary procedures. In conclusion, there is evidence for thorough debridement and irrigation with saline, early soft tissue coverage and the use of systemic and local antibiotics. Except for a short-term soft tissue coverage VAC seems not to be beneficial and rhBMP-2 is an additional tool in Gustilo-Anderson type III open fractures. Fractures of the lower extremity are a common type of childhood injury and many can be treated without surgery. Dislocated and open fractures are an indication for fracture stabilization via either intramedullary nailing or, in the case of complicated fractures, external fixation. But if complications are likely because of diseases and disabilities (for example, a neuropathy) that can complicate the post-operative procedure and rehabilitation, what options does one have? We report a nine-year-old Caucasian girl who had hereditary motor and sensory neuropathy type I and who was admitted with a grade I open tibia fracture after a fall from a small height. Plain radiographs showed a dislocated tibia and fibula fracture. An open reduction with internal fixation with a compression plate osteosynthesis was performed, and soft tissue debridement combined with an external fixateur was undertaken. Three months later, she was re-admitted with localized swelling and signs of a local soft tissue infection in the middle of her tibia. Plain radiographs showed a non-union of the tibia fracture, and microbiological analysis confirmed a wound infection with cefuroxime-sensitive Staphylococcus aureus. Because of the non-union, the osteosynthesis was replaced with an Ilizarov external fixateur, and appropriate antibiotic therapy was initiated. Four months after the initial accident, the fracture was consolidated and we removed the external fixateur. If there is a pre-existing neuropathy and if disease makes it difficult for a child to follow all post-operative instructions, salvage procedures should be kept in mind in case of complications. There are multiple therapeutic options, including osteosynthesis, intramedullary nailing systems, cast therapy, or an external fixateur like the Ilizarov or Taylor spatial frame system. The initial use of an external fixateur such as an Ilizarov or Taylor spatial frame in patients with pre-existing neuropathies should be kept in mind as a possible treatment option in complicated fractures, especially in a child with pre-existing neurological or endocrine pathologies. Recombinant human bone morphogenetic protein-2 (rhBMP-2) improves healing of open tibial fractures treated with intramedullary nail fixation. However, routine use has not occurred. The purposes of the current study were to provide a systematic review of the literature using rhBMP-2 in the treatment of acute open tibial fractures treated with intramedullary nail fixation and to provide a meta-analysis of the randomized, controlled trials. Multiple databases, reference lists of relative articles, and main orthopedic journals were searched. The basic information and major results were compared. Four studies with a total of 609 patients were included.The secondary intervention rate in the standard-of-care (SOC) group was significantly higher than in the rhBMP-2 combined with absorbable collagen sponge (rhBMP-2/ACS) group (27.1% vs 17.5%, respectively; P&lt;.01). The treatment failure rate in the SOC group was significantly higher (34.3% vs. 21.4%, respectively; P&lt;.01). No significant differences were found in infection rate, hardware failure rate, fracture healing rate at 20 weeks, and postoperative pain level. For patients treated with reamed intramedullary nail fixation, only the treatment failure rate in the SOC group was significantly higher (21.5% vs 14.2%, respectively; P=.02); no other significant difference was observed. Adding rhBMP-2 to the treatment of Gustilo-Anderson grade IIIA and B open tibial fractures led to net savings of approximately $6000 per case.Recombinant human bone morphogenetic protein-2 added to intramedullary nail fixation of open tibial fractures could reduce the frequency of secondary interventions and total health care costs. For reamed patients, adding rhBMP-2 reduced treatment failure. This analysis supports the clinical efficacy of rhBMP-2/ACS for the treatment of these severe fractures. To explore the clinical effects of VSD combined with continual irrigation in treating the infection of limbs fracture after internal fixation. From March 2010 to June 2015, 10 patients with infection of limbs fracture after internal fixation were treated with VSD combined with continual irrigation. There were 7 males and 3 females, aged from 11 to 58 years with an average of 34.4 years. Course of disease was from 1 to 8 months with an average of 4.8 months. Postoperative infection occurred in fractures of ulna and radius of 4 cases, tibiofibular fractures of 3 cases, calcaneal fractures of 2 cases, femoral fractures of 1 case. Eight infections were open fracture and 2 infections were close fracture. In additon to above treatment, antibiotics, dressing changing or skingrafting were used in the patients. Informations of wound surface healing, change dressings, original infection focus were observed. All infections got control, the wound healing after change dressings or skingrafting, and no complications such as osteomyelitis were found. The mean treatment time was 38.4 days(ranged, 29 to 45 days) and replacement times was 2.2 times(ranged, 1 to 4 times). All patients were followed up, no recurrent infections were found at 1 year after fracture healing. VSD combined with continual irrigation can effectively decrease the incidence of complications and promote the wound growth, healing and considerably shorten the healing time. It is an effective method for the treatment of infection of limbs fracture after internal fixation. Treatment of tibial diaphyseal nonunions are rather difficult. Plate-screw, intramedullary nailing and external fixation are the methods used for treatment. The aim of this study is to evaluate the treatment results of aseptic diaphyseal nonunions following tibia fractures by intramedullary compressive tibia nailing (IMCN) with or without bone graft. Twenty eight patients who had aseptic tibial nonunion without bone defects operated between 2005 and 2015 were included in the study. The mean age of our patients was 36.4 years (range 20-56 years). There were 22 males and 6 females. Fifteen of the patients exhibited hypertrophic nonunion and thirteen exhibited atrophic nonunion. The average time between fracture occurrence and presentation to our department was 1.6 years (range 1-20 years). All patients underwent fibular osteotomy by removal of a 2 cm bone block from the middle one-third of the fibulas. In all cases, IMCN was applied following the reaming procedure, then maximum bone contacts were achieved manually between proximal and distal bone fragments afterward, and dynamic compressive fixation with 1 mm of compression was performed by a single rotation of the compression screw at the top of the nail. Direct X-ray images were assessed according to the Rust criteria, and functional outcomes were assessed according to the Johner-Wrush criteria. Finite-element analysis was performed for 1 mm of compression. For statistical analysis, Fisher's exact test, Pearson's Chi-square test, and Mann-Whitney U-test were used. Union was achieved in all patients. Radiological union was obtained at an average of 15.5 ± 1.86 weeks. Functional results were found to be good or excellent in 25 (89.2%) patients and average or poor in 3 (10.8%) patients. One patient developed skin necrosis at the wound site, which was treated with rotational flap and skin graft. None of the patients developed implant failure, thromboembolism, deep-vein thrombosis, or infection. The use of compressive intramedullary nailing with or without bone graft is an effective method for the treatment of tibial nonunion. In treating patients who present with an extensive non-union due to infected intramedullary nail, bone healing can be achieved within a few weeks through a policy of active management. Following excision of the infected tissue and thorough irrigation, the fracture site is stabilized by a plate fixation and a packet with cancellous bone. The wound overlying the bone is left open to granulate. No complications were observed during the course of healing in 7 cases (5 tibia, 2 femur) managed this way. The method is based on classical principles of orthopedics and the treatment of infection. Such has been its impressive success, that it would seem to warrant not only close attention but also strong recommendation. Tibia fracture caused by high velocity missiles is mostly comminuted and followed by bone defect which makes their healing process extremely difficult and prone to numerous complications. A 34-year-old male was wounded at close range by a semi-automatic gun missile. He was wounded in the distal area of the left tibia and suffered a massive defect of the bone and soft tissue. After the primary treatment of the wound, the fracture was stabilized with an external fixator type Mitkovic, with convergent orientation of the pins. The wound in the medial region of the tibia was closed with the secondary stitch, whereas the wound in the lateral area was closed with the skin transplant after Thiersch. Due to massive bone defect in the area of the rifle-missile wound six months after injury, a medical team placed a reconstructive external skeletal fixator type Mitkovic and performed corticotomy in the proximal metaphyseal area of the tibia. By the method of bone transport (distractive osteogenesis), the bone defect of the tibia was replaced. After the fracture healing seven months from the secondary surgery, the fixator was removed and the patient was referred to physical therapy. Surgical treatment of wounds, external fixation, performing necessary debridement, adequate antibiotic treatment and soft and bone tissue reconstruction are essential in achieving good results in patients with the open tibial fracture with bone defect caused by high velocity missiles. Reconstruction of bone defect can be successfully treated by reconstructive external fixator Mitkovic.\nHere is the question:\nORTHOPEDIC SURGERY AND TRAUMATOLOGY: A 70-year-old woman, diabetic and hypertensive, who suffers a fall at home, presenting a 9 cm wound communicating with a fracture site of the right tibia. Radiographically, a short oblique fracture of the mid-distal third of the tibia was observed. An emergency operation was performed by cleaning (Friederich) and placement of an endomedullary steel-plated nail. At 11 months he presents with atrophic pseudarthrosis of the tibia with suppuration in the wound area. What will be his best immediate therapeutic option?\nHere are the potential choices:\n1. Triple antibiotherapy (gram-positive, gram-negative and anaerobic) and cleaning of the surgical wound, removing the distal locks to promote bone consolidation.\n2. Expectant attitude and antibiotic treatment with quinolones.\n3. Autologous graft and growth factors (BMP 2 and 7) to stimulate the bone consolidation process, which is slowing.\n4. Removal of the nail, debridement, placement of external fixator and antibiotherapy adjusted to culture results.\nThe correct answer is: ",
        "gold_answer": "4 Removal of the nail, debridement, placement of external fixator and antibiotherapy adjusted to culture results.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n To explore methods of treating middle and distal tibia nonunion with the treatment of advanced bone graft combined with locking compression plate. From January 2011 to December 2012, 12 patients with middle and distal tibia nonunion were treated with advanced bone graft combined with locking compression plate. Among patients, there were 8 males and 4 females aged from 20 to 69 with an average of 47 years old. The time from first injuries to bone nonunion was from 9 months to 5 years, avergaed 19 months. Four cases were treated with external fixation, 6 cases were treated with plate fixation, 2 cases of 12 patients occurred broken of plate and nail. Eleven patients were non-infective bone nonunion and 1 patient was infective bone nonunion. Preoperative X-ray and CT showed all patients had sequestration and formation of ossified bone with different degrees. Operative time, blood loss, wound healing were observed, fracture healing time was evaluated by postoperative X-ray. Johner-Wruhs scoring standards was used to evaluate ankle joint function after operation at 10 months. Operative time ranged from 90 to 185 min with an average of (125.00±20.15) min; blood loss ranged from 225 to 750 ml with an average of (415.00±120.00) ml. All patients were followed up from 10 months to 2.5 years with an average of 1.5 years. Postoperative X-ray showed bone union was formed around fracture after operation at 4 months in all patients, 3 cases obtained bone healing within 6 months after operation, 9 cases obtained from 8 to 12 months. No infection, injury of nerve and vessles, and broken of plate and nail were ocurred. According to Johner-Wruhs scoring at 10 months after operation, 10 cases obtained excellent results, 1 good and 1 moderate. Advanced bone graft combined with locking compression plate, which can build fracture multi-point supporting based on full compression of bone nonunion to get effective fixation, is an effective method in treating middle and distal tibia nonunion. To evaluate the limbs shortening and re-lengthening in the treatment of tibial infectious bone defect and chronic osteomyelitis. Between January 2011 and April 2016, 19 cases of tibial infectious bone defect and chronic osteomyelitis were treated with the limbs shortening and re-lengthening technique. There were 13 males and 6 females, aged from 22 to 62 years (mean, 44 years). The causes of injury included traffic accident injury in 16 cases, crush injury in 1 case, and falling from height in 2 cases. One patient was infected after plate internal fixation of closed tibial fracture and 18 patients after external fixation of open tibial fractures (Gustilo type IIIB). The mean previous operation times was 3 times (range, 2-5 times). The time from injury to bone transport operation was 3-11 months (mean, 6.5 months). The bone defect length was 2.0-5.5 cm (mean, 4.3 cm) after debridement. After tibial shortening, limb peripheral blood supply should be checked after release of the tourniquet. Seven wounds were closed directly, 5 were repaired with adjacent skin flap, 5 were repaired with sural neurovascular flap, 1 was repaired with medial head of gastrocnemius muscle flap, and 1 underwent skin grafting. Single arm external fixator or ring type external fixator were used, and completely sawed off between 2 sets of external fixation screws at proximal and distal metaphysis of the tibia. Limb lengthening was performed after 1 week with the speed of 1 mm/d. All patients were followed up 10-36 months with an average of 14 months. Two cases delayed healing of the wound after operation, and the other wounds healed primarily. Natural healing of the opposite end of the bone were found in 18 cases, and 1 case had nonunion in the opposite end of the bone because of incomplete removal of lesion bone. There were 5 cases of slow growth of the callus, and healed smoothly by \"accordion\" technology and injecting red bone marrow in 4 cases, and by bone grafting and internal fixation in 1 case. The time of bone lengthening was 1-3 months, the prolongation index was 1.6-2.7 cm/month (2.20 cm/month). The bone healing time was 7-13 months (mean, 11.1 months). According to tibial stem diagnostic criteria Johner-Wruhs score, 9 cases were excellent, 8 cases were good, 2 cases were fair, with an excellent and good rate of 89.5%. Limbs shortening and re-lengthening is an effective method for the treatment of tibial infectious bone defect and chronic osteomyelitis, with the advantages of improving the immediate alignment of the osteotomy ends, significantly shortening the bone healing time of opposite ends of bone. Tibia fracture is the most common long bone fracture. The fractures of tibia are commonly open fractures due to subcutaneous position of the tibia. The choice of technique for stabilization of open tibia fractures includes - External fixation, unreamed intra-medullary nails [URTN], Reamed intra-medullary nails, ORIF with Plating. To evaluate &amp; compare the results of Unreamed Intra-Medullary Nail Versus Half Pin External Fixator in Grade III [A &amp; B] Open tibia fractures. This prospective clinical study [Randomized chit box] was done on 50 patients presenting to our institute within 24 h of injury. Only those who were skeletally mature with open tibia fracture Grade IIIA &amp; IIIB [Gustilo-Anderson] were included in this study. After initial management, radiological assessment was done. Following this adequate wound debridement, skeletal stabilization with either primary URTN or external fixator was done. Inspection and debridement were repeated at 48-h intervals until the wound was considered clean. 50 cases [25 each group] were compared in terms of - Final Alignment of the Fracture, Presence of Infection/Non-union/Mal-union, Hardware failure, Time to Bone Union, Number of Operative Procedures after index admission. Mean time to full weight bearing was 20.96 weeks in URTN group versus 24.8 weeks in Ex-fix group. 5 in URTN group required further surgery for non-union versus 11 patients in Ex-fix group. There were 6 significant pin track infection. Removal of nail was required in 1 case of deep infection. This study supports the use of the URTN over External fixator in the treatment of severe open tibia fractures. Osteomyelitis with multiresistant bacteria in non-union following fracture treated with osteosynthesis requires complete removal of infected sequestrum and dead bone. For consecutive bone defects, it is frequently necessary to bridge with a fixator external. The treatment is not only challenging due to reduced bone stock but also characterized by decreased bioavailability of antibiotics. We report a two-step-surgery approach to preserve the bone stock using autologous cancellous bone in a bacterial infected non-union for subsequently leg length reconstruction. The 24-year-old male patient from Belarus was admitted to our department with persistent wound secretion and subsequent osteomyelitis of the right femur 3 years after initial surgery, several revisions, and several different antibiotic therapies. Biopsy revealed methicillin-resistant and borderline oxacillin-resistant Staphylococcus aureus. Firstly, the Ilizarov ring fixator was removed and a vigorous debridement was performed by refreshing the pseudarthrosis, removing of sequestrum, and dead bone. Finally, an AO fixator external was applied for 10 weeks combined with appropriate antibiotic treatment followed by 5 weeks antibiotic-free window. The bone defect was stabilized by a long gamma trochanteric nail after removal of the AO fixateurexterne. A wide resection of the fragments was performed and the resected bone tissue was crushed and placed adjacent to the nail. Noteworthy, the biopsies of both re-section sides revealed same germs as detected in initial biopsies. Thus, antibiotics were administered for additional 3 months. Frequent radiographic and clinical controls showed a remodeling of the femur during a period of 3 years and no signs of infection. Subsequently, we restored leg length of 4 cm using a fully implantable motorized lengthening nail. In the end, the patient achieved full weight-bearing with unlimited range of motion in hip and knee. No further germ could be revealed in biopsies. In this case report, we used autologous bone from the infected side, crushed, and placed it adjacent to an intramedullary nail. Crushed bone tissue might improve bioavailability of antibiotics when dealing with multiresistant bacteria in non-union healed fracture side. Furthermore, this approach was able to provide new bone formation in a limb resulting in full weight-bearing. Single-stage approach: This involves surgical debridement of all non-viable tissues and bone ends, multiple cultures to be taken from the nonunion site or canal reaming followed by revision open reduction and internal fixation or exchange nailing. Antibiotic administration is tailored to culture results and sensitivities [24] [25] . When open treatment is essential, autologous bone grafting has been recommended as an adjunct [16] . Staged approach: usually indicated for septic tibial nonunion. This involves steps to control infection followed by definitive surgery. As mentioned above, correlation between cultures of bone and those of wound swabs or wound punctures is poor. Antibiotic treatment should be based on bone culture. If no bone biopsy is performed, empirical therapy chosen in light of the most common infecting agents and the type of clinical syndrome should be given. Wound debridement combined with a 4to 6-week course of antibiotics has been shown to render amputation unnecessary in about two-thirds of patients. According to the 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections, the following management strategies should be considered. If a foot ulcer is clinically infected, prompt empirical antimicrobial therapy may prevent progression to osteomyelitis. When the risk of methicillin-resistant S. aureus is considered high, an agent active against these strains (e.g., vancomycin) should be chosen. If the patient has not recently received antibiotics, the Management of the large gap in long bone fractures is a challenging problem after compound injuries. A novel technique called as Masquelet's technique of \"induced membrane formation\", is used to bridge a gap of more than 5 cm using bone cement as a spacer in first stage and autologous cancellous bone graft to fill the gap in second stage. We present two different and difficult cases with bone defects after open injuries associated with long bone fractures in this paper. First case is a 50-year-old lady with grade IIIa open fracture right distal femur with intra-articular extension and bone loss. She underwent wound debriment, stabilization of the fracture with locking compression plate along with antibiotic cement spacer, which is removed latter and underwent bone grafting. Another is a 15-year-old boy with open grade IIIb fracture tibia and fibula (mid-distal third junction) of right leg, wound debridement and ankle spanning triangular external fixation was applied on same day and after two months, external fixation was removed due to florid infection and plaster of Paris was applied. Instead of the tedious and demanding treatment options like Ilizarov, a new technique described by Masquelet is used here. It uses bone cement as a spacer to fill the cavity to form pseudo-membrane around it and in the second stage autologous cancellous bone graft fills the gap of even more than 5 cm, to achieve union. The membrane also secretes vascular and osteo-inductive factors to stimulate bone regeneration and also prevents resorption of the bone graft and achieves early fracture healing avoiding tedious options like bone transport in external fixator. By this two staged technique, union occurred clinically and radiologically in these two cases. In a follow up study of 47 patients with infected pseudarthrosis of tibia therapy and results are declared. The most important matter in therapy is the osteosyntesis with compression of the pseudarthrosis. In the majority of cases externe stabilisation is used; seldom compression plate or medullary nailing is indicated. Such cases require much experience in the therapy of bone infection, although if the stabilisation with the fibula is tryed. Flush drainage, suction drainage, antibiotic therapy and cancellous bone grafting are necessary for localisation and decreasing of infection and for induction and acceleration of bone union. In some cases amutation can't be prevented. With correct judgement and consequent treatment in the majority of cases bone union will be obtained. Distal radius fractures are one of the most common fractures in the United States. Treatment usually involves internal fixation using a volar Henry approach with placement of a volar locking plate. Optimal treatment becomes less apparent when significant bone loss occurs. No case of an open distal radius fracture treated using a staged Masquelet technique involving proximal tibial autograft is available in the literature. Herein, we describe and discuss a case report of a novel technique to treat a large (5 cm) bone defect for an open distal radius fracture. A 59-year-old man suffered an open, comminuted, and intra-articular distal radius fracture with 5 cm of bone loss. He was treated using a staged Masquelet technique with incorporation of ipsilateral proximal tibial autograft with a bone harvester to obtain cancellous autograft and bone marrow graft. The patient initially underwent emergent I and D, acute carpal tunnel release, and internal and external fixation. A 5 cm bone void was filled with antibiotic cement. Four weeks later, the antibiotic cement was removed, cancellous bone graft and marrow were harvested from the proximal tibia, and the graft was placed within the prior bone void. Fracture site healing was confirmed radiographically and with computer-tomography imaging 3 months later. The patient has demonstrated excellent results 1 year post-operative with 60° of wrist flexion, 40° of wrist extension with mild pain, and full finger range of motion with radiographic union. Internal fixation with placement of a volar locking plate remains the mainstay of treatment for distal radial fractures. However, in more comminuted fractures with bone loss, treatment becomes more challenging. We have presented a unique case utilizing a staged Masquelet technique with incorporation of a proximal tibial autograft to educate readers on an alternative option and technique for autograft donor sites in these more complicated fractures. From 1988 to 1990 a total of 187 fractures of the tibia (92 compound, 95 closed fractures) were treated with a primary osteosynthesis. In 102 fractures an external fixation was performed, 85 internal fixations were divided into 58 intramedullary nails and 27 plates. In a follow-up study the fracture healing was analysed, 90% of the patients were examined about 18 months after the accident. The mean healing time was between 12 weeks (internal fixation) and 16 weeks (external fixateur). After primary Fixateur externe 54 were treated by secondary internal fixation, intramedullary nailing was the method of choice. Contamination rate of the tibia, taken by an intraoperative wound swab before nailing was 30%. Infection occurred in 3.2%, non union and refractures in 1.5% and 1%. Over all 80% excellent and good results were found after consolidation. 10% fair and 10% bad results including three amputations after III degrees compound fractures and three death after polytrauma. In the treatment of Gustilo Type 3B open tibial fractures, it is important to perform soft tissue reconstruction and bone reconstruction simultaneously. Gastrocnemius muscle and soleus muscle flaps are generally used as rotational flaps for the tibia. The distal third of the tibia can often not be covered with the gastrocnemius muscle and soleus muscle flaps. Treatment distal to the distal third of the tibia is difficult because fewer flap options are available. In the present report, we describe our experience with a Gustilo Type 3B open tibial fracture treated by gastrocnemius muscle and soleus muscle flaps, along with an additional proximally based flexor hallucis longus flap, which is a rare procedure. The participant was a 17-year-old male who injured his left tibia in a motorcycle traffic accident. Physical examination revealed a wound of 13 cm × 7 cm extending from the medial lower leg to the posterior aspect, with extensive skin loss. There was no nerve or vascular injury. The tibia was exposed, with detachment of the periosteum. The radiograph revealed a tibial shaft fracture. The AO/OTA classification was 42-A3.3, and it was classified as a Gustilo-Anderson Type 3B fracture. Gastrocnemius muscle and soleus muscle flaps were lifted in the area of the soft-tissue defect and then, placed over the tibia. Despite this, the distal portion of the tibia remained uncovered. Therefore, a flexor hallucis longus flap was lifted and placed over the distal portion of the tibia. On day 7 after the injury, the external fixation device was removed and the tibial shaft was fixated with two Ender nails (4.5 mm in diameter). The clinical course was satisfactory, and the skin graft and flap were successful. Bone union was achieved without infection, and the resulting range of motion was normal. For the treatment of Gustilo-Anderson Type 3B open tibial fractures, early treatment of the soft-tissue defect is vital. We surgically treated a Gustilo-Anderson Type 3B open tibial fracture with gastrocnemius muscle and soleus muscle flaps, along with an additional proximally based flexor hallucis longus flap, which is a rare procedure. In the event of a soft-tissue defect in the distal third of the tibia, the use of a proximally based flexor hallucis longus flap is an effective surgical approach. Soft tissue management and fracture fixation including initial external fixation in Gustilo-Anderson type II and type III open fractures are cornerstones in the treatment but details on timing and type of wound closure, irrigation and debridement, systemic and local antibiotics, antimicrobial-coated implants and the use of Bone Morphogenetic Protein-2 remain controversial. This article looks at current clinical evidence of these items for the management of open fractures. Timing of debridement and wound closure remains critical. Early debridement by an experienced team within 24 h seems adequate while gross contamination, a devascularized limb, a multi-injured patient and compartment syndrome require immediate surgical intervention. Wound closure during the first surgery was shown to result in reduced rates for infections and nonunion. If soft-tissue reconstruction is needed, it should be performed within the first 7 days. Regarding types of irrigation fluid, antiseptic and antibacterial solutions did not prove to be superior to saline. High pressure irrigation has not been demonstrated to be beneficial whereas antibiotic administration as soon as possible has been proven to be favorable. Administration of more than 72 h was not superior to shorter systemic antibiotic intervals. For Gustilo-Anderson type I and II, broad spectrum antibiotic therapy is reasonable. Additional aminoglycosides for broader coverage are recommended in Gustilo-Anderson type III fractures. There is newer literature on the beneficial effects of the use of local antibiotics, e.g. by antibiotic beads. Coating of internal fixation devices is a modern approach to improve infection prophylaxis and gentamicin-coated implants have been demonstrated to be safe in clinical application. Vacuum assisted closure (VAC) could not evidence negative pressure wound therapy to reduce infection risk, improve self-rated disability or quality of life in open fractures, however, enhance treatment costs. Recombinant human bone morphogenetic proteins (rhBMP)-2 showed promising data in Gustilo-Anderson type III open tibial shaft fractures with lower rates of invasive secondary procedures. In conclusion, there is evidence for thorough debridement and irrigation with saline, early soft tissue coverage and the use of systemic and local antibiotics. Except for a short-term soft tissue coverage VAC seems not to be beneficial and rhBMP-2 is an additional tool in Gustilo-Anderson type III open fractures. Fractures of the lower extremity are a common type of childhood injury and many can be treated without surgery. Dislocated and open fractures are an indication for fracture stabilization via either intramedullary nailing or, in the case of complicated fractures, external fixation. But if complications are likely because of diseases and disabilities (for example, a neuropathy) that can complicate the post-operative procedure and rehabilitation, what options does one have? We report a nine-year-old Caucasian girl who had hereditary motor and sensory neuropathy type I and who was admitted with a grade I open tibia fracture after a fall from a small height. Plain radiographs showed a dislocated tibia and fibula fracture. An open reduction with internal fixation with a compression plate osteosynthesis was performed, and soft tissue debridement combined with an external fixateur was undertaken. Three months later, she was re-admitted with localized swelling and signs of a local soft tissue infection in the middle of her tibia. Plain radiographs showed a non-union of the tibia fracture, and microbiological analysis confirmed a wound infection with cefuroxime-sensitive Staphylococcus aureus. Because of the non-union, the osteosynthesis was replaced with an Ilizarov external fixateur, and appropriate antibiotic therapy was initiated. Four months after the initial accident, the fracture was consolidated and we removed the external fixateur. If there is a pre-existing neuropathy and if disease makes it difficult for a child to follow all post-operative instructions, salvage procedures should be kept in mind in case of complications. There are multiple therapeutic options, including osteosynthesis, intramedullary nailing systems, cast therapy, or an external fixateur like the Ilizarov or Taylor spatial frame system. The initial use of an external fixateur such as an Ilizarov or Taylor spatial frame in patients with pre-existing neuropathies should be kept in mind as a possible treatment option in complicated fractures, especially in a child with pre-existing neurological or endocrine pathologies. Recombinant human bone morphogenetic protein-2 (rhBMP-2) improves healing of open tibial fractures treated with intramedullary nail fixation. However, routine use has not occurred. The purposes of the current study were to provide a systematic review of the literature using rhBMP-2 in the treatment of acute open tibial fractures treated with intramedullary nail fixation and to provide a meta-analysis of the randomized, controlled trials. Multiple databases, reference lists of relative articles, and main orthopedic journals were searched. The basic information and major results were compared. Four studies with a total of 609 patients were included.The secondary intervention rate in the standard-of-care (SOC) group was significantly higher than in the rhBMP-2 combined with absorbable collagen sponge (rhBMP-2/ACS) group (27.1% vs 17.5%, respectively; P&lt;.01). The treatment failure rate in the SOC group was significantly higher (34.3% vs. 21.4%, respectively; P&lt;.01). No significant differences were found in infection rate, hardware failure rate, fracture healing rate at 20 weeks, and postoperative pain level. For patients treated with reamed intramedullary nail fixation, only the treatment failure rate in the SOC group was significantly higher (21.5% vs 14.2%, respectively; P=.02); no other significant difference was observed. Adding rhBMP-2 to the treatment of Gustilo-Anderson grade IIIA and B open tibial fractures led to net savings of approximately $6000 per case.Recombinant human bone morphogenetic protein-2 added to intramedullary nail fixation of open tibial fractures could reduce the frequency of secondary interventions and total health care costs. For reamed patients, adding rhBMP-2 reduced treatment failure. This analysis supports the clinical efficacy of rhBMP-2/ACS for the treatment of these severe fractures. To explore the clinical effects of VSD combined with continual irrigation in treating the infection of limbs fracture after internal fixation. From March 2010 to June 2015, 10 patients with infection of limbs fracture after internal fixation were treated with VSD combined with continual irrigation. There were 7 males and 3 females, aged from 11 to 58 years with an average of 34.4 years. Course of disease was from 1 to 8 months with an average of 4.8 months. Postoperative infection occurred in fractures of ulna and radius of 4 cases, tibiofibular fractures of 3 cases, calcaneal fractures of 2 cases, femoral fractures of 1 case. Eight infections were open fracture and 2 infections were close fracture. In additon to above treatment, antibiotics, dressing changing or skingrafting were used in the patients. Informations of wound surface healing, change dressings, original infection focus were observed. All infections got control, the wound healing after change dressings or skingrafting, and no complications such as osteomyelitis were found. The mean treatment time was 38.4 days(ranged, 29 to 45 days) and replacement times was 2.2 times(ranged, 1 to 4 times). All patients were followed up, no recurrent infections were found at 1 year after fracture healing. VSD combined with continual irrigation can effectively decrease the incidence of complications and promote the wound growth, healing and considerably shorten the healing time. It is an effective method for the treatment of infection of limbs fracture after internal fixation. Treatment of tibial diaphyseal nonunions are rather difficult. Plate-screw, intramedullary nailing and external fixation are the methods used for treatment. The aim of this study is to evaluate the treatment results of aseptic diaphyseal nonunions following tibia fractures by intramedullary compressive tibia nailing (IMCN) with or without bone graft. Twenty eight patients who had aseptic tibial nonunion without bone defects operated between 2005 and 2015 were included in the study. The mean age of our patients was 36.4 years (range 20-56 years). There were 22 males and 6 females. Fifteen of the patients exhibited hypertrophic nonunion and thirteen exhibited atrophic nonunion. The average time between fracture occurrence and presentation to our department was 1.6 years (range 1-20 years). All patients underwent fibular osteotomy by removal of a 2 cm bone block from the middle one-third of the fibulas. In all cases, IMCN was applied following the reaming procedure, then maximum bone contacts were achieved manually between proximal and distal bone fragments afterward, and dynamic compressive fixation with 1 mm of compression was performed by a single rotation of the compression screw at the top of the nail. Direct X-ray images were assessed according to the Rust criteria, and functional outcomes were assessed according to the Johner-Wrush criteria. Finite-element analysis was performed for 1 mm of compression. For statistical analysis, Fisher's exact test, Pearson's Chi-square test, and Mann-Whitney U-test were used. Union was achieved in all patients. Radiological union was obtained at an average of 15.5 ± 1.86 weeks. Functional results were found to be good or excellent in 25 (89.2%) patients and average or poor in 3 (10.8%) patients. One patient developed skin necrosis at the wound site, which was treated with rotational flap and skin graft. None of the patients developed implant failure, thromboembolism, deep-vein thrombosis, or infection. The use of compressive intramedullary nailing with or without bone graft is an effective method for the treatment of tibial nonunion. In treating patients who present with an extensive non-union due to infected intramedullary nail, bone healing can be achieved within a few weeks through a policy of active management. Following excision of the infected tissue and thorough irrigation, the fracture site is stabilized by a plate fixation and a packet with cancellous bone. The wound overlying the bone is left open to granulate. No complications were observed during the course of healing in 7 cases (5 tibia, 2 femur) managed this way. The method is based on classical principles of orthopedics and the treatment of infection. Such has been its impressive success, that it would seem to warrant not only close attention but also strong recommendation. Tibia fracture caused by high velocity missiles is mostly comminuted and followed by bone defect which makes their healing process extremely difficult and prone to numerous complications. A 34-year-old male was wounded at close range by a semi-automatic gun missile. He was wounded in the distal area of the left tibia and suffered a massive defect of the bone and soft tissue. After the primary treatment of the wound, the fracture was stabilized with an external fixator type Mitkovic, with convergent orientation of the pins. The wound in the medial region of the tibia was closed with the secondary stitch, whereas the wound in the lateral area was closed with the skin transplant after Thiersch. Due to massive bone defect in the area of the rifle-missile wound six months after injury, a medical team placed a reconstructive external skeletal fixator type Mitkovic and performed corticotomy in the proximal metaphyseal area of the tibia. By the method of bone transport (distractive osteogenesis), the bone defect of the tibia was replaced. After the fracture healing seven months from the secondary surgery, the fixator was removed and the patient was referred to physical therapy. Surgical treatment of wounds, external fixation, performing necessary debridement, adequate antibiotic treatment and soft and bone tissue reconstruction are essential in achieving good results in patients with the open tibial fracture with bone defect caused by high velocity missiles. Reconstruction of bone defect can be successfully treated by reconstructive external fixator Mitkovic.\nHere is the question:\nORTHOPEDIC SURGERY AND TRAUMATOLOGY: A 70-year-old woman, diabetic and hypertensive, who suffers a fall at home, presenting a 9 cm wound communicating with a fracture site of the right tibia. Radiographically, a short oblique fracture of the mid-distal third of the tibia was observed. An emergency operation was performed by cleaning (Friederich) and placement of an endomedullary steel-plated nail. At 11 months he presents with atrophic pseudarthrosis of the tibia with suppuration in the wound area. What will be his best immediate therapeutic option?\nHere are the potential choices:\n1. Triple antibiotherapy (gram-positive, gram-negative and anaerobic) and cleaning of the surgical wound, removing the distal locks to promote bone consolidation.\n2. Expectant attitude and antibiotic treatment with quinolones.\n3. Autologous graft and growth factors (BMP 2 and 7) to stimulate the bone consolidation process, which is slowing.\n4. Removal of the nail, debridement, placement of external fixator and antibiotherapy adjusted to culture results.\nThe correct answer is: 4. Removal of the nail, debridement, placement of external fixator and antibiotherapy adjusted to culture results."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Presentation Primary lesions of small and large blisters, known as vesicles and bullae, are found on the skin and sometimes on the mucous membranes. Non-bullous pemphigoid In some patients, pemphigoid starts off with cutaneous manifestations of BP without bullae, as the only sign of the disease. Pruritic eczematous, papular, or urticaria-like skin lesions may also persist for weeks to months. Bullous phase The bullous stage of BP shows vesicles and bulla, appearing on apparently normal or erythematous skin, predominantly at the flexural aspects of the extremities and the lower trunk. Mucosal lesions, which typically are erosions of the oral mucosa, are present in 10 to 30 percent of patients. Occasionally, the blister fluid becomes blood-tinged. The blisters are tense, about 1–4 cm in diameter, leaving eroded and crusted areas, together with urticarial and infiltrated papules and plaques in an annular or figurate pattern. Other mucous membranes Less common sites that might get involved are nasopharynx, esophagus, and urethra. Nasopharyngeal involvement can lead to ulcerations of the septum and airway obstruction which might require tracheostomy. Esophageal disease may present with ulcerations, dysphagia, odynophagia, and stenosis. Stenosis at urethra, vaginal orifice and rectal have also resulted from chronic inflammation and scarring. Skin disease About 25% of patients have cutaneous lesions, with tense vesicles or bullae, mainly on the face, neck, and scalp. Healing of erosion is either with or without atrophic scars. Cutaneous lesions of mucous membrane pemphigoid presents in 2 subtypes: (1)presents as generalized eruption of tense bullae without scarring (2) presents as localised blisters on an erythematous base, resulting in atrophic scarring. Clinical assessment Presence of tense blisters and erosions that occur on skin without another identifiable cause. Desquamative gingivitis or mucositis involving oral, ocular, nasal, genital, anal, pharyngeal, laryngeal, and/or esophageal mucosae Presence of pruritic eczematous eruptions, or urticarial plaques without identifiable cause. Patient's age over 60 years old. Histopathology Lesional tissue, preferably of an intact vesicle or the edge of an intact bulla is obtained using punch biopsy for Haemotoxylin and Eosin (H&E) staining. The findings are sub-epidermal blister with dermal infiltrated with lymphocytes, neutrophils and eosinophils. Additional findings include sub-epidermal fibrosis which is consistent with the scarring nature of mucous membrane pemphigoid in older lesions and plasma cell infiltration. Other drug rashes Toxic shock syndrome(usually present with early multiorgan failures and unique cutaneous manifestations in the form of macular rashes affecting palm and soles that later on evolve to desquamation over the period of 14 days) Paraneoplastic pemphigus(as a mucocutaneous manifestation of malignancy) Exfoliative erythroderma(usually affects skin only and spares mucous membrane and is painless in most of the cases) Staphylococcal scalded skin syndrome in children: (evidence of staphylococcal infection, no history of drug intake, and it usually spares mucus membranes) Skin biopsy is also an important tool to differentiate TEN and SJS from these disorders. Staphylococcal scalded skin syndrome (SSSS) is a dermatological condition caused by Staphylococcus aureus. Signs and symptoms The disease presents with the widespread formation of fluid-filled blisters that are thin walled and easily ruptured, and the patient can be positive for Nikolsky's sign. Ritter's disease of the newborn is the most severe form of SSSS, with similar signs and symptoms. SSSS often includes a widespread painful erythroderma, often involving the face, diaper, and other intertriginous areas. Extensive areas of desquamation might be present. Perioral crusting and fissuring are seen early in the course. Unlike toxic epidermal necrolysis, SSSS spares the mucous membranes. It is most common in children under 6 years, but can be seen in adults who are immunosuppressed or have kidney failure. Erythema multiforme is usually a reaction of the skin and mucous membranes that occurs suddenly. It appears as a symmetrical rash and may include the mucous membrane lesions. This means that the body is sensitive to something that causes the skin and mucous membranes to react. The more common mild form is refer to as EM minor. It consists of a skin rash that involve no more than one mucosal surface. The sudden onset will progress rapidly as symmetrical lesions with circular color changes in some or all of the lesions. Rash will spread towards center or trunk of the body. Evenly distributed bumps on the skin become classic iris or target lesions. They have bright red borders and small white bumps in the center. The physical examination of the skin and its appendages, as well as the mucous membranes, forms the cornerstone of an accurate diagnosis of cutaneous conditions. Most of these conditions present with cutaneous surface changes termed \"lesions,\" which have more or less distinct characteristics. Often proper examination will lead the physician to obtain appropriate historical information and/or laboratory tests that are able to confirm the diagnosis. Upon examination, the important clinical observations are the (1) morphology, (2) configuration, and (3) distribution of the lesion(s). With regard to morphology, the initial lesion that characterizes a condition is known as the \"primary lesion\", and identification of such a lesions is the most important aspect of the cutaneous examination. Over time, these primary lesions may continue to develop or be modified by regression or trauma, producing \"secondary lesions\". However, with that being stated, the lack of standardization of basic In the following paper the most common drug eruptions and auto-immune, blistering skin diseases in which mucous lesions precede skin lesions development are discussed. Non-characteristic clinical pictures of mucous lesions result in diagnostic difficulties of these diseases, and prognosis is dependent on prompt and precise diagnosis. The aim of the work was to describe clinical features of mucous membranes lesions and point to differential diagnosis. Loxoscelism is the clinical condition produced by the venom of spiders belonging to the genus Loxosceles. Human cases of loxoscelism have been observed in diverse countries of different continents in temperate and tropical regions. In Chile loxoscelism is caused by Loxosceles laeta, spider with domestic habits. Loxoscelism can be observed into two well definited clinical variants: cutaneous loxoscelism (CL) and systemic or viscerocutaneous loxoscelism (VCL) which occur in around 83.3 and 16.7% cases respectively. Within the universe of CL patients a clinical modality in which necrotic lesion is not present or is insignificant, but presenting a remarkable edema, particularly when the bite is on the face, which has received the name of CL with an edematous predominance (CLEP). In this paper the individual description and the assambled analysis of 10 cases, four males and six females, age ranging from 6 to 68 years, of CLEP are presented. Nine cases occurred in warm periods spring through fall and one in winter. In six cases the accident causing spider was seen and two of these were identified as L. laeta adult females. In all cases the patients went or were transported to emergency medical services 4-24 h after the bite. The predominant initial symptom was a burning stinging sensation at the site of the bite, followed by intensive pain which expanded the neighbour areas concomitantly with the emerging and progressive edema. In four of the nine patients in who the bite was on the face, the edema involved all of it, closed both eyelids and expanded to the neck and upper part of the thorax. In three cases the enormous edema was the only significant clinical manifestation, whereas in the remaining seven conjunctly with the edema, a small violaceous plaque or a blister of serous content gave place to a little livedoid plaque (diameter 0.3-0.8 cm) which evolved to desquamation without leaving any scarring. The edema was characterized by its brilliant rose color, painful and hard which is not accompanied by regional adenopathy. Treatment of the 10 patients depended on the moment in they were seen by us. It consisted on parenteral administration, according to age and weight, of 5-10 mg of chloroprofenpyridamine maleate every 8 hours for be continued every 12-24 hours until the patient was discharged. Parenteral route was preferred in order that it was going to be adequately absorbed. With the beginning of the antihistaminic treatment a clear diminution of pain and edema was obtained, being possible its total disappearance within 4-10 days. CLEP occurs in about 4% of loxoscelism cases, has a benign prognosis and an early response to adequate medical treatment. Without discarding the sensibility factor of the affected individual, there exist the impression that the edema may abort the necrotic process when it dilutes the enzymatic process produced by L.laeta venom. In Chile, the differential diagnosis must be planted with the following clinical entities: bites of hematophagous insects on the face, bee stings, Chagas' disease with facial port of entry and angioneurotic edema. Mucosal lesions are common, mostly in the mouth, but also in the genital and ocular mucous membranes. They are initially bullous, then quickly turn into painful erosions. Thick hemorrhagic crusts may cover the labial lesions, and a fibrin-whitish coating may line the mucosal erosions of the cheeks, palate, and genitalia. These mucosal lesions occur most often at the same time as the skin lesions but can be shifted a few days before or after the eruption of targets. While skin lesions are nonpainful, mucosal lesions are frequently painful. Pulmonary signs may also be present, such as a cough and dyspnea. They testify to a respiratory attack most often related to the inducing infection of the EM (mainly due to Mycoplasma pneumoniae). When extensive skin involvement occurs, some patients may show signs of dehydration. Others with mucosal involvement may lose weight because of difficulty eating. A 29-year-old, normotensive, nondiabetic man presented with a 9-day history of a scaly, pruritic eruption involving the right chest, axilla, and arm. He had a history of herpes zoster involving the same areas about 4 weeks ago. The present eruption started after the herpetic lesions had healed. Examination revealed scaly, erythematous plaques and papules involving the right side of the chest, axilla, and arm in a dermatomal pattern (figure 1). Removal of the scales revealed underlying bleeding points (positive Auspitz sign). The rest of the body, including scalp, palms, soles, and nails, were normal. There was no history suggestive of psoriasis in any family member. Systemic examination and routine investigations were noncontributory. A clinical diagnosis of psoriasis was made and confirmed by histopathologic examination of a skin biopsy sample. The patient was prescribed a topical clobetasol cream and oral levocetirizine. The eruption resolved completely after 3 weeks. A 43-year-old normotensive, nondiabetic woman presented with a 2-day history of fever, arthalgias, and generalized erythematous dermatitis. Five days ago, the patient had a toothache for which she was prescribed injectable ampicillin. After receiving ampicillin for 3 days, she developed fever, myalgias, and arthalgias, which was followed several hours later by an erythematous eruption. The dermatitis started on the trunk and, over a period of several hours, progressed to involve the face and limbs. The eruption was slightly pruritic. History revealed herpes zoster 7 months ago involving left thoracic dermatomes, for which the patient was treated with valacyclovir (1 g thrice a day x 7 days) and analgesics. There was no history of post-zoster neuralgia. On examination, the patient was febrile (oral temperature 102 degrees F), her heart rate was 118 beats per minute, and her blood pressure was 110/70 mm Hg. Cutaneous examination revealed an erythematous, maculopapular dermatitis involving the face and limbs in a bilaterally symmetrical pattern; the palms and soles were also bilaterally involved. The whole of the trunk was involved with erythematous and, in places, violaceous, maculopapular eruption except for a small area on the left side corresponding to T8 and T9 thoracic dermatomes (Figure 2). Complete blood cell counts revealed eosinophilia (9%) and liver function tests, kidney function tests, random blood sugar, routine urine examination, and blood and urine cultures were noncontributory. Histopathologic examination of lesional skin biopsy revealed an intense mononuclear cell infiltration with many eosinophils and an interface dermatitis with hydropic degeneration of basal keratinocytes, while in the spared area, only slight lymphocytic infiltration was present in a perivascular distribution. Based on the history and examination, a diagnosis of ampicillin-induced drug dermatitis was made. The ampicillin was stopped and the patient was put on a short course of oral prednisolone, antipyretics, and topical calamine. The patient was afebrile in 2 days and the eruption resolved completely in 8 days. Staphylococcal scalded-skin syndrome (SSSS) and bullous impetigo are two blistering disorders associated with staphylococcal (phage group II) infection. In SSSS, the initial findings are redness and tenderness of the central face, neck, trunk, and intertriginous zones. This is followed by short-lived flaccid bullae and a slough or exfoliation of the superficial epidermis. Crusted areas then develop, characteristically around the mouth in a radial pattern. SSSS is distinguished from TEN by the following features: younger age group (primarily infants), more superficial site of blister formation, no oral lesions, shorter course, lower morbidity and mortality rates, and an association with staphylococcal exfoliative toxin (“exfoliatin”), not drugs. A rapid diagnosis of SSSS versus TEN can be made by a frozen section of the blister roof or exfoliative cytology of the blister contents. In SSSS, the site of staphylococcal infection is usually extracutaneous (conjunctivitis, rhinorrhea, Urticarial allergic eruption is a cutaneous condition characterized by annular or gyrate urticarial plaques that persist for greater than 24 hours. See also Urticaria List of cutaneous conditions References External links Urticaria and angioedema The prognosis is mainly related to the body surface area detached. The healing is obtained spontaneously in 2 to 3 weeks for the EMm and 4 to 6 weeks for the EMM. The mucosal lesions always take longer to heal. The healing of the mucocutaneous lesions is without scarring but with frequent dyschromia. Recurrences are seen in less than 5% of cases, mainly in forms due to herpes infection. Clindamycin is a lincomycin-derived antibiotic useful for the treatment of anaerobic and Gram-positive aerobic bacterial infections. Cutaneous adverse reactions are usually maculopapular exanthemas, although hypersensitivity syndrome, acute generalized exanthematous pustulosis, and Stevens-Johnson syndrome have also been reported (1). We report the case of a patient with a maculopapular rash triggered by clindamycin who developed cutaneous lesions on striae distensae (SD). A 47-year-old woman was referred to our clinic for pruritic cutaneous lesions which had started 6 days earlier. Her past clinical history included hypertension, hypothyroidism, hyperuricemia, cholecystectomy, caesarean section, and endometriosis-related abdominal surgery, and she was taking levothyroxine, allopurinol, imidapril, and omeprazole. The skin rash first developed on her neck and back on the 3rd day of clindamycin oral treatment (300 mg every 6 hours), which was prescribed as antibiotic prophylaxis for a tooth implant. General malaise (but not fever) was also reported. Physical examination revealed an erythematous maculopapular eruption symmetrically distributed on the neck, abdomen, and back (Figure 1, A), with isolated lesions involving the proximal upper and lower limbs (Figure 1, B). There was a striking vertical distribution of skin lesions along the SD on the lateral sides of the abdomen (Figure 1, C). No mucosal involvement was found, and laboratory studies showed no abnormalities. Clindamycin withdrawal was followed by prescription of a course of oral deflazacort, starting at 30 mg daily and tapering down during a 9-day period. On the 5th day of treatment, the rash had almost cleared with minimal desquamation (Figure 1, D). Eight weeks after clearance of the skin rash, informed consent was obtained in order to perform an allergological evaluation of clindamycin, including prick and intradermal (ID) tests on the forearm and patch tests on the upper back (2). For patch testing, powder of the commercial capsules (Dalacin®) was diluted in petrolatum (pet.) and water (aq.), resulting in a final 1% clindamycin dilution. Parenteral clindamycin preparations were used in therapeutic concentrations for prick tests (150 mg/mL) and dilutions in saline of 1/100 and 1/10 for the ID test. Other authors have reported that these concentrations do not seem to irritate the skin (3-6). Prick and ID tests were assessed after 20 min and 24 hours, respectively. Patch tests were removed after the 2nd day, and late reactions were evaluated on day 2 and day 4. Prick and ID test results after 20 min were negative. Late results of ID tests with clindamycin (1.5 and 15 mg/mL) were positive: erythematous infiltrated papules about 7×7 mm and 18×15 mm were observed at 24 hours and lasted until the 8th day. Patch tests with clindamycin 1% in pet. and 1% in aq. were also positive (+ on day 2 and day 4). Positive late skin tests suggested delayed-type non-IgE-mediated allergic clindamycin hypersensitivity. Oral challenge tests are considered to be the gold standard to establish or exclude drug hypersensitivity. Due to the positive result of late skin test to clindamycin, oral challenge was not performed in our patient (3,5). The Koebner isomorphic phenomenon has been described in cutaneous reactions induced by drugs, such as antibiotics and chemotherapy. Chronic pressure on the skin is probably involved in the onset of skin lesions in hand-foot eruptions induced by tyrosine kinase inhibitors (sorafenib and sutinib). Solar exposure and cutaneous trauma also seem to play a role in the location of papulopustular eruptions caused by endothelial growth factor receptor inhibitors (erlotinib) (7). More frequent involvement in traumatized skin and surgical scars has been reported in the context of linear IgA bullous dermatosis and leukocytoclastic vasculitis triggered by vancomycin and cefuroxime (8). SD are produced by non-penetrating physical trauma, similar to friction or pressure. Different dermatoses can develop along SD skin lesions (like plaque psoriasis, pustular psoriasis, lichen planus, vitiligo, discoid lupus erythematosus, lupus vasculitis, urticarial vasculitis, or chronic graft-versus-host disease) (9). Bevacizumab, etretinate, and corticosteroid-induced ulcers, hyperpigmentation caused by bleomycin, and urticariform lesions triggered by diclofenac are examples of different type of drug-induced abnormalities involving SD (10). In summary, we identified clindamycin as the cause of the cutaneous reactions that occurred in our patient on the basis of the results of the skin tests and clinical history. Our findings confirmed a delayed-type hypersensitivity reaction, possibly involving a T-cell-mediated immunologic mechanism. Intradermal and patch tests were found to be useful in order to confirm the diagnosis (4,5). We did not find reports in the literature of drug-induced cutaneous eruptions along the SD as a manifestation of a Koebner phenomenon. Clinical underreporting of this phenomenon could explain the scarce literature on this cutaneous adverse reaction. Mucosal erosions in bullous diseases and leading to mucosal sequelae are widely described in toxic epidermal necrolysis (TEN). These complications cause disfigurement and functional impairment. They are more rarely reported in erythema multiforme (EM). We report a case of lip adhesion following EM induced by Mycoplasma pneumoniae. A 12-year-old boy was hospitalized in a paediatric intensive care unit. He had a prominent target skin rash on the palms and soles. Mucosal injury was associated with conjunctivitis, balanitis without dysuria and hyperalgesic stomatitis. M. pneumoniae serology was positive with immunoglobulin M. We made a diagnosis of EM secondary to M. pneumoniae infection. Two months later, the skin lesions had completely disappeared but the patient's mouth opening was limited to 25 mm and he presented bilateral adhesions between the upper and lower lips of 5mm on the right and 8mm on the left resulting in aesthetic and functional damage. Mucosal damage and its sequelae have been widely described in TEN. Ophthalmic sequelae are more frequent. A case of labial synechiae secondary to TEN has been reported. In EM, mucosal lesions occur in 100% of cases with a further mucosal problem being present in 50% of patients. Mucosal damage has been reported during EM flares but there are no studies of side-effects after the acute episode. Oral mucosal adhesions can cause cosmetic sequelae, but above all they hinder functional prognosis. These complications must be prevented by making gutters of vestibular deepening and lip movements with maximum mouth opening several times a day, starting as soon as possible. Appropriate pain management should be undertaken to ensure patient comfort and avoid the need for analgesics and restriction of movement. Mucosal sequelae exist in EM. Whatever their cause, complications involving the mucosa must be prevented through early, tailored and multidisciplinary treatment. Adequate pain management must not be overlooked. Annular lesions can present in a variety of diseases. Knowledge of the physical appearance and history of presentation of these skin findings can help in the diagnosis. A pruritic, annular, erythematous patch that grows centrifugally should prompt evaluation for tinea corporis. Tinea corporis may be diagnosed through potassium hydroxide examination of scrapings. Recognizing erythema migrans is important in making the diagnosis of Lyme disease so that antibiotics can be initiated promptly. Plaque psoriasis generally presents with sharply demarcated, erythematous silver plaques. Erythema multiforme, which is due to a hypersensitivity reaction, presents with annular, raised lesions with central clearing. Lichen planus characteristically appears as planar, purple, polygonal, pruritic papules and plaques. Nummular eczema presents as a rash composed of coin-shaped papulovesicular erythematous lesions. Treatment is aimed at reducing skin dryness. Pityriasis rosea presents with multiple erythematous lesions with raised, scaly borders, and is generally self-limited. Urticaria results from the release of histamines and appears as well-circumscribed, erythematous lesions with raised borders and blanched centers. Annular lesions occur less commonly in persons with fixed drug eruptions, leprosy, immunoglobulin A vasculitis, secondary syphilis, sarcoidosis, subacute cutaneous lupus erythematosus, and granuloma annulare. Oral mucosa is one of the first barriers to the outside world which encounters various antigens, microorganisms and physical agents. Numerous oral pathologies challenge the dermatologists. Some may be the first sign of an underlying immunosuppression, while others are the inevitable serious outcomes of long-lasting mucosal disease. The differential diagnosis is crucial in terms of prompt and effective treatment. Tumid lupus erythematosus is a rare, but distinctive entity in which patients present with edematous erythematous plaques, usually on the trunk. Lupus erythematosus tumidus (LET) was reported by Henri Gougerot and Burnier R. in 1930. It is a photosensitive skin disorder, a different subtype of cutaneous lupus erythematosus (CLE) from discoid lupus erythematosus (DLE) or subacute CLE (SCLE). LET is usually found on sun-exposed areas of the body. Skin lesions are edematous, urticarialike annular papules and plaques. Topical corticosteroids are not effective as treatment for LET, but many will respond to chloroquine. LET resolves with normal skin, no residual scarring, no hyperpigmentation or hypopigmentation. Cigarette smokers who have LET may not respond very well to chloroquine. It has been suggested that it is equivalent to Jessner lymphocytic infiltrate of the skin. See also Lupus erythematosus List of cutaneous conditions References Cutaneous lupus erythematosus Mucous Membrane Pemphigoid: Autoimmune disease which affects only mucous membranes with clinical presentation of hard and rigid blisters which then rupture eventually into deep ulcers. Cutaneous Lupus Erythematosus: These present as oral discoid lesions which may be present on the inner cheek and behind the lips. White papules may also be present. A 23-year-old woman was seen for widespread skin lesions present since the age of 2.5 years. Twenty years ago, she developed a brown macular lesion on her right buttock. The lesion became hyperkeratotic and subsequently spread through the posterior aspect of her right leg. It later spread to the right side of the trunk and to the right arm. When she was 9 years old, she developed similar lesions on her left arm and leg. After she was 13 years old, no new skin lesions appeared. There was no family history of similar lesions. On examination, there were numerous linear and whorled, reddish-brown, hyperkeratotic plaques, with central atrophy and raised borders, following Blaschko's lines on all of the extremities. These lesions on the extremities extended to the dorsum of the hands and feet (Fig. 1). She had hyperkeratotic lesions on the pressure points of both of the soles, but no palm involvement. The number of lesions on the right side was greater than that on the left. Reddish-brown annular plaques with central atrophy and raised borders, appearing in zosteriform configuration, and numerous individual 2-3-mm erythematous lichenoid papules were observed on the right side of the thorax and the right inguinal region (Fig. 2). No face, scalp, or mucous membrane involvement was seen. The nails of the second and fifth fingers of the right hand and the nail of the third finger of the left hand showed nail dystrophy with longitudinal ridges and pterygium. All the nails of the right foot and the nails of the first and fifth toes of the left foot showed dystrophic changes with subungual keratosis. The patient was otherwise in good health. Two biopsy specimens taken from a hyperkeratotic plaque and a lichenoid papule showed an epidermal invagination with angulated parakeratotic tier, denoting cornoid lamella. The epidermis just underneath the cornoid lamella displayed vacuolization and the granular layer was absent. The adjacent epidermis was atrophic, and hydropic degeneration within the basal cell layer was seen. In the dermis, a nonspecific, mild, chronic, inflammatory cell infiltrate, telangiectatic vessels, and pigment-laden macrophages were present. These findings were consistent with linear porokeratosis (Fig. 3). Microscopic examinations and mycologic cultures of the nails were negative. We decided to treat our case systemically with retinoids, but the patient refused this therapy. So, topical tretinoin 0.05% was started once a day. A marked improvement was observed in hyperkeratosis through the first 4 weeks of treatment and plateaued at 8 weeks. After 10 weeks, the lesions had almost disappeared. We planned to continue the applications every other day. One year later, she remains stable with application of topical tretinoin 0.05% twice a week and is satisfied with the final appearance. She is under regular follow-up. Pemphigus is a rare autoimmune disease of the skin and mucous membranes. It is characterized by autoantibodies directed against the desmosomal adhesion proteins of epithelial cells (desmoglein type I and III) resulting in acantholysis of the epithelium. Painful blisters or erosions are typical clinical findings. Pemphigus is a severe disease that may be fatal. Early diagnosis of pemphigus is important in order to be able to start the treatment as soon as possible and to halt the progression of the disease and avoid serious secondary infections.\nHere is the question:\nDERMATOLOGY: A 14-year-old female patient in good general condition presents since 4 days ago a very pruritic generalized cutaneous eruption formed by erythematous-edematous plaques between 2 and 15 cm in diameter without desquamation with a tendency to acquire an annular morphology that individually disappear in less than 24 hours. The mucous membranes are respected. Your first diagnostic impression would be:\nHere are the potential choices:\n1. Urticaria.\n2. Rubella.\n3. Toxicoderma.\n4. Staphylococcal toxic shock.\n5. Scabies.\nThe correct answer is: ",
        "gold_answer": "1 Urticaria.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Presentation Primary lesions of small and large blisters, known as vesicles and bullae, are found on the skin and sometimes on the mucous membranes. Non-bullous pemphigoid In some patients, pemphigoid starts off with cutaneous manifestations of BP without bullae, as the only sign of the disease. Pruritic eczematous, papular, or urticaria-like skin lesions may also persist for weeks to months. Bullous phase The bullous stage of BP shows vesicles and bulla, appearing on apparently normal or erythematous skin, predominantly at the flexural aspects of the extremities and the lower trunk. Mucosal lesions, which typically are erosions of the oral mucosa, are present in 10 to 30 percent of patients. Occasionally, the blister fluid becomes blood-tinged. The blisters are tense, about 1–4 cm in diameter, leaving eroded and crusted areas, together with urticarial and infiltrated papules and plaques in an annular or figurate pattern. Other mucous membranes Less common sites that might get involved are nasopharynx, esophagus, and urethra. Nasopharyngeal involvement can lead to ulcerations of the septum and airway obstruction which might require tracheostomy. Esophageal disease may present with ulcerations, dysphagia, odynophagia, and stenosis. Stenosis at urethra, vaginal orifice and rectal have also resulted from chronic inflammation and scarring. Skin disease About 25% of patients have cutaneous lesions, with tense vesicles or bullae, mainly on the face, neck, and scalp. Healing of erosion is either with or without atrophic scars. Cutaneous lesions of mucous membrane pemphigoid presents in 2 subtypes: (1)presents as generalized eruption of tense bullae without scarring (2) presents as localised blisters on an erythematous base, resulting in atrophic scarring. Clinical assessment Presence of tense blisters and erosions that occur on skin without another identifiable cause. Desquamative gingivitis or mucositis involving oral, ocular, nasal, genital, anal, pharyngeal, laryngeal, and/or esophageal mucosae Presence of pruritic eczematous eruptions, or urticarial plaques without identifiable cause. Patient's age over 60 years old. Histopathology Lesional tissue, preferably of an intact vesicle or the edge of an intact bulla is obtained using punch biopsy for Haemotoxylin and Eosin (H&E) staining. The findings are sub-epidermal blister with dermal infiltrated with lymphocytes, neutrophils and eosinophils. Additional findings include sub-epidermal fibrosis which is consistent with the scarring nature of mucous membrane pemphigoid in older lesions and plasma cell infiltration. Other drug rashes Toxic shock syndrome(usually present with early multiorgan failures and unique cutaneous manifestations in the form of macular rashes affecting palm and soles that later on evolve to desquamation over the period of 14 days) Paraneoplastic pemphigus(as a mucocutaneous manifestation of malignancy) Exfoliative erythroderma(usually affects skin only and spares mucous membrane and is painless in most of the cases) Staphylococcal scalded skin syndrome in children: (evidence of staphylococcal infection, no history of drug intake, and it usually spares mucus membranes) Skin biopsy is also an important tool to differentiate TEN and SJS from these disorders. Staphylococcal scalded skin syndrome (SSSS) is a dermatological condition caused by Staphylococcus aureus. Signs and symptoms The disease presents with the widespread formation of fluid-filled blisters that are thin walled and easily ruptured, and the patient can be positive for Nikolsky's sign. Ritter's disease of the newborn is the most severe form of SSSS, with similar signs and symptoms. SSSS often includes a widespread painful erythroderma, often involving the face, diaper, and other intertriginous areas. Extensive areas of desquamation might be present. Perioral crusting and fissuring are seen early in the course. Unlike toxic epidermal necrolysis, SSSS spares the mucous membranes. It is most common in children under 6 years, but can be seen in adults who are immunosuppressed or have kidney failure. Erythema multiforme is usually a reaction of the skin and mucous membranes that occurs suddenly. It appears as a symmetrical rash and may include the mucous membrane lesions. This means that the body is sensitive to something that causes the skin and mucous membranes to react. The more common mild form is refer to as EM minor. It consists of a skin rash that involve no more than one mucosal surface. The sudden onset will progress rapidly as symmetrical lesions with circular color changes in some or all of the lesions. Rash will spread towards center or trunk of the body. Evenly distributed bumps on the skin become classic iris or target lesions. They have bright red borders and small white bumps in the center. The physical examination of the skin and its appendages, as well as the mucous membranes, forms the cornerstone of an accurate diagnosis of cutaneous conditions. Most of these conditions present with cutaneous surface changes termed \"lesions,\" which have more or less distinct characteristics. Often proper examination will lead the physician to obtain appropriate historical information and/or laboratory tests that are able to confirm the diagnosis. Upon examination, the important clinical observations are the (1) morphology, (2) configuration, and (3) distribution of the lesion(s). With regard to morphology, the initial lesion that characterizes a condition is known as the \"primary lesion\", and identification of such a lesions is the most important aspect of the cutaneous examination. Over time, these primary lesions may continue to develop or be modified by regression or trauma, producing \"secondary lesions\". However, with that being stated, the lack of standardization of basic In the following paper the most common drug eruptions and auto-immune, blistering skin diseases in which mucous lesions precede skin lesions development are discussed. Non-characteristic clinical pictures of mucous lesions result in diagnostic difficulties of these diseases, and prognosis is dependent on prompt and precise diagnosis. The aim of the work was to describe clinical features of mucous membranes lesions and point to differential diagnosis. Loxoscelism is the clinical condition produced by the venom of spiders belonging to the genus Loxosceles. Human cases of loxoscelism have been observed in diverse countries of different continents in temperate and tropical regions. In Chile loxoscelism is caused by Loxosceles laeta, spider with domestic habits. Loxoscelism can be observed into two well definited clinical variants: cutaneous loxoscelism (CL) and systemic or viscerocutaneous loxoscelism (VCL) which occur in around 83.3 and 16.7% cases respectively. Within the universe of CL patients a clinical modality in which necrotic lesion is not present or is insignificant, but presenting a remarkable edema, particularly when the bite is on the face, which has received the name of CL with an edematous predominance (CLEP). In this paper the individual description and the assambled analysis of 10 cases, four males and six females, age ranging from 6 to 68 years, of CLEP are presented. Nine cases occurred in warm periods spring through fall and one in winter. In six cases the accident causing spider was seen and two of these were identified as L. laeta adult females. In all cases the patients went or were transported to emergency medical services 4-24 h after the bite. The predominant initial symptom was a burning stinging sensation at the site of the bite, followed by intensive pain which expanded the neighbour areas concomitantly with the emerging and progressive edema. In four of the nine patients in who the bite was on the face, the edema involved all of it, closed both eyelids and expanded to the neck and upper part of the thorax. In three cases the enormous edema was the only significant clinical manifestation, whereas in the remaining seven conjunctly with the edema, a small violaceous plaque or a blister of serous content gave place to a little livedoid plaque (diameter 0.3-0.8 cm) which evolved to desquamation without leaving any scarring. The edema was characterized by its brilliant rose color, painful and hard which is not accompanied by regional adenopathy. Treatment of the 10 patients depended on the moment in they were seen by us. It consisted on parenteral administration, according to age and weight, of 5-10 mg of chloroprofenpyridamine maleate every 8 hours for be continued every 12-24 hours until the patient was discharged. Parenteral route was preferred in order that it was going to be adequately absorbed. With the beginning of the antihistaminic treatment a clear diminution of pain and edema was obtained, being possible its total disappearance within 4-10 days. CLEP occurs in about 4% of loxoscelism cases, has a benign prognosis and an early response to adequate medical treatment. Without discarding the sensibility factor of the affected individual, there exist the impression that the edema may abort the necrotic process when it dilutes the enzymatic process produced by L.laeta venom. In Chile, the differential diagnosis must be planted with the following clinical entities: bites of hematophagous insects on the face, bee stings, Chagas' disease with facial port of entry and angioneurotic edema. Mucosal lesions are common, mostly in the mouth, but also in the genital and ocular mucous membranes. They are initially bullous, then quickly turn into painful erosions. Thick hemorrhagic crusts may cover the labial lesions, and a fibrin-whitish coating may line the mucosal erosions of the cheeks, palate, and genitalia. These mucosal lesions occur most often at the same time as the skin lesions but can be shifted a few days before or after the eruption of targets. While skin lesions are nonpainful, mucosal lesions are frequently painful. Pulmonary signs may also be present, such as a cough and dyspnea. They testify to a respiratory attack most often related to the inducing infection of the EM (mainly due to Mycoplasma pneumoniae). When extensive skin involvement occurs, some patients may show signs of dehydration. Others with mucosal involvement may lose weight because of difficulty eating. A 29-year-old, normotensive, nondiabetic man presented with a 9-day history of a scaly, pruritic eruption involving the right chest, axilla, and arm. He had a history of herpes zoster involving the same areas about 4 weeks ago. The present eruption started after the herpetic lesions had healed. Examination revealed scaly, erythematous plaques and papules involving the right side of the chest, axilla, and arm in a dermatomal pattern (figure 1). Removal of the scales revealed underlying bleeding points (positive Auspitz sign). The rest of the body, including scalp, palms, soles, and nails, were normal. There was no history suggestive of psoriasis in any family member. Systemic examination and routine investigations were noncontributory. A clinical diagnosis of psoriasis was made and confirmed by histopathologic examination of a skin biopsy sample. The patient was prescribed a topical clobetasol cream and oral levocetirizine. The eruption resolved completely after 3 weeks. A 43-year-old normotensive, nondiabetic woman presented with a 2-day history of fever, arthalgias, and generalized erythematous dermatitis. Five days ago, the patient had a toothache for which she was prescribed injectable ampicillin. After receiving ampicillin for 3 days, she developed fever, myalgias, and arthalgias, which was followed several hours later by an erythematous eruption. The dermatitis started on the trunk and, over a period of several hours, progressed to involve the face and limbs. The eruption was slightly pruritic. History revealed herpes zoster 7 months ago involving left thoracic dermatomes, for which the patient was treated with valacyclovir (1 g thrice a day x 7 days) and analgesics. There was no history of post-zoster neuralgia. On examination, the patient was febrile (oral temperature 102 degrees F), her heart rate was 118 beats per minute, and her blood pressure was 110/70 mm Hg. Cutaneous examination revealed an erythematous, maculopapular dermatitis involving the face and limbs in a bilaterally symmetrical pattern; the palms and soles were also bilaterally involved. The whole of the trunk was involved with erythematous and, in places, violaceous, maculopapular eruption except for a small area on the left side corresponding to T8 and T9 thoracic dermatomes (Figure 2). Complete blood cell counts revealed eosinophilia (9%) and liver function tests, kidney function tests, random blood sugar, routine urine examination, and blood and urine cultures were noncontributory. Histopathologic examination of lesional skin biopsy revealed an intense mononuclear cell infiltration with many eosinophils and an interface dermatitis with hydropic degeneration of basal keratinocytes, while in the spared area, only slight lymphocytic infiltration was present in a perivascular distribution. Based on the history and examination, a diagnosis of ampicillin-induced drug dermatitis was made. The ampicillin was stopped and the patient was put on a short course of oral prednisolone, antipyretics, and topical calamine. The patient was afebrile in 2 days and the eruption resolved completely in 8 days. Staphylococcal scalded-skin syndrome (SSSS) and bullous impetigo are two blistering disorders associated with staphylococcal (phage group II) infection. In SSSS, the initial findings are redness and tenderness of the central face, neck, trunk, and intertriginous zones. This is followed by short-lived flaccid bullae and a slough or exfoliation of the superficial epidermis. Crusted areas then develop, characteristically around the mouth in a radial pattern. SSSS is distinguished from TEN by the following features: younger age group (primarily infants), more superficial site of blister formation, no oral lesions, shorter course, lower morbidity and mortality rates, and an association with staphylococcal exfoliative toxin (“exfoliatin”), not drugs. A rapid diagnosis of SSSS versus TEN can be made by a frozen section of the blister roof or exfoliative cytology of the blister contents. In SSSS, the site of staphylococcal infection is usually extracutaneous (conjunctivitis, rhinorrhea, Urticarial allergic eruption is a cutaneous condition characterized by annular or gyrate urticarial plaques that persist for greater than 24 hours. See also Urticaria List of cutaneous conditions References External links Urticaria and angioedema The prognosis is mainly related to the body surface area detached. The healing is obtained spontaneously in 2 to 3 weeks for the EMm and 4 to 6 weeks for the EMM. The mucosal lesions always take longer to heal. The healing of the mucocutaneous lesions is without scarring but with frequent dyschromia. Recurrences are seen in less than 5% of cases, mainly in forms due to herpes infection. Clindamycin is a lincomycin-derived antibiotic useful for the treatment of anaerobic and Gram-positive aerobic bacterial infections. Cutaneous adverse reactions are usually maculopapular exanthemas, although hypersensitivity syndrome, acute generalized exanthematous pustulosis, and Stevens-Johnson syndrome have also been reported (1). We report the case of a patient with a maculopapular rash triggered by clindamycin who developed cutaneous lesions on striae distensae (SD). A 47-year-old woman was referred to our clinic for pruritic cutaneous lesions which had started 6 days earlier. Her past clinical history included hypertension, hypothyroidism, hyperuricemia, cholecystectomy, caesarean section, and endometriosis-related abdominal surgery, and she was taking levothyroxine, allopurinol, imidapril, and omeprazole. The skin rash first developed on her neck and back on the 3rd day of clindamycin oral treatment (300 mg every 6 hours), which was prescribed as antibiotic prophylaxis for a tooth implant. General malaise (but not fever) was also reported. Physical examination revealed an erythematous maculopapular eruption symmetrically distributed on the neck, abdomen, and back (Figure 1, A), with isolated lesions involving the proximal upper and lower limbs (Figure 1, B). There was a striking vertical distribution of skin lesions along the SD on the lateral sides of the abdomen (Figure 1, C). No mucosal involvement was found, and laboratory studies showed no abnormalities. Clindamycin withdrawal was followed by prescription of a course of oral deflazacort, starting at 30 mg daily and tapering down during a 9-day period. On the 5th day of treatment, the rash had almost cleared with minimal desquamation (Figure 1, D). Eight weeks after clearance of the skin rash, informed consent was obtained in order to perform an allergological evaluation of clindamycin, including prick and intradermal (ID) tests on the forearm and patch tests on the upper back (2). For patch testing, powder of the commercial capsules (Dalacin®) was diluted in petrolatum (pet.) and water (aq.), resulting in a final 1% clindamycin dilution. Parenteral clindamycin preparations were used in therapeutic concentrations for prick tests (150 mg/mL) and dilutions in saline of 1/100 and 1/10 for the ID test. Other authors have reported that these concentrations do not seem to irritate the skin (3-6). Prick and ID tests were assessed after 20 min and 24 hours, respectively. Patch tests were removed after the 2nd day, and late reactions were evaluated on day 2 and day 4. Prick and ID test results after 20 min were negative. Late results of ID tests with clindamycin (1.5 and 15 mg/mL) were positive: erythematous infiltrated papules about 7×7 mm and 18×15 mm were observed at 24 hours and lasted until the 8th day. Patch tests with clindamycin 1% in pet. and 1% in aq. were also positive (+ on day 2 and day 4). Positive late skin tests suggested delayed-type non-IgE-mediated allergic clindamycin hypersensitivity. Oral challenge tests are considered to be the gold standard to establish or exclude drug hypersensitivity. Due to the positive result of late skin test to clindamycin, oral challenge was not performed in our patient (3,5). The Koebner isomorphic phenomenon has been described in cutaneous reactions induced by drugs, such as antibiotics and chemotherapy. Chronic pressure on the skin is probably involved in the onset of skin lesions in hand-foot eruptions induced by tyrosine kinase inhibitors (sorafenib and sutinib). Solar exposure and cutaneous trauma also seem to play a role in the location of papulopustular eruptions caused by endothelial growth factor receptor inhibitors (erlotinib) (7). More frequent involvement in traumatized skin and surgical scars has been reported in the context of linear IgA bullous dermatosis and leukocytoclastic vasculitis triggered by vancomycin and cefuroxime (8). SD are produced by non-penetrating physical trauma, similar to friction or pressure. Different dermatoses can develop along SD skin lesions (like plaque psoriasis, pustular psoriasis, lichen planus, vitiligo, discoid lupus erythematosus, lupus vasculitis, urticarial vasculitis, or chronic graft-versus-host disease) (9). Bevacizumab, etretinate, and corticosteroid-induced ulcers, hyperpigmentation caused by bleomycin, and urticariform lesions triggered by diclofenac are examples of different type of drug-induced abnormalities involving SD (10). In summary, we identified clindamycin as the cause of the cutaneous reactions that occurred in our patient on the basis of the results of the skin tests and clinical history. Our findings confirmed a delayed-type hypersensitivity reaction, possibly involving a T-cell-mediated immunologic mechanism. Intradermal and patch tests were found to be useful in order to confirm the diagnosis (4,5). We did not find reports in the literature of drug-induced cutaneous eruptions along the SD as a manifestation of a Koebner phenomenon. Clinical underreporting of this phenomenon could explain the scarce literature on this cutaneous adverse reaction. Mucosal erosions in bullous diseases and leading to mucosal sequelae are widely described in toxic epidermal necrolysis (TEN). These complications cause disfigurement and functional impairment. They are more rarely reported in erythema multiforme (EM). We report a case of lip adhesion following EM induced by Mycoplasma pneumoniae. A 12-year-old boy was hospitalized in a paediatric intensive care unit. He had a prominent target skin rash on the palms and soles. Mucosal injury was associated with conjunctivitis, balanitis without dysuria and hyperalgesic stomatitis. M. pneumoniae serology was positive with immunoglobulin M. We made a diagnosis of EM secondary to M. pneumoniae infection. Two months later, the skin lesions had completely disappeared but the patient's mouth opening was limited to 25 mm and he presented bilateral adhesions between the upper and lower lips of 5mm on the right and 8mm on the left resulting in aesthetic and functional damage. Mucosal damage and its sequelae have been widely described in TEN. Ophthalmic sequelae are more frequent. A case of labial synechiae secondary to TEN has been reported. In EM, mucosal lesions occur in 100% of cases with a further mucosal problem being present in 50% of patients. Mucosal damage has been reported during EM flares but there are no studies of side-effects after the acute episode. Oral mucosal adhesions can cause cosmetic sequelae, but above all they hinder functional prognosis. These complications must be prevented by making gutters of vestibular deepening and lip movements with maximum mouth opening several times a day, starting as soon as possible. Appropriate pain management should be undertaken to ensure patient comfort and avoid the need for analgesics and restriction of movement. Mucosal sequelae exist in EM. Whatever their cause, complications involving the mucosa must be prevented through early, tailored and multidisciplinary treatment. Adequate pain management must not be overlooked. Annular lesions can present in a variety of diseases. Knowledge of the physical appearance and history of presentation of these skin findings can help in the diagnosis. A pruritic, annular, erythematous patch that grows centrifugally should prompt evaluation for tinea corporis. Tinea corporis may be diagnosed through potassium hydroxide examination of scrapings. Recognizing erythema migrans is important in making the diagnosis of Lyme disease so that antibiotics can be initiated promptly. Plaque psoriasis generally presents with sharply demarcated, erythematous silver plaques. Erythema multiforme, which is due to a hypersensitivity reaction, presents with annular, raised lesions with central clearing. Lichen planus characteristically appears as planar, purple, polygonal, pruritic papules and plaques. Nummular eczema presents as a rash composed of coin-shaped papulovesicular erythematous lesions. Treatment is aimed at reducing skin dryness. Pityriasis rosea presents with multiple erythematous lesions with raised, scaly borders, and is generally self-limited. Urticaria results from the release of histamines and appears as well-circumscribed, erythematous lesions with raised borders and blanched centers. Annular lesions occur less commonly in persons with fixed drug eruptions, leprosy, immunoglobulin A vasculitis, secondary syphilis, sarcoidosis, subacute cutaneous lupus erythematosus, and granuloma annulare. Oral mucosa is one of the first barriers to the outside world which encounters various antigens, microorganisms and physical agents. Numerous oral pathologies challenge the dermatologists. Some may be the first sign of an underlying immunosuppression, while others are the inevitable serious outcomes of long-lasting mucosal disease. The differential diagnosis is crucial in terms of prompt and effective treatment. Tumid lupus erythematosus is a rare, but distinctive entity in which patients present with edematous erythematous plaques, usually on the trunk. Lupus erythematosus tumidus (LET) was reported by Henri Gougerot and Burnier R. in 1930. It is a photosensitive skin disorder, a different subtype of cutaneous lupus erythematosus (CLE) from discoid lupus erythematosus (DLE) or subacute CLE (SCLE). LET is usually found on sun-exposed areas of the body. Skin lesions are edematous, urticarialike annular papules and plaques. Topical corticosteroids are not effective as treatment for LET, but many will respond to chloroquine. LET resolves with normal skin, no residual scarring, no hyperpigmentation or hypopigmentation. Cigarette smokers who have LET may not respond very well to chloroquine. It has been suggested that it is equivalent to Jessner lymphocytic infiltrate of the skin. See also Lupus erythematosus List of cutaneous conditions References Cutaneous lupus erythematosus Mucous Membrane Pemphigoid: Autoimmune disease which affects only mucous membranes with clinical presentation of hard and rigid blisters which then rupture eventually into deep ulcers. Cutaneous Lupus Erythematosus: These present as oral discoid lesions which may be present on the inner cheek and behind the lips. White papules may also be present. A 23-year-old woman was seen for widespread skin lesions present since the age of 2.5 years. Twenty years ago, she developed a brown macular lesion on her right buttock. The lesion became hyperkeratotic and subsequently spread through the posterior aspect of her right leg. It later spread to the right side of the trunk and to the right arm. When she was 9 years old, she developed similar lesions on her left arm and leg. After she was 13 years old, no new skin lesions appeared. There was no family history of similar lesions. On examination, there were numerous linear and whorled, reddish-brown, hyperkeratotic plaques, with central atrophy and raised borders, following Blaschko's lines on all of the extremities. These lesions on the extremities extended to the dorsum of the hands and feet (Fig. 1). She had hyperkeratotic lesions on the pressure points of both of the soles, but no palm involvement. The number of lesions on the right side was greater than that on the left. Reddish-brown annular plaques with central atrophy and raised borders, appearing in zosteriform configuration, and numerous individual 2-3-mm erythematous lichenoid papules were observed on the right side of the thorax and the right inguinal region (Fig. 2). No face, scalp, or mucous membrane involvement was seen. The nails of the second and fifth fingers of the right hand and the nail of the third finger of the left hand showed nail dystrophy with longitudinal ridges and pterygium. All the nails of the right foot and the nails of the first and fifth toes of the left foot showed dystrophic changes with subungual keratosis. The patient was otherwise in good health. Two biopsy specimens taken from a hyperkeratotic plaque and a lichenoid papule showed an epidermal invagination with angulated parakeratotic tier, denoting cornoid lamella. The epidermis just underneath the cornoid lamella displayed vacuolization and the granular layer was absent. The adjacent epidermis was atrophic, and hydropic degeneration within the basal cell layer was seen. In the dermis, a nonspecific, mild, chronic, inflammatory cell infiltrate, telangiectatic vessels, and pigment-laden macrophages were present. These findings were consistent with linear porokeratosis (Fig. 3). Microscopic examinations and mycologic cultures of the nails were negative. We decided to treat our case systemically with retinoids, but the patient refused this therapy. So, topical tretinoin 0.05% was started once a day. A marked improvement was observed in hyperkeratosis through the first 4 weeks of treatment and plateaued at 8 weeks. After 10 weeks, the lesions had almost disappeared. We planned to continue the applications every other day. One year later, she remains stable with application of topical tretinoin 0.05% twice a week and is satisfied with the final appearance. She is under regular follow-up. Pemphigus is a rare autoimmune disease of the skin and mucous membranes. It is characterized by autoantibodies directed against the desmosomal adhesion proteins of epithelial cells (desmoglein type I and III) resulting in acantholysis of the epithelium. Painful blisters or erosions are typical clinical findings. Pemphigus is a severe disease that may be fatal. Early diagnosis of pemphigus is important in order to be able to start the treatment as soon as possible and to halt the progression of the disease and avoid serious secondary infections.\nHere is the question:\nDERMATOLOGY: A 14-year-old female patient in good general condition presents since 4 days ago a very pruritic generalized cutaneous eruption formed by erythematous-edematous plaques between 2 and 15 cm in diameter without desquamation with a tendency to acquire an annular morphology that individually disappear in less than 24 hours. The mucous membranes are respected. Your first diagnostic impression would be:\nHere are the potential choices:\n1. Urticaria.\n2. Rubella.\n3. Toxicoderma.\n4. Staphylococcal toxic shock.\n5. Scabies.\nThe correct answer is: 1. Urticaria."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Disorders of thirst and vasopressin secretion present clinically in one of three ways: as hypotonic polyuria (DI), as hypodipsic hyponatremia, and as hyponatremia. In evaluating a patient with DI, the major challenge is to differentiate between primary polydipsia and neurogenic and nephrogenic DI. This is best accomplished through a series of steps that start with simple clinical observation, and progress, as necessary, to more complicated diagnostic procedures (Fig. 1). If the diagnosis is not clear from the clinical setting and the patient's history, the first step is to measure plasma osmolality and sodium under conditions of ad libitum fluid intake. If the results are clearly above the upper limit of normal range, primary polydipsia is excluded and the work-up can proceed directly to administration of vasopressin or DDAVP and/or a measurement of plasma vasopressin levels to differentiate between neurogenic and nephrogenic DI. If basal plasma osmolality and sodium fall within normal range, the standard dehydration test should be performed. If urine osmolality does not increase above that of plasma despite evident dehydration, primary polydipsia is excluded and the effect of vasopressin or DDAVP on urine osmolality should be examined to differentiate between neurogenic and nephrogenic DI. If administration of antidiuretic hormone increases urine osmolality by more than 50 per cent, the patient has severe neurogenic DI. If the increase in urine osmolality is less than 50 per cent, the patient has nephrogenic DI. In patients who do not concentrate urine above that of plasma in response to dehydration, the best approach is to measure plasma vasopressin, osmolality, and sodium after the latter have been increased above normal range by dehydration and/or infusion of hypertonic saline. When these results are plotted on a suitable nomogram (Fig. 2), neurogenic DI can be clearly diagnosed from the relative deficiency of vasopressin. In patients with normal vasopressin levels, primary polydipsia can be differentiated from nephrogenic DI by examining the relationship of urine osmolality to plasma vasopressin (Fig. 3), obtained during dehydration and/or graded vasopressin infusion. In evaluating a patient with sustained hypernatremia, it is only necessary to assess thirst, which can be done by a simple bedside observation. In a patient without obvious neurologic or cognitive impairment, absence of thirst in the face of plasma osmolality above 305 mosm/kg (plasma sodium above 150 mEq/L) is diagnostic for hypodipsic hypernatremia. In a patient who presents with hyponatremia, the main objective is to differentiate between hyper-, hypo-, and euvolemic (SIADH) types A 20-year-old patient was evaluated because of polydipsia and polyuria; by means of the dehydration test a partial defect in the secretion of antidiuretic hormone (ADH) was demonstrated, since the urinary osmolality after the administration of exogenous vasopressin was superior by 25 percent to the maximum spontaneous urinary osmolality reached after a period of fluid restriction. Nevertheless, there was also a component of psychogenic polydipsia because the daily basal fluid intake was superior to 15 liters, and in view of the fact that the urinary osmolality could reach 600 mOsm/kg, the endocrine defect cannot totally be responsible for the enormous volume of fluid intake. This is the first case in the world literature in which the association between potomania and deficiency in the secretion of ADH is reported. Since ADH is one of the factors which regulate the behaviour of various animal species it is possible that its deficiency may be directly responsible for the psychic disorder which led to the potomania. It is also possible that an anatomical hypothalamic lesion, too small to be demonstrated, might have a simultaneous effect on the centers regulating thirst and the neurons producing vasopressin. A water deprivation test or a hypertonic saline infusion test with the measurement of plasma osmolality and plasma vasopressin are the gold standard tests in the differential diagnosis of polyuric syndromes. Because commercially available vasopressin kits are too insensitive for this approach, and the concentration of vasopressin in urine is much higher than in plasma, urinary vasopressin measurements may be an alternative to the more difficult plasma vasopressin measurement. The diagnostic value of the measurement of urinary vasopressin with a rather insensitive commercially available vasopressin kit was compared with plasma vasopressin measurement by a highly sensitive radioimmunoassay (RIA). Thirteen normal subjects and 27 patients with polyuria/polydipsia were examined by an 8-h fluid deprivation test. In all blood samples (0800 h, 1200 h, 1400 h and 1600 h) and in all urine collections (2-hourly fractions), osmolality as well as vasopressin were measured. Using plasma vasopressin measurement with a highly sensitive RIA as gold standard test, nine patients were classified as having primary polydipsia, whereas 18 had partial or complete cranial diabetes insipidus. Whereas the substitution of plasma vasopressin measurement by urinary vasopressin measurement alone did not provide 100% separation between both groups, the product of urinary vasopressin and urinary osmolality related to plasma osmolality completely separated the patients with primary polydipsia from those with diabetes insipidus. Urinary measurement of vasopressin and osmolality alone, which was recommended as a noninvasive diagnostic procedure in children, was too insensitive for exact differential diagnosis in our adult patients. The simultaneous measurement of plasma vasopressin and plasma osmolality in a dehydration test is the most powerful diagnostic tool in the differential diagnosis of polyuria/polydipsia. However, if highly sensitive assays for plasma vasopressin measurements are not available, the measurement of urinary vasopressin with commercially available, less sensitive RIAs may be a diagnostic alternative, which showed nearly the same sensitivity as plasma vasopressin measurement in our study population. Nephrogenic diabetes insipidus (NDI) is caused by the inability of renal collecting duct cells to respond to arginine vasopressin (AVP)/antidiuretic hormone (ADH). We present the case of a 7-year-old boy with a history of excretion of large amounts of dilute urine and polydipsia since infancy. The boy had several vomiting episodes with mild dehydration during the first 3 years of life. There was no evidence of headaches, dizziness or visual problems. He drinks between 2 and 3 L/day and has 24-hour diuresis of 2 liters, now. He has prepubertal appearance with appropriate weight [+0.85 standard deviation score (SDS)] and height (+0.15 SDS) for his age. His intelligence was also normal. The water deprivation test showed low urine osmolality after 8 hours of dehydration. After desmopressin administration, urine osmolality remained low. Serum osmolality was in the normal range for sex and age before and after desmopressin administration. This indicated a nephrogenic form of diabetes insipidus. Molecular analyses revealed a P286L [p.Pro(CCC)286Leu(CTC)] mutation in the AVPR2 gene, that was inherited from his mother. This patient is the first case with genetically confirmed X-linked inherited form of NDI in the Republic of Macedonia. Molecular analysis confirmed the clinical diagnosis and enabled genetic advice for this family.  Hyponatremia is a frequent condition in elderly patients. In diagnostic workup, a 24-hour urine sample is used to measure urinary osmolality and urinary sodium concentration necessary to confirm the diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). This study was undertaken to test the hypothesis that a spot urine sample would be sufficient for urinalysis. In nine patients with SIADH, morning spot and 24-hour urine samples were examined for osmolality and sodium concentration. Levels of arginine vasopressin, atrial natriuretic and brain natriuretic peptides, renin, and aldosterone were measured in the supine and upright positions of patients and compared with nine healthy age-matched control patients. The patients had low plasma osmolality (median 266 mOsm/kg) and measurable levels of arginine vasopressin (median 1.8 pg/mL). Values of osmolality in the spot urine (median 298 mOsm/kg) and in the 24-hour urine (median 215 mOsm/kg) did not differ significantly; neither did sodium concentration (medians 80 mmol/L in the spot urine versus 45 mmol/L in the 24-hour urine). Patients had significantly elevated plasma levels of brain natriuretic peptide (P = 0.007), elevated mean arterial blood pressure (P = 0.03), and lower plasma levels of creatinine (P = 0.002) compared to the controls. A spot urine sample seems to be sufficient to confirm the diagnosis of SIADH. Urine osmolality reaches the normal reference range. Urine osmolality is stable on two to three consecutive hourly measurements, even with rising plasma osmolality. Plasma osmolality is higher than 295 to 300 mOsm/kg Plasma Na greater than 145 mEq If AVP-R is suspected in newborns and young infants, the diagnostic test of choice is DDAVP (1 mcg subcutaneously or intravenously over 20 minutes, maximum dose of 0.4 mcg/kg). In children, the water deprivation test should be closely monitored. If one of the following endpoints is reached, discontinue the trial: Urine osmolality reaches the normal reference range. Plasma osmolality greater than 295 mOsm/kg to 300 mOsm/kg Plasma sodium greater than 145 meq/L Loss of 5% of body weight or signs of volume depletion A fluid or water deprivation test is a medical test which can be used to determine whether the patient has diabetes insipidus as opposed to other causes of polydipsia (a condition of excessive thirst that causes an excessive intake of water). The patient is required, for a prolonged period, to forgo intake of water completely, to determine the cause of the thirst. This test measures changes in body weight, urine output, and urine composition when fluids are withheld. Sometimes measuring blood levels of ADH (a synonym for vasopressin) during this test is also necessary. If there is no change in the water loss despite fluid deprivation, desmopressin may be administered to distinguish between the two types of diabetes insipidus which are central & nephrogenic diabetes insipidus. The time of deprivation may vary from 4 to 18 hours. The serum osmolality and urine osmolality are both measured in the test. Interpretation of WDT The conditions can be distinguished in the following way: Diabetes insipidus (DI) and primary polydipsia (PP) are characterised by polyuria and polydipsia. It is crucial to differentiate between these two disorders since the treatment is different. The aim of this study was to evaluate the diagnostic value of the short and an extended variant of the water deprivation test (WDT) and of measuring urinary vasopressin (AVP) in patients with polyuria and polydipsia. A retrospective, single-centre study based on WDTs performed between 2004 and 2014 including 104 consecutive patients with the polyuria-polydipsia syndrome. During a strict water deprivation, weight, urinary osmolality, urinary vasopressin and specific gravity were collected until one of the following was reached: i) &gt;3% weight reduction, ii) Urinary specific gravity &gt;1.020 or, urinary osmolality &gt;800 mOsm/L, iii) Intolerable adverse symptoms such as excessive thirst. Out of 104 patients (67 women, 37 men), 21 (20%) were diagnosed with DI and 83 (80%) with PP. The median (interquartile range; range) test duration was 14 hours (10-16; 3-36) in patients with DI and 18 hours (14-24; 7-48) in patients with PP (P=0.011). Of those diagnosed with PP, 22 (26%) did not reach urinary specific gravity &gt;1.020 nor urine osmolality &gt;800 mOsm/L. Urine AVP did not overlap between patients with PP and patients with central DI. The short WDT is of limited value in the diagnostic work-up of polydipsia and polyuria and a partial DI may have been missed in every fourth patient diagnosed with PP. Urinary AVP has excellent potential in discriminating PP from central DI. A 66-year-old Japanese man presented with persistent hyponatremia without polydipsia and polyuria. Laboratory examination showed serum sodium of 117 mEq/l, plasma osmolality 239 mosm/kg, urine sodium 108 mEq/l, urine osmolality 577 mosm/kg, and normal levels (less than 2.0 pg/ml) of serum antidiuretic hormone (ADH). ADH release was regulated normally with changes in plasma osmolality. No obvious cause for the syndrome of inappropriate secretion of ADH (SIADH) could be detected. However, 20 months later, the patient had bouts of hematuria and was found to have cancer of the urinary bladder. Increased renal sensitivity to ADH was suspected as the underlying mechanism of SIADH. Combined deficits in arginine vasopressin secretion (AVP) and thirst sensation can result in life threatening hyperosmolality and hypernatremia. Complications include seizures, profound volume contraction and renal failure. Fortunately, this is an uncommon clinical condition, with approximately 70 cases reported in the literature over the past 47 years [1]. Defects in AVP secretion and/or synthesis produce central diabetes insipidus (DI), polyuria with polydipsia, hypernatremia and hyperosmolality. Most awake and alert patients with an intact thirst stimulus will \"drink\" themselves back to a normal serum sodium and osmolality. However, if there is concomitant destruction of the osmoreceptors that regulate thirst, osmolal and volume homeostasis cannot be maintained. The relationships between urine osmolarity and serum osmolarity and plasma vasopressin levels are vital for distinguishing a reset osmostat from central DI. After obtaining approval from our institutional review board, we retrospectively reviewed the medical record of a 37-year-old patient who presented to our institution with a serum sodium of 176 mEq/l. Admission laboratory examination revealed: hemoglobin 12.8 g/dl; white blood cell count 4.7 × 103/µl, with a normal differential; random serum glucose 91 mg/dl ; sodium 176 mEq/l; plasma osmolality 366 mOsm/kg; BUN 33 mg/dl; serum creatinine 1 mg/dl; calcium 9.5 mg/dl; urine specific gravity 1.032; and urine osmolality 1,172 mOsm/kg. An MRI with contrast of the sella/ pituitary revealed an enhancing mass centered within the suprasellar cistern and anterior third ventricle, measuring 3.0 × 3.9 × 3.4 cm. The lesion appeared to involve the hypothalamus and displaced the optic chiasm inferiorly. Evaluation of pituitary function revealed normal serum levels of thyroid stimulating hormone, AM cortisol, luteinizing hormone, follicle stimulating hormone and prolactin. Figure 1 illustrates the relationship between measured serum AVP levels and serum osmolality. Figure 2 shows the relationship between measured urine and serum osmolality. If the serum AVP levels were not available, it would appear as though the patient had a reset osmostat. The kidneys appear to appropriately generate maximally concentrated urine at a serum osmolality above 348 but are unable to below this value. When compared with the normal curve, our patient's AVP levels were lower than expected for the corresponding osmolality. This pattern is consistent with a partial central DI. She does not have a reset osmostat. In the presence of significant volume contraction and a reduced GFR, her kidneys produced more concentrated urine despite markedly decreased central vasopressin production. As the volume contraction abated and the GFR improved, polyuria recurred, despite persistent hyperosmolarity and hypernatremia. Hypertonic saline test is indispensable for the evaluation of posterior pituitary function. However the test is not simple, including water loading, urine sampling and at least 45 min of hypertonic saline infusion, mostly because the test relies on urinary osmolality as an index of ADH secretion. The object of this study is try to simplify the test by directly measuring plasma ADH concentration before and after 10 min of hypertonic saline infusion. Intravenous infusion of hypertonic saline (5% NaCl, 0.24 ml/kg/min, for 10 min) was performed on normal subjects, patients with diabetes insipidus and patients with renal failure under chronic hemodialysis. Venous blood samples were obtained seriously including just before and after 10 min of the infusion. ADH was extracted from plasma using Sep-Pak C18 column and assayed by specific RIA. Minimum sensitivity of the assay was 0.25 pg/ml. The hypertonic saline infusion resulted in an increase of plasma osmolality by about 8 mOsm/kg H2O and plasma sodium concentration by 4 mEq/l. Plasma ADH increased from 0.77 +/- 0.09 to 3.42 +/- 0.73 pg/ml (m +/- SE, n = 8, p less than 0.01) in normal subjects of ad lib. water drinking and from 0.55 +/- 0.33 to 2.34 +/- 0.33 (m +/- SE, n = 4, p less than 0.05) in water loaded normal subjects (20 ml/kg of water, 60 min before hypertonic saline infusion).(ABSTRACT TRUNCATED AT 250 WORDS) After polyuria (>40-50 ml/kg/24hrs) is confirmed, and urine osmolality is <800 mOsm/kg, serum sodium level has to be checked. If the serum sodium level is <135 meq, it is diagnostic of PP. If the serum sodium levels are >147, it is diagnostic of diabetes insipidus. If the serum sodium is between 135 and 147, the next step would be the water deprivation test. The traditional test that has been utilized by providers for a long time is the indirect water deprivation test that indirectly measures the activity of AVP. This test is started once hypotonic polyuria is confirmed, and serum sodium is between 135 and 147. Polyuria in primary polydipsia decreases with water deprivation (typically >8hrs), and urine osmolality increases (>800 mOsm/kg typically), this is diagnostic of PP. In diabetes insipidus, polyuria does not get better with water deprivation. If the urine osmolality remains <300 mOsm/kg after water deprivation, it is diagnostic of DI. A 12-year-old female child, with a history of polyuria and polydipsia of about three years duration, was admitted to Ethio-Swedish Paediatric Hospital, in Addis Abeba. Urine output in 24 hours averaged 5-6 litres, with a frequency of 15 times during the day and 7-8 times during the night. Random urine analysis showed an osmolality of 60 mOsm/kg, Na+ 27.1 mmol/L and K+ was 7.6 mmol/L. Basal plasma osmolality was 313 mOsm/kg with Na+ being 156 mmol/L and K+ 4.06 mmol/L. Water deprivation for nine hours failed to produce a concentrated urine, which was only 138 mOsm/kg at the end of the test, with a corresponding plasma osmolality of 336 mOsm/kg. After nine hours of water deprivation, urine Na+ increased from 27.1 to 37.3 mmol/L while K+ increased from 7.1 to 18.7 mmol/L. Lypressin, a vasopressin analogue, at a concentration of 0.3 IU/kg injected intramuscularly, resulted in a marked increase in urine osmolality to 586 mOsm/kg within two hours, associated with relief of symptoms. Urinary excretion of K+ was markedly increased during the vasopressin test while Na+ excretion was little affected. A case of central diabetes insipidus of undefined etiology is presented and the possibility of altered renal handling of electrolytes and an abnormal response to vasopressin in such cases is noted. The problem of management and the currently available treatment options are summarized. Serum and urine sodium, serum and urine osmolality, hourly urine output, 24-hour urine volume, and specific gravity must be obtained. Central DI must be distinguished from nephrogenic DI. A water deprivation test can be used with or without desmopressin injection. In central DI, the vasopressin will correct urine osmolality while in nephrogenic DI, the correction will be suboptimal. [3] [25] [26] Criteria for the diagnosis of central DI: Polyuria in two consecutive hours of > 300 ml/hr or 4 to 5 ml/kg/hr in two consecutive hours Polyuria > 3L/24 hours or > 2ml/kg/hr in 24 hours Serum osmolality > 300 mOsm/kg Urine osmolality < 300 mOsm/kg Urine/plasma osmolality <  1 The specific gravity of less than 1.005 The hyperosmolar hyperglycemic state (HHS), an acute complication of diabetes mellitus with plasma hyperosmolarity, promotes the secretion of anti-diuretic hormone (ADH) and reduces the storage of ADH. Magnetic resonance T1-weighted imaging reflects ADH storage in the posterior pituitary lobe, which disappears when the storage is depleted. Whether the HHS induces ADH depletion leading to clinical manifestations has been unclear. A 55-year-old Japanese woman was admitted to our center because of mental disturbance and hypotension. She had received lithium carbonate for bipolar disorder and presented with polydipsia and polyuria from 15 years of age. On admission, she had mental disturbance (Glasgow Coma Scale, E4V1M1), hypotension (systolic blood pressure, 50 mmHg), and tachycardia (pulse rate, 123/min). Plasma glucose was 697 mg/dL osmolality was 476 mOsm/kg•H<sub2</subO, and bicarbonate was 23.7 mmol/L. The diagnoses of HHS and hypovolemic shock were made. During treatment with fluid replacement and insulin therapy, the urine volume continued to be approximately 3 to 4 L/day, and an endocrine examination revealed ADH insufficiency and nephrogenic diabetes insipidus. Desmopressin 10 μg/day and trichlormethiazide 2 mg/day were necessary and administered, and the endogenous ADH secretion improved gradually. The signal intensity of the pituitary posterior lobe, initially decreased on magnetic resonance T1 images, was also improved. This patient had ADH insufficiency associated with ADH depletion due to hyperosmolarity and nephrogenic diabetes insipidus. Clinicians should be aware of the risk of the development of critical HHS and relative ADH insufficiency in patients being treated with lithium carbonate. This test measures the changes in body weight, urine output, and urine composition when fluids are withheld to induce dehydration. The body's normal response to dehydration is to conserve water by concentrating the urine. Those with DI continue to urinate large amounts of dilute urine in spite of water deprivation. In primary polydipsia, the urine osmolality should increase and stabilize at above 280 mOsm/kg with fluid restriction, while a stabilization at a lower level indicates diabetes insipidus. Stabilization in this test means, more specifically, when the increase in urine osmolality is less than 30 Osm/kg per hour for at least three hours. Sometimes measuring blood levels of ADH toward the end of this test is also necessary, but is more time consuming to perform. To differentiate AVP-D and AVP-R and primary polydipsia, perform a water deprivation test and desmopressin (DDAVP) trial. Typically a 7-hour deprivation test is adequate to diagnose DI. Primary polydipsia may require more extended dehydration periods. The basic principle behind the water deprivation test is that in individuals with normal posterior pituitary and renal function (or those with primary polydipsia), an increase in plasma osmolality from dehydration stimulates AVP release from the posterior pituitary, which then leads to water reabsorption in the nephrons, thus resulting in concentration of urine and an increase in urine osmolality. In AVP-D or AVP-R, the urine fails to concentrate optimally with water deprivation, and there is persistent excretion of hypotonic urine. In adults, the water restriction test should be discontinued when one of the following is reached: Diagnosis Diagnosis is based on clinical and laboratory findings of low serum osmolality and low serum sodium. Urinalysis reveals a highly concentrated urine with a high fractional excretion of sodium (high sodium urine content compared to the serum sodium). A suspected diagnosis is based on a serum sodium under 138. A confirmed diagnosis has seven elements: 1) a decreased effective serum osmolality - <275 mOsm/kg of water; 2) urinary sodium concentration high - over 40 mEq/L with adequate dietary salt intake; 3) no recent diuretic usage; 4) no signs of ECF volume depletion or excess; 5) no signs of decreased arterial blood volume - cirrhosis, nephrosis, or congestive heart failure; 6) normal adrenal and thyroid function; and 7) no evidence of hyperglycemia (diabetes mellitus), hypertriglyceridemia, or hyperproteinia (myeloma). We present here the results of water restriction test (WRT) and hypertonic saline loading test (HSLT) in normal children. Maximal urine osmolality during WRT (W-Umax; 1040 +/- 154 mOsm/kg) may be age-dependent (W-Umax = 812 + 23*age, r = 0.52, p &lt; 0.05), although maximal arginine vasopressin (AVP) levels during WRT did not show any correlation with age. The relationship between plasma osmolality (Posm) and AVP during HSLT in children (AVP = 0.31* (Posm-277)) was similar to that in normal adults. A plateau urine osmolality during HSLT (H-Umax) was 713 +/- 109 mOsm/kg. It did not increase with age. AVP levels 3 h after the infusion did not correlate with age. Minimal AVP and Posm values (about 6 pg/ml, 295 mOsm/kg, respectively) for creating H-Umax apparently existed during HSLT. The minimal AVP value (about 6 pg/ml) for H-Umax (during HSLT) was higher than the AVP levels (2.41 +/- 1.37 pg/ml) at W-Umax (during WRT). W-Umax (1040 +/- 154 mOsm/kg) was significantly higher than H-Umax (713 +/- 109 mOsm/kg). Judging from the above comparison of AVP and Uosm (W, H-Umax) at the plateau state of WRT and HSLT in normal children, a change in the apparent tubular response to AVP may be one of the important factors to maintain circulatory volume (CV). Brain MRI Urinary frequency, nocturia, enuresis 24-h urine volume and osmolarity on unrestrictedfluid intake Volume >40 mL/kg Osmolarity <300 mosm/L Basal plasma AVP >1 pg/mL <1 pg/mL Pituitary bright spot Present Absent Anatomy Pathology? GU evaluation Volume <40 mL/kg Osmolarity >300 mosm/L If MRI and/or AVP assays with the requisite sensitivity and specificity are unavailable and a fluid deprivation test is impractical or undesirable, a third way to differentiate between pituitary DI, nephrogenic DI, and primary polydipsia is a trial of desmopressin therapy. Such a trial should be conducted with very close monitoring of serum sodium as well as urine output, preferably in hospital, because desmopressin will produce hyponatremia in 8–24 h if the patient has primary polydipsia. Osmolality of blood increases with dehydration and decreases with overhydration. In normal people, increased osmolality in the blood will stimulate secretion of antidiuretic hormone (ADH). This will result in increased water reabsorption, more concentrated urine, and less concentrated blood plasma. A low serum osmolality will suppress the release of ADH, resulting in decreased water reabsorption and more concentrated plasma. Syndrome of inappropriate ADH secretion occurs when excessive release of antidiuretic hormone results in inappropriately elevated urine osmolality (>100 mOsmol/L) relative to the blood plasma, leading to hyponatraemia. This ADH secretion may occur in excessive amounts from the posterior pituitary gland, or from ectopic sources such as small-cell carcinoma of the lung. Elevation may be associated with stroke mortality. Calculated osmolarity (CO)\nHere is the question:\nENDOCRINOLOGY: A 34-year-old woman is admitted for polyuria and polydipsia. In the first 24 hours of admission a diuresis of 8.2 liters is found and a blood test shows a glycemia of 96 mg/dL, natremia of 148 mEq/L and plasma osmolality of 309 mOsm/kg with urinary osmolality of 89 mOsmlkg. What diagnostic test should be performed next?\nHere are the potential choices:\n1. Hypertonic saline infusion test for serial determination of antidiuretic hormone.\n2. Dehydration test (Miller test).\n3. Administration of desmopressin with serial monitoring of urine osmolality.\n4. Determination of antidiuretic hormone in plasma.\nThe correct answer is: ",
        "gold_answer": "3 Administration of desmopressin with serial monitoring of urine osmolality.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Disorders of thirst and vasopressin secretion present clinically in one of three ways: as hypotonic polyuria (DI), as hypodipsic hyponatremia, and as hyponatremia. In evaluating a patient with DI, the major challenge is to differentiate between primary polydipsia and neurogenic and nephrogenic DI. This is best accomplished through a series of steps that start with simple clinical observation, and progress, as necessary, to more complicated diagnostic procedures (Fig. 1). If the diagnosis is not clear from the clinical setting and the patient's history, the first step is to measure plasma osmolality and sodium under conditions of ad libitum fluid intake. If the results are clearly above the upper limit of normal range, primary polydipsia is excluded and the work-up can proceed directly to administration of vasopressin or DDAVP and/or a measurement of plasma vasopressin levels to differentiate between neurogenic and nephrogenic DI. If basal plasma osmolality and sodium fall within normal range, the standard dehydration test should be performed. If urine osmolality does not increase above that of plasma despite evident dehydration, primary polydipsia is excluded and the effect of vasopressin or DDAVP on urine osmolality should be examined to differentiate between neurogenic and nephrogenic DI. If administration of antidiuretic hormone increases urine osmolality by more than 50 per cent, the patient has severe neurogenic DI. If the increase in urine osmolality is less than 50 per cent, the patient has nephrogenic DI. In patients who do not concentrate urine above that of plasma in response to dehydration, the best approach is to measure plasma vasopressin, osmolality, and sodium after the latter have been increased above normal range by dehydration and/or infusion of hypertonic saline. When these results are plotted on a suitable nomogram (Fig. 2), neurogenic DI can be clearly diagnosed from the relative deficiency of vasopressin. In patients with normal vasopressin levels, primary polydipsia can be differentiated from nephrogenic DI by examining the relationship of urine osmolality to plasma vasopressin (Fig. 3), obtained during dehydration and/or graded vasopressin infusion. In evaluating a patient with sustained hypernatremia, it is only necessary to assess thirst, which can be done by a simple bedside observation. In a patient without obvious neurologic or cognitive impairment, absence of thirst in the face of plasma osmolality above 305 mosm/kg (plasma sodium above 150 mEq/L) is diagnostic for hypodipsic hypernatremia. In a patient who presents with hyponatremia, the main objective is to differentiate between hyper-, hypo-, and euvolemic (SIADH) types A 20-year-old patient was evaluated because of polydipsia and polyuria; by means of the dehydration test a partial defect in the secretion of antidiuretic hormone (ADH) was demonstrated, since the urinary osmolality after the administration of exogenous vasopressin was superior by 25 percent to the maximum spontaneous urinary osmolality reached after a period of fluid restriction. Nevertheless, there was also a component of psychogenic polydipsia because the daily basal fluid intake was superior to 15 liters, and in view of the fact that the urinary osmolality could reach 600 mOsm/kg, the endocrine defect cannot totally be responsible for the enormous volume of fluid intake. This is the first case in the world literature in which the association between potomania and deficiency in the secretion of ADH is reported. Since ADH is one of the factors which regulate the behaviour of various animal species it is possible that its deficiency may be directly responsible for the psychic disorder which led to the potomania. It is also possible that an anatomical hypothalamic lesion, too small to be demonstrated, might have a simultaneous effect on the centers regulating thirst and the neurons producing vasopressin. A water deprivation test or a hypertonic saline infusion test with the measurement of plasma osmolality and plasma vasopressin are the gold standard tests in the differential diagnosis of polyuric syndromes. Because commercially available vasopressin kits are too insensitive for this approach, and the concentration of vasopressin in urine is much higher than in plasma, urinary vasopressin measurements may be an alternative to the more difficult plasma vasopressin measurement. The diagnostic value of the measurement of urinary vasopressin with a rather insensitive commercially available vasopressin kit was compared with plasma vasopressin measurement by a highly sensitive radioimmunoassay (RIA). Thirteen normal subjects and 27 patients with polyuria/polydipsia were examined by an 8-h fluid deprivation test. In all blood samples (0800 h, 1200 h, 1400 h and 1600 h) and in all urine collections (2-hourly fractions), osmolality as well as vasopressin were measured. Using plasma vasopressin measurement with a highly sensitive RIA as gold standard test, nine patients were classified as having primary polydipsia, whereas 18 had partial or complete cranial diabetes insipidus. Whereas the substitution of plasma vasopressin measurement by urinary vasopressin measurement alone did not provide 100% separation between both groups, the product of urinary vasopressin and urinary osmolality related to plasma osmolality completely separated the patients with primary polydipsia from those with diabetes insipidus. Urinary measurement of vasopressin and osmolality alone, which was recommended as a noninvasive diagnostic procedure in children, was too insensitive for exact differential diagnosis in our adult patients. The simultaneous measurement of plasma vasopressin and plasma osmolality in a dehydration test is the most powerful diagnostic tool in the differential diagnosis of polyuria/polydipsia. However, if highly sensitive assays for plasma vasopressin measurements are not available, the measurement of urinary vasopressin with commercially available, less sensitive RIAs may be a diagnostic alternative, which showed nearly the same sensitivity as plasma vasopressin measurement in our study population. Nephrogenic diabetes insipidus (NDI) is caused by the inability of renal collecting duct cells to respond to arginine vasopressin (AVP)/antidiuretic hormone (ADH). We present the case of a 7-year-old boy with a history of excretion of large amounts of dilute urine and polydipsia since infancy. The boy had several vomiting episodes with mild dehydration during the first 3 years of life. There was no evidence of headaches, dizziness or visual problems. He drinks between 2 and 3 L/day and has 24-hour diuresis of 2 liters, now. He has prepubertal appearance with appropriate weight [+0.85 standard deviation score (SDS)] and height (+0.15 SDS) for his age. His intelligence was also normal. The water deprivation test showed low urine osmolality after 8 hours of dehydration. After desmopressin administration, urine osmolality remained low. Serum osmolality was in the normal range for sex and age before and after desmopressin administration. This indicated a nephrogenic form of diabetes insipidus. Molecular analyses revealed a P286L [p.Pro(CCC)286Leu(CTC)] mutation in the AVPR2 gene, that was inherited from his mother. This patient is the first case with genetically confirmed X-linked inherited form of NDI in the Republic of Macedonia. Molecular analysis confirmed the clinical diagnosis and enabled genetic advice for this family.  Hyponatremia is a frequent condition in elderly patients. In diagnostic workup, a 24-hour urine sample is used to measure urinary osmolality and urinary sodium concentration necessary to confirm the diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). This study was undertaken to test the hypothesis that a spot urine sample would be sufficient for urinalysis. In nine patients with SIADH, morning spot and 24-hour urine samples were examined for osmolality and sodium concentration. Levels of arginine vasopressin, atrial natriuretic and brain natriuretic peptides, renin, and aldosterone were measured in the supine and upright positions of patients and compared with nine healthy age-matched control patients. The patients had low plasma osmolality (median 266 mOsm/kg) and measurable levels of arginine vasopressin (median 1.8 pg/mL). Values of osmolality in the spot urine (median 298 mOsm/kg) and in the 24-hour urine (median 215 mOsm/kg) did not differ significantly; neither did sodium concentration (medians 80 mmol/L in the spot urine versus 45 mmol/L in the 24-hour urine). Patients had significantly elevated plasma levels of brain natriuretic peptide (P = 0.007), elevated mean arterial blood pressure (P = 0.03), and lower plasma levels of creatinine (P = 0.002) compared to the controls. A spot urine sample seems to be sufficient to confirm the diagnosis of SIADH. Urine osmolality reaches the normal reference range. Urine osmolality is stable on two to three consecutive hourly measurements, even with rising plasma osmolality. Plasma osmolality is higher than 295 to 300 mOsm/kg Plasma Na greater than 145 mEq If AVP-R is suspected in newborns and young infants, the diagnostic test of choice is DDAVP (1 mcg subcutaneously or intravenously over 20 minutes, maximum dose of 0.4 mcg/kg). In children, the water deprivation test should be closely monitored. If one of the following endpoints is reached, discontinue the trial: Urine osmolality reaches the normal reference range. Plasma osmolality greater than 295 mOsm/kg to 300 mOsm/kg Plasma sodium greater than 145 meq/L Loss of 5% of body weight or signs of volume depletion A fluid or water deprivation test is a medical test which can be used to determine whether the patient has diabetes insipidus as opposed to other causes of polydipsia (a condition of excessive thirst that causes an excessive intake of water). The patient is required, for a prolonged period, to forgo intake of water completely, to determine the cause of the thirst. This test measures changes in body weight, urine output, and urine composition when fluids are withheld. Sometimes measuring blood levels of ADH (a synonym for vasopressin) during this test is also necessary. If there is no change in the water loss despite fluid deprivation, desmopressin may be administered to distinguish between the two types of diabetes insipidus which are central & nephrogenic diabetes insipidus. The time of deprivation may vary from 4 to 18 hours. The serum osmolality and urine osmolality are both measured in the test. Interpretation of WDT The conditions can be distinguished in the following way: Diabetes insipidus (DI) and primary polydipsia (PP) are characterised by polyuria and polydipsia. It is crucial to differentiate between these two disorders since the treatment is different. The aim of this study was to evaluate the diagnostic value of the short and an extended variant of the water deprivation test (WDT) and of measuring urinary vasopressin (AVP) in patients with polyuria and polydipsia. A retrospective, single-centre study based on WDTs performed between 2004 and 2014 including 104 consecutive patients with the polyuria-polydipsia syndrome. During a strict water deprivation, weight, urinary osmolality, urinary vasopressin and specific gravity were collected until one of the following was reached: i) &gt;3% weight reduction, ii) Urinary specific gravity &gt;1.020 or, urinary osmolality &gt;800 mOsm/L, iii) Intolerable adverse symptoms such as excessive thirst. Out of 104 patients (67 women, 37 men), 21 (20%) were diagnosed with DI and 83 (80%) with PP. The median (interquartile range; range) test duration was 14 hours (10-16; 3-36) in patients with DI and 18 hours (14-24; 7-48) in patients with PP (P=0.011). Of those diagnosed with PP, 22 (26%) did not reach urinary specific gravity &gt;1.020 nor urine osmolality &gt;800 mOsm/L. Urine AVP did not overlap between patients with PP and patients with central DI. The short WDT is of limited value in the diagnostic work-up of polydipsia and polyuria and a partial DI may have been missed in every fourth patient diagnosed with PP. Urinary AVP has excellent potential in discriminating PP from central DI. A 66-year-old Japanese man presented with persistent hyponatremia without polydipsia and polyuria. Laboratory examination showed serum sodium of 117 mEq/l, plasma osmolality 239 mosm/kg, urine sodium 108 mEq/l, urine osmolality 577 mosm/kg, and normal levels (less than 2.0 pg/ml) of serum antidiuretic hormone (ADH). ADH release was regulated normally with changes in plasma osmolality. No obvious cause for the syndrome of inappropriate secretion of ADH (SIADH) could be detected. However, 20 months later, the patient had bouts of hematuria and was found to have cancer of the urinary bladder. Increased renal sensitivity to ADH was suspected as the underlying mechanism of SIADH. Combined deficits in arginine vasopressin secretion (AVP) and thirst sensation can result in life threatening hyperosmolality and hypernatremia. Complications include seizures, profound volume contraction and renal failure. Fortunately, this is an uncommon clinical condition, with approximately 70 cases reported in the literature over the past 47 years [1]. Defects in AVP secretion and/or synthesis produce central diabetes insipidus (DI), polyuria with polydipsia, hypernatremia and hyperosmolality. Most awake and alert patients with an intact thirst stimulus will \"drink\" themselves back to a normal serum sodium and osmolality. However, if there is concomitant destruction of the osmoreceptors that regulate thirst, osmolal and volume homeostasis cannot be maintained. The relationships between urine osmolarity and serum osmolarity and plasma vasopressin levels are vital for distinguishing a reset osmostat from central DI. After obtaining approval from our institutional review board, we retrospectively reviewed the medical record of a 37-year-old patient who presented to our institution with a serum sodium of 176 mEq/l. Admission laboratory examination revealed: hemoglobin 12.8 g/dl; white blood cell count 4.7 × 103/µl, with a normal differential; random serum glucose 91 mg/dl ; sodium 176 mEq/l; plasma osmolality 366 mOsm/kg; BUN 33 mg/dl; serum creatinine 1 mg/dl; calcium 9.5 mg/dl; urine specific gravity 1.032; and urine osmolality 1,172 mOsm/kg. An MRI with contrast of the sella/ pituitary revealed an enhancing mass centered within the suprasellar cistern and anterior third ventricle, measuring 3.0 × 3.9 × 3.4 cm. The lesion appeared to involve the hypothalamus and displaced the optic chiasm inferiorly. Evaluation of pituitary function revealed normal serum levels of thyroid stimulating hormone, AM cortisol, luteinizing hormone, follicle stimulating hormone and prolactin. Figure 1 illustrates the relationship between measured serum AVP levels and serum osmolality. Figure 2 shows the relationship between measured urine and serum osmolality. If the serum AVP levels were not available, it would appear as though the patient had a reset osmostat. The kidneys appear to appropriately generate maximally concentrated urine at a serum osmolality above 348 but are unable to below this value. When compared with the normal curve, our patient's AVP levels were lower than expected for the corresponding osmolality. This pattern is consistent with a partial central DI. She does not have a reset osmostat. In the presence of significant volume contraction and a reduced GFR, her kidneys produced more concentrated urine despite markedly decreased central vasopressin production. As the volume contraction abated and the GFR improved, polyuria recurred, despite persistent hyperosmolarity and hypernatremia. Hypertonic saline test is indispensable for the evaluation of posterior pituitary function. However the test is not simple, including water loading, urine sampling and at least 45 min of hypertonic saline infusion, mostly because the test relies on urinary osmolality as an index of ADH secretion. The object of this study is try to simplify the test by directly measuring plasma ADH concentration before and after 10 min of hypertonic saline infusion. Intravenous infusion of hypertonic saline (5% NaCl, 0.24 ml/kg/min, for 10 min) was performed on normal subjects, patients with diabetes insipidus and patients with renal failure under chronic hemodialysis. Venous blood samples were obtained seriously including just before and after 10 min of the infusion. ADH was extracted from plasma using Sep-Pak C18 column and assayed by specific RIA. Minimum sensitivity of the assay was 0.25 pg/ml. The hypertonic saline infusion resulted in an increase of plasma osmolality by about 8 mOsm/kg H2O and plasma sodium concentration by 4 mEq/l. Plasma ADH increased from 0.77 +/- 0.09 to 3.42 +/- 0.73 pg/ml (m +/- SE, n = 8, p less than 0.01) in normal subjects of ad lib. water drinking and from 0.55 +/- 0.33 to 2.34 +/- 0.33 (m +/- SE, n = 4, p less than 0.05) in water loaded normal subjects (20 ml/kg of water, 60 min before hypertonic saline infusion).(ABSTRACT TRUNCATED AT 250 WORDS) After polyuria (>40-50 ml/kg/24hrs) is confirmed, and urine osmolality is <800 mOsm/kg, serum sodium level has to be checked. If the serum sodium level is <135 meq, it is diagnostic of PP. If the serum sodium levels are >147, it is diagnostic of diabetes insipidus. If the serum sodium is between 135 and 147, the next step would be the water deprivation test. The traditional test that has been utilized by providers for a long time is the indirect water deprivation test that indirectly measures the activity of AVP. This test is started once hypotonic polyuria is confirmed, and serum sodium is between 135 and 147. Polyuria in primary polydipsia decreases with water deprivation (typically >8hrs), and urine osmolality increases (>800 mOsm/kg typically), this is diagnostic of PP. In diabetes insipidus, polyuria does not get better with water deprivation. If the urine osmolality remains <300 mOsm/kg after water deprivation, it is diagnostic of DI. A 12-year-old female child, with a history of polyuria and polydipsia of about three years duration, was admitted to Ethio-Swedish Paediatric Hospital, in Addis Abeba. Urine output in 24 hours averaged 5-6 litres, with a frequency of 15 times during the day and 7-8 times during the night. Random urine analysis showed an osmolality of 60 mOsm/kg, Na+ 27.1 mmol/L and K+ was 7.6 mmol/L. Basal plasma osmolality was 313 mOsm/kg with Na+ being 156 mmol/L and K+ 4.06 mmol/L. Water deprivation for nine hours failed to produce a concentrated urine, which was only 138 mOsm/kg at the end of the test, with a corresponding plasma osmolality of 336 mOsm/kg. After nine hours of water deprivation, urine Na+ increased from 27.1 to 37.3 mmol/L while K+ increased from 7.1 to 18.7 mmol/L. Lypressin, a vasopressin analogue, at a concentration of 0.3 IU/kg injected intramuscularly, resulted in a marked increase in urine osmolality to 586 mOsm/kg within two hours, associated with relief of symptoms. Urinary excretion of K+ was markedly increased during the vasopressin test while Na+ excretion was little affected. A case of central diabetes insipidus of undefined etiology is presented and the possibility of altered renal handling of electrolytes and an abnormal response to vasopressin in such cases is noted. The problem of management and the currently available treatment options are summarized. Serum and urine sodium, serum and urine osmolality, hourly urine output, 24-hour urine volume, and specific gravity must be obtained. Central DI must be distinguished from nephrogenic DI. A water deprivation test can be used with or without desmopressin injection. In central DI, the vasopressin will correct urine osmolality while in nephrogenic DI, the correction will be suboptimal. [3] [25] [26] Criteria for the diagnosis of central DI: Polyuria in two consecutive hours of > 300 ml/hr or 4 to 5 ml/kg/hr in two consecutive hours Polyuria > 3L/24 hours or > 2ml/kg/hr in 24 hours Serum osmolality > 300 mOsm/kg Urine osmolality < 300 mOsm/kg Urine/plasma osmolality <  1 The specific gravity of less than 1.005 The hyperosmolar hyperglycemic state (HHS), an acute complication of diabetes mellitus with plasma hyperosmolarity, promotes the secretion of anti-diuretic hormone (ADH) and reduces the storage of ADH. Magnetic resonance T1-weighted imaging reflects ADH storage in the posterior pituitary lobe, which disappears when the storage is depleted. Whether the HHS induces ADH depletion leading to clinical manifestations has been unclear. A 55-year-old Japanese woman was admitted to our center because of mental disturbance and hypotension. She had received lithium carbonate for bipolar disorder and presented with polydipsia and polyuria from 15 years of age. On admission, she had mental disturbance (Glasgow Coma Scale, E4V1M1), hypotension (systolic blood pressure, 50 mmHg), and tachycardia (pulse rate, 123/min). Plasma glucose was 697 mg/dL osmolality was 476 mOsm/kg•H<sub2</subO, and bicarbonate was 23.7 mmol/L. The diagnoses of HHS and hypovolemic shock were made. During treatment with fluid replacement and insulin therapy, the urine volume continued to be approximately 3 to 4 L/day, and an endocrine examination revealed ADH insufficiency and nephrogenic diabetes insipidus. Desmopressin 10 μg/day and trichlormethiazide 2 mg/day were necessary and administered, and the endogenous ADH secretion improved gradually. The signal intensity of the pituitary posterior lobe, initially decreased on magnetic resonance T1 images, was also improved. This patient had ADH insufficiency associated with ADH depletion due to hyperosmolarity and nephrogenic diabetes insipidus. Clinicians should be aware of the risk of the development of critical HHS and relative ADH insufficiency in patients being treated with lithium carbonate. This test measures the changes in body weight, urine output, and urine composition when fluids are withheld to induce dehydration. The body's normal response to dehydration is to conserve water by concentrating the urine. Those with DI continue to urinate large amounts of dilute urine in spite of water deprivation. In primary polydipsia, the urine osmolality should increase and stabilize at above 280 mOsm/kg with fluid restriction, while a stabilization at a lower level indicates diabetes insipidus. Stabilization in this test means, more specifically, when the increase in urine osmolality is less than 30 Osm/kg per hour for at least three hours. Sometimes measuring blood levels of ADH toward the end of this test is also necessary, but is more time consuming to perform. To differentiate AVP-D and AVP-R and primary polydipsia, perform a water deprivation test and desmopressin (DDAVP) trial. Typically a 7-hour deprivation test is adequate to diagnose DI. Primary polydipsia may require more extended dehydration periods. The basic principle behind the water deprivation test is that in individuals with normal posterior pituitary and renal function (or those with primary polydipsia), an increase in plasma osmolality from dehydration stimulates AVP release from the posterior pituitary, which then leads to water reabsorption in the nephrons, thus resulting in concentration of urine and an increase in urine osmolality. In AVP-D or AVP-R, the urine fails to concentrate optimally with water deprivation, and there is persistent excretion of hypotonic urine. In adults, the water restriction test should be discontinued when one of the following is reached: Diagnosis Diagnosis is based on clinical and laboratory findings of low serum osmolality and low serum sodium. Urinalysis reveals a highly concentrated urine with a high fractional excretion of sodium (high sodium urine content compared to the serum sodium). A suspected diagnosis is based on a serum sodium under 138. A confirmed diagnosis has seven elements: 1) a decreased effective serum osmolality - <275 mOsm/kg of water; 2) urinary sodium concentration high - over 40 mEq/L with adequate dietary salt intake; 3) no recent diuretic usage; 4) no signs of ECF volume depletion or excess; 5) no signs of decreased arterial blood volume - cirrhosis, nephrosis, or congestive heart failure; 6) normal adrenal and thyroid function; and 7) no evidence of hyperglycemia (diabetes mellitus), hypertriglyceridemia, or hyperproteinia (myeloma). We present here the results of water restriction test (WRT) and hypertonic saline loading test (HSLT) in normal children. Maximal urine osmolality during WRT (W-Umax; 1040 +/- 154 mOsm/kg) may be age-dependent (W-Umax = 812 + 23*age, r = 0.52, p &lt; 0.05), although maximal arginine vasopressin (AVP) levels during WRT did not show any correlation with age. The relationship between plasma osmolality (Posm) and AVP during HSLT in children (AVP = 0.31* (Posm-277)) was similar to that in normal adults. A plateau urine osmolality during HSLT (H-Umax) was 713 +/- 109 mOsm/kg. It did not increase with age. AVP levels 3 h after the infusion did not correlate with age. Minimal AVP and Posm values (about 6 pg/ml, 295 mOsm/kg, respectively) for creating H-Umax apparently existed during HSLT. The minimal AVP value (about 6 pg/ml) for H-Umax (during HSLT) was higher than the AVP levels (2.41 +/- 1.37 pg/ml) at W-Umax (during WRT). W-Umax (1040 +/- 154 mOsm/kg) was significantly higher than H-Umax (713 +/- 109 mOsm/kg). Judging from the above comparison of AVP and Uosm (W, H-Umax) at the plateau state of WRT and HSLT in normal children, a change in the apparent tubular response to AVP may be one of the important factors to maintain circulatory volume (CV). Brain MRI Urinary frequency, nocturia, enuresis 24-h urine volume and osmolarity on unrestrictedfluid intake Volume >40 mL/kg Osmolarity <300 mosm/L Basal plasma AVP >1 pg/mL <1 pg/mL Pituitary bright spot Present Absent Anatomy Pathology? GU evaluation Volume <40 mL/kg Osmolarity >300 mosm/L If MRI and/or AVP assays with the requisite sensitivity and specificity are unavailable and a fluid deprivation test is impractical or undesirable, a third way to differentiate between pituitary DI, nephrogenic DI, and primary polydipsia is a trial of desmopressin therapy. Such a trial should be conducted with very close monitoring of serum sodium as well as urine output, preferably in hospital, because desmopressin will produce hyponatremia in 8–24 h if the patient has primary polydipsia. Osmolality of blood increases with dehydration and decreases with overhydration. In normal people, increased osmolality in the blood will stimulate secretion of antidiuretic hormone (ADH). This will result in increased water reabsorption, more concentrated urine, and less concentrated blood plasma. A low serum osmolality will suppress the release of ADH, resulting in decreased water reabsorption and more concentrated plasma. Syndrome of inappropriate ADH secretion occurs when excessive release of antidiuretic hormone results in inappropriately elevated urine osmolality (>100 mOsmol/L) relative to the blood plasma, leading to hyponatraemia. This ADH secretion may occur in excessive amounts from the posterior pituitary gland, or from ectopic sources such as small-cell carcinoma of the lung. Elevation may be associated with stroke mortality. Calculated osmolarity (CO)\nHere is the question:\nENDOCRINOLOGY: A 34-year-old woman is admitted for polyuria and polydipsia. In the first 24 hours of admission a diuresis of 8.2 liters is found and a blood test shows a glycemia of 96 mg/dL, natremia of 148 mEq/L and plasma osmolality of 309 mOsm/kg with urinary osmolality of 89 mOsmlkg. What diagnostic test should be performed next?\nHere are the potential choices:\n1. Hypertonic saline infusion test for serial determination of antidiuretic hormone.\n2. Dehydration test (Miller test).\n3. Administration of desmopressin with serial monitoring of urine osmolality.\n4. Determination of antidiuretic hormone in plasma.\nThe correct answer is: 2. Dehydration test (Miller test)."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Epstein-Barr virus (EBV) infection typically presents with pharyngeal symptoms and subclinical transaminitis. We present a case of a 27-year-old woman with no known past medical history who presented with painless jaundice and dark-colored urine for three days. Her review of systems was negative for fever, sore throat, nausea, vomiting, pruritus, or rash. Her last sexual contact was six months ago with a male partner, and she only drank alcohol socially. Family and surgical history were non-significant. Physical examination revealed 3+ bilateral conjunctival icterus without abdominal tenderness or organomegaly. She had elevated transaminases: alanine transaminase (ALT) of 1287U/L and aspartate aminotransferase of (AST) 1057U/L but her alkaline phosphatase (ALP) was only slightly above normal at 109U/L (normal range 35-104U/L), with a direct hyperbilirubinemia - total bilirubin 9.5mg/dl, direct bilirubin 6.8mg/dl; the abdominal ultrasound revealed non-dilated bile ducts. Hepatitis A, B, and C serology was negative, but her EBV serology showed an infection. She had incidental thalassemia minor without splenomegaly or asterixis. She was managed conservatively, and her liver enzymes trended down with supportive management. Although EBV is an uncommon cause of painless jaundice, this diagnosis should be considered, especially when other more common causes of jaundice have been ruled out. A high index of suspicion should be maintained to detect EBV hepatitis as it can easily be diagnosed through serological testing. Roddick explained that her hepatitis C was unexpectedly diagnosed in 2004, following a blood test that was part of a medical examination needed for a life insurance policy. The blood test indicated abnormal liver function and subsequent blood tests diagnosed hepatitis C. Roddick explained that she had a large blood transfusion in 1971, after the birth of her younger daughter, and that she was convinced that the transfusion had infected her with hepatitis C. This was about twenty years before blood donors in the United Kingdom were screened for hepatitis C. She reported that she had developed cirrhosis of the liver, and that her main symptoms were itching and poor concentration. She briefly mentioned that medical treatment with interferon did not suit her. Roddick explained that she kept fit and active, and that she attended biannual out-patient hospital appointments in Southampton, as well as being under review by the liver transplant team at the Addenbrooke's Hospital in Cambridge. Hepatitis is a disease of the liver that has been recognised since antiquity. Symptoms include jaundice, a yellowing of the skin, eyes and body fluids. There are numerous causes, including viruses – particularly hepatitis A virus, hepatitis B virus and hepatitis C virus. Throughout history epidemics of jaundice have been reported, mainly affecting soldiers at war. This \"campaign jaundice\" was common in the Middle Ages. It occurred among Napoleon's armies and during most of the major conflicts of the 19th and 20th centuries, including the American Civil War, where over 40,000 cases and around 150 deaths were reported. The viruses that cause epidemic jaundice were not discovered until the middle of the 20th century. The names for epidemic jaundice, hepatitis A, and for blood-borne infectious jaundice, hepatitis B, were first used in 1947, following a publication in 1946 giving evidence that the two diseases were distinct. In the 1960s, the first virus that could cause hepatitis was Approach to the Patient with Liver Disease Suspected Liver Disease Abnormal liver tests Acute < 6 months Chronic > 6 months Diagnostic evaluation 1. IgM Anti-HAV 2. HBsAg 3. IgM Anti-HBc 4. Anti-HCV 5. ANA, SMA 6. Monospot, heterophile 7. Ceruloplasmin 8. Alcohol history 9. Drug history Diagnostic evaluation 1. AMA 2. Drug history 3. Ultrasound/MRI 4. MRCP/ERCP Liver biopsy in acute liver disease: Reserved for patients in whom the diagnosis remains unclear despite medical evaluation Liver biopsy in chronic liver disease: Often valuable for diagnosis as well as staging and grading liver disease Diagnostic evaluation 1. HBsAg 2. Anti-HCV 3. Fe saturation, ferritin 4. Ceruloplasmin 5. ˜1AT 6. ANA, SMA 7. Ultrasound 8. Alcohol history Diagnostic evaluation 1. Drug history 2. AMA 3. P-ANCA 4. Ultrasound 5. MRCP/ERCP Hepatitic: °°ALT Mixed: ˛ALT, ˛AlkP Cholestatic: °°AlkP, °°gGT, ˛ALT Hepatitic: °°ALT Mixed: ˛ALT, ˛AlkP Cholestatic: °°AlkP, °°gGT, ˛ALT Her social history is significant for alcohol use (three to four glasses of wine/night). Her vital signs include the following: temperature 99.8°F, blood pressure 132/64 mm Hg, pulse 78 bpm, and respiratory rate 15/min. On physical examination, she had left upper abdominal tenderness with evidence of hepatomegaly and mild scleral icterus. Laboratory data revealed the following: alanine aminotransferase, 527 IU/L (normal 10–35 IU/L); aspartate aminotransferase, 425 IU/L (normal < 35 IU/L); and bilirubin, 2.9 mg/dL (normal 0.1–0.3 mg/dL). What medications do OTC cold and flu preparations typically contain? Which of the OTC medications might have contrib-uted to the patient’s current symptoms? KH, a 55-year-old woman, presents to the emergency department with nausea, vomiting, and complaints of new-onset flu symptoms over the past several days. Her past medical history is significant for allergic rhinitis and chronic lower back pain secondary to a work-related fall 2 years ago. Her Patients usually present with varying symptoms apart from yellowish discoloration of skin along with pruritus, thus providing clues to narrow down the etiology or can also be asymptomatic. A thorough questioning regarding the use of drugs, alcohol or other toxic substances, risk factors for hepatitis (travel, unsafe sexual practices), HIV status, personal or family history of any inherited disorders or hemolytic disorders is vital. Other important points include the duration of jaundice; and the presence of any coexisting signs and symptoms, like a joint ache, rash, myalgia, changes in urine and stool. [22] A history of arthralgias and myalgias before yellowing indicates hepatitis, either due to drugs or viral infections. Phase 2 (prodromal phase) - Patients in this phase usually present with anorexia, nausea, vomiting, malaise, pruritus, urticaria, arthralgias, and fatigue. Many times these patients are misdiagnosed as having gastroenteritis or viral infection. Phase 3 (icteric phase) - Patients in this phase present with dark-colored urine and pale-colored stool. Some patients develop jaundice and right upper quadrant pain with liver enlargement. Phase 4 (convalescent phase) - Patients typically start noticing the resolution of symptoms, and laboratory studies show liver enzymes returning to normal levels. [32] Viral infections during pregnancy can pose serious threats to mother and fetus from the time of conception to the time of delivery. These lead to congenital defects, spontaneous abortion and even death. The definitive diagnosis and management of pregnancy-related viral infections may be challenging especially in less resourced countries. We present clinical and laboratory responses to the diagnosis and management of three cases of fulminant hepatitis secondary to Hepatitis E viral infection in pregnancy.Case 1 was a 31-year-old Ghanaian woman who presented with a week's history of passing dark urine as well as yellowish discoloration of the eyes. She subsequently developed fulminant hepatitis secondary to Hepatitis E viral infection, spontaneously aborted at 24 weeks of gestation and later died.Case 2 was also a 31-year-old Ghanaian woman who was admitted with a four-day history of jaundice. She had low grade fever, but no history of abdominal pain, haematuria, pale stool or pruritus. She next developed fulminant hepatitis secondary to Hepatitis E viral infection. However, she did not miscarry but died at 28 weeks of gestation.Case 3 was a 17-year-old Ghanaian woman who was referred to the tertiary health facility on account of jaundice and anaemia. She had delivered a live male infant at maturity of 32 weeks but noticed she was jaundiced and had a presentation of active disease 3 days prior to delivery. The baby was icteric at birth and on evaluation, had elevated bilirubin (mixed type) with normal liver enzymes. Hepatitis E virus infection was confirmed in both mother and baby. However, the jaundice and the hepatomegaly resolved in mother and baby after 5 and 12 days respectively. To the best of our knowledge, these are the first documented cases of fatal fulminant hepatic failures resulting from HEV infection in Ghana. Analysis of serum copper (Cu) level dynamics during the acute phase of hepatitis acute B and the early convalescence in compliance with gravity of the acute disease course. The study included 39 patients (12 men and 27 women), aged 18 to 76 years. They were hospitalised in the Department of Infectious Diseases of Medical Academy in Lublin because of the hepatitis acute B, without coexisting diseases. The diagnosis was based on the epidemiologic anamnesis, clinical symptoms, biochemical and serological examinations. The studied group was divided in respect to sex and the course of the disease as: light, medium-weighty and weighty. In all examined patients, the serum Cu level was determined according to the following scheme: at the first, tenth, twentieth and the last day of the hospitalisation and additionally one time at four weeks after discharging from the clinic. The serum Cu level was made by atomic absorption spectrometry (AAS) at the wave length of 324.8 nm. The received data were subjected to statistical analysis according to t-Student's test and in cases of significant differences according to the variants of c-Cochran and Cox's tests. According to the SI Unit Conversion Guide, the values 11.22 to 23.58 mumol/l were taken as the normal range. The values derived from the control group of 24 healthy persons (13 men and 11 women) aged 22 to 69 years. The significant increase of serum Cu level in comparison with the control values was found both in the acute phase of hepatitis B and the early convalescence. It could be observed a correlation between serum Cu level and the course of hepatitis viralis acuta B. The statistics proved that approximately 25% of the patients with acute HCV present with jaundice, and only 10-20% develop gastrointestinal symptoms. We present the case of a 58 year-old woman, with prior antecedents of arterial hypertension and diabetes mellitus since 25 years old, hypercholesterolemia and hypertriglyceridemia, psoriasis, epilepsy and depressive syndrome. She clinically presents asthenia, anorexia, itching, jaundice and choluria. The objective examination showed an orientated patient, without flapping, hemorrhagic dyscrasia or signs of chronic hepatic disease, with icteric mucosa and skin, abdominal pain, with hepatomegaly and splenomegaly. The laboratory tests have been compatible with acute hepatitis with colestatic pattern: AST/ALT 969/798 UI/ml, FA 796 UI/ml, GGT 2476 UI/ml, BT/BD 7.39/6.10, INR 0.9. The abdominal echography showed: hepatomegaly, regular borders, hepatic steatosis, splenomegaly without ascitic fluid. The viral serological tests revealed protection for hepatitis A ( IgM neg/IgG pos), negative for HVB infection (AgHBs neg, anti-HBc neg), negative for HVE and other viruses (CMV Herpes virus, Epstein Barr, HIV), positive antibodies for HCV and positive RNA VHC (164200 UI/ml), HCV genotype 3a, IL-28B CT, negative autoimmunity. The previous HCV tests were negative, sustaining the recent infection. We assumed an acute hepatitis C. The patient was symptomatically treated with hydroxyzine for the skin itch, with vitamin K for INR correction and she was closely monitored. She had good clinical and laboratorial evolution and she was discharged after one week, maintaining hepatology consultation. She spontaneously cleared HCV infection after 3 months, maintaining negative RNA VHC 6 months after infection. The patient has cured the HCV infection with no need for antiviral treatment. 302 liver cirrhoses obtained from the post-mortem material 1970 to 1979 have been examined for the occurrence of the cuprous protein complexes by means of the orcein-staining according to Shikata. The part of the B-posthepatic cirrhoses (89%) could be simultaneously determined with the help of this method. Cuprous protein complexes have been found in bilious (100%), alcoholic (43.9%), etiologically uncertain (34.4%), and B-posthepatic (25,9%) liver cirrhoses. They prove an existing or experienced chronic cholestasis. The demonstration of copper has no principal significance for the etiologic classification of cirrhoses. In the bioptic diagnostics the demonstration of copper has a certain significance for the differentiation of the primary destructive cholangitis from chronically active hepatites of other genesis. The investigations incidentally revealed that HBsAg-containing hepatocytes could be identified by means of orcein in sections performed on archive material after destaining independent of the age of the sections and their primary staining. History The Tenpō Tsūhō came around a century after the introduction of the Hōei Tsūhō (Kyūjitai: 寳永通寳 ; Shinjitai: 宝永通宝) during the 5th year of the Hōei era (1708), which had a face value of 10 mon (while only containing 3 times as much copper as a 1 mon Kan'ei Tsūhō coin), but was discontinued shortly after it started circulating as it wasn't accepted for its nominal value. A 37-year-old woman presented with increasing abdominal pain and jaundice. Six weeks before admission, she developed persistent diarrhea and jaundice of the skin. She also bruised easily, and her gums bled. In the subsequent weeks, her appetite decreased, she was fatigued, and she had nausea, vomiting, and abdominal distension. She had a history of drinking 1 quart of vodka every day for 20 years, with brief periods of abstinence; she stopped consuming alcohol 11 days before admission because it no longer provided symptomatic relief. Her past medical history was also notable for depression, including a suicide attempt 4 years earlier. She did not smoke, use illicit drugs, or have unprotected sexual intercourse. She had received no blood transfusions and had not traveled recently. She took no medications, except for occasional ibuprofen. On physical examination, she was thin and deeply jaundiced, and she trembled and responded slowly to questions. She was afebrile but tachypneic, and she had orthostatic hypotension. Her HEENT examination was notable for scleral and sublingual icterus, as well as crusted blood on her gums and teeth. The jugular veins were flat. The cardiac examination revealed tachycardia (heart rate, 103 beats per minute) without murmurs, rubs, or gallops. The abdomen was nontender and protuberant, with hypoactive bowel sounds; the spleen was not palpable, and there was no fluid wave or caput medusae. The liver percussed to 18 cm, with a smooth edge extending 10 cm below the costal margin. She had cutaneous telangiectases on her chest and bilateral palmar erythema. There was no peripheral edema. The neurologic examination was notable for asterixis. Her stool was guaiac positive. Laboratory studies revealed the following values: hematocrit, 21.2%; white blood cells, 17,310/mm(3); ammonia, 42 micromol/L; serum creatinine, 3.9 mg/dL; serum urea nitrogen, 70 mg/dL; albumin, 2.1 g/dL; total bilirubin, 26.8 mg/dL; alanine aminotransferase, 14 U/L; aspartate aminotransferase, 77 U/L; alkaline phosphatase, 138 U/L; prothrombin time, 103 seconds (international normalized ratio, 10.6); and urinary sodium, &lt;5 mg/dL. Urinalysis revealed an elevated specific gravity and numerous muddy granular casts. Hepatitis A, B, and C serologies were negative. On abdominal ultrasound examination, there was no ascites, and the liver was echogenic. The portal and hepatic veins were patent, and the hepatic arteries were normal. The spleen measured 14 cm. What is the diagnosis? Wilson disease is a disease of excessive copper accumulation. It is associated with psychiatric disturbances due to copper accumulation in the basal ganglia. Kayser-Fleischer rings are pathognomonic for Wilson disease but are not completely sensitive (requires an expert ophthalmologist to confirm this finding). Laboratory evaluation that favors a diagnosis of Wilson disease includes low serum ceruloplasmin levels and elevated urinary copper, and if abnormal, requires further evaluation by a hepatologist. Alcoholic hepatitis Autoimmune hepatitis Cirrhosis Drug-induced liver injury Hemochromatosis Hepatitis A Hepatitis C Hepatitis D Hepatitis E Hepatocellular carcinoma Human immunodeficiency virus Wilson disease Hydralazine is a commonly used oral antihypertensive agent. We report a rare case of hydralazine-induced hepatotoxicity in the form of subacute hepatic necrosis. A 75-year-old African American woman presented with jaundice of 7-day duration. She was started on hydralazine 100 mg 3 times a day 10 weeks before presentation. On physical examination, scleral icterus was noted. Workup revealed elevated liver transaminases, alkaline phosphatase, and conjugated bilirubin. She had no history of liver disease, and liver function tests had been normal before starting hydralazine. Other etiologies, including viruses, common toxins, drugs, autoimmune, and copper-induced hepatitis, were excluded. Abdominal imaging studies did not show any evidence of intrahepatic or extrahepatic biliary ductal dilatation, and no pathologies were seen in the liver and pancreas. The patient's liver biopsy revealed extensive lobular hepatitis, significant necrosis, mixed inflammatory infiltrate, and no significant fibrosis, supporting a diagnosis of drug-induced liver injury. Hydralazine was immediately discontinued. She showed improvement of clinical and laboratory abnormalities within 5 days after discontinuation of hydralazine. To establish the diagnosis of hydralazine-induced liver injury, we used assessment tool outlined by the Council for International Organization of Medical Sciences (CIOMS) scale that led to \"high probable\" relationship. Although rare, clinically significant, and potentially life-threatening liver injury can result from use of hydralazine. Both clinical and histological presentations in our patient suggest acute liver injury. The hydralazine-induced hepatitis seems to be reversible as discontinuation of the drug improves clinical outcomes. We highly recommend monitoring of the liver function during hydralazine treatment.  Occult hepatitis B (ОHB) characterized by the absence of blood HBsAg attracts the attention of specialists of different profiles; however, its clinical morphological aspects have not been practically studied. to estimate the proportion of OHB in the structure of fatal outcomes in chronic viral hepatitis (CVH) and to characterize its clinical course and structural changes on autopsy materials. A total of 455 autopsy cases of CVH were examined for its etiology in the S.P. Botkin Clinical Hospital of Infectious Diseases in 2014-2016. An in-depth prospective clinical analysis was made to investigate 28 cases of OHB in the stage of decompensated liver cirrhosis, which had subsequently culminated in death. The criteria of inclusion were history data and clinical symptoms of CVH in the detection of markers for hepatitis A, C, and D and HIV in serum HBcAb in the absence of HBsAg. HBsAbs were also determined. Along with the traditional morphological examination, immunohistochemistry (IHC) for HBsAg and HBcAg was carried out. There were 108 CVHB cases (23.7% of the total cases of CVH), including 77 OHB cases (71.3% of those of CVHB) while HBsAg was not determined. HBsAb-negative patients were more often observed to have clinical signs of jaundice (p&lt;0.05) and skin itching (p&lt;0.05). Dyspepsia and hemorrhagic manifestations prevailed in patients with HBsAb (more than 10 IU/l) (p&lt;0.05). All the cases were found to have characteristic morphological signs of CVH, including intranuclear inclusions and nuclear polymorphism in 10.7% of deaths. There was an IHC-positive reaction to VHB antigens in 28.6% of the patients and a doubtful reaction in 25.0%. Serum НВсAb may serve as a diagnostic marker for HBV infection. Clinical and morphological correlations enabled the authors to state that CVHB was present in all cases in the absence of serum HBsAg in the patients. Diagnosing NAFLD requires demonstration of increased liver fat in the absence of hazardous levels of alcohol consumption. Thresholds for potentially dangerous alcohol ingestion have been set at more than one drink per day in women and two drinks per day in men based on epidemiologic evidence that the prevalence of serum aminotransferase elevations increases when alcohol consumption habitually exceeds these levels. In those studies, one drink was defined as having 10 g of ethanol and, thus, is equivalent to one can of beer, 4 ounces of wine, or 1.5 ounces (one shot) of distilled spirits. Other causes of liver fat accumulation (particularly exposure to certain drugs; Table 364-2) and liver injury (e.g., viral hepatitis, autoimmune liver disease, iron or copper overload, α1 antitrypsin deficiency) must also be excluded. Thus, establishing the diagnosis of NAFLD does not require invasive testing: it can be accomplished by history and physical examination, liver imaging (ultrasound is an Ginseng is commonly used as a medicinal herb for memory and concentration and general well-being. Drug-induced liver injury (DILI) is one of the most challenging disorders and trending events in the United States which are related to body building and weight loss supplements. Currently, herbal and dietary supplementation is the second most common cause of DILI. Here, we report on a 45-year-old healthy Chinese woman who presented with dull intermittent left upper quadrant abdomen pain for a month. Upon thorough history taking, she had been taking ginseng tea and supplementation for her menopausal symptoms for almost 3 months. Physical examination was unremarkable except mild tenderness in left upper quadrant of the abdomen. Liver function test showed aspartate transaminase (AST) 717 U/L, alanine transaminase (ALT) 343 U/L, total bilirubin 5 mg/dL, direct bilirubin 3.3 mg/dL, alkaline phosphatase 182 U/L, with international normalized ratio (INR) 1.2. Prior liver enzymes (6 months earlier) showed AST 21 U/L, ALT 18 U/L, total bilirubin 0.8 mg/dL, direct bilirubin 0.3 mg/dL, alkaline phosphatase 34 U/L, with INR 0.7. Viral serology for acute hepatitis B, C, E, cytomegalovirus, Epstein-Barr virus, and varicella zoster virus was negative. She was immune to hepatitis A. Her antinuclear antibody was positive. Her anti-Smith antibody, anti-smooth muscle antibody, HFE gene mutation, ceruloplasmin, alpha-1 antitrypsin serologies were within normal references. An abdomen sonogram showed fatty infiltration. Liver biopsy showed moderate to severe portal inflammation and marked lobular disarray. Portal and lobular inflammatory infiltrates consisted of a mixture of histiocytes, lymphocytes, plasma cells, eosinophils, and neutrophils with centrilobular necrosis and focal bridging necrosis, and necro-inflammation. After 6 weeks of follow-up, the patient improved physically, and the abdomen pain resolved. Ginseng has been widely used in the Chinese community as medicinal herb for a variety of conditions for decades. However, proper research has never been done regarding its pharmacokinetics, efficacy, and safety issues. In our case report, the idiosyncratic DILI resulted from ingestion of ginseng as herbal supplementation for premenopausal symptoms. Physicians should be aware of and suspect DILI in any patient with acute liver injury, and patients should be reminded that all medications and supplements have a potential to cause DILI. The results of the bilirubin, enzymes, and liver function tests will direct the diagnosis towards a hepatocellular or cholestatic cause and offer some idea of the duration and severity of the disease. Further evaluation can be conducted based on the initial assessment. Hepatocellular workup: viral serologies, autoimmune antibodies, serum ceruloplasmin, ferritin. A 38-year-old woman presented with general weakness and vaginal bleeding. One month prior, she had been diagnosed with Evans syndrome (haemolytic anemia with positive Coombs test and thrombocytopenia) and was given oral steroid as maintenance therapy. Her serology examination was negative for hepatitis B, hepatitis C, and human immunodeficiency virus (HIV). Her obstetrical history was marked by miscarriage in second pregnancy and preeclampsia in third pregnancy. She used hormonal contraceptives until 5 months prior to admission. On physical examination, she had anemic conjunctiva and no organomegaly. Blood tests were significant for anemia (3.4 g/dl) and thrombocytopenia (28,000/µl). Her vaginal bleeding had ceased, however her platelet continued decreasing to 12,000/µl during first several days of hospitalization despite receiving platelet transfusion. On the tenth hospital day, she suddenly complained of severe headache and blurred vision. She had bilateral edema and erythema of palpebral, chemosis, decreased in visual acuity, and reduced ocular motility. Ear and nose examination were normal. Peripheral blood smear showed no blast. Prothrombine time (PT), INR, APTT tests were normal and D Dimer was slightly increased (3.3 mg/l; NV ≤0.5 mg/l). Urine examination revealed proteinuria with 24 hour urine protein was 1,863 mg (NV &lt;150 mg/day). We assessed her as cavernous sinus thrombosis and treated her empirically with intravenous broad-spectrum antibiotics, morphine drip. Either digital subtraction angiography or anticoagulant was deferred due to low platelet. Further examination revealed positive for ANA, anti-SSA, and diagnosis of SLE was established. Anticardiolipin antibodies of IgG and IgM and anti-beta2 glycoprotein antibodies of IgM and IgG tests were non reactive. Methylprednisolone pulse therapy (1g/day) was given for 3 consecutive days, and then tapered to oral methylprednisolone. She additionally received azathioprine 50 mg tab BID. Meanwhile her clinical symptoms alleviated and platelet count was increased, brain MRI and MR venography finally performed suggesting cerebral venous sinus thrombosis. She got additional oral anticoagulant rivaroxaban 15 mg tab BID and eventually discharged. Cerebral venous sinus thrombosis may be the presenting symptoms or occur concomitantly within the onset of SLE. Our patient had SLE, meeting 4 of the Systemic Lupus International Collaborating Clinic classification criteria (hemolytic anemia, thrombocytopenia, renal involvement, and positive for ANA test). Vasculitis due to endothelial cell injury mediated by immune-complex deposition is proposed to be the pathogenesis of CVST in SLE. Hypercoagulable state could be other etiology factor. Antiphospholipid antibodies were absent in our case as reported in some cases, emphasizing vasculitis as the underlying mechanism. Treatment of CVST in SLE consisting of anticoagulant, steroid, and immunosuppressant. This case elicits intriguing problem: CVST and thrombocytopenia. Anticoagulant treatment is proposed as the cornerstone treatment for CVST, however it was deferred due to risk of bleeding in thrombocytopenia. Steroid plays role in treatment of CVST in SLE, owing to its anti-inflammatory property. As shown in previous cases, the patient had remarkable response to high dose steroid treatment and eventually got anticoagulant after her platelet had increased. In summary, prompt diagnosis and treatment of CVST are important for a favorable prognosis.\nHere is the question:\nDIGESTIVE: A 52-year-old woman consulted because she had noticed during the previous week a yellowish discoloration of the conjunctivae. She does not refer to risky sexual behaviors or epidemiological history of risk of viral hepatitis. She does not consume alcohol or hepatotoxic drugs. She reports a one-year history of generalized pruritus, asthenia, dry mouth and absence of lacrimation with no known cause. Rest of the anamnesis without pathological data. Physical examination showed scratching lesions, conjunctival jaundice and non-painful hepatomegaly. The patient brings a blood test carried out in his company with the following pathological results: Bilirubin 3 mg/dl, FA 400 UI/ VSG 40mm 1 hour. Indicate which would be the best recommendation to establish the etiological diagnosis of the patient's condition:\nHere are the potential choices:\n1. Anti-mitochondrial antibodies.\n2. Study of Fe metabolism.\n3. Study of copper metabolism.\n4. Hepatic MRI.\n5. Serology for B and C viruses.\nThe correct answer is: ",
        "gold_answer": "1 Anti-mitochondrial antibodies.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Epstein-Barr virus (EBV) infection typically presents with pharyngeal symptoms and subclinical transaminitis. We present a case of a 27-year-old woman with no known past medical history who presented with painless jaundice and dark-colored urine for three days. Her review of systems was negative for fever, sore throat, nausea, vomiting, pruritus, or rash. Her last sexual contact was six months ago with a male partner, and she only drank alcohol socially. Family and surgical history were non-significant. Physical examination revealed 3+ bilateral conjunctival icterus without abdominal tenderness or organomegaly. She had elevated transaminases: alanine transaminase (ALT) of 1287U/L and aspartate aminotransferase of (AST) 1057U/L but her alkaline phosphatase (ALP) was only slightly above normal at 109U/L (normal range 35-104U/L), with a direct hyperbilirubinemia - total bilirubin 9.5mg/dl, direct bilirubin 6.8mg/dl; the abdominal ultrasound revealed non-dilated bile ducts. Hepatitis A, B, and C serology was negative, but her EBV serology showed an infection. She had incidental thalassemia minor without splenomegaly or asterixis. She was managed conservatively, and her liver enzymes trended down with supportive management. Although EBV is an uncommon cause of painless jaundice, this diagnosis should be considered, especially when other more common causes of jaundice have been ruled out. A high index of suspicion should be maintained to detect EBV hepatitis as it can easily be diagnosed through serological testing. Roddick explained that her hepatitis C was unexpectedly diagnosed in 2004, following a blood test that was part of a medical examination needed for a life insurance policy. The blood test indicated abnormal liver function and subsequent blood tests diagnosed hepatitis C. Roddick explained that she had a large blood transfusion in 1971, after the birth of her younger daughter, and that she was convinced that the transfusion had infected her with hepatitis C. This was about twenty years before blood donors in the United Kingdom were screened for hepatitis C. She reported that she had developed cirrhosis of the liver, and that her main symptoms were itching and poor concentration. She briefly mentioned that medical treatment with interferon did not suit her. Roddick explained that she kept fit and active, and that she attended biannual out-patient hospital appointments in Southampton, as well as being under review by the liver transplant team at the Addenbrooke's Hospital in Cambridge. Hepatitis is a disease of the liver that has been recognised since antiquity. Symptoms include jaundice, a yellowing of the skin, eyes and body fluids. There are numerous causes, including viruses – particularly hepatitis A virus, hepatitis B virus and hepatitis C virus. Throughout history epidemics of jaundice have been reported, mainly affecting soldiers at war. This \"campaign jaundice\" was common in the Middle Ages. It occurred among Napoleon's armies and during most of the major conflicts of the 19th and 20th centuries, including the American Civil War, where over 40,000 cases and around 150 deaths were reported. The viruses that cause epidemic jaundice were not discovered until the middle of the 20th century. The names for epidemic jaundice, hepatitis A, and for blood-borne infectious jaundice, hepatitis B, were first used in 1947, following a publication in 1946 giving evidence that the two diseases were distinct. In the 1960s, the first virus that could cause hepatitis was Approach to the Patient with Liver Disease Suspected Liver Disease Abnormal liver tests Acute < 6 months Chronic > 6 months Diagnostic evaluation 1. IgM Anti-HAV 2. HBsAg 3. IgM Anti-HBc 4. Anti-HCV 5. ANA, SMA 6. Monospot, heterophile 7. Ceruloplasmin 8. Alcohol history 9. Drug history Diagnostic evaluation 1. AMA 2. Drug history 3. Ultrasound/MRI 4. MRCP/ERCP Liver biopsy in acute liver disease: Reserved for patients in whom the diagnosis remains unclear despite medical evaluation Liver biopsy in chronic liver disease: Often valuable for diagnosis as well as staging and grading liver disease Diagnostic evaluation 1. HBsAg 2. Anti-HCV 3. Fe saturation, ferritin 4. Ceruloplasmin 5. ˜1AT 6. ANA, SMA 7. Ultrasound 8. Alcohol history Diagnostic evaluation 1. Drug history 2. AMA 3. P-ANCA 4. Ultrasound 5. MRCP/ERCP Hepatitic: °°ALT Mixed: ˛ALT, ˛AlkP Cholestatic: °°AlkP, °°gGT, ˛ALT Hepatitic: °°ALT Mixed: ˛ALT, ˛AlkP Cholestatic: °°AlkP, °°gGT, ˛ALT Her social history is significant for alcohol use (three to four glasses of wine/night). Her vital signs include the following: temperature 99.8°F, blood pressure 132/64 mm Hg, pulse 78 bpm, and respiratory rate 15/min. On physical examination, she had left upper abdominal tenderness with evidence of hepatomegaly and mild scleral icterus. Laboratory data revealed the following: alanine aminotransferase, 527 IU/L (normal 10–35 IU/L); aspartate aminotransferase, 425 IU/L (normal < 35 IU/L); and bilirubin, 2.9 mg/dL (normal 0.1–0.3 mg/dL). What medications do OTC cold and flu preparations typically contain? Which of the OTC medications might have contrib-uted to the patient’s current symptoms? KH, a 55-year-old woman, presents to the emergency department with nausea, vomiting, and complaints of new-onset flu symptoms over the past several days. Her past medical history is significant for allergic rhinitis and chronic lower back pain secondary to a work-related fall 2 years ago. Her Patients usually present with varying symptoms apart from yellowish discoloration of skin along with pruritus, thus providing clues to narrow down the etiology or can also be asymptomatic. A thorough questioning regarding the use of drugs, alcohol or other toxic substances, risk factors for hepatitis (travel, unsafe sexual practices), HIV status, personal or family history of any inherited disorders or hemolytic disorders is vital. Other important points include the duration of jaundice; and the presence of any coexisting signs and symptoms, like a joint ache, rash, myalgia, changes in urine and stool. [22] A history of arthralgias and myalgias before yellowing indicates hepatitis, either due to drugs or viral infections. Phase 2 (prodromal phase) - Patients in this phase usually present with anorexia, nausea, vomiting, malaise, pruritus, urticaria, arthralgias, and fatigue. Many times these patients are misdiagnosed as having gastroenteritis or viral infection. Phase 3 (icteric phase) - Patients in this phase present with dark-colored urine and pale-colored stool. Some patients develop jaundice and right upper quadrant pain with liver enlargement. Phase 4 (convalescent phase) - Patients typically start noticing the resolution of symptoms, and laboratory studies show liver enzymes returning to normal levels. [32] Viral infections during pregnancy can pose serious threats to mother and fetus from the time of conception to the time of delivery. These lead to congenital defects, spontaneous abortion and even death. The definitive diagnosis and management of pregnancy-related viral infections may be challenging especially in less resourced countries. We present clinical and laboratory responses to the diagnosis and management of three cases of fulminant hepatitis secondary to Hepatitis E viral infection in pregnancy.Case 1 was a 31-year-old Ghanaian woman who presented with a week's history of passing dark urine as well as yellowish discoloration of the eyes. She subsequently developed fulminant hepatitis secondary to Hepatitis E viral infection, spontaneously aborted at 24 weeks of gestation and later died.Case 2 was also a 31-year-old Ghanaian woman who was admitted with a four-day history of jaundice. She had low grade fever, but no history of abdominal pain, haematuria, pale stool or pruritus. She next developed fulminant hepatitis secondary to Hepatitis E viral infection. However, she did not miscarry but died at 28 weeks of gestation.Case 3 was a 17-year-old Ghanaian woman who was referred to the tertiary health facility on account of jaundice and anaemia. She had delivered a live male infant at maturity of 32 weeks but noticed she was jaundiced and had a presentation of active disease 3 days prior to delivery. The baby was icteric at birth and on evaluation, had elevated bilirubin (mixed type) with normal liver enzymes. Hepatitis E virus infection was confirmed in both mother and baby. However, the jaundice and the hepatomegaly resolved in mother and baby after 5 and 12 days respectively. To the best of our knowledge, these are the first documented cases of fatal fulminant hepatic failures resulting from HEV infection in Ghana. Analysis of serum copper (Cu) level dynamics during the acute phase of hepatitis acute B and the early convalescence in compliance with gravity of the acute disease course. The study included 39 patients (12 men and 27 women), aged 18 to 76 years. They were hospitalised in the Department of Infectious Diseases of Medical Academy in Lublin because of the hepatitis acute B, without coexisting diseases. The diagnosis was based on the epidemiologic anamnesis, clinical symptoms, biochemical and serological examinations. The studied group was divided in respect to sex and the course of the disease as: light, medium-weighty and weighty. In all examined patients, the serum Cu level was determined according to the following scheme: at the first, tenth, twentieth and the last day of the hospitalisation and additionally one time at four weeks after discharging from the clinic. The serum Cu level was made by atomic absorption spectrometry (AAS) at the wave length of 324.8 nm. The received data were subjected to statistical analysis according to t-Student's test and in cases of significant differences according to the variants of c-Cochran and Cox's tests. According to the SI Unit Conversion Guide, the values 11.22 to 23.58 mumol/l were taken as the normal range. The values derived from the control group of 24 healthy persons (13 men and 11 women) aged 22 to 69 years. The significant increase of serum Cu level in comparison with the control values was found both in the acute phase of hepatitis B and the early convalescence. It could be observed a correlation between serum Cu level and the course of hepatitis viralis acuta B. The statistics proved that approximately 25% of the patients with acute HCV present with jaundice, and only 10-20% develop gastrointestinal symptoms. We present the case of a 58 year-old woman, with prior antecedents of arterial hypertension and diabetes mellitus since 25 years old, hypercholesterolemia and hypertriglyceridemia, psoriasis, epilepsy and depressive syndrome. She clinically presents asthenia, anorexia, itching, jaundice and choluria. The objective examination showed an orientated patient, without flapping, hemorrhagic dyscrasia or signs of chronic hepatic disease, with icteric mucosa and skin, abdominal pain, with hepatomegaly and splenomegaly. The laboratory tests have been compatible with acute hepatitis with colestatic pattern: AST/ALT 969/798 UI/ml, FA 796 UI/ml, GGT 2476 UI/ml, BT/BD 7.39/6.10, INR 0.9. The abdominal echography showed: hepatomegaly, regular borders, hepatic steatosis, splenomegaly without ascitic fluid. The viral serological tests revealed protection for hepatitis A ( IgM neg/IgG pos), negative for HVB infection (AgHBs neg, anti-HBc neg), negative for HVE and other viruses (CMV Herpes virus, Epstein Barr, HIV), positive antibodies for HCV and positive RNA VHC (164200 UI/ml), HCV genotype 3a, IL-28B CT, negative autoimmunity. The previous HCV tests were negative, sustaining the recent infection. We assumed an acute hepatitis C. The patient was symptomatically treated with hydroxyzine for the skin itch, with vitamin K for INR correction and she was closely monitored. She had good clinical and laboratorial evolution and she was discharged after one week, maintaining hepatology consultation. She spontaneously cleared HCV infection after 3 months, maintaining negative RNA VHC 6 months after infection. The patient has cured the HCV infection with no need for antiviral treatment. 302 liver cirrhoses obtained from the post-mortem material 1970 to 1979 have been examined for the occurrence of the cuprous protein complexes by means of the orcein-staining according to Shikata. The part of the B-posthepatic cirrhoses (89%) could be simultaneously determined with the help of this method. Cuprous protein complexes have been found in bilious (100%), alcoholic (43.9%), etiologically uncertain (34.4%), and B-posthepatic (25,9%) liver cirrhoses. They prove an existing or experienced chronic cholestasis. The demonstration of copper has no principal significance for the etiologic classification of cirrhoses. In the bioptic diagnostics the demonstration of copper has a certain significance for the differentiation of the primary destructive cholangitis from chronically active hepatites of other genesis. The investigations incidentally revealed that HBsAg-containing hepatocytes could be identified by means of orcein in sections performed on archive material after destaining independent of the age of the sections and their primary staining. History The Tenpō Tsūhō came around a century after the introduction of the Hōei Tsūhō (Kyūjitai: 寳永通寳 ; Shinjitai: 宝永通宝) during the 5th year of the Hōei era (1708), which had a face value of 10 mon (while only containing 3 times as much copper as a 1 mon Kan'ei Tsūhō coin), but was discontinued shortly after it started circulating as it wasn't accepted for its nominal value. A 37-year-old woman presented with increasing abdominal pain and jaundice. Six weeks before admission, she developed persistent diarrhea and jaundice of the skin. She also bruised easily, and her gums bled. In the subsequent weeks, her appetite decreased, she was fatigued, and she had nausea, vomiting, and abdominal distension. She had a history of drinking 1 quart of vodka every day for 20 years, with brief periods of abstinence; she stopped consuming alcohol 11 days before admission because it no longer provided symptomatic relief. Her past medical history was also notable for depression, including a suicide attempt 4 years earlier. She did not smoke, use illicit drugs, or have unprotected sexual intercourse. She had received no blood transfusions and had not traveled recently. She took no medications, except for occasional ibuprofen. On physical examination, she was thin and deeply jaundiced, and she trembled and responded slowly to questions. She was afebrile but tachypneic, and she had orthostatic hypotension. Her HEENT examination was notable for scleral and sublingual icterus, as well as crusted blood on her gums and teeth. The jugular veins were flat. The cardiac examination revealed tachycardia (heart rate, 103 beats per minute) without murmurs, rubs, or gallops. The abdomen was nontender and protuberant, with hypoactive bowel sounds; the spleen was not palpable, and there was no fluid wave or caput medusae. The liver percussed to 18 cm, with a smooth edge extending 10 cm below the costal margin. She had cutaneous telangiectases on her chest and bilateral palmar erythema. There was no peripheral edema. The neurologic examination was notable for asterixis. Her stool was guaiac positive. Laboratory studies revealed the following values: hematocrit, 21.2%; white blood cells, 17,310/mm(3); ammonia, 42 micromol/L; serum creatinine, 3.9 mg/dL; serum urea nitrogen, 70 mg/dL; albumin, 2.1 g/dL; total bilirubin, 26.8 mg/dL; alanine aminotransferase, 14 U/L; aspartate aminotransferase, 77 U/L; alkaline phosphatase, 138 U/L; prothrombin time, 103 seconds (international normalized ratio, 10.6); and urinary sodium, &lt;5 mg/dL. Urinalysis revealed an elevated specific gravity and numerous muddy granular casts. Hepatitis A, B, and C serologies were negative. On abdominal ultrasound examination, there was no ascites, and the liver was echogenic. The portal and hepatic veins were patent, and the hepatic arteries were normal. The spleen measured 14 cm. What is the diagnosis? Wilson disease is a disease of excessive copper accumulation. It is associated with psychiatric disturbances due to copper accumulation in the basal ganglia. Kayser-Fleischer rings are pathognomonic for Wilson disease but are not completely sensitive (requires an expert ophthalmologist to confirm this finding). Laboratory evaluation that favors a diagnosis of Wilson disease includes low serum ceruloplasmin levels and elevated urinary copper, and if abnormal, requires further evaluation by a hepatologist. Alcoholic hepatitis Autoimmune hepatitis Cirrhosis Drug-induced liver injury Hemochromatosis Hepatitis A Hepatitis C Hepatitis D Hepatitis E Hepatocellular carcinoma Human immunodeficiency virus Wilson disease Hydralazine is a commonly used oral antihypertensive agent. We report a rare case of hydralazine-induced hepatotoxicity in the form of subacute hepatic necrosis. A 75-year-old African American woman presented with jaundice of 7-day duration. She was started on hydralazine 100 mg 3 times a day 10 weeks before presentation. On physical examination, scleral icterus was noted. Workup revealed elevated liver transaminases, alkaline phosphatase, and conjugated bilirubin. She had no history of liver disease, and liver function tests had been normal before starting hydralazine. Other etiologies, including viruses, common toxins, drugs, autoimmune, and copper-induced hepatitis, were excluded. Abdominal imaging studies did not show any evidence of intrahepatic or extrahepatic biliary ductal dilatation, and no pathologies were seen in the liver and pancreas. The patient's liver biopsy revealed extensive lobular hepatitis, significant necrosis, mixed inflammatory infiltrate, and no significant fibrosis, supporting a diagnosis of drug-induced liver injury. Hydralazine was immediately discontinued. She showed improvement of clinical and laboratory abnormalities within 5 days after discontinuation of hydralazine. To establish the diagnosis of hydralazine-induced liver injury, we used assessment tool outlined by the Council for International Organization of Medical Sciences (CIOMS) scale that led to \"high probable\" relationship. Although rare, clinically significant, and potentially life-threatening liver injury can result from use of hydralazine. Both clinical and histological presentations in our patient suggest acute liver injury. The hydralazine-induced hepatitis seems to be reversible as discontinuation of the drug improves clinical outcomes. We highly recommend monitoring of the liver function during hydralazine treatment.  Occult hepatitis B (ОHB) characterized by the absence of blood HBsAg attracts the attention of specialists of different profiles; however, its clinical morphological aspects have not been practically studied. to estimate the proportion of OHB in the structure of fatal outcomes in chronic viral hepatitis (CVH) and to characterize its clinical course and structural changes on autopsy materials. A total of 455 autopsy cases of CVH were examined for its etiology in the S.P. Botkin Clinical Hospital of Infectious Diseases in 2014-2016. An in-depth prospective clinical analysis was made to investigate 28 cases of OHB in the stage of decompensated liver cirrhosis, which had subsequently culminated in death. The criteria of inclusion were history data and clinical symptoms of CVH in the detection of markers for hepatitis A, C, and D and HIV in serum HBcAb in the absence of HBsAg. HBsAbs were also determined. Along with the traditional morphological examination, immunohistochemistry (IHC) for HBsAg and HBcAg was carried out. There were 108 CVHB cases (23.7% of the total cases of CVH), including 77 OHB cases (71.3% of those of CVHB) while HBsAg was not determined. HBsAb-negative patients were more often observed to have clinical signs of jaundice (p&lt;0.05) and skin itching (p&lt;0.05). Dyspepsia and hemorrhagic manifestations prevailed in patients with HBsAb (more than 10 IU/l) (p&lt;0.05). All the cases were found to have characteristic morphological signs of CVH, including intranuclear inclusions and nuclear polymorphism in 10.7% of deaths. There was an IHC-positive reaction to VHB antigens in 28.6% of the patients and a doubtful reaction in 25.0%. Serum НВсAb may serve as a diagnostic marker for HBV infection. Clinical and morphological correlations enabled the authors to state that CVHB was present in all cases in the absence of serum HBsAg in the patients. Diagnosing NAFLD requires demonstration of increased liver fat in the absence of hazardous levels of alcohol consumption. Thresholds for potentially dangerous alcohol ingestion have been set at more than one drink per day in women and two drinks per day in men based on epidemiologic evidence that the prevalence of serum aminotransferase elevations increases when alcohol consumption habitually exceeds these levels. In those studies, one drink was defined as having 10 g of ethanol and, thus, is equivalent to one can of beer, 4 ounces of wine, or 1.5 ounces (one shot) of distilled spirits. Other causes of liver fat accumulation (particularly exposure to certain drugs; Table 364-2) and liver injury (e.g., viral hepatitis, autoimmune liver disease, iron or copper overload, α1 antitrypsin deficiency) must also be excluded. Thus, establishing the diagnosis of NAFLD does not require invasive testing: it can be accomplished by history and physical examination, liver imaging (ultrasound is an Ginseng is commonly used as a medicinal herb for memory and concentration and general well-being. Drug-induced liver injury (DILI) is one of the most challenging disorders and trending events in the United States which are related to body building and weight loss supplements. Currently, herbal and dietary supplementation is the second most common cause of DILI. Here, we report on a 45-year-old healthy Chinese woman who presented with dull intermittent left upper quadrant abdomen pain for a month. Upon thorough history taking, she had been taking ginseng tea and supplementation for her menopausal symptoms for almost 3 months. Physical examination was unremarkable except mild tenderness in left upper quadrant of the abdomen. Liver function test showed aspartate transaminase (AST) 717 U/L, alanine transaminase (ALT) 343 U/L, total bilirubin 5 mg/dL, direct bilirubin 3.3 mg/dL, alkaline phosphatase 182 U/L, with international normalized ratio (INR) 1.2. Prior liver enzymes (6 months earlier) showed AST 21 U/L, ALT 18 U/L, total bilirubin 0.8 mg/dL, direct bilirubin 0.3 mg/dL, alkaline phosphatase 34 U/L, with INR 0.7. Viral serology for acute hepatitis B, C, E, cytomegalovirus, Epstein-Barr virus, and varicella zoster virus was negative. She was immune to hepatitis A. Her antinuclear antibody was positive. Her anti-Smith antibody, anti-smooth muscle antibody, HFE gene mutation, ceruloplasmin, alpha-1 antitrypsin serologies were within normal references. An abdomen sonogram showed fatty infiltration. Liver biopsy showed moderate to severe portal inflammation and marked lobular disarray. Portal and lobular inflammatory infiltrates consisted of a mixture of histiocytes, lymphocytes, plasma cells, eosinophils, and neutrophils with centrilobular necrosis and focal bridging necrosis, and necro-inflammation. After 6 weeks of follow-up, the patient improved physically, and the abdomen pain resolved. Ginseng has been widely used in the Chinese community as medicinal herb for a variety of conditions for decades. However, proper research has never been done regarding its pharmacokinetics, efficacy, and safety issues. In our case report, the idiosyncratic DILI resulted from ingestion of ginseng as herbal supplementation for premenopausal symptoms. Physicians should be aware of and suspect DILI in any patient with acute liver injury, and patients should be reminded that all medications and supplements have a potential to cause DILI. The results of the bilirubin, enzymes, and liver function tests will direct the diagnosis towards a hepatocellular or cholestatic cause and offer some idea of the duration and severity of the disease. Further evaluation can be conducted based on the initial assessment. Hepatocellular workup: viral serologies, autoimmune antibodies, serum ceruloplasmin, ferritin. A 38-year-old woman presented with general weakness and vaginal bleeding. One month prior, she had been diagnosed with Evans syndrome (haemolytic anemia with positive Coombs test and thrombocytopenia) and was given oral steroid as maintenance therapy. Her serology examination was negative for hepatitis B, hepatitis C, and human immunodeficiency virus (HIV). Her obstetrical history was marked by miscarriage in second pregnancy and preeclampsia in third pregnancy. She used hormonal contraceptives until 5 months prior to admission. On physical examination, she had anemic conjunctiva and no organomegaly. Blood tests were significant for anemia (3.4 g/dl) and thrombocytopenia (28,000/µl). Her vaginal bleeding had ceased, however her platelet continued decreasing to 12,000/µl during first several days of hospitalization despite receiving platelet transfusion. On the tenth hospital day, she suddenly complained of severe headache and blurred vision. She had bilateral edema and erythema of palpebral, chemosis, decreased in visual acuity, and reduced ocular motility. Ear and nose examination were normal. Peripheral blood smear showed no blast. Prothrombine time (PT), INR, APTT tests were normal and D Dimer was slightly increased (3.3 mg/l; NV ≤0.5 mg/l). Urine examination revealed proteinuria with 24 hour urine protein was 1,863 mg (NV &lt;150 mg/day). We assessed her as cavernous sinus thrombosis and treated her empirically with intravenous broad-spectrum antibiotics, morphine drip. Either digital subtraction angiography or anticoagulant was deferred due to low platelet. Further examination revealed positive for ANA, anti-SSA, and diagnosis of SLE was established. Anticardiolipin antibodies of IgG and IgM and anti-beta2 glycoprotein antibodies of IgM and IgG tests were non reactive. Methylprednisolone pulse therapy (1g/day) was given for 3 consecutive days, and then tapered to oral methylprednisolone. She additionally received azathioprine 50 mg tab BID. Meanwhile her clinical symptoms alleviated and platelet count was increased, brain MRI and MR venography finally performed suggesting cerebral venous sinus thrombosis. She got additional oral anticoagulant rivaroxaban 15 mg tab BID and eventually discharged. Cerebral venous sinus thrombosis may be the presenting symptoms or occur concomitantly within the onset of SLE. Our patient had SLE, meeting 4 of the Systemic Lupus International Collaborating Clinic classification criteria (hemolytic anemia, thrombocytopenia, renal involvement, and positive for ANA test). Vasculitis due to endothelial cell injury mediated by immune-complex deposition is proposed to be the pathogenesis of CVST in SLE. Hypercoagulable state could be other etiology factor. Antiphospholipid antibodies were absent in our case as reported in some cases, emphasizing vasculitis as the underlying mechanism. Treatment of CVST in SLE consisting of anticoagulant, steroid, and immunosuppressant. This case elicits intriguing problem: CVST and thrombocytopenia. Anticoagulant treatment is proposed as the cornerstone treatment for CVST, however it was deferred due to risk of bleeding in thrombocytopenia. Steroid plays role in treatment of CVST in SLE, owing to its anti-inflammatory property. As shown in previous cases, the patient had remarkable response to high dose steroid treatment and eventually got anticoagulant after her platelet had increased. In summary, prompt diagnosis and treatment of CVST are important for a favorable prognosis.\nHere is the question:\nDIGESTIVE: A 52-year-old woman consulted because she had noticed during the previous week a yellowish discoloration of the conjunctivae. She does not refer to risky sexual behaviors or epidemiological history of risk of viral hepatitis. She does not consume alcohol or hepatotoxic drugs. She reports a one-year history of generalized pruritus, asthenia, dry mouth and absence of lacrimation with no known cause. Rest of the anamnesis without pathological data. Physical examination showed scratching lesions, conjunctival jaundice and non-painful hepatomegaly. The patient brings a blood test carried out in his company with the following pathological results: Bilirubin 3 mg/dl, FA 400 UI/ VSG 40mm 1 hour. Indicate which would be the best recommendation to establish the etiological diagnosis of the patient's condition:\nHere are the potential choices:\n1. Anti-mitochondrial antibodies.\n2. Study of Fe metabolism.\n3. Study of copper metabolism.\n4. Hepatic MRI.\n5. Serology for B and C viruses.\nThe correct answer is: 1. Anti-mitochondrial antibodies."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The aim of this retrospective study was to analyze the characteristics of delayed panfacial fractures and evaluate treatment results. Thirty-three patients with delayed panfacial fractures were treated in the Maxillofacial Trauma Center of Peking University, School and Hospital of Stomatology between 1998 and 2004. Each patient was examined by computed tomography (CT) scans before operation. For those who had no severe opening restriction, dental impressions were taken to fabricate dental casts. For those with severely comminuted fractures, 3-dimensional (3D) models of the facial skeleton were used. Re-establishing the continuity of the mandible was the first step and then used as a platform to reconstruct the maxillary fractures via maxillomandibular fixation after Le Fort I osteotomy. The third step was to restore the mid- and upper-facial width and projection by coronal approach to expose the zygomatic complex and frontal bone/sinus and/or naso-orbito-ethmoid (NOE) fractures. There were 3 types of mandibular fractures that affected the treatment plan: 1) type I, mandibular body/symphysis fracture(s) (17/33, 51.52%); 2) type II, mandibular angle and/or condylar fracture(s) (6/33, 18.18%); and 3) type III, both mandibular body/symphysis and angle/condylar fractures (10/33, 30.30%). Fourteen cases were associated with NOE fractures (42.42%) and 3 cases had frontal sinus fractures (9.1%). Twelve cases had enophthalmos (36.36%) and 3 lost 1 eyeball. The order of treatment was dependent on the mandibular fracture type. For type I fractures, reconstructing the mandibular arch was the first step. For type II fractures, repairing the angle, ascending rami, and condylar areas was the first step. For type III fractures, when both mandibular height and arch were disrupted, freeing the malunited angle or condyle was the first step before restoring the mandibular arch form. Reconstruction of the mandibular height and projection was then carried out. For all 3 types, the second step was to restore the mid- and upper facial width and projection by reducing the zygomatic complex and frontal bone/sinus or NOE fractures. Maxillary fixation across the Le Fort I level was the last step. Le Fort I osteotomy was used for all 33 cases. Bone grafts and soft tissue suspension also were used. Twenty-one cases (63.64%) had good results, 7 (21.21%) cases were acceptable, and 5 (15.15%) were not good. There were 7 cases (21.21%) that still had soft tissue problems that needed secondary operations. Reconstruction of the mandible first with Le Fort I osteotomy is a good way to treat delayed panfacial fractures. Computed tomography and 3D CT, model surgery, and occasionally 3D models are necessary aids for diagnosis and treatment. Soft tissue problems, including lacerations and asymmetries, were often the factors that caused an unfavorable outcome. A prospective study on mid-face fractures was carried out in the Department of Oral and Maxillofacial Surgery at College of Dentistry, Indore, from August 2007 to September 2009 to analyze etiology, incidence and patterns of midface fractures and associated ocular injuries. Two hundred patients were included in this study, amongst those who reported to the Department of OMFS, College of Dentistry, Indore. After confirmed diagnosis of mid face fracture all the patients were stratified according to age, sex, cause of the accident, influence of alcohol, location, type of fractures and associated ocular injuries. The study included 200 patients with a mean age of 29.6 years. The most frequently injured patients belonged to the 21-30 year-old age group. The male predilection was 76 %. Road traffic accident was the most common causative factor (64 %), followed by assault (21 %), cases of fall (9.5 %) and other causes (5.5 %). The most common fracture in this study was found to be zygomatic complex fractures (62.5 %) (more in the age group of 21-30 years). This was followed by Lefort II fractures (23 %), multiple fractures (10 %) and Lefort I fractures (6 %), Lefort III fractures (4.5 %) and Naso-ethmoidal fractures (4 %) in descending order. 84.5 % subjects were having ocular involvement. Subconjunctival hemorrhage was present mostly in 83.5 % followed by remaining as corneal injury 15 %, reduced acuity 11.5 %, diplopia 10.5 %, enophthalmos 8.5 %, telecanthus 5 %, hyphema 3.5 %, blindness 3 % and proptosis 0.5 %. Zygomatic complex fractures were the most frequent type of injury that was complicated by blindness or a serious eye injury (61 %). Collection of data regarding the epidemiology of maxillofacial fractures is important because it may assist healthcare providers to provide necessary information for the development and evaluation of preventive measures. Ocular injuries should have an early ophthalmological examination at the time of trauma to detect any kind of ocular dysfunction.  The worldwide population is increasingly aging. Maxillofacial fractures of the geriatric population have been increased. Evaluation of the demographic variables, causes and the patterns of maxillofacial traumas in the elderly population is the main aim of this study. Seven hundred thirteen maxillofacial tomography images which were scanned between 2010 and 2019 were evaluated. Data from 50 patients aged 65 years old and/or older, who were treated for maxillofacial fracture at the Department of Otorhinolaryngology, Gaziantep University, were retrospectively analyzed. Two groups were created according to the facial fracture pattern. Facial fractures were reclassified into 2 groups; mandibula, orbital, zygomaticomaxillary complex group fractures and the other group of frontal, naso-orbito-ethmoid fractures and were used as a comparison. The mean age of the patients was 72.5 (min 65- max 93). The gender distribution was 17 females (34%) and 33 males (66%). The most common fractured bone was the nasal bone and the least one is the frontal bone. Approximately one-quarter of 50 fractures were seen in 70 to 79 years old. Falling is more common in females and men are more prone to work-related accidents than home-related accidents. Facial fractures in the elderly often seen in midface location. Falling is the common etiology of facial fracture in all genders at elderly. However, male dominance is seen in other etiological factors. Additional diseases in the elderly seem to increase the severity of facial fracture. To determine the incidence and types of ophthalmic complications associated with maxillofacial trauma over a period of 24 months. An institutional prospective study was conducted on 62 patients presenting with maxillofacial trauma to study the correlation between facial trauma and ophthalmic complications. Road traffic accidents were reported to be the primary etiologic factor for most trauma cases studied. Zygomaticomaxillary complex (ZMC) fracture was associated with more ophthalmic complications while fractures involving the orbital rims and walls were associated with severe complications. Maxillofacial trauma, particularly those associated with midface, including ZMC fracture, Le Fort II, Le Fort III, and naso-orbito-ethmoidal fractures, can commonly cause ophthalmic complications and blindness in rare cases. Hence, every patient with maxillofacial trauma should undergo an ophthalmic examination and should be placed under close observation for necessary treatment when required. The upper midface area comprises mainly the naso-orbito-ethmoidal (NOE) region which plays a paramount role in facial expression. Fractures of this area often result in neglected bony defects in the fragile periorbital region with major secondary impairments such as traumatic telecanthus, orbital dystopia, and/or enophthalmos. Permanent cranial nerve deficits also can occur as the result of post-traumatic/post-operative sequelae. Seventy-one patients (age range 7-78 years) with severe high midface trauma, treated from January 1989 to December 1996, were reviewed with a minimum follow-up of 2 years. The patient population has been distributed according to the fracture type in three groups: Group 1 (n = 35): Isolated NOE with/without associated central midface injury; Group 2 (n = 22): NOE associated with craniofacial injury and Group 3 (n = 14): NOE associated with orbital displacement. The estimated post-surgical parameters included qualitative and quantitative data from the long-term clinical evaluation. Persistent headache and/or concentration difficulties were mainly noted in Group 1. Smell reduction or anosmia was reported mainly in Group 2. Deficits of the trigeminal and/or the facial nerve were found in Group 3. Enophthalmos and/or telecanthus were predominantly seen with injuries associated with orbital displacement. The purpose of this study was to report on the pattern of occurrence of nasoorbitoethmoid (NOE) fractures in Odisha and the various factors that influence their distribution. The study period was from January 1, 2016 to December 15, 2017. After approval from the Institutional Ethics Committee, all patients diagnosed with naso-orbito-ethmoid fractures reporting to the department of OMFS and Level-1 trauma centers were included in the study. Sociodemographic data along with the etiology and type of fracture were mentioned. Associated injuries to other body parts were noted. Open reduction was possible only in five cases of NOE fractures. The treatment plan including the operative approach and postoperative results was evaluated. A total of 1192 patients with facial fracture were seen, of which 52 (4.36%) patients had NOE fractures. Males far outnumbered females in a ratio of 9:1. Thirty-three patients (63.46%) had unilateral NOE fracture, while the rest 19 (36.54%) had bilateral NOE fracture. Sixteen (30.76%) cases were classified as Type I, 35 (67.30%) as Type II, and 1 (1.92%) as Type III. Road traffic accidents were the most common cause of NOE fractures (69%), followed by fall (17%) and assault (10%). The most common neurological injury to be associated with NOE fractures was pneumocephalus (29%), followed by diffuse axonal injury (8%). Telecanthus (100%) was found to be the primary clinical feature in patients of NOE fracture, followed by a depressed nasal bridge (92%). Fracture of the nasal bone was invariably associated with NOE fracture. Complications observed due to untreated NOE fractures included a shortened and retruded nose, shortened palpebral fissures, telecanthus, and enophthalmos. Contemporary management of NOE complex fractures demands precise diagnosis and immediate surgical management with anatomic reduction and rigid fixation of the involved bone segments. With an improvement in socioeconomic status and increased awareness among maxillofacial surgeons, hopefully, a greater number of NOE fracture patients will avail the benefits of open reduction in future. The incidence of maxillofacial injuries is on the rise due to motor vehicle accidents and increased incidence of violence in recent times. The aim of this retrospective study was to determine the incidence, aetiology, the pattern of fractures, their management with open reduction and internal fixation (ORIF) and complications, if any. A retrospective analysis of 621 fractures in 361 patients managed by ORIF over a four year period was carried out. The average age of patients was 24.3 years with a male to female ratio of 21.2:1. Panfacial fractures comprised 4.7%, frontal bone fractures 8.9%, orbital fractures 0.7%, naso-orbito-ethmoid complex (NOE) fractures 0.7%, zygomatic complex fractures 23.5%, fracture maxilla 11.5% and mandibular fractures 52.2% of all facial fractures. All the cases were successfully managed by ORIF under general anaesthesia (GA). Complications were noticed in 6.8% of cases in the form of reactive implants in 3.6%, deranged occlusion in 1% and infection at operated site in 1% cases which were managed satisfactorily. The findings of this study reveal sharp annual increase in the number of cases of maxillofacial trauma. Road traffic accidents (RTA) were the commonest cause and the age group most affected was between 20-25 years. ORIF of these fractures was chosen for its obvious advantages of direct anatomical reduction, early return to function and minimal complications. Orbital fractures are classified as diseases usually related to common midface trauma. It represents the most challenging treatment due to the complex anatomy, physiology, and aesthetic role. A midface trauma involves also the zygomatic complex and the nose, however the orbit fracture seems to be a more frequent disease due to its anatomical features. The purpose of this work is to retrospectively evaluate and record the frequency of the midfacial traumas and orbital fractures observed in the North Eastern Sicily. The results of the present data may be useful for the clinicians in order to recognize the kind of fracture just from the first general visit having a quick diagnosis and management. In the years between 2001 and 2016, about 1200 patients with midfacial trauma and about 100 patients involving the orbital floor have been evaluated. All those patients underwent the surgical fracture reduction and a CT scan follow up control at one month, three months, six months and one year. Data showed high percentage of orbital floor, nose and mandibular body and ramus fractures; moreover the most frequent causes of fractures seem to be related to motor vehicle accident, followed by assaults, work and fall. The results have highlighted the changing trends in the causes of facial injuries, particularly the increasing incidence of assaults and the falling incidence of motor vehicle accidents in developed countries. The quick diagnosis and management proved fundamental for the successful treatment. Clinicians should be able to recognize the first symptoms in order to avoid possible complications. A considerable number of patients experiencing facial trauma are diagnosed with blowout fracture. Preoperative computed tomographic scan is often different from the actual surgical area. This study is restricted to orbital floor fracture. This study is expected to help speculating fracture site and making surgical plans according to symptoms of periorbital trauma. From March 2005 to September 2013, a total of 150 cases of orbital floor fracture surgeries have been analyzed. This study analyzed the preoperative symptoms at the certain fractured area of orbital floor, at the aspects of sagittal view of computed tomography, which is sectioned into anterior one-third, middle one-third, posterior one-third, and mixed types. Symptoms for analysis are diplopia, extraocular movement limitation, enophthalmos and other combined facial bone fractures, and the like. Fracture areas of orbital floor are 21 cases (14%) of anterior one-third, 47 cases (31%) of middle one-third, 7 cases (5%) of posterior one-third, and 75 cases (50%) of the mixed. Frequency of diplopia was 0 case, 24 cases (42.1%), 4 cases (7.0%), and 29 cases (50.9%), respectively. In the case of extraocular movement limitation, 0 case, 15 cases (39.5%), 2 cases (5.3%), and 21 cases (55.2%) were found, respectively. In the case of enophthalmos, 0 case, 5 cases (16.7%), 7 cases (23.3%), and 18 cases (60.0%) were found, respectively. The most commonly associated other facial bone fractures were nasal bone fractures. In the case of blowout fracture, diplopia, extraocular movement limitation, enophthalmos, and other symptoms are checked through physical examination. This study would help speculating fracture site and making surgical plans according to symptoms of periorbital trauma. To explore the secondary surgical reconstruction for orbital bone deformities accompanied with canthus dislocation after trauma. From June 1998 to July 2007, 37 patients with secondary orbital bone fracture deformity accompanied with medial or lateral canthal ligament dislocation posttraumatically were treated, among whom there were 22 males and 15 females, aged 13-46 years old (21 on average). There were 29 cases of traffic accident, 6 of boxing injury and 2 of beating injury by sticks. The latest reconstruction was performed on these 37 cases during 3 months to 8 years after injuries. There were 11 cases of orbital maxillary zygoma (OMZ) fracture, 15 of naso-orbito-ethmoid (NOE) fracture, 8 of OMZ and NOE fracture and 3 of frontal fracture. There were 31 patients who were reconstructed for the first time and 6 for the second time. Typical bicoronal and subciliary incisions and intra-oral approach were employed to expose all the fractured sites. According to the fractured position and the degree of deformity and dislocation, the orbito-zygomatic fracture was repositioned after osteotomy and rigid fixation, or the healed fragments were trimmed with a burr and the depressed fragments were filled with autogenous bone such as ilium, cranial outer table or Medpor in order to reconstruct orbital wall framework; the orbital walls were repaired to correct the enophthalmos with autogenous bone or Medpor after the herniated orbital contents were released. The medial canthal ligament was anchored superior-posteriorly to the lacrimal fossa with transnasal wires fixation or fixed with titanium miniplates and nails. The 36 patients' incisions obtained healing by first intention after the operation, and 1 case failed because of wound infection from maxillary sinusitis. There were 24 patients who were cured successfully with facial appearance and function improved significantly. During the follow-up for 3-6 months, no complication was found such as dislocation of the implant, rejection and infection. Two patients still showed slight enophthalmos while 3 patients with canthus dislocation regained improved appearances but not satisfactory. At 6 months after operation, the CT scan conducted in 3 patients with autogenous bone and Medpor grafting showed all fractures were fixed rigidly. Surgical reduction combined with bone grafting is a satisfactory method for the correction of secondary orbital bone deformity, and the repair of canthus dislocation and correction of enophthalmos should be considered at the same time. An ideal result could be achieved only through all-round consideration and comprehensive treatment. Trauma is the fourth major cause of mortality in the Western countries, of which approximately one half involve maxillofacial injury. Statistics reported by emergency room officials show motor vehicles cause many of the injuries and deaths that occur in Iran. Having completed a retrospective descriptive study of 200 patients who experienced maxillofacial trauma, the authors report its occurrence with respect to age, sex, trauma type, and site of injury so as to evaluate the operational functionality of the Department of Otolaryngology and Head &amp; Neck Surgery of Hazrat-e Rasoul Akram Hospital from 2000 to 2004. Mandibular fractures (36.2%) occurred in the subsequently listed sites and at the specified frequencies: mandibular angle (9.7%), mandible body (6.9%), parasymphysis, ramus and subcondyle at 5.6% each, and symphysis at 2.8%. No condylar fractures were reported. Frontal bone fracture was observed in 9.7% of the patients with eye globe injury occurring simultaneously in 8.3% of corresponding cases. Orbital fracture (63.9%) also occurred in various cases as follows: orbital floor 39%, lateral rim 24%, inferior rim 22%, medial wall 11%, and the superior rim and orbital roof at 2% each. Motor vehicle accidents were the most common causes of trauma (42%). The most common fracture was in the zygoma (43%) with 8.3% of them being orbital injury. Fractures of mandibular bones (36.2%) and the maxilla (33%) were the most commonly seen in trauma occurring to the maxillomandibular region. Mandibular condyle fractures develop frequently and show the variable type of injury and complication. New opinions have emerged from recent investigation into condylar fractures. The author investigated 246 patients with condylar fractures who visited SNUDH from January 1980 to August, 1988, 8. with regard to clinical and treatment aspects, area and displacement of fractures, associated teeth injury and other body injury, complications. At last I have got the following results. 1. The incidence to condylar fractures in a series of 765 mandibular fractures may be as high as 32.2%. 2. The male patients are 3 times more than female patients. The highest frequency was recorded in the group 21-30 years of age. (34.1%). 3. Falls caused the greatest number of condylar fractures (45.2%) and next was in assult (25.6%), traffic accidents (22.4%). 4. Unilateral condylar fractures were present in 74.8%, giving a left: right ratio of 1.2:1. In cases of unilateral fracture, subcondylar fractures were by far the commonest (32.9%) but in cases of bilateral fracture, condylar neck fractures were by far the commonest. In children under 15 years of age, condylar neck fractures were more common but in patients over 16 years of age, subcondylar fractures were common. 5. Anteromedial fracture dislocations were by far the commonest (20.3%). In children under 15 years of age, fracture deviations were common but in patients over 16 years of age, fracture displacements were common. 6. 44.7% of patients with condylar fractures sustained the teeth injuries. Teeth fractures were by far the commonest. 7. Single condylar fractures showed a frequency of 30.5%. Of the concomitant fractures elsewhere in the mandible, symphysis fractures were by far the commonest (54.1%). 8. Associated other body injuries showed a frequency of 28.0%. Of them, head injuries were by far the commonest. 9. The mean interval from injury to treatment was 14.3 days. Of the treatment of condylar fractures, open reduction was by far the commonest (70.3%). Closed reduction comprised 19.9% and functional therapy comprised 8.5%. 10. In 67 patients with possible follow up period, the following complications were developed, two ankylosis, anterior open bite, mouth opening limitation, mouth opening deviation. Morbidity and mortality among children is usually the result of trauma. Because a child's face is retruded relative to the protecting skull, has a thicker layer of adipose tissue, more elastic bones, flexible sutures lines, the presence of tooth buds within the jaws, and the lack of pneumatisation of the sinuses, the facial bones fracture less commonly than in adults. Our aim was to assess the patterns of such fractures in children who presented to the department of Oral and Maxillofacial Surgery, King Edward Medical University/Mayo Hospital Lahore, Pakistan. All 535 eligible children between the ages of 1-16 years who presented during the two years December 2009 - December 2011 were included in the study. Facial fractures were diagnosed by clinical examination, plain radiographs, and computed tomography, and the pattern of fractures of the facial bones including the frontal bone, orbital bones, maxilla, zygoma, naso-orbito-ethmoidal complex, mandible, and dentoalveolar region was documented. The male:female ratio was 2:1 with 369 male (70%) and 166 female (31%) patients. Fall was the cause in 212 (39%), and in 167 (31%) it was road traffic accidents, while sports were the cause in 135 (25%). The naso-orboto-ethmoid complex was fractured in 37 cases (7%) while 104 children (19%) presented with isolated fractures of the zygomatic bone. The maxilla was fractured in 195 cases (36%), the mandible in 380 (71%), and dentoalveolar trauma was the cause in 256 (50%). The mandible was the bone that was most often fractured (mostly in boys and usually as a result of falls during summer vacations), with the peak occurring in those aged 8-12 years. Given the variability of the timing and order of surgeries, it is difficult to choose the best treatment for patients with complex facial fractures. Based on the clinical experiences, the authors have reviewed their experience with the timing and order of operations depending on the sites of complex facial fractures and their concurrent injuries. The current study was based on a total of 105 patients with complex facial fractures from the year 2002 to 2011. After assessing the patients' clinical records, radiological data, and clinical photographs, the following data were analyzed: patients' age and sex, causes of injury, concurrent injuries, sites of fractures, the interval between trauma and the operations, the presence of additional surgeries, and the aesthetic and functional outcomes.For most of the patients, early operation was performed (within 2 weeks in 95.2%). Additional surgeries within 1 month after injuries were performed in 22 patients. Usually, a top-to-bottom direction repair was applied when head injuries were involved, and bottom-to-top direction repair was applied when occlusal problems were involved. Of 105 patients whom we were able to follow up, 49 patients showed complications or were dissatisfied with the outcomes. However, except them, most of the patients were satisfied with the outcomes of surgical treatments. There were 14 cases of cheek asymmetry, 9 enophthalmos, 30 paresthesia, 4 malocclusion, and a single case of persistent trismus.In the current study, satisfactory results could be achievable under the following principles: a repair should be done in the early stage after the onset of the injury; supportive surgeries should be done, if necessary, within 2 weeks (no later than 4 weeks); and the order of surgical treatment should be determined by the severity of bone fracture and the systemic status. Damages to the middle third of the facial bone generally involve the orbital skeleton and can lead to eye impairment. In this study, it is attempted to determine the incidence of ophthalmic injuries in maxillofacial trauma with zygomatic bone fractures. One hundred and fifteen cases with ophthalmic (ocular) involvement after maxillofacial trauma were referred to the Shariati Hospital, Tehran, Iran, and were visited at the Ophthalmology Department between 2016 and 2018. Zygomatic fractures and resulting ocular complications were evaluated in 87 males and 28 females with the mean ages of 26 and 32 years, respectively. Subconjunctival ecchymosis was detected in 23.07% of men and 21.05% of women. Displacement of the palpebral fissure was detected in 26.5% of men and 27.6% of women. Furthermore, the unequal pupillary level was observed in 18.37% of men and 15.78% of women. Diplopia was detected in 8.9% of men and 10.5% of women. Additionally, enophthalmos was observed in 23.1% of men and 25% of women. The most common ocular presentations in midfacial trauma are diplopia and reduced visual acuity. Even after the operation, a significant number of patients experience poor vision and diplopia. Ophthalmology consultation is essential for these patients. Mental health issues, as patients with facial injuries, are at greater risk of developing post-traumatic stress disorder or anxiety-related disorders, particularly those who were victims of assault. [31] With an increased popularity of sport and active living worldwide, our study aims to explore the incidence and features of sports-related orbital fractures in Singapore. 1421 computer tomography (CT) imaging scans of the face and orbits done at the National University Hospital over a 24-month period from January 2013 and December 2014 were reviewed retrospectively for orbital fractures. We identified 483 orbital fractures of which sports injury was the fourth most common etiology (n = 65; 13.5%) after road traffic accident (n = 131; 27.1%), geriatric fall (n = 81; 16.8%) and workplace injury (n = 67; 13.9%). The three most common sport in orbital fractures were soccer (n = 20; 30.8%), bicycling (n = 11; 16.9%) and jogging (n = 8; 12.3%). The three most common fracture patterns were zygomatico-maxillary complex fractures (n = 24; 36.9%), isolated one wall blowout fractures (n = 19; 29.2%) and naso-orbito-ethmoid fractures (n = 7; 10.8%). Sports-related orbital fractures were associated with a low mean age of patients (45.9 years, range, 14-79 years), a higher proportion of males (n = 58; 89.2%) than that from geriatric falls (n = 37, 45.6%) (P &lt; 0.01), a higher likelihood of unilaterality (n = 62; 95.4%) than that from traffic accidents (n = 99; 75.6%) (P &lt; 0.01) and a lower likelihood of pan-facial involvement (n = 4; 6.15%) than that from traffic accident (n = 60; 45.8%) (P &lt; 0.01). Sports-related orbital fractures are the fourth most common cause of orbital fractures. Though commonly seen in young male adults, in view of the aging population and people exercising more regularly, education of safety measures among sports users is paramount to preventing sports-related orbital fractures.\nHere is the question:\nOPHTHALMOLOGY (ECTOPIC): 20-year-old patient who comes to the emergency department after suffering a bicycle accident with facial trauma. A cranial CT scan was performed showing a fracture of the middle third of the face involving the orbito-malar region. One of the most frequent complications of this type of fracture is:\nHere are the potential choices:\n1. Temporomandibular ankylosis.\n2. Dental malocclusion.\n3. Naso-ethmoidal pseudoarthrosis.\n4. Enophthalmos.\nThe correct answer is: ",
        "gold_answer": "4 Enophthalmos.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The aim of this retrospective study was to analyze the characteristics of delayed panfacial fractures and evaluate treatment results. Thirty-three patients with delayed panfacial fractures were treated in the Maxillofacial Trauma Center of Peking University, School and Hospital of Stomatology between 1998 and 2004. Each patient was examined by computed tomography (CT) scans before operation. For those who had no severe opening restriction, dental impressions were taken to fabricate dental casts. For those with severely comminuted fractures, 3-dimensional (3D) models of the facial skeleton were used. Re-establishing the continuity of the mandible was the first step and then used as a platform to reconstruct the maxillary fractures via maxillomandibular fixation after Le Fort I osteotomy. The third step was to restore the mid- and upper-facial width and projection by coronal approach to expose the zygomatic complex and frontal bone/sinus and/or naso-orbito-ethmoid (NOE) fractures. There were 3 types of mandibular fractures that affected the treatment plan: 1) type I, mandibular body/symphysis fracture(s) (17/33, 51.52%); 2) type II, mandibular angle and/or condylar fracture(s) (6/33, 18.18%); and 3) type III, both mandibular body/symphysis and angle/condylar fractures (10/33, 30.30%). Fourteen cases were associated with NOE fractures (42.42%) and 3 cases had frontal sinus fractures (9.1%). Twelve cases had enophthalmos (36.36%) and 3 lost 1 eyeball. The order of treatment was dependent on the mandibular fracture type. For type I fractures, reconstructing the mandibular arch was the first step. For type II fractures, repairing the angle, ascending rami, and condylar areas was the first step. For type III fractures, when both mandibular height and arch were disrupted, freeing the malunited angle or condyle was the first step before restoring the mandibular arch form. Reconstruction of the mandibular height and projection was then carried out. For all 3 types, the second step was to restore the mid- and upper facial width and projection by reducing the zygomatic complex and frontal bone/sinus or NOE fractures. Maxillary fixation across the Le Fort I level was the last step. Le Fort I osteotomy was used for all 33 cases. Bone grafts and soft tissue suspension also were used. Twenty-one cases (63.64%) had good results, 7 (21.21%) cases were acceptable, and 5 (15.15%) were not good. There were 7 cases (21.21%) that still had soft tissue problems that needed secondary operations. Reconstruction of the mandible first with Le Fort I osteotomy is a good way to treat delayed panfacial fractures. Computed tomography and 3D CT, model surgery, and occasionally 3D models are necessary aids for diagnosis and treatment. Soft tissue problems, including lacerations and asymmetries, were often the factors that caused an unfavorable outcome. A prospective study on mid-face fractures was carried out in the Department of Oral and Maxillofacial Surgery at College of Dentistry, Indore, from August 2007 to September 2009 to analyze etiology, incidence and patterns of midface fractures and associated ocular injuries. Two hundred patients were included in this study, amongst those who reported to the Department of OMFS, College of Dentistry, Indore. After confirmed diagnosis of mid face fracture all the patients were stratified according to age, sex, cause of the accident, influence of alcohol, location, type of fractures and associated ocular injuries. The study included 200 patients with a mean age of 29.6 years. The most frequently injured patients belonged to the 21-30 year-old age group. The male predilection was 76 %. Road traffic accident was the most common causative factor (64 %), followed by assault (21 %), cases of fall (9.5 %) and other causes (5.5 %). The most common fracture in this study was found to be zygomatic complex fractures (62.5 %) (more in the age group of 21-30 years). This was followed by Lefort II fractures (23 %), multiple fractures (10 %) and Lefort I fractures (6 %), Lefort III fractures (4.5 %) and Naso-ethmoidal fractures (4 %) in descending order. 84.5 % subjects were having ocular involvement. Subconjunctival hemorrhage was present mostly in 83.5 % followed by remaining as corneal injury 15 %, reduced acuity 11.5 %, diplopia 10.5 %, enophthalmos 8.5 %, telecanthus 5 %, hyphema 3.5 %, blindness 3 % and proptosis 0.5 %. Zygomatic complex fractures were the most frequent type of injury that was complicated by blindness or a serious eye injury (61 %). Collection of data regarding the epidemiology of maxillofacial fractures is important because it may assist healthcare providers to provide necessary information for the development and evaluation of preventive measures. Ocular injuries should have an early ophthalmological examination at the time of trauma to detect any kind of ocular dysfunction.  The worldwide population is increasingly aging. Maxillofacial fractures of the geriatric population have been increased. Evaluation of the demographic variables, causes and the patterns of maxillofacial traumas in the elderly population is the main aim of this study. Seven hundred thirteen maxillofacial tomography images which were scanned between 2010 and 2019 were evaluated. Data from 50 patients aged 65 years old and/or older, who were treated for maxillofacial fracture at the Department of Otorhinolaryngology, Gaziantep University, were retrospectively analyzed. Two groups were created according to the facial fracture pattern. Facial fractures were reclassified into 2 groups; mandibula, orbital, zygomaticomaxillary complex group fractures and the other group of frontal, naso-orbito-ethmoid fractures and were used as a comparison. The mean age of the patients was 72.5 (min 65- max 93). The gender distribution was 17 females (34%) and 33 males (66%). The most common fractured bone was the nasal bone and the least one is the frontal bone. Approximately one-quarter of 50 fractures were seen in 70 to 79 years old. Falling is more common in females and men are more prone to work-related accidents than home-related accidents. Facial fractures in the elderly often seen in midface location. Falling is the common etiology of facial fracture in all genders at elderly. However, male dominance is seen in other etiological factors. Additional diseases in the elderly seem to increase the severity of facial fracture. To determine the incidence and types of ophthalmic complications associated with maxillofacial trauma over a period of 24 months. An institutional prospective study was conducted on 62 patients presenting with maxillofacial trauma to study the correlation between facial trauma and ophthalmic complications. Road traffic accidents were reported to be the primary etiologic factor for most trauma cases studied. Zygomaticomaxillary complex (ZMC) fracture was associated with more ophthalmic complications while fractures involving the orbital rims and walls were associated with severe complications. Maxillofacial trauma, particularly those associated with midface, including ZMC fracture, Le Fort II, Le Fort III, and naso-orbito-ethmoidal fractures, can commonly cause ophthalmic complications and blindness in rare cases. Hence, every patient with maxillofacial trauma should undergo an ophthalmic examination and should be placed under close observation for necessary treatment when required. The upper midface area comprises mainly the naso-orbito-ethmoidal (NOE) region which plays a paramount role in facial expression. Fractures of this area often result in neglected bony defects in the fragile periorbital region with major secondary impairments such as traumatic telecanthus, orbital dystopia, and/or enophthalmos. Permanent cranial nerve deficits also can occur as the result of post-traumatic/post-operative sequelae. Seventy-one patients (age range 7-78 years) with severe high midface trauma, treated from January 1989 to December 1996, were reviewed with a minimum follow-up of 2 years. The patient population has been distributed according to the fracture type in three groups: Group 1 (n = 35): Isolated NOE with/without associated central midface injury; Group 2 (n = 22): NOE associated with craniofacial injury and Group 3 (n = 14): NOE associated with orbital displacement. The estimated post-surgical parameters included qualitative and quantitative data from the long-term clinical evaluation. Persistent headache and/or concentration difficulties were mainly noted in Group 1. Smell reduction or anosmia was reported mainly in Group 2. Deficits of the trigeminal and/or the facial nerve were found in Group 3. Enophthalmos and/or telecanthus were predominantly seen with injuries associated with orbital displacement. The purpose of this study was to report on the pattern of occurrence of nasoorbitoethmoid (NOE) fractures in Odisha and the various factors that influence their distribution. The study period was from January 1, 2016 to December 15, 2017. After approval from the Institutional Ethics Committee, all patients diagnosed with naso-orbito-ethmoid fractures reporting to the department of OMFS and Level-1 trauma centers were included in the study. Sociodemographic data along with the etiology and type of fracture were mentioned. Associated injuries to other body parts were noted. Open reduction was possible only in five cases of NOE fractures. The treatment plan including the operative approach and postoperative results was evaluated. A total of 1192 patients with facial fracture were seen, of which 52 (4.36%) patients had NOE fractures. Males far outnumbered females in a ratio of 9:1. Thirty-three patients (63.46%) had unilateral NOE fracture, while the rest 19 (36.54%) had bilateral NOE fracture. Sixteen (30.76%) cases were classified as Type I, 35 (67.30%) as Type II, and 1 (1.92%) as Type III. Road traffic accidents were the most common cause of NOE fractures (69%), followed by fall (17%) and assault (10%). The most common neurological injury to be associated with NOE fractures was pneumocephalus (29%), followed by diffuse axonal injury (8%). Telecanthus (100%) was found to be the primary clinical feature in patients of NOE fracture, followed by a depressed nasal bridge (92%). Fracture of the nasal bone was invariably associated with NOE fracture. Complications observed due to untreated NOE fractures included a shortened and retruded nose, shortened palpebral fissures, telecanthus, and enophthalmos. Contemporary management of NOE complex fractures demands precise diagnosis and immediate surgical management with anatomic reduction and rigid fixation of the involved bone segments. With an improvement in socioeconomic status and increased awareness among maxillofacial surgeons, hopefully, a greater number of NOE fracture patients will avail the benefits of open reduction in future. The incidence of maxillofacial injuries is on the rise due to motor vehicle accidents and increased incidence of violence in recent times. The aim of this retrospective study was to determine the incidence, aetiology, the pattern of fractures, their management with open reduction and internal fixation (ORIF) and complications, if any. A retrospective analysis of 621 fractures in 361 patients managed by ORIF over a four year period was carried out. The average age of patients was 24.3 years with a male to female ratio of 21.2:1. Panfacial fractures comprised 4.7%, frontal bone fractures 8.9%, orbital fractures 0.7%, naso-orbito-ethmoid complex (NOE) fractures 0.7%, zygomatic complex fractures 23.5%, fracture maxilla 11.5% and mandibular fractures 52.2% of all facial fractures. All the cases were successfully managed by ORIF under general anaesthesia (GA). Complications were noticed in 6.8% of cases in the form of reactive implants in 3.6%, deranged occlusion in 1% and infection at operated site in 1% cases which were managed satisfactorily. The findings of this study reveal sharp annual increase in the number of cases of maxillofacial trauma. Road traffic accidents (RTA) were the commonest cause and the age group most affected was between 20-25 years. ORIF of these fractures was chosen for its obvious advantages of direct anatomical reduction, early return to function and minimal complications. Orbital fractures are classified as diseases usually related to common midface trauma. It represents the most challenging treatment due to the complex anatomy, physiology, and aesthetic role. A midface trauma involves also the zygomatic complex and the nose, however the orbit fracture seems to be a more frequent disease due to its anatomical features. The purpose of this work is to retrospectively evaluate and record the frequency of the midfacial traumas and orbital fractures observed in the North Eastern Sicily. The results of the present data may be useful for the clinicians in order to recognize the kind of fracture just from the first general visit having a quick diagnosis and management. In the years between 2001 and 2016, about 1200 patients with midfacial trauma and about 100 patients involving the orbital floor have been evaluated. All those patients underwent the surgical fracture reduction and a CT scan follow up control at one month, three months, six months and one year. Data showed high percentage of orbital floor, nose and mandibular body and ramus fractures; moreover the most frequent causes of fractures seem to be related to motor vehicle accident, followed by assaults, work and fall. The results have highlighted the changing trends in the causes of facial injuries, particularly the increasing incidence of assaults and the falling incidence of motor vehicle accidents in developed countries. The quick diagnosis and management proved fundamental for the successful treatment. Clinicians should be able to recognize the first symptoms in order to avoid possible complications. A considerable number of patients experiencing facial trauma are diagnosed with blowout fracture. Preoperative computed tomographic scan is often different from the actual surgical area. This study is restricted to orbital floor fracture. This study is expected to help speculating fracture site and making surgical plans according to symptoms of periorbital trauma. From March 2005 to September 2013, a total of 150 cases of orbital floor fracture surgeries have been analyzed. This study analyzed the preoperative symptoms at the certain fractured area of orbital floor, at the aspects of sagittal view of computed tomography, which is sectioned into anterior one-third, middle one-third, posterior one-third, and mixed types. Symptoms for analysis are diplopia, extraocular movement limitation, enophthalmos and other combined facial bone fractures, and the like. Fracture areas of orbital floor are 21 cases (14%) of anterior one-third, 47 cases (31%) of middle one-third, 7 cases (5%) of posterior one-third, and 75 cases (50%) of the mixed. Frequency of diplopia was 0 case, 24 cases (42.1%), 4 cases (7.0%), and 29 cases (50.9%), respectively. In the case of extraocular movement limitation, 0 case, 15 cases (39.5%), 2 cases (5.3%), and 21 cases (55.2%) were found, respectively. In the case of enophthalmos, 0 case, 5 cases (16.7%), 7 cases (23.3%), and 18 cases (60.0%) were found, respectively. The most commonly associated other facial bone fractures were nasal bone fractures. In the case of blowout fracture, diplopia, extraocular movement limitation, enophthalmos, and other symptoms are checked through physical examination. This study would help speculating fracture site and making surgical plans according to symptoms of periorbital trauma. To explore the secondary surgical reconstruction for orbital bone deformities accompanied with canthus dislocation after trauma. From June 1998 to July 2007, 37 patients with secondary orbital bone fracture deformity accompanied with medial or lateral canthal ligament dislocation posttraumatically were treated, among whom there were 22 males and 15 females, aged 13-46 years old (21 on average). There were 29 cases of traffic accident, 6 of boxing injury and 2 of beating injury by sticks. The latest reconstruction was performed on these 37 cases during 3 months to 8 years after injuries. There were 11 cases of orbital maxillary zygoma (OMZ) fracture, 15 of naso-orbito-ethmoid (NOE) fracture, 8 of OMZ and NOE fracture and 3 of frontal fracture. There were 31 patients who were reconstructed for the first time and 6 for the second time. Typical bicoronal and subciliary incisions and intra-oral approach were employed to expose all the fractured sites. According to the fractured position and the degree of deformity and dislocation, the orbito-zygomatic fracture was repositioned after osteotomy and rigid fixation, or the healed fragments were trimmed with a burr and the depressed fragments were filled with autogenous bone such as ilium, cranial outer table or Medpor in order to reconstruct orbital wall framework; the orbital walls were repaired to correct the enophthalmos with autogenous bone or Medpor after the herniated orbital contents were released. The medial canthal ligament was anchored superior-posteriorly to the lacrimal fossa with transnasal wires fixation or fixed with titanium miniplates and nails. The 36 patients' incisions obtained healing by first intention after the operation, and 1 case failed because of wound infection from maxillary sinusitis. There were 24 patients who were cured successfully with facial appearance and function improved significantly. During the follow-up for 3-6 months, no complication was found such as dislocation of the implant, rejection and infection. Two patients still showed slight enophthalmos while 3 patients with canthus dislocation regained improved appearances but not satisfactory. At 6 months after operation, the CT scan conducted in 3 patients with autogenous bone and Medpor grafting showed all fractures were fixed rigidly. Surgical reduction combined with bone grafting is a satisfactory method for the correction of secondary orbital bone deformity, and the repair of canthus dislocation and correction of enophthalmos should be considered at the same time. An ideal result could be achieved only through all-round consideration and comprehensive treatment. Trauma is the fourth major cause of mortality in the Western countries, of which approximately one half involve maxillofacial injury. Statistics reported by emergency room officials show motor vehicles cause many of the injuries and deaths that occur in Iran. Having completed a retrospective descriptive study of 200 patients who experienced maxillofacial trauma, the authors report its occurrence with respect to age, sex, trauma type, and site of injury so as to evaluate the operational functionality of the Department of Otolaryngology and Head &amp; Neck Surgery of Hazrat-e Rasoul Akram Hospital from 2000 to 2004. Mandibular fractures (36.2%) occurred in the subsequently listed sites and at the specified frequencies: mandibular angle (9.7%), mandible body (6.9%), parasymphysis, ramus and subcondyle at 5.6% each, and symphysis at 2.8%. No condylar fractures were reported. Frontal bone fracture was observed in 9.7% of the patients with eye globe injury occurring simultaneously in 8.3% of corresponding cases. Orbital fracture (63.9%) also occurred in various cases as follows: orbital floor 39%, lateral rim 24%, inferior rim 22%, medial wall 11%, and the superior rim and orbital roof at 2% each. Motor vehicle accidents were the most common causes of trauma (42%). The most common fracture was in the zygoma (43%) with 8.3% of them being orbital injury. Fractures of mandibular bones (36.2%) and the maxilla (33%) were the most commonly seen in trauma occurring to the maxillomandibular region. Mandibular condyle fractures develop frequently and show the variable type of injury and complication. New opinions have emerged from recent investigation into condylar fractures. The author investigated 246 patients with condylar fractures who visited SNUDH from January 1980 to August, 1988, 8. with regard to clinical and treatment aspects, area and displacement of fractures, associated teeth injury and other body injury, complications. At last I have got the following results. 1. The incidence to condylar fractures in a series of 765 mandibular fractures may be as high as 32.2%. 2. The male patients are 3 times more than female patients. The highest frequency was recorded in the group 21-30 years of age. (34.1%). 3. Falls caused the greatest number of condylar fractures (45.2%) and next was in assult (25.6%), traffic accidents (22.4%). 4. Unilateral condylar fractures were present in 74.8%, giving a left: right ratio of 1.2:1. In cases of unilateral fracture, subcondylar fractures were by far the commonest (32.9%) but in cases of bilateral fracture, condylar neck fractures were by far the commonest. In children under 15 years of age, condylar neck fractures were more common but in patients over 16 years of age, subcondylar fractures were common. 5. Anteromedial fracture dislocations were by far the commonest (20.3%). In children under 15 years of age, fracture deviations were common but in patients over 16 years of age, fracture displacements were common. 6. 44.7% of patients with condylar fractures sustained the teeth injuries. Teeth fractures were by far the commonest. 7. Single condylar fractures showed a frequency of 30.5%. Of the concomitant fractures elsewhere in the mandible, symphysis fractures were by far the commonest (54.1%). 8. Associated other body injuries showed a frequency of 28.0%. Of them, head injuries were by far the commonest. 9. The mean interval from injury to treatment was 14.3 days. Of the treatment of condylar fractures, open reduction was by far the commonest (70.3%). Closed reduction comprised 19.9% and functional therapy comprised 8.5%. 10. In 67 patients with possible follow up period, the following complications were developed, two ankylosis, anterior open bite, mouth opening limitation, mouth opening deviation. Morbidity and mortality among children is usually the result of trauma. Because a child's face is retruded relative to the protecting skull, has a thicker layer of adipose tissue, more elastic bones, flexible sutures lines, the presence of tooth buds within the jaws, and the lack of pneumatisation of the sinuses, the facial bones fracture less commonly than in adults. Our aim was to assess the patterns of such fractures in children who presented to the department of Oral and Maxillofacial Surgery, King Edward Medical University/Mayo Hospital Lahore, Pakistan. All 535 eligible children between the ages of 1-16 years who presented during the two years December 2009 - December 2011 were included in the study. Facial fractures were diagnosed by clinical examination, plain radiographs, and computed tomography, and the pattern of fractures of the facial bones including the frontal bone, orbital bones, maxilla, zygoma, naso-orbito-ethmoidal complex, mandible, and dentoalveolar region was documented. The male:female ratio was 2:1 with 369 male (70%) and 166 female (31%) patients. Fall was the cause in 212 (39%), and in 167 (31%) it was road traffic accidents, while sports were the cause in 135 (25%). The naso-orboto-ethmoid complex was fractured in 37 cases (7%) while 104 children (19%) presented with isolated fractures of the zygomatic bone. The maxilla was fractured in 195 cases (36%), the mandible in 380 (71%), and dentoalveolar trauma was the cause in 256 (50%). The mandible was the bone that was most often fractured (mostly in boys and usually as a result of falls during summer vacations), with the peak occurring in those aged 8-12 years. Given the variability of the timing and order of surgeries, it is difficult to choose the best treatment for patients with complex facial fractures. Based on the clinical experiences, the authors have reviewed their experience with the timing and order of operations depending on the sites of complex facial fractures and their concurrent injuries. The current study was based on a total of 105 patients with complex facial fractures from the year 2002 to 2011. After assessing the patients' clinical records, radiological data, and clinical photographs, the following data were analyzed: patients' age and sex, causes of injury, concurrent injuries, sites of fractures, the interval between trauma and the operations, the presence of additional surgeries, and the aesthetic and functional outcomes.For most of the patients, early operation was performed (within 2 weeks in 95.2%). Additional surgeries within 1 month after injuries were performed in 22 patients. Usually, a top-to-bottom direction repair was applied when head injuries were involved, and bottom-to-top direction repair was applied when occlusal problems were involved. Of 105 patients whom we were able to follow up, 49 patients showed complications or were dissatisfied with the outcomes. However, except them, most of the patients were satisfied with the outcomes of surgical treatments. There were 14 cases of cheek asymmetry, 9 enophthalmos, 30 paresthesia, 4 malocclusion, and a single case of persistent trismus.In the current study, satisfactory results could be achievable under the following principles: a repair should be done in the early stage after the onset of the injury; supportive surgeries should be done, if necessary, within 2 weeks (no later than 4 weeks); and the order of surgical treatment should be determined by the severity of bone fracture and the systemic status. Damages to the middle third of the facial bone generally involve the orbital skeleton and can lead to eye impairment. In this study, it is attempted to determine the incidence of ophthalmic injuries in maxillofacial trauma with zygomatic bone fractures. One hundred and fifteen cases with ophthalmic (ocular) involvement after maxillofacial trauma were referred to the Shariati Hospital, Tehran, Iran, and were visited at the Ophthalmology Department between 2016 and 2018. Zygomatic fractures and resulting ocular complications were evaluated in 87 males and 28 females with the mean ages of 26 and 32 years, respectively. Subconjunctival ecchymosis was detected in 23.07% of men and 21.05% of women. Displacement of the palpebral fissure was detected in 26.5% of men and 27.6% of women. Furthermore, the unequal pupillary level was observed in 18.37% of men and 15.78% of women. Diplopia was detected in 8.9% of men and 10.5% of women. Additionally, enophthalmos was observed in 23.1% of men and 25% of women. The most common ocular presentations in midfacial trauma are diplopia and reduced visual acuity. Even after the operation, a significant number of patients experience poor vision and diplopia. Ophthalmology consultation is essential for these patients. Mental health issues, as patients with facial injuries, are at greater risk of developing post-traumatic stress disorder or anxiety-related disorders, particularly those who were victims of assault. [31] With an increased popularity of sport and active living worldwide, our study aims to explore the incidence and features of sports-related orbital fractures in Singapore. 1421 computer tomography (CT) imaging scans of the face and orbits done at the National University Hospital over a 24-month period from January 2013 and December 2014 were reviewed retrospectively for orbital fractures. We identified 483 orbital fractures of which sports injury was the fourth most common etiology (n = 65; 13.5%) after road traffic accident (n = 131; 27.1%), geriatric fall (n = 81; 16.8%) and workplace injury (n = 67; 13.9%). The three most common sport in orbital fractures were soccer (n = 20; 30.8%), bicycling (n = 11; 16.9%) and jogging (n = 8; 12.3%). The three most common fracture patterns were zygomatico-maxillary complex fractures (n = 24; 36.9%), isolated one wall blowout fractures (n = 19; 29.2%) and naso-orbito-ethmoid fractures (n = 7; 10.8%). Sports-related orbital fractures were associated with a low mean age of patients (45.9 years, range, 14-79 years), a higher proportion of males (n = 58; 89.2%) than that from geriatric falls (n = 37, 45.6%) (P &lt; 0.01), a higher likelihood of unilaterality (n = 62; 95.4%) than that from traffic accidents (n = 99; 75.6%) (P &lt; 0.01) and a lower likelihood of pan-facial involvement (n = 4; 6.15%) than that from traffic accident (n = 60; 45.8%) (P &lt; 0.01). Sports-related orbital fractures are the fourth most common cause of orbital fractures. Though commonly seen in young male adults, in view of the aging population and people exercising more regularly, education of safety measures among sports users is paramount to preventing sports-related orbital fractures.\nHere is the question:\nOPHTHALMOLOGY (ECTOPIC): 20-year-old patient who comes to the emergency department after suffering a bicycle accident with facial trauma. A cranial CT scan was performed showing a fracture of the middle third of the face involving the orbito-malar region. One of the most frequent complications of this type of fracture is:\nHere are the potential choices:\n1. Temporomandibular ankylosis.\n2. Dental malocclusion.\n3. Naso-ethmoidal pseudoarthrosis.\n4. Enophthalmos.\nThe correct answer is: 4. Enophthalmos."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Tendinopathy, a type of tendon disorder that results in pain, swelling, and impaired function. The pain is typically worse with movement. It most commonly occurs around the shoulder (rotator cuff tendinitis, biceps tendinitis), elbow (tennis elbow, golfer's elbow), wrist, hip, knee (jumper's knee, popliteus tendinopathy), or ankle (Achilles tendinitis). Causes may include an injury or repetitive activities. Groups at risk include people who do manual labor, musicians, and athletes. Less common causes include infection, arthritis, gout, thyroid disease, and diabetes. Diagnosis is typically based on symptoms, examination, and occasionally medical imaging. A few weeks following an injury little inflammation remains, with the underlying problem related to weak or disrupted tendon fibrils. X-rays are indicated to evaluate chronic hand pain and hip pain thought to be due to OA, as the diagnosis is often unclear without confirming radiographs. For knee pain, x-rays should be obtained if symptoms or signs are not typical of OA or if knee pain persists after inauguration of effective treatment. In OA, radiographic findings (Fig. 394-7) correlate poorly with the presence and severity of pain. Further, radiographs may be normal in early disease as they are insensitive to cartilage loss and other early findings. Although MRI may reveal the extent of pathology in an osteoarthritic joint, it is not indicated as part of the diagnostic workup. Findings such as meniscal tears andcartilage and bone lesions occurin most patients with OA in the knee, but almost never warrant a change in therapy. Knee pain affects approximately 25% of adults, and its prevalence has increased almost 65% over the past 20 years, accounting for nearly 4 million primary care visits annually. Initial evaluation should emphasize excluding urgent causes while considering the need for referral. Key aspects of the patient history include age; location, onset, duration, and quality of pain; associated mechanical or systemic symptoms; history of swelling; description of precipitating trauma; and pertinent medical or surgical history. Patients requiring urgent referral generally have severe pain, swelling, and instability or inability to bear weight in association with acute trauma or have signs of joint infection such as fever, swelling, erythema, and limited range of motion. A systematic approach to examination of the knee includes inspection, palpation, evaluation of range of motion and strength, neurovascular testing, and special (provocative) tests. Radiographic imaging should be reserved for chronic knee pain (more than six weeks) or acute traumatic pain in patients who meet specific evidence-based criteria. Musculoskeletal ultrasonography allows for detailed evaluation of effusions, cysts (e.g., Baker cyst), and superficial structures. Magnetic resonance imaging is rarely used for patients with emergent cases and should generally be an option only when surgery is considered or when a patient experiences persistent pain despite adequate conservative treatment. When the initial history and physical examination suggest but do not confirm a specific diagnosis, laboratory tests can be used as a confirmatory or diagnostic tool. There are several reports of symptomatic ganglion cysts near the anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), and lateral and medial meniscus, but symptomatic ganglia arising from the anterior horn of the medial meniscus to the ACL have not been reported. Here we report the arthroscopic resection of a ganglion cyst arising from the anterior horn of the medial meniscus with a meniscal tear to the ACL. A 43-year-old female presented with a 10-year history of continuous aching pain in the right knee, but without any history of trauma. Clinical examination revealed right-sided knee pain in the medial joint line, exacerbated by end range flexion and extension, a -10°-100° active range of movement, and a -5°-110° passive range of movement。McMurray's, patellar compression, and compression rotation tests were positive. Magnetic resonance imaging (MRI) and arthroscopic examination revealed a cyst related to the ACL and medial meniscus. Histological examination confirmed the cyst to be a ganglion cyst. We present a new type of ganglion cyst, this is the first reported case of an ganglion cyst impinged between the ACL and the medial meniscus. It is hoped that this study will provide a better understanding of the condition and lead to better diagnosis and treatment. Gonalgia is a frequent reason for consultation of a primary care physician. The road leading to diagnosis is mainly clinical. A detailed medical history and physical examination are capital for establishing diagnostic hypotheses and choosing the most appropriate imaging test. Initially, a simple X-ray of the knee joint is the most common exam, even though it is not always needed, especially after a minor trauma. MRI and CT-scan allow a more detailed examination of the structures; however, they should only be ordered to answer a specific question. Most of the time, echography is reserved to extra-articular pathologies and for guiding an articular tap. Additional imaging techniques may possess greater diagnostic sensitivity and facilitate early diagnosis in a limited number of articular disorders and in selected circumstances and are indicated when conventional radiography is inadequate or nondiagnostic (Table 393-5). Ultrasonography is useful in the detection of soft tissue abnormalities, such as tendinitis, tenosynovitis, enthesitis, bursitis, and entrapment neuropathies. Wider use, lower cost, better technology, and enhanced site-specific transducers now allow for routine use in outpatient care. Owing to low cost, portability, and wider use, ultrasound use has grown and is the preferred method for the evaluation of synovial (Baker’s) cysts, rotator cuff tears, tendinitis and tendon injury, and Approach to Articular and Musculoskeletal Disorders Strongly consider synovial fluid aspiration and analysis if there is Trauma with joint effusion Monarthritis in a patient with chronic polyarthritis A thorough history and physical exam (with a focused musculoskeletal exam) should be performed on all patients, with some findings summarized above. OA is a clinical diagnosis and can be diagnosed with confidence if the following are present: 1) pain worse with activity and better with rest, 2) age more than 45 years, 3) morning stiffness lasting less than 30 minutes, 4) bony joint enlargement, and 5) limitation in range of motion. A differential diagnosis should include rheumatoid arthritis, psoriatic arthritis, crystalline arthritis, hemochromatosis, bursitis, avascular necrosis, tendinitis, radiculopathy, among other soft tissue abnormalities. [9] [10] Calcific tendinitis most commonly occurs to the shoulder, but may also involve other structures of the locomotor system. It is a rare cause of knee pain. We report a 46-year-old woman with severe medial knee pain and limitation of movement in her right knee. There was a marked tenderness site at the proximal insertion of the medial collateral ligament (MCL). Flexion was able to provoke the painful symptoms in the medial knee. The involvement of differentiated diagnoses were excluded by history, laboratory and radiograph examinations, while X-ray, CT and MRI suggested calcific tendonitis of the MCL. Due to the failure of conservative treatments, we offered her arthroscopic excision of calcific deposit which was sent for biopsy. Histopathological evaluation confirmed the diagnosis of calcific tendinitis. This patient recovered shortly afterwards with immediate resolution of symptoms following excision. Thus far, calcifications involving the MCL have been documented thrice. Calcific tendonitis of the MCL diagnosed and treated by arthroscopy has not previously been reported, which can be challenging to diagnose and treat because of its rarity. Although conservative treatment appears to be frequently satisfactory, arthroscopic excision may be a better option for the refractory or severe cases. Etymology The word patella originated in the late 17th century from the diminutive form of Latin or or paten, meaning shallow dish. See also Patellar reflex Knee pain Osteoarthritis Lateral retinaculum Lateral release References External links Knee Sesamoid bones Bones of the lower limb The unicompartimental knee prosthesis known as \"Oxford\" is a non constraint prosthesis, entrusting the whole of its stability to an intact ligamentary apparatus. Where the support surfaces of most prostheses remain limited, even punctiform, the originality of the Goodfellow prosthesis lies in the fact that the prosthetic condyle, whatever the flexion angle is, leans against a mobile prosthetic meniscus with spheric superior concavity of the same radius as the condylian radius, which increases considerably the prosthetic leaning surfaces and therefore lessens the pressure constraints. The superior surface, concave, of this prosthetic meniscus takes charge of the rolling, where the inferior plane surface realizes the gliding on the metallic tibial plate. The total conformity of the components minimizes the forces of friction.Between July 1988 and March 1993, 24 patients underwent the placing of UCP. Three patients died and 2 were lost of sight. 19 patients could be seen again or checked, corresponding of 21 operated knees. Two knees benefited from the start from UCP (medial and lateral) and 2 knees had a UCP in the first instance and then a second UCP in the compartment left safe primarily. For the 21 UCP, there are 16 medial and 3 lateral. Our mean drawback is of 3 years and 3 months, all the drawbacks being superior to 1 year and 4 months. The mean age is of 64 years. There were 17 female and 2 male patients. The mean weight is of nearly 80 kg (79,8) and nearly 52% of the operated patients have an important overweight (Body Mass Index superior to 30). Preoperative clinical analysis. It is based on a retrospective study of files using the quotation described by AUBRIOT for the «GUEPAR» group. This one establishes a gradation of four levels for each of the three criteria retained (Pain, Mobility, Instability), thus determining a global result imposed by the lowest level retained.For walking, other factors than just the state of the operated knee may intervene, this being the reason why it doesn't show in this chart. The GUEPAR group quantifies it with letters A, B, C, D.Concerning pain, all 21 knees were quoted as \"Bad\" in preoperative. Pain constitutes the decisive argument for the operative indication. In our series, only one knee had an average amplitude, all the others had a mobility superior to 89°. In 5 cases there was a flessum between 11 and 20° (penalizing of a level). Concerning walking and stability, they were taken into account, thanks to a precise questionnaire about the daily life acts. Concerning the walking perimeter, it was found as unlimited (A) in 1 case, superior to 500 m (B) in 2 cases, inferior to 500 m (C) in 17 cases and limited to home (D) in 1 case. The early after effects. At the end of the intervention, the knee is placed into a splint with limited flexion. As soon as the second day the patient is sat on the border of his bed. The first partial support at the third of the body weight is authorized between the fourth and the fifth day, when at the same time flexion exercises on electrical splint are started, as soon as the Redon draining is removed. The average hospitalization length was of a fortnight. Among secondary late complications and retakes, let us stop on meniscal luxations which constitute a specific complication of the Oxford arthroplasty. They concern 3 times the medial compartment and 4 lateral compartment. They happened in 1 case early, at D 22, in 3 cases within the 6 first months and in 3 cases after 2 years. They were treated : 3 times by reduction under general anæsthetic, no more ; 3 times changing the meniscusus for a meniscusus of superior size and once by placing a total prosthesis at the place of the UCP. The deteriorations of the opposed compartment not prosthesized occured in three cases. They were treated by unicompartmental additional arthroplasty in two cases and by total prosthesis in the third case. The clinical results on pain are very satisfactory as from the early check up onwards we have 17 successes (no pain 11 cases and occasional pains 6 cases) and as after 3 years and 5 months in average, we have 19 successes (no pain : 10 cases - occasional pain : 9 cases). At the maximal drawback, the mobility is quoted very good in 7 cases and good in 13 cases, mean in 1 case. At the latest check up, we note an excellent stability in 17 cases and good in 3 cases, that is to say 20 successes and 1 case of stability quoted as mean. At the latest check up we note 17 successes (A and B) and 4 relative failures (C) concerning the quality of walking.At the question «are you pleased with the intervention and would you advise it to a friend?» and with the nuance «very pleased» and «simply satisfied», we get 10 cases «very pleased», 8 cases «pleased» and 3 cases «moderately satisfied»; only those 3 cases advise against the intervention. The radiological results are less satisfying as they show frequent imperfections : • for the 16 medial UCP : only 9 cases hypocorrected or normo axed, but 1 case strongly hypocorrected (residual varus of 7°) and 6 hypercorrected cases. • for the 5 lateral UCP : 3 normo-axed cases, 1 case strongly hypocorrected (residual valgus of 6°) and 1 case strongly hypercorrected (10° varus). • the failures due to rapid deterioration of the non prosthetized compartment occurred on hypercorrected knees. • on 21 knees, 14 borders of tibial plate were noticed, out of which 9 had no plate displacement and 5 had a slight displacement, at the origin of a small angular loss. • accumulations of cement on the tibial side, towards the back or in medial were noticed in 8 cases, which explains a slope of the tibial plate to the back inferior to 5° in 11 cases (should be of 7°). • 4 femoral components seem to be too posterior and one shows curved.In total, only 7 cases out of 21 were estimated with no peculiarities on the radiological point of view. It seems difficult to place a UCP well. The meniscal luxations are favored by an alignment rotational defect of the tibial plate, specially for the lateral UCP, the meniscus coming to hit the lip of the tibial plate during the lifting from a sitting position. For 5 of these luxations, we must recognize the existence of a ligamentary collateral laxity which should have altered the surgical indication either to an osteotomy, or to a total arthroplasty. Conclusions. Under the condition of respecting the absolute counter indications, of thoroughly evaluating the relative counter indications and of reducing at the best the defects linked to the surgical technique, the unicompartmental arthroplasty, including that of Oxford, gives good functional results after more than three years. In our series, the result on pain is constant if we exclude the cases with risk with ligamentary laxity and that of centered gonarthrosis at obese subject, that is to say 15 successes on 15 knees thus selected retrospectively. The gain on mobility is weak, of 5° in average. The result on stability is, as for pain, excellent, if we exclude the cases with risk, as we get then also 15 successes on 15 knees. Concerning the global result according to the quotation of Aubriot-Guepar, we note 14 successes and 1 relative failure. 4 knees were bad indications and should have benefited from a total arthroplasty or from an osteotomy.  Brodie's abscess is an uncommon form of subacute osteomyelitis where the main presenting symptom is mild to moderate pain of insidious onset for several months' duration. We report a case of a patient presenting with acute leg pain resembling that of a deep vein thrombosis, and a beginning leg compartment syndrome following a suspected ruptured Baker's cyst. Our case is unusual because of the acute presentation of the Brodie's abscess with acute leg pain and acute swelling without any preceding trauma; to the best of our knowledge, this presentation has not been reported before. A 17-year-old white boy presented to our out-patient clinic with a 6-month history of pain in his left knee joint of insidious onset. There was no history of trauma to the extremity. After performing physical and radiological (X-ray) examinations, we initially diagnosed medial meniscus damage. One week later he presented to our emergency department with acute sudden increase in the pain and swelling of his left knee, and pain and swelling of his left leg, without any trauma. Deep vein thrombosis and beginning leg compartment syndrome from ruptured Baker's cyst were initially diagnosed. Magnetic resonance imaging was performed and Brodie's abscess was the most probable diagnosis. We performed open surgical debridement and curettage with drainage of the abscess and administered postoperative antibiotics. He presented to our out-patient clinic 3 months postoperatively, where he was pain-free with no residual local tenderness. In cases of sudden acute increase in joint or extremity pain or swelling that has been insidiously present for months, Brodie's abscess should be considered as one of the differential diagnoses, as it may present acutely in cases with accompanying fasciitis and myositis and be clinically mistaken for deep vein thrombosis or limb compartment. Magnetic resonance imaging remains the gold standard imaging study, and surgical treatment followed by postoperative antibiotics remains the standard treatment. Popliteus tendinopathies are rare injuries that can occur from overuse, trauma, or secondary causes, such as sesamoid bones or calcifications. They present with nonspecific symptoms and should be considered in any patient with posterolateral knee pain, instability, popliteus tenderness, and a positive Garrick test. Diagnosis can be made with magnetic resonance imaging, but arthroscopy remains the criterion standard. For minor popliteus tendinopathies, initial management involves conservative treatment, including rest, activity modification, physical therapy, and quadriceps strengthening. For more severe or refractory disease, corticosteroid injections and arthroscopy should be considered. [<iOrthopedics</i. 20XX;XX(X):xx-xx.]. Resident's case problem. A 21-year-old healthy athletic male military cadet with complaint of worsening diffuse left knee pain was evaluated 4 days after onset. The knee pain began 2 hours after completing a long car trip, worsened over the subsequent 3 days, and became almost unbearable during the return trip. The patient reported constant pain, limited knee motion, and difficulty ambulating. In addition, he was unable to perform physical military training or attend academic classes due to the severe left knee pain. Past medical history revealed a mild left lateral calf strain 21/2 weeks prior, which completely resolved within 24 hours of onset. Our physical examination led us to either monoarticular arthritis, pseudothrombophlebitis (ruptured Baker's cyst), or a lower leg deep vein thrombosis (DVT) as the cause of knee pain. Diagnostic imaging of this patient revealed a left superficial femoral vein thrombosis and popliteal DVT, with bilateral pulmonary emboli (PE). A systematic differential diagnosis was undertaken to rule out a potentially fatal DVT diagnosis as the cause of knee pain, despite minimal DVT risk factors. The physical therapist in a direct-access setting must ensure timely evaluation and referral of a suspected DVT, even when patient demographics cause the practitioner to question the likelihood of this diagnosis. The physical examination findings, clinical suspicion, and established clinical prediction rules can accurately dictate the appropriate referral action necessary. Periarticular Disorders of the Extremities 2248 by hip extension and flexion. Anserine bursitis is an inflammation of the sartorius bursa located over the medial side of the tibia just below the knee and under the conjoint tendon and is manifested by pain on climbing stairs. Tenderness is present over the insertion of the conjoint tendon of the sartorius, gracilis, and semitendinosus. Prepatellar bursitis occurs in the bursa situated between the patella and overlying skin and is caused by kneeling on hard surfaces. Gout or infection may also occur at this site. Bursitis is typically diagnosed by history and physical examination, but visualization by ultrasound may play a useful role in selected instances for diagnosis and directed guidance of glucocorticoid injection. Treatment of bursitis consists of prevention of the aggravating situation, rest of the involved part, administration of a nonsteroidal anti-inflammatory drug (NSAID) where appropriate for an individual patient, or local This is a case report detailing the use of in-office needle arthroscopy (mi-eye 2™) in a patient with chronic knee pain and inconclusive magnetic resonance imaging findings. The patient is a 40-year-old male who presented to our clinic after an extended history of right knee pain along the medial aspect with previous failed treatments. Magnetic resonance imaging without contrast had demonstrated full-thickness chondral fissuring of the lateral patellar facet, mild abnormal signals of the proximal patellar tendon and Hoffa's fat pad, and intact anterior cruciate ligament and posterior cruciate ligament. The patient was previously treated with an ultrasound-guided injection of 2 cm<sup3</sup of 1% lidocaine without epinephrine and 1 cm<sup3</sup of Kenalog-40 and scheduled for follow-up. At follow-up, clinical examination showed antalgic gait, minimal tenderness along medial joint line, medial pain in deep flexion, and no pain when in varus or valgus. Due to continued discomfort with a negative magnetic resonance imaging, in-office diagnostic arthroscopy was performed using mi-eye 2 revealing a tear of the mid-body of the medial meniscus. The patient subsequently underwent arthroscopic repair and is recovering well with complete resolution of medial joint pain. This report highlights the clinical utility of in-office diagnostic arthroscopy in the management of patients with persistent knee pain and negative or equivocal findings on magnetic resonance imaging. Family physicians play a key role in the diagnosis and management of patients with osteoarthritis. Diagnosis is mainly clinical and radiological. A complete history should be taken with meticulous physical examination of the joints. The history-taking should aim to detect risk factors and compatible clinical symptoms. Pain characteristics should be identified, distinguishing between mechanical and inflammatory pain, and an exhaustive examination of the joints should be performed, with evaluation of the presence of pain, deformity, mobility restrictions (both active and passive), crepitus, joint effusion, and inflammation. A differential diagnosis should be made with all diseases that affect the joints and/or produce joint stiffness.  Tarsal tunnel syndrome is defined as an extrinsic and/or intrinsic compressive neuropathy of the posterior tibial nerve or one of its branches. Its causes include venous insufficiency. Clinical case: 51 year-old female patient from León, Guanajuato. Hypertensive, with Guillain-Barré syndrome for eight years, vascular insufficiency and obesity. Her condition started with left ankle and heel pain; she was treated with NSAIDs and rehabilitation and achieved partial improvement. X-rays and MRI of the left ankle showed posterior impingement. She underwent arthroscopy and improved but one month later she presented with severe pain in the left ankle and sole and dysesthesias. Electromyography showed a lesion of the posterior tibial nerve. We had the patient's case history, preoperative tests, and dorsoplantar and lateral X-ray views. The arthroscopic diagnosis was Flexor Hallucis Longus (FHL) tendinitis, synovitis and posterior ankle impingement. Synovectomy, decompression and smoothening of the FHL tendon were performed. The patient did poorly and underwent electromyography with axonotmesis of the medial plantar branch. After the nerve was released, Lazorthes venous plexus was found to be tortuous and compressing the entire nerve tract. The possible causes for this include intrinsic compression secondary to tumors, and anatomical changes of the tarsal tunnel. However, less often varices may confound the diagnosis and cause irreversible damage if not treated timely. The patient is currently pain free and can walk, has mild dysesthesias of the first toe and limited flexion. Prompt and effective diagnosis and treatment for common knee problems depend on practitioners' ability to distinguish between traumatic and inflammatory knee conditions. This article aims to enable practitioners to make accurate assessments, carry out knee examinations and undertake selected special tests as necessary before discharging or referring patients. PURPOSE OF THE STUDY In the retrospective study of two South Bohemian centres we present the comparison of pre-operative anamnestic clinical signs in relation to the arthroscopic intraoperative finding. The obtained data is used also to evaluate the arthroscopic finding in relation to age and sex. MATERIAL AND METHODS The arthroscopic findings of patients who underwent surgery in 2013-2014 period (1.1.2013-31.12.2014) at the Department of Trauma Surgery of České Budějovice Hospital, a.s. and in 2014 (1.1.-31.12.2014) at the Department of Orthopaedics and Traumatology of Písek Hospital, a.s. were evaluated. In total, 1 021 patients underwent surgery, with the mean age of 44 years. The patients were not selected. The group includes all the patients who underwent surgery, including those in whom repeat arthroscopy was performed, in the respective period of time, regardless of the mechanism of difficulties. A preoperative MRI scan was carried out in 470 patients. The referring physician was present during the examination. In all the patients undergoing surgery, the main clinical preoperative sign was examined based on the documentation, namely in the following order - hemarthros, locked knee, hydrops or merely a pain. In the arthroscopic finding, the medial meniscal lesion - anterior and posterior horn, and complete tear was assessed. The same was done for lateral meniscus. In anterior cruciate ligament - ACL - partial or complete tear was assessed. We identified the frequency of findings in relation to age and evaluated the correlations between the clinical signs and the arthroscopic finding. We calculated the sensitivity and specificity of hemarthros as a sign of ACL tear. The analysis was conducted based on the medical history in medical record documentation and the surgical protocol. The cartilage was not assessed. RESULTS Analysis of clinical and anamnestic signs in relation to arthroscopic findings 1. Negative arthroscopic findings (potential cartilage damage with no damage to other soft structures and normal arthroscopic findings) are in 83% accompanied by a mere knee pain. 2. High percentage of isolated locked joint (15%) in negative findings 3. Complete ACL tears are most frequently reported in the under-35 age category - 43% of 191 men who underwent surgery and 33% of 102 women. 4. Isolated injuries to ACL without the meniscus tear are frequent in younger patients - 30% - 40% of the total number of patients with injured ACL. 5. In patients older than 56 years of age the ACL damage is accompanied by concurrent meniscus tear (96% in men, 100% in women). 6. Sensitivity of hemarthros (68%) for complete ACL tear. Specificity of the presence of hemarthros in complete ACL lesions (91%) indicates that there are also complete ACL tears with no hemarthros whatsoever in the medical history. For partial tears the values of sensitivity and specificity are 27% and 67%, respectively. In partial tear, the presence of hemarthros is not a diagnostic lead. 7. In 15% of negative findings a \"locked knee\" was present. It was not a genuinely locked knee, but rather an antalgic position. Not every locked knee must necessarily mean a meniscus lesion or ACL tear. 8. Isolated meniscus tear is in 75% accompanied only by pain. 9. In our group of patients, isolated osteoarthrosis or malacic cartilage without any damage to ligaments or menisci was rare - only in 22 cases (2% of the entire group). DISCUSSION There are lots of studies which focus on comparing the clinical findings with perioperative pathology of knee joint and the importance of pre-operative clinical examination. Our extensive retrospective study proved that in 56-plus age category virtually each ACL injury is accompanied by a meniscal lesion, which can be explained by a possible ACL damage at a young age and subsequent instability resulting in meniscus tear or frequent presence of degenerative meniscal changes at an older age. A small number of isolated degenerative cartilage damage was established (2%). We fully agree with the authors who prove that the degenerative cartilage changes are ever since the very beginning accompanied by changes of the other soft structure of the knee. We revealed a high percentage of locked knee joint in negative arthroscopic findings. According to the clinical pre-operative examination, the locked knee does not automatically mean the meniscal lesion or ACL tear. In agreement with the others we prove a close association between hemarthros and ACL injury. CONCLUSIONS 1. A clinical examination, a detailed medical history is necessary 2. With hemarthros in medical history, there is a likelihood of complete ACL tear. Conversely, even a seemingly trivial knee sprain without hemarthros or locked knee can mean the ACL tear. 3. Where a mere pain is present, it mostly indicates an isolated meniscal damage or a negative finding. 4. Degenerative cartilage changes are accompanied by degeneration of menisci and ligaments. 5. Our group of patients did not include any case of hemarthros in the medical history with a negative arthroscopic finding. Hemarthros always indicated a more serious damage to knee soft structures. Key words: knee joint injuries, knee arthroscopy, sensitivity, specificity, hemarthros. Patellar tendinopathy is mainly a clinical diagnosis made through a detailed history and meticulous physical examination. Appropriate questions which will cue in the diagnosis: Sport practiced, schedule of practice and competition, which position the athlete plays, and level of performance. The patient will usually complain of well-localized pain and tenderness on the inferior tip of the patella. [12] [2]\nHere is the question:\nORTHOPEDIC SURGERY AND TRAUMATOLOGY: A 73-year-old woman with a history of obesity, type 2 diabetes mellitus, hypertension and dyslipidemia. She consults for unbearable pain in the right knee of 5 days of evolution, without previous trauma. Examination: globular knee, moderate varus, extension and flexion limited by pain, diffuse medial pain. X-ray shows osteophytes and mild impingement of the medial interlining. What would be his initial management?\nHere are the potential choices:\n1. Explanation of the diagnosis, relative rest, paracetamol 1g/8h plus metamizol 500 mg/ 8 h rescue naproxen.\n2. Preferential referral to Traumatology outpatients for evaluation of total cemented prosthesis.\n3. Preferential referral to Traumatology outpatient clinic for arthroscopic debridement.\n4. Preferred MRI request for evaluation of meniscopathy, Baker's cyst and/or tendinitis.\nThe correct answer is: ",
        "gold_answer": "1 Explanation of the diagnosis, relative rest, paracetamol 1g/8h plus metamizol 500 mg/ 8 h rescue naproxen.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Tendinopathy, a type of tendon disorder that results in pain, swelling, and impaired function. The pain is typically worse with movement. It most commonly occurs around the shoulder (rotator cuff tendinitis, biceps tendinitis), elbow (tennis elbow, golfer's elbow), wrist, hip, knee (jumper's knee, popliteus tendinopathy), or ankle (Achilles tendinitis). Causes may include an injury or repetitive activities. Groups at risk include people who do manual labor, musicians, and athletes. Less common causes include infection, arthritis, gout, thyroid disease, and diabetes. Diagnosis is typically based on symptoms, examination, and occasionally medical imaging. A few weeks following an injury little inflammation remains, with the underlying problem related to weak or disrupted tendon fibrils. X-rays are indicated to evaluate chronic hand pain and hip pain thought to be due to OA, as the diagnosis is often unclear without confirming radiographs. For knee pain, x-rays should be obtained if symptoms or signs are not typical of OA or if knee pain persists after inauguration of effective treatment. In OA, radiographic findings (Fig. 394-7) correlate poorly with the presence and severity of pain. Further, radiographs may be normal in early disease as they are insensitive to cartilage loss and other early findings. Although MRI may reveal the extent of pathology in an osteoarthritic joint, it is not indicated as part of the diagnostic workup. Findings such as meniscal tears andcartilage and bone lesions occurin most patients with OA in the knee, but almost never warrant a change in therapy. Knee pain affects approximately 25% of adults, and its prevalence has increased almost 65% over the past 20 years, accounting for nearly 4 million primary care visits annually. Initial evaluation should emphasize excluding urgent causes while considering the need for referral. Key aspects of the patient history include age; location, onset, duration, and quality of pain; associated mechanical or systemic symptoms; history of swelling; description of precipitating trauma; and pertinent medical or surgical history. Patients requiring urgent referral generally have severe pain, swelling, and instability or inability to bear weight in association with acute trauma or have signs of joint infection such as fever, swelling, erythema, and limited range of motion. A systematic approach to examination of the knee includes inspection, palpation, evaluation of range of motion and strength, neurovascular testing, and special (provocative) tests. Radiographic imaging should be reserved for chronic knee pain (more than six weeks) or acute traumatic pain in patients who meet specific evidence-based criteria. Musculoskeletal ultrasonography allows for detailed evaluation of effusions, cysts (e.g., Baker cyst), and superficial structures. Magnetic resonance imaging is rarely used for patients with emergent cases and should generally be an option only when surgery is considered or when a patient experiences persistent pain despite adequate conservative treatment. When the initial history and physical examination suggest but do not confirm a specific diagnosis, laboratory tests can be used as a confirmatory or diagnostic tool. There are several reports of symptomatic ganglion cysts near the anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), and lateral and medial meniscus, but symptomatic ganglia arising from the anterior horn of the medial meniscus to the ACL have not been reported. Here we report the arthroscopic resection of a ganglion cyst arising from the anterior horn of the medial meniscus with a meniscal tear to the ACL. A 43-year-old female presented with a 10-year history of continuous aching pain in the right knee, but without any history of trauma. Clinical examination revealed right-sided knee pain in the medial joint line, exacerbated by end range flexion and extension, a -10°-100° active range of movement, and a -5°-110° passive range of movement。McMurray's, patellar compression, and compression rotation tests were positive. Magnetic resonance imaging (MRI) and arthroscopic examination revealed a cyst related to the ACL and medial meniscus. Histological examination confirmed the cyst to be a ganglion cyst. We present a new type of ganglion cyst, this is the first reported case of an ganglion cyst impinged between the ACL and the medial meniscus. It is hoped that this study will provide a better understanding of the condition and lead to better diagnosis and treatment. Gonalgia is a frequent reason for consultation of a primary care physician. The road leading to diagnosis is mainly clinical. A detailed medical history and physical examination are capital for establishing diagnostic hypotheses and choosing the most appropriate imaging test. Initially, a simple X-ray of the knee joint is the most common exam, even though it is not always needed, especially after a minor trauma. MRI and CT-scan allow a more detailed examination of the structures; however, they should only be ordered to answer a specific question. Most of the time, echography is reserved to extra-articular pathologies and for guiding an articular tap. Additional imaging techniques may possess greater diagnostic sensitivity and facilitate early diagnosis in a limited number of articular disorders and in selected circumstances and are indicated when conventional radiography is inadequate or nondiagnostic (Table 393-5). Ultrasonography is useful in the detection of soft tissue abnormalities, such as tendinitis, tenosynovitis, enthesitis, bursitis, and entrapment neuropathies. Wider use, lower cost, better technology, and enhanced site-specific transducers now allow for routine use in outpatient care. Owing to low cost, portability, and wider use, ultrasound use has grown and is the preferred method for the evaluation of synovial (Baker’s) cysts, rotator cuff tears, tendinitis and tendon injury, and Approach to Articular and Musculoskeletal Disorders Strongly consider synovial fluid aspiration and analysis if there is Trauma with joint effusion Monarthritis in a patient with chronic polyarthritis A thorough history and physical exam (with a focused musculoskeletal exam) should be performed on all patients, with some findings summarized above. OA is a clinical diagnosis and can be diagnosed with confidence if the following are present: 1) pain worse with activity and better with rest, 2) age more than 45 years, 3) morning stiffness lasting less than 30 minutes, 4) bony joint enlargement, and 5) limitation in range of motion. A differential diagnosis should include rheumatoid arthritis, psoriatic arthritis, crystalline arthritis, hemochromatosis, bursitis, avascular necrosis, tendinitis, radiculopathy, among other soft tissue abnormalities. [9] [10] Calcific tendinitis most commonly occurs to the shoulder, but may also involve other structures of the locomotor system. It is a rare cause of knee pain. We report a 46-year-old woman with severe medial knee pain and limitation of movement in her right knee. There was a marked tenderness site at the proximal insertion of the medial collateral ligament (MCL). Flexion was able to provoke the painful symptoms in the medial knee. The involvement of differentiated diagnoses were excluded by history, laboratory and radiograph examinations, while X-ray, CT and MRI suggested calcific tendonitis of the MCL. Due to the failure of conservative treatments, we offered her arthroscopic excision of calcific deposit which was sent for biopsy. Histopathological evaluation confirmed the diagnosis of calcific tendinitis. This patient recovered shortly afterwards with immediate resolution of symptoms following excision. Thus far, calcifications involving the MCL have been documented thrice. Calcific tendonitis of the MCL diagnosed and treated by arthroscopy has not previously been reported, which can be challenging to diagnose and treat because of its rarity. Although conservative treatment appears to be frequently satisfactory, arthroscopic excision may be a better option for the refractory or severe cases. Etymology The word patella originated in the late 17th century from the diminutive form of Latin or or paten, meaning shallow dish. See also Patellar reflex Knee pain Osteoarthritis Lateral retinaculum Lateral release References External links Knee Sesamoid bones Bones of the lower limb The unicompartimental knee prosthesis known as \"Oxford\" is a non constraint prosthesis, entrusting the whole of its stability to an intact ligamentary apparatus. Where the support surfaces of most prostheses remain limited, even punctiform, the originality of the Goodfellow prosthesis lies in the fact that the prosthetic condyle, whatever the flexion angle is, leans against a mobile prosthetic meniscus with spheric superior concavity of the same radius as the condylian radius, which increases considerably the prosthetic leaning surfaces and therefore lessens the pressure constraints. The superior surface, concave, of this prosthetic meniscus takes charge of the rolling, where the inferior plane surface realizes the gliding on the metallic tibial plate. The total conformity of the components minimizes the forces of friction.Between July 1988 and March 1993, 24 patients underwent the placing of UCP. Three patients died and 2 were lost of sight. 19 patients could be seen again or checked, corresponding of 21 operated knees. Two knees benefited from the start from UCP (medial and lateral) and 2 knees had a UCP in the first instance and then a second UCP in the compartment left safe primarily. For the 21 UCP, there are 16 medial and 3 lateral. Our mean drawback is of 3 years and 3 months, all the drawbacks being superior to 1 year and 4 months. The mean age is of 64 years. There were 17 female and 2 male patients. The mean weight is of nearly 80 kg (79,8) and nearly 52% of the operated patients have an important overweight (Body Mass Index superior to 30). Preoperative clinical analysis. It is based on a retrospective study of files using the quotation described by AUBRIOT for the «GUEPAR» group. This one establishes a gradation of four levels for each of the three criteria retained (Pain, Mobility, Instability), thus determining a global result imposed by the lowest level retained.For walking, other factors than just the state of the operated knee may intervene, this being the reason why it doesn't show in this chart. The GUEPAR group quantifies it with letters A, B, C, D.Concerning pain, all 21 knees were quoted as \"Bad\" in preoperative. Pain constitutes the decisive argument for the operative indication. In our series, only one knee had an average amplitude, all the others had a mobility superior to 89°. In 5 cases there was a flessum between 11 and 20° (penalizing of a level). Concerning walking and stability, they were taken into account, thanks to a precise questionnaire about the daily life acts. Concerning the walking perimeter, it was found as unlimited (A) in 1 case, superior to 500 m (B) in 2 cases, inferior to 500 m (C) in 17 cases and limited to home (D) in 1 case. The early after effects. At the end of the intervention, the knee is placed into a splint with limited flexion. As soon as the second day the patient is sat on the border of his bed. The first partial support at the third of the body weight is authorized between the fourth and the fifth day, when at the same time flexion exercises on electrical splint are started, as soon as the Redon draining is removed. The average hospitalization length was of a fortnight. Among secondary late complications and retakes, let us stop on meniscal luxations which constitute a specific complication of the Oxford arthroplasty. They concern 3 times the medial compartment and 4 lateral compartment. They happened in 1 case early, at D 22, in 3 cases within the 6 first months and in 3 cases after 2 years. They were treated : 3 times by reduction under general anæsthetic, no more ; 3 times changing the meniscusus for a meniscusus of superior size and once by placing a total prosthesis at the place of the UCP. The deteriorations of the opposed compartment not prosthesized occured in three cases. They were treated by unicompartmental additional arthroplasty in two cases and by total prosthesis in the third case. The clinical results on pain are very satisfactory as from the early check up onwards we have 17 successes (no pain 11 cases and occasional pains 6 cases) and as after 3 years and 5 months in average, we have 19 successes (no pain : 10 cases - occasional pain : 9 cases). At the maximal drawback, the mobility is quoted very good in 7 cases and good in 13 cases, mean in 1 case. At the latest check up, we note an excellent stability in 17 cases and good in 3 cases, that is to say 20 successes and 1 case of stability quoted as mean. At the latest check up we note 17 successes (A and B) and 4 relative failures (C) concerning the quality of walking.At the question «are you pleased with the intervention and would you advise it to a friend?» and with the nuance «very pleased» and «simply satisfied», we get 10 cases «very pleased», 8 cases «pleased» and 3 cases «moderately satisfied»; only those 3 cases advise against the intervention. The radiological results are less satisfying as they show frequent imperfections : • for the 16 medial UCP : only 9 cases hypocorrected or normo axed, but 1 case strongly hypocorrected (residual varus of 7°) and 6 hypercorrected cases. • for the 5 lateral UCP : 3 normo-axed cases, 1 case strongly hypocorrected (residual valgus of 6°) and 1 case strongly hypercorrected (10° varus). • the failures due to rapid deterioration of the non prosthetized compartment occurred on hypercorrected knees. • on 21 knees, 14 borders of tibial plate were noticed, out of which 9 had no plate displacement and 5 had a slight displacement, at the origin of a small angular loss. • accumulations of cement on the tibial side, towards the back or in medial were noticed in 8 cases, which explains a slope of the tibial plate to the back inferior to 5° in 11 cases (should be of 7°). • 4 femoral components seem to be too posterior and one shows curved.In total, only 7 cases out of 21 were estimated with no peculiarities on the radiological point of view. It seems difficult to place a UCP well. The meniscal luxations are favored by an alignment rotational defect of the tibial plate, specially for the lateral UCP, the meniscus coming to hit the lip of the tibial plate during the lifting from a sitting position. For 5 of these luxations, we must recognize the existence of a ligamentary collateral laxity which should have altered the surgical indication either to an osteotomy, or to a total arthroplasty. Conclusions. Under the condition of respecting the absolute counter indications, of thoroughly evaluating the relative counter indications and of reducing at the best the defects linked to the surgical technique, the unicompartmental arthroplasty, including that of Oxford, gives good functional results after more than three years. In our series, the result on pain is constant if we exclude the cases with risk with ligamentary laxity and that of centered gonarthrosis at obese subject, that is to say 15 successes on 15 knees thus selected retrospectively. The gain on mobility is weak, of 5° in average. The result on stability is, as for pain, excellent, if we exclude the cases with risk, as we get then also 15 successes on 15 knees. Concerning the global result according to the quotation of Aubriot-Guepar, we note 14 successes and 1 relative failure. 4 knees were bad indications and should have benefited from a total arthroplasty or from an osteotomy.  Brodie's abscess is an uncommon form of subacute osteomyelitis where the main presenting symptom is mild to moderate pain of insidious onset for several months' duration. We report a case of a patient presenting with acute leg pain resembling that of a deep vein thrombosis, and a beginning leg compartment syndrome following a suspected ruptured Baker's cyst. Our case is unusual because of the acute presentation of the Brodie's abscess with acute leg pain and acute swelling without any preceding trauma; to the best of our knowledge, this presentation has not been reported before. A 17-year-old white boy presented to our out-patient clinic with a 6-month history of pain in his left knee joint of insidious onset. There was no history of trauma to the extremity. After performing physical and radiological (X-ray) examinations, we initially diagnosed medial meniscus damage. One week later he presented to our emergency department with acute sudden increase in the pain and swelling of his left knee, and pain and swelling of his left leg, without any trauma. Deep vein thrombosis and beginning leg compartment syndrome from ruptured Baker's cyst were initially diagnosed. Magnetic resonance imaging was performed and Brodie's abscess was the most probable diagnosis. We performed open surgical debridement and curettage with drainage of the abscess and administered postoperative antibiotics. He presented to our out-patient clinic 3 months postoperatively, where he was pain-free with no residual local tenderness. In cases of sudden acute increase in joint or extremity pain or swelling that has been insidiously present for months, Brodie's abscess should be considered as one of the differential diagnoses, as it may present acutely in cases with accompanying fasciitis and myositis and be clinically mistaken for deep vein thrombosis or limb compartment. Magnetic resonance imaging remains the gold standard imaging study, and surgical treatment followed by postoperative antibiotics remains the standard treatment. Popliteus tendinopathies are rare injuries that can occur from overuse, trauma, or secondary causes, such as sesamoid bones or calcifications. They present with nonspecific symptoms and should be considered in any patient with posterolateral knee pain, instability, popliteus tenderness, and a positive Garrick test. Diagnosis can be made with magnetic resonance imaging, but arthroscopy remains the criterion standard. For minor popliteus tendinopathies, initial management involves conservative treatment, including rest, activity modification, physical therapy, and quadriceps strengthening. For more severe or refractory disease, corticosteroid injections and arthroscopy should be considered. [<iOrthopedics</i. 20XX;XX(X):xx-xx.]. Resident's case problem. A 21-year-old healthy athletic male military cadet with complaint of worsening diffuse left knee pain was evaluated 4 days after onset. The knee pain began 2 hours after completing a long car trip, worsened over the subsequent 3 days, and became almost unbearable during the return trip. The patient reported constant pain, limited knee motion, and difficulty ambulating. In addition, he was unable to perform physical military training or attend academic classes due to the severe left knee pain. Past medical history revealed a mild left lateral calf strain 21/2 weeks prior, which completely resolved within 24 hours of onset. Our physical examination led us to either monoarticular arthritis, pseudothrombophlebitis (ruptured Baker's cyst), or a lower leg deep vein thrombosis (DVT) as the cause of knee pain. Diagnostic imaging of this patient revealed a left superficial femoral vein thrombosis and popliteal DVT, with bilateral pulmonary emboli (PE). A systematic differential diagnosis was undertaken to rule out a potentially fatal DVT diagnosis as the cause of knee pain, despite minimal DVT risk factors. The physical therapist in a direct-access setting must ensure timely evaluation and referral of a suspected DVT, even when patient demographics cause the practitioner to question the likelihood of this diagnosis. The physical examination findings, clinical suspicion, and established clinical prediction rules can accurately dictate the appropriate referral action necessary. Periarticular Disorders of the Extremities 2248 by hip extension and flexion. Anserine bursitis is an inflammation of the sartorius bursa located over the medial side of the tibia just below the knee and under the conjoint tendon and is manifested by pain on climbing stairs. Tenderness is present over the insertion of the conjoint tendon of the sartorius, gracilis, and semitendinosus. Prepatellar bursitis occurs in the bursa situated between the patella and overlying skin and is caused by kneeling on hard surfaces. Gout or infection may also occur at this site. Bursitis is typically diagnosed by history and physical examination, but visualization by ultrasound may play a useful role in selected instances for diagnosis and directed guidance of glucocorticoid injection. Treatment of bursitis consists of prevention of the aggravating situation, rest of the involved part, administration of a nonsteroidal anti-inflammatory drug (NSAID) where appropriate for an individual patient, or local This is a case report detailing the use of in-office needle arthroscopy (mi-eye 2™) in a patient with chronic knee pain and inconclusive magnetic resonance imaging findings. The patient is a 40-year-old male who presented to our clinic after an extended history of right knee pain along the medial aspect with previous failed treatments. Magnetic resonance imaging without contrast had demonstrated full-thickness chondral fissuring of the lateral patellar facet, mild abnormal signals of the proximal patellar tendon and Hoffa's fat pad, and intact anterior cruciate ligament and posterior cruciate ligament. The patient was previously treated with an ultrasound-guided injection of 2 cm<sup3</sup of 1% lidocaine without epinephrine and 1 cm<sup3</sup of Kenalog-40 and scheduled for follow-up. At follow-up, clinical examination showed antalgic gait, minimal tenderness along medial joint line, medial pain in deep flexion, and no pain when in varus or valgus. Due to continued discomfort with a negative magnetic resonance imaging, in-office diagnostic arthroscopy was performed using mi-eye 2 revealing a tear of the mid-body of the medial meniscus. The patient subsequently underwent arthroscopic repair and is recovering well with complete resolution of medial joint pain. This report highlights the clinical utility of in-office diagnostic arthroscopy in the management of patients with persistent knee pain and negative or equivocal findings on magnetic resonance imaging. Family physicians play a key role in the diagnosis and management of patients with osteoarthritis. Diagnosis is mainly clinical and radiological. A complete history should be taken with meticulous physical examination of the joints. The history-taking should aim to detect risk factors and compatible clinical symptoms. Pain characteristics should be identified, distinguishing between mechanical and inflammatory pain, and an exhaustive examination of the joints should be performed, with evaluation of the presence of pain, deformity, mobility restrictions (both active and passive), crepitus, joint effusion, and inflammation. A differential diagnosis should be made with all diseases that affect the joints and/or produce joint stiffness.  Tarsal tunnel syndrome is defined as an extrinsic and/or intrinsic compressive neuropathy of the posterior tibial nerve or one of its branches. Its causes include venous insufficiency. Clinical case: 51 year-old female patient from León, Guanajuato. Hypertensive, with Guillain-Barré syndrome for eight years, vascular insufficiency and obesity. Her condition started with left ankle and heel pain; she was treated with NSAIDs and rehabilitation and achieved partial improvement. X-rays and MRI of the left ankle showed posterior impingement. She underwent arthroscopy and improved but one month later she presented with severe pain in the left ankle and sole and dysesthesias. Electromyography showed a lesion of the posterior tibial nerve. We had the patient's case history, preoperative tests, and dorsoplantar and lateral X-ray views. The arthroscopic diagnosis was Flexor Hallucis Longus (FHL) tendinitis, synovitis and posterior ankle impingement. Synovectomy, decompression and smoothening of the FHL tendon were performed. The patient did poorly and underwent electromyography with axonotmesis of the medial plantar branch. After the nerve was released, Lazorthes venous plexus was found to be tortuous and compressing the entire nerve tract. The possible causes for this include intrinsic compression secondary to tumors, and anatomical changes of the tarsal tunnel. However, less often varices may confound the diagnosis and cause irreversible damage if not treated timely. The patient is currently pain free and can walk, has mild dysesthesias of the first toe and limited flexion. Prompt and effective diagnosis and treatment for common knee problems depend on practitioners' ability to distinguish between traumatic and inflammatory knee conditions. This article aims to enable practitioners to make accurate assessments, carry out knee examinations and undertake selected special tests as necessary before discharging or referring patients. PURPOSE OF THE STUDY In the retrospective study of two South Bohemian centres we present the comparison of pre-operative anamnestic clinical signs in relation to the arthroscopic intraoperative finding. The obtained data is used also to evaluate the arthroscopic finding in relation to age and sex. MATERIAL AND METHODS The arthroscopic findings of patients who underwent surgery in 2013-2014 period (1.1.2013-31.12.2014) at the Department of Trauma Surgery of České Budějovice Hospital, a.s. and in 2014 (1.1.-31.12.2014) at the Department of Orthopaedics and Traumatology of Písek Hospital, a.s. were evaluated. In total, 1 021 patients underwent surgery, with the mean age of 44 years. The patients were not selected. The group includes all the patients who underwent surgery, including those in whom repeat arthroscopy was performed, in the respective period of time, regardless of the mechanism of difficulties. A preoperative MRI scan was carried out in 470 patients. The referring physician was present during the examination. In all the patients undergoing surgery, the main clinical preoperative sign was examined based on the documentation, namely in the following order - hemarthros, locked knee, hydrops or merely a pain. In the arthroscopic finding, the medial meniscal lesion - anterior and posterior horn, and complete tear was assessed. The same was done for lateral meniscus. In anterior cruciate ligament - ACL - partial or complete tear was assessed. We identified the frequency of findings in relation to age and evaluated the correlations between the clinical signs and the arthroscopic finding. We calculated the sensitivity and specificity of hemarthros as a sign of ACL tear. The analysis was conducted based on the medical history in medical record documentation and the surgical protocol. The cartilage was not assessed. RESULTS Analysis of clinical and anamnestic signs in relation to arthroscopic findings 1. Negative arthroscopic findings (potential cartilage damage with no damage to other soft structures and normal arthroscopic findings) are in 83% accompanied by a mere knee pain. 2. High percentage of isolated locked joint (15%) in negative findings 3. Complete ACL tears are most frequently reported in the under-35 age category - 43% of 191 men who underwent surgery and 33% of 102 women. 4. Isolated injuries to ACL without the meniscus tear are frequent in younger patients - 30% - 40% of the total number of patients with injured ACL. 5. In patients older than 56 years of age the ACL damage is accompanied by concurrent meniscus tear (96% in men, 100% in women). 6. Sensitivity of hemarthros (68%) for complete ACL tear. Specificity of the presence of hemarthros in complete ACL lesions (91%) indicates that there are also complete ACL tears with no hemarthros whatsoever in the medical history. For partial tears the values of sensitivity and specificity are 27% and 67%, respectively. In partial tear, the presence of hemarthros is not a diagnostic lead. 7. In 15% of negative findings a \"locked knee\" was present. It was not a genuinely locked knee, but rather an antalgic position. Not every locked knee must necessarily mean a meniscus lesion or ACL tear. 8. Isolated meniscus tear is in 75% accompanied only by pain. 9. In our group of patients, isolated osteoarthrosis or malacic cartilage without any damage to ligaments or menisci was rare - only in 22 cases (2% of the entire group). DISCUSSION There are lots of studies which focus on comparing the clinical findings with perioperative pathology of knee joint and the importance of pre-operative clinical examination. Our extensive retrospective study proved that in 56-plus age category virtually each ACL injury is accompanied by a meniscal lesion, which can be explained by a possible ACL damage at a young age and subsequent instability resulting in meniscus tear or frequent presence of degenerative meniscal changes at an older age. A small number of isolated degenerative cartilage damage was established (2%). We fully agree with the authors who prove that the degenerative cartilage changes are ever since the very beginning accompanied by changes of the other soft structure of the knee. We revealed a high percentage of locked knee joint in negative arthroscopic findings. According to the clinical pre-operative examination, the locked knee does not automatically mean the meniscal lesion or ACL tear. In agreement with the others we prove a close association between hemarthros and ACL injury. CONCLUSIONS 1. A clinical examination, a detailed medical history is necessary 2. With hemarthros in medical history, there is a likelihood of complete ACL tear. Conversely, even a seemingly trivial knee sprain without hemarthros or locked knee can mean the ACL tear. 3. Where a mere pain is present, it mostly indicates an isolated meniscal damage or a negative finding. 4. Degenerative cartilage changes are accompanied by degeneration of menisci and ligaments. 5. Our group of patients did not include any case of hemarthros in the medical history with a negative arthroscopic finding. Hemarthros always indicated a more serious damage to knee soft structures. Key words: knee joint injuries, knee arthroscopy, sensitivity, specificity, hemarthros. Patellar tendinopathy is mainly a clinical diagnosis made through a detailed history and meticulous physical examination. Appropriate questions which will cue in the diagnosis: Sport practiced, schedule of practice and competition, which position the athlete plays, and level of performance. The patient will usually complain of well-localized pain and tenderness on the inferior tip of the patella. [12] [2]\nHere is the question:\nORTHOPEDIC SURGERY AND TRAUMATOLOGY: A 73-year-old woman with a history of obesity, type 2 diabetes mellitus, hypertension and dyslipidemia. She consults for unbearable pain in the right knee of 5 days of evolution, without previous trauma. Examination: globular knee, moderate varus, extension and flexion limited by pain, diffuse medial pain. X-ray shows osteophytes and mild impingement of the medial interlining. What would be his initial management?\nHere are the potential choices:\n1. Explanation of the diagnosis, relative rest, paracetamol 1g/8h plus metamizol 500 mg/ 8 h rescue naproxen.\n2. Preferential referral to Traumatology outpatients for evaluation of total cemented prosthesis.\n3. Preferential referral to Traumatology outpatient clinic for arthroscopic debridement.\n4. Preferred MRI request for evaluation of meniscopathy, Baker's cyst and/or tendinitis.\nThe correct answer is: 1. Explanation of the diagnosis, relative rest, paracetamol 1g/8h plus metamizol 500 mg/ 8 h rescue naproxen."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Acute pyrexia of unknown origin (Acute PUO) was reported to affect approximately 200,000-400,000 patients each year reported by the national Annual Epidemiological Surveillance Report. The patients usually present with fever of less than two-week duration and non-specific symptoms such as malaise, myalgia, headache and loss of appetite. Its mortality rate is less than 0.02 percent. It would be interesting to find the etiologies and propose a management plan if the etiologies are discovered. This prospective epidemiologic study aimed to discover the etiologies of acute undifferentiated febrile illness in a tropical region like Thailand. Ten community-based hospitals were chosen as representatives in each part of Thailand to enroll patients into the study. Patients aged over two years old who presented with fever at the participating hospitals during year 1991-1993 were eligible for the study. Entry criteria of acute undifferentiated febrile illnesses (AUFI) included oral temperature over 38.3 degrees C within the last 24 hours, duration of fever ranging from 3-14 days, no specific single organ involvement by history taking and physical examination, normal or non-specific results of the following investigations: complete blood count, thick film for malaria, urinalysis and chest roentgenogram. The patients were hospitalized and a preset diagnostic protocol was performed. Other diagnostic procedures deemed necessary by attending physicians were perform. Patients were followed up within one month after hospital discharge. 1,240 patients were enrolled but only 1,137 case records and results of the serological tests were available for analysis. Etiologies could be found in 471 cases (38.7%). Primary bacteremia was detected in 36 cases (3.2%). E. coli, streptococci, salmonella, Enterobacter spp. and S. aureus were the five most common blood isolates. Serological studies revealed positive results for scrub typhus (7.5%), influenza (6.0%), dengue fever (5.7%), murine typhus (5.3%), enteric fever (1.9%), chikunkunya infection (1.1%), leptospirosis (1.1%) and melioidosis (0.9%). Thirteen cases succumbed (1.1%) in this study. The etiologies in the majority (61.3%) of AUFI remained unknown. Rickettsial infection, influenza and dengue fever are the most common identifiable diseases in a tropical country like Thailand especially during the rainy season. A management guideline for diagnosis and treatment of the AUFI with emphasis on primary bacteremia and antimicrobial-treatable AUFI was proposed. Leptospirosis is frequently misdiagnosed as a result of its protean and nonspecific presentation. Leptospirosis, a zoonosis with global distribution, commonly occurs in tropical and subtropical regions; most reported cases in the United States occur in Hawaii. All laboratory-confirmed leptospirosis cases in the State of Hawaii from 1974 through 1998 (n=353) were clinically evaluated. The most common presentation involved nonspecific signs or symptoms, including fever, myalgia, and headache. Jaundice occurred in 39% of cases; conjunctival suffusion was described in 28% of these cases. Initiation of antibiotics before the seventh day of symptoms was associated with a significantly shortened duration of illness. Because early recognition and initiation of antibiotic therapy are important, clinicians should familiarize themselves with the clinical presentation of leptospirosis, and when evaluating a patient with a febrile illness, they should obtain exposure and travel histories and entertain the possibility of leptospirosis in the differential diagnosis. Leptospirosis is a zoonotic and disaster-related infectious disease. It is mainly endemic in subtropical or tropical countries and has not been reported since 2009 in the Tohoku region (northern Japan), including the Yamagata and Miyagi Prefectures. However, we experienced four patients with leptospirosis in the Tohoku region from 2012 to 2014; three patients (#1-3) live in the agricultural areas of the Yamagata Prefecture and one patient (#4) was a visitor to the Miyagi Prefecture. Patient 1 (81-year-old female) is a villager, with a rat bite, while Patient 2 (77-year-old male) and Patient 3 (84-year-old female) are farmers and were infected probably during agriculture work. Patient 4 (40-year-old male US citizen) was infected while traveling in Thailand. They had chief complaint of fever, headache, and myalgia and showed manifestations of hyperbilirubinemia (mean, 4.35 mg/dL), thrombocytopenia and acute kidney injury (AKI). All patients were diagnosed by polymerase chain reaction using blood and/or urine samples and a microscopic agglutination test for the anti-Leptospira antibody. All the patients were treated with infused antibiotics, including minocycline. The patients underwent hemodialysis due to severe AKI (mean serum creatinine, 4.44 mg/dL), except for Patient 2 with the normal serum creatinine level (1.12 mg/dL). All the patients recovered and were discharged. The presence of the three patients in the Yamagata Prefecture implies that leptospirosis does re-emerge in the Tohoku region. Therefore, careful survey of the pathogen is necessary for febrile patients with AKI who engage in agriculture or have a recent history of travelling in subtropical or tropical countries.  African tick-bite fever is an increasingly common cause for fever in the returning traveller. It needs to be considered in the febrile returning traveller with a characteristic rash: a black eschar. We describe a 51-year-old man returning from South Africa who presented to our emergency department with fever, headache, myalgia, and chills. On careful history and skin examination, a black eschar was found on the patient's left lateral shoulder, pointing toward a diagnosis of African tick-bite fever. The patient was treated with doxycycline and rapidly improved. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: In the emergency department, the diagnosis of African tick-bite fever is often overlooked in the pursuit of ruling out other travel-related illnesses, such as malaria. A thorough history, a complete physical examination, and a high level of suspicion are essential to the timely diagnosis and treatment of African tick-bite fever in the returning traveller. An increasing number of travelers from western countries visit tropical regions, questioning western physicians on the prophylaxis, the diagnosis and the therapeutic management of patients with travel-associated infection. In July 2014, a French couple stayed for an adventure-travel in Columbia without malaria prophylaxis. A week after their return the woman presented with fever, myalgia, and retro-orbital pain. Three days later, her husband presented similar symptoms. In both patients, testing for malaria, arboviruses and blood cultures remained negative. An empirical treatment with doxycycline and ceftriaxone was initiated for both patients. Serum collected from the female patient yielded positive IgM for leptospirosis but was negative for her husband. Positive Real-Time PCR were observed in blood and urine from both patients, confirming leptospirosis. Three lessons are noteworthy from this case report. First, after exclusion of malaria, as enteric fever, leptospirosis and rickettsial infection are the most prevalent travel-associated infections, empirical treatment with doxycycline and third generation cephalosporin should be considered. In addition, the diagnosis of leptospirosis requires both serology and PCR performed in both urine and blood samples. Finally, prophylaxis using doxycycline, also effective against leptospirosis, rickettsial infections or travellers' diarrhea should be recommended for adventure travelers in malaria endemic areas.  Severe leptospirosis rarely presents with primary pulmonary manifestations, without any associated jaundice or renal dysfunction. The authors report a nine-year-old boy who presented with complaints of abrupt onset of high fever; with myalgia, headache, and pain in right chest region, productive cough with hemoptysis and vomiting developing over the past 72 hours. Chest radiograph showed consolidation in the right upper lobe with air bronchogram. A history of contact with sewage water and presence of conjunctival suffusion in a child with pneumonia made us suspect leptospirosis. Following prompt initiation of parenteral penicillin therapy the child's complaints resolved over the next five days. Dri-Dot test to detect anti-Leptospira antibodies was positive. The diagnosis of leptospirosis was confirmed by a positive microagglutination test to Leptospira interrogans serovar Australis by a fourfold rise in antibody titer in paired sera collected during convalescence. Leptospirosis presenting with pulmonary hemorrhage has been associated with significant mortality but it can be successfully treated with early clinical suspicion of alveolar hemorrhage and prompt therapy. Fever in a traveller returning from an area endemic with malaria is a medical emergency. Although malaria is rare in Canada, it is one of the commonest communicable diseases in the world. A history of prophylaxis is no guarantee that malaria has not been contracted. This case history details an example of failed prophylaxis, emergency room presentation, and emergency treatment for Plasmodium falciparum. Clinical manifestations of the disease can occur up to six months after return from a malarial region, especially if chemoprophylaxis delays initial presentation. Symptoms include the sudden onset of chills, rigor, fever, profuse sweating, prostration, malaise, myalgia, headache, anorexia, nausea, vomiting and diarrhea. A single negative blood film does not exclude the diagnosis. Physicians in areas not endemic for schistosomiasis face considerable diagnostic challenges. In the most common clinical presentation, a traveler returns with symptoms and signs of acute syndromes of schistosomiasis—namely, cercarial dermatitis or Katayama syndrome. Central to a correct diagnosis is a thorough inquiry into the patient’s history of travel and exposure to freshwater bodies—whether slowor fast-running—in an endemic area. Differential diagnosis of fever in returned travelers includes a spectrum of infections whose etiologies are viral (e.g., dengue fever), bacterial (e.g., enteric fever, leptospirosis), rickettsial, or protozoal (e.g., malaria). In cases of Katayama syndrome, prompt diagnosis is essential and is based on clinical presentation, high-level peripheral-blood eosinophilia, and a positive serologic assay for schistosomal antibodies. Two tests are available at the CDC: the Falcon assay screening test/enzyme-linked immunosorbent assay (FAST-ELISA) and the The differential diagnosis for Leptospirosis is extremely large and varies from benign processes like viral upper respiratory tract infections, other viral flu-like illnesses, to severe infections from rarer \"travel\" conditions including Dengue Fever, malaria, Hantavirus, hemorrhagic fevers, and typhoid fever. Also consider other more common conditions (which one would be likely to consider unless specific exposure history is known) like cholecystitis, mononucleosis, primary HIV, or if unvaccinated measles or rubella. A 23 year old university student comes to see you with a febrile illness and a rash. She has just returned from a 6 week holiday in South East Asia having visited Thailand, Vietnam, Hong Kong and the Philippines. Prior to going away she went to a travel clinic, was appropriately immunised and given malaria prophylaxis which she has taken assiduously. Her symptoms have been present for about 3 days and consist of severe retro-orbital headache, diffuse myalgias, fevers and chills, and anorexia. The rash appeared the day before on her trunk and is now beginning to involve her arms with a slight papular element. She also has conjunctival haemorrhages and is febrile with a temperature of 38.9 degrees C. A full blood count done urgently does not show any malaria parasites but does reveal a low platelet count of 85,000 x 10(6)/L. Mild Leptospirosis Most patients are asymptomatic or only mildly ill and do not seek medical attention. Serologic evidence of past inapparent infection is frequently found in persons who have been exposed but have not become ill. Mild symptomatic leptospirosis usually presents as a flu-like illness of sudden onset, with fever, chills, headache, nausea, vomiting, abdominal pain, conjunctival suffusion (redness without exudate), and myalgia. Muscle pain is intense and especially affects the calves, back, and abdomen. The headache is intense, localized to the frontal or retroorbital region (resembling that occurring in dengue), and sometimes accompanied by photophobia. Aseptic meningitis may be present and is more common among children than among adults. Although Leptospira can be cultured from the cerebrospinal fluid (CSF) in the early phase, the majority of cases follow a benign course with regard to the central nervous system; symptoms disappear within a few days but may persist for The delayed onset of symptoms of leptospirosis can make it difficult to detect and distinguish. After an incubation period of typically 5 to 10 days, but potentially as early as 2 days and up to 30 days after infection, people infected with leptospira bacteria can develop flu-like symptoms including fever, chills, headache, myalgia (muscle pain), cough, vomiting, and diarrhea. The early signs are vague and often too general to be able to make a confident presumptive diagnosis of leptospirosis. In some cases, patients may present with only febrile illness with other differentials considered including meningitis, influenza, sepsis and many others. Other patients will present with the fulminant infection exhibiting signs of end stage liver failure, acute renal failure or severe pulmonary hemorrhage syndrome (SPHS). The test considered to be the gold standard for leptospirosis diagnosis by the WHO is one that is not very sensitive in the early stages of the disease, before the body The differential diagnosis of leptospirosis is broad, reflecting the diverse clinical presentations of the disease. Although leptospirosis transmission is more common in tropical and subtropical regions, the absence of a travel history does not exclude the diagnosis. When fever, headache, and myalgia predominate, influenza and other common and less common (e.g., dengue and chikungunya) viral infections should be considered. Malaria, typhoid fever, ehrlichiosis, viral hepatitis, and acute HIV infection may mimic the early stages of leptospirosis and are important to recognize. Rickettsial diseases, hantavirus infections (hemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome), and dengue share epidemiologic and clinical features with leptospirosis. Dual infections have been reported. In this light, it is advisable to conduct serologic testing for hantavirus, rickettsiae, and dengue virus when leptospirosis is suspected. When bleeding is detected, dengue Malaria is a very common cause of fever in tropical countries. The first symptoms of malaria are nonspecific; the lack of a sense of wellbeing, headache, fatigue, abdominal discomfort, and muscle aches followed by fever are all similar to the symptoms of a minor viral illness. In some instances, a prominence of headache, chest pain, abdominal pain, cough, arthralgia, myalgia, or diarrhea may suggest another diagnosis. Although headache may be severe in malaria, the neck stiffness and photophobia seen in meningitis do not occur. While myalgia may be prominent, it is not usually as severe as in dengue fever, and the muscles are not tender as in leptospirosis or typhus. Nausea, vomiting, and orthostatic hypotension are common. The classic malarial paroxysms, in which fever spikes, chills, and rigors occur at regular intervals, are relatively unusual and suggest infection with P. vivax or P. ovale. The fever is usually irregular at first (that of falciparum malaria may never become To the best of our knowledge, there are no reports of serological evidence of human leptospirosis from Uttarakhand state in India. The aim of this study was to screen for serological evidence of leptospirosis in patients with acute undifferentiated febrile illness at a tertiary care teaching hospital in Uttarakhand. A pilot study was conducted from March to November 2017. Fifty-three adult patients who presented in Medicine outpatient Department with a history of fever of ≥7 up to 14 days duration with or without other associated symptoms such as a headache, rashes, myalgia, arthralgia, and conjunctival suffusion were enrolled in the study using convenience sampling technique. Blood samples of these patients were collected and subjected to peripheral smear examination for malaria parasites, dengue immunoglobulin M (IgM) immunochromatographic card test, IgM Typhidot, Leptospira and Scrub typhus IgM ELISA, respectively. Aerobic blood culture was performed in 24 cases. Relevant clinico-epidemiological details were obtained as per the pro forma formulated in accordance with the modified Faine's criteria. Descriptive statistics. The study population consisted of 50.94% of males and 49.06% of females with a mean age ± standard deviation of 34.2 ± 15.2 years. Fifty febrile patients had additional symptoms of which myalgia was the most common (81.1%) followed by arthralgia (22.6%). Peripheral smears of all patients were negative for malaria parasites. Dengue and Typhidot IgM positivity was observed in two and eight patients, respectively. Six and five patients were tested positive by leptospira and scrub typhus IgM ELISA, respectively. <iSalmonella</i Typhi was isolated from blood sample of only one patient. Serum samples of two patients showed dual positivity. All six leptospira seropositive patients satisfied modified Faine's criteria. Leptospirosis is a seemingly unexplored infection in Uttarakhand and should be considered as a differential diagnosis in patients with acute undifferentiated febrile illness. Leptospirosis is a zoonotic infection that typically presents with fever, myalgias, nausea, and vomiting after contact with contaminated waters or infected animals (typically rodents); and their excrements. Conditions favorable to the transmission of leptospirosis are common in LA and, without treatment, leptospirosis can lead to both liver and renal failure, meningitis, pulmonary hemorrhage and ultimately death. A 56 year old woman with no past medical history presented to the Emergency Department with weakness, myalgias, jaundice and decreased urine output for one week. On arrival, she appeared septic with a heart rate of 130 and fever. Her exam was significant for significant jaundice and diffuse abdominal pain. Laboratory studies were notable for WBC 14, hemoglobin of 12 and platelet count of 63. Creatinine was 8.5mg/dL with a blood-urea nitrogen of 96mg/dl. Total bilirubin was 19.4mg/dL and direct bilirubin was 13.7mg/dL. AST/ALT were 69/38 U/L, respectively and the alkaline phosphate was 160U/L. The patient was admitted to the hospital medicine wards for sepsis and multi-organ failure. She was started on broad spectrum antibiotics but her clinical condition continued to worsen with progressive decline in her hemoglobin and thrombocytopenia and worsening liver failure. She quickly became anuric necessitating dialysis and developed respiratory distress with bilateral pulmonary infiltrates and hemoptysis. Additional history was obtained from her employer that she works at a local New Orleans bar and had been cleaning out rats from the kitchen. Leptospirosis antibody was sent, which returned as positive. Her antibiotics were de-escalated to IV Ceftriaxone. She made a slow recovery over the next two-week period. Since 1987, there has been an average of 3 cases of Leptospirosis diagnosed per year, most of which have been from southeast LA. This case illustrates the importance of considering the diagnosis of Leptospirosis and Weil's Disease in patients in the southeast region of LA who present with multi-organ failure. In addition, our patient's occupational exposure was key to her diagnosis which emphasizes the importance of a detailed history in clinical decision making and patient outcomes. The main symptom of O. tsutsugamushi infection is high (febrile) fever; however, the symptom is similar to other vector-borne tropical diseases such as malaria, leptospirosis, typhoid, murine typhus, chikungunya, and dengue fever. This makes precise clinical diagnosis difficult, which often leads to misdiagnosis. The initial indications are fever with chills, associated with headache, muscle pain (myalgia), sweating and vomiting. The appearance of symptoms (the incubation period) takes between 6 and 21 days. A simple visual diagnosis is the presence of an inflamed scar-like scab called eschar, which is regarded as \"the most useful diagnostic clue in patients with acute febrile illness\". Eschar is formed on the skin where an infected mite bit, usually seen in the armpit, groin or any abdominal area (Figure 7). In rare cases, it can be seen on the cheek, ear lobe and dorsum of the feet. But, the problem is that eschar is not always present; at the highest record, only 55% of scrub FIGuRE 211-2 Eschar at the site of the mite bite in a patient with rickettsialpox. (Reprinted from A Krusell et al: Emerg Infect Dis 8:727, 2002. Photo obtained by Dr. Kenneth Kaye.) FIGuRE 211-3 Top: Papulovesicular lesions on the trunk of the patient with rickettsialpox shown in Fig. 211-2. Bottom: Close-up of lesions from the same patient. (Reprinted from A Krusell et al: Emerg Infect Dis 8:727, 2002. Photos obtained by Dr. Kenneth Kaye.) 10–17 days, during which the eschar and regional lymphadenopathy frequently go unnoticed, disease onset is marked by malaise, chills, fever, headache, and myalgia. A macular rash appears 2–6 days after onset and usually evolves sequentially into papules, vesicles, and crusts that heal without scarring (Fig. 211-3); in some cases, the rash remains macular or maculopapular. Some patients develop nausea, vomiting, abdominal pain, cough, conjunctivitis, or photophobia. Without treatment, fever lasts 6–10 days. Since the initial discovery of Plasmodium knowlesi in Malaysia, cases have been reported from several neighbouring countries. Tourism has also resulted in an increasing number of cases diagnosed in Europe, America, and Oceania. In this review we focus on the risk of the travel-associated acquisition of P. knowlesi malaria. A search of the literature in PubMed was carried out to identify articles and literature on the distribution of P. knowlesi infections in Southeast Asia and details of its acquisition and importation by travellers to other continents. The cut-off date for the search was December 1, 2013. Search words used were: \"Plasmodium knowlesi\", \"Plasmodium knowlesi infections\", \"Plasmodium knowlesi travellers\", \"Plasmodium knowlesi prevalence\", \"Plasmodium knowlesi host\", \"Plasmodium knowlesi vector\" \"Plasmodium knowlesi RDT\", and \"Plasmodium knowlesi Malaysia\". Traveller numbers to Malaysia were obtained from the Tourism Malaysia website. A total of 103 articles were found. Using a selection of these and others identified from the reference lists of the papers, we based our review on a total of 66 articles. P. knowlesi malaria appears to be the most common malaria species in Malaysian Borneo and is also widely distributed on the Malaysian mainland. Furthermore, locally transmitted cases of P. knowlesi malaria have been reported in Thailand, the Philippines, Vietnam, Singapore, Myanmar, Indonesian Borneo, and Cambodia. Two cases have been reported from non-endemic countries in Asia (Japan and Taiwan) in people with a history of travel to Malaysia and the Philippines. Twelve cases were imported to their home countries by travellers from other continents: two from the USA, two from the Netherlands, two from Germany, and one each from Spain, France, Sweden, Finland, Australia, and New Zealand. In most cases, the infection was associated with a trip to or near forested areas. The symptoms were fever (n=12), headache (n=6), chills (n=6), nausea (n=4), myalgia (n=3), back pain (n=3), abdominal problems (n=1), anorexia (n=2), fatigue (n=2), malaise (n=1), arthralgia (n=1), sore throat (n=1) vomiting (n=2), and jaundice (n=1). All patients were treated successfully with currently available antimalaria treatments. The identification of the pathogen by microscopy can be problematic due to the morphological similarity of P. knowlesi to Plasmodium malariae. P. knowlesi appears to be a threat not only to the local population in Malaysia, but also to the estimated 25 million annual tourists and occupational travellers to Malaysia, especially those who visit rural, forested areas of the country. The P. knowlesi risk is not limited to Malaysia, and travellers from Southeast Asia presenting with possible malaria should be considered for a diagnostic work-up that includes P. knowlesi. We report 79 cases of acute schistosomiasis. Most of these cases were young, male travelers who acquired their infection in Lake Malawi. Twelve had a normal eosinophil count at presentation and 11 had negative serology, although two had neither eosinophilia nor positive serology when first seen. Acute schistosomiasis should be considered in any febrile traveler with a history of fresh water exposure in an endemic area once malaria has been excluded. Three unrelated patients presented within three months at the Central Hospital of Augsburg, Southern Germany, with jaundice of initially unknown etiology. Patient (Pt.) 1, a 51-year old man was admitted with a history of nausea, vomiting, diarrhea, jaundice and anuria. Pt. 2 was a 58-year-old man who had fever and shivering, and had developed jaundice after a fishing-trip to Canada. Pt. 3 was a 66-year-old woman who presented at the Emergency Unit with recently developed jaundice and pain in the right lateral epigastric area. Laboratory results showed elevated levels for bilirubin, CK, BUN, creatinine and low thrombocytes in patients 1 and 2. An elevated lipase level was found in Pt 1, while Pt 3 had an elevated bilirubin and thrombocytopenia. In Pt 1 and 2 active leptospirosis was diagnosed by serological tests. The third patient showed a subsided leptospirosis, the jaundice having been due to a histologically confirmed drug-associated hepatitis. Patients 1 and 2, who had active disease, showed the full-blown clinical picture of Weil's disease with jaundice, renal failure and thrombocytopenia. After administration of penicillin G and a third generation cephalosporin (ceftriaxone), respectively, all symptoms disappeared. The 66-year-old woman (Pt 3) developed pneumonia and died of multiple organ failure. Leptospirosis is an important differential diagnosis in patients with recent onset of jaundice and acute renal failure. A detailed history may offer the crucial hint and serological tests provide proof. The clinical outcome mainly depends on starting antimicrobial therapy with penicillin G or a third generation cephalosporin as soon as practicable. Following the Bataan Death March, Brown endured a three-year imprisonment in a Japanese POW camp from 1942 until he was liberated in the middle of September 1945. He ate nothing but rice while in the camp. Brown became afflicted with more than twelve diseases while in the camp, including dengue fever, malaria and dysentery. He also suffered a broken neck and back. He was released from the camp when he was 40 years old. He was nearly blind from maltreatment and had lost more than eighty pounds, then weighing less than one hundred pounds. A doctor told Brown that he would not live to be 50 years old due to the extent of his injuries. However, he lived to be 105 years old. Leptospirosis is a widespread zoonosis, which is diagnosed less frequently in children than might be expected from the level of exposure to hazards, especially in tropical areas. A 15 1/2-year-old Gabonese boy was admitted following five days of fever, headache, myalgia, abdominal pain, diarrhea, intestinal bleeding, jaundice and conjunctival suffusion. Laboratory data showed abnormal liver and renal function tests, and diagnosis of Plasmodium falciparum malaria was confirmed by thin blood smear. The patient did not clinically improve despite antimalarial treatment and then leptospirosis was suspected. Serologic tests were performed and leptospirosis was later confirmed. Antibiotic treatment (cefuroxim) was given. The outcome was good, liver and renal tests returned to normal in a few days. In tropical area, leptospirosis should be considered in children who are diagnosed with either an unexplained fever, a pseudo-influenza syndrome, or jaundice with hepatorenal involvement and gastrointestinal bleeding. The most important cause of fever in the returned traveler is malaria. All febrile patients in which malaria is epidemiologically possible require urgent evaluation for P. falciparum malaria, which can be rapidly fatal in the nonimmune patient. Early diagnosis and therapy can prevent severe morbidity and mortality. Other less common causes of undifferentiated fever include acute schistosomiasis, the enteric fevers, rickettsial diseases, leptospirosis, and dengue fever. Early empiric therapy for suspected leptospirosis and the rickettsial infections is encouraged to decrease morbidity and mortality. About a quarter of febrile patients do not have an etiologic agent determined for their illness but recover without sequelae. Patients with fever and hemorrhagic manifestations within 3 weeks of their return need to be isolated for the remote possibility of a highly transmissible agent. Although the febrile traveler is always a challenge, the real world differential diagnosis is limited and a systematic approach via the history, physical examination, and selected laboratory tests is usually sufficient to confirm the diagnosis or eliminate potentially serious infections.\nHere is the question:\nINFECTIOUS DISEASES: A 25-year-old man with no past history of interest presents to the emergency department with fever, headache, myalgia, nausea, vomiting, abdominal pain, jaundice and conjunctival injection, 2 weeks after traveling to Thailand to participate in a freshwater regatta. What is the most likely diagnosis?\nHere are the potential choices:\n1. Malaria.\n2. Schistosomiasis.\n3. Leptospirosis.\n4. Rabies.\nThe correct answer is: ",
        "gold_answer": "3 Leptospirosis.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Acute pyrexia of unknown origin (Acute PUO) was reported to affect approximately 200,000-400,000 patients each year reported by the national Annual Epidemiological Surveillance Report. The patients usually present with fever of less than two-week duration and non-specific symptoms such as malaise, myalgia, headache and loss of appetite. Its mortality rate is less than 0.02 percent. It would be interesting to find the etiologies and propose a management plan if the etiologies are discovered. This prospective epidemiologic study aimed to discover the etiologies of acute undifferentiated febrile illness in a tropical region like Thailand. Ten community-based hospitals were chosen as representatives in each part of Thailand to enroll patients into the study. Patients aged over two years old who presented with fever at the participating hospitals during year 1991-1993 were eligible for the study. Entry criteria of acute undifferentiated febrile illnesses (AUFI) included oral temperature over 38.3 degrees C within the last 24 hours, duration of fever ranging from 3-14 days, no specific single organ involvement by history taking and physical examination, normal or non-specific results of the following investigations: complete blood count, thick film for malaria, urinalysis and chest roentgenogram. The patients were hospitalized and a preset diagnostic protocol was performed. Other diagnostic procedures deemed necessary by attending physicians were perform. Patients were followed up within one month after hospital discharge. 1,240 patients were enrolled but only 1,137 case records and results of the serological tests were available for analysis. Etiologies could be found in 471 cases (38.7%). Primary bacteremia was detected in 36 cases (3.2%). E. coli, streptococci, salmonella, Enterobacter spp. and S. aureus were the five most common blood isolates. Serological studies revealed positive results for scrub typhus (7.5%), influenza (6.0%), dengue fever (5.7%), murine typhus (5.3%), enteric fever (1.9%), chikunkunya infection (1.1%), leptospirosis (1.1%) and melioidosis (0.9%). Thirteen cases succumbed (1.1%) in this study. The etiologies in the majority (61.3%) of AUFI remained unknown. Rickettsial infection, influenza and dengue fever are the most common identifiable diseases in a tropical country like Thailand especially during the rainy season. A management guideline for diagnosis and treatment of the AUFI with emphasis on primary bacteremia and antimicrobial-treatable AUFI was proposed. Leptospirosis is frequently misdiagnosed as a result of its protean and nonspecific presentation. Leptospirosis, a zoonosis with global distribution, commonly occurs in tropical and subtropical regions; most reported cases in the United States occur in Hawaii. All laboratory-confirmed leptospirosis cases in the State of Hawaii from 1974 through 1998 (n=353) were clinically evaluated. The most common presentation involved nonspecific signs or symptoms, including fever, myalgia, and headache. Jaundice occurred in 39% of cases; conjunctival suffusion was described in 28% of these cases. Initiation of antibiotics before the seventh day of symptoms was associated with a significantly shortened duration of illness. Because early recognition and initiation of antibiotic therapy are important, clinicians should familiarize themselves with the clinical presentation of leptospirosis, and when evaluating a patient with a febrile illness, they should obtain exposure and travel histories and entertain the possibility of leptospirosis in the differential diagnosis. Leptospirosis is a zoonotic and disaster-related infectious disease. It is mainly endemic in subtropical or tropical countries and has not been reported since 2009 in the Tohoku region (northern Japan), including the Yamagata and Miyagi Prefectures. However, we experienced four patients with leptospirosis in the Tohoku region from 2012 to 2014; three patients (#1-3) live in the agricultural areas of the Yamagata Prefecture and one patient (#4) was a visitor to the Miyagi Prefecture. Patient 1 (81-year-old female) is a villager, with a rat bite, while Patient 2 (77-year-old male) and Patient 3 (84-year-old female) are farmers and were infected probably during agriculture work. Patient 4 (40-year-old male US citizen) was infected while traveling in Thailand. They had chief complaint of fever, headache, and myalgia and showed manifestations of hyperbilirubinemia (mean, 4.35 mg/dL), thrombocytopenia and acute kidney injury (AKI). All patients were diagnosed by polymerase chain reaction using blood and/or urine samples and a microscopic agglutination test for the anti-Leptospira antibody. All the patients were treated with infused antibiotics, including minocycline. The patients underwent hemodialysis due to severe AKI (mean serum creatinine, 4.44 mg/dL), except for Patient 2 with the normal serum creatinine level (1.12 mg/dL). All the patients recovered and were discharged. The presence of the three patients in the Yamagata Prefecture implies that leptospirosis does re-emerge in the Tohoku region. Therefore, careful survey of the pathogen is necessary for febrile patients with AKI who engage in agriculture or have a recent history of travelling in subtropical or tropical countries.  African tick-bite fever is an increasingly common cause for fever in the returning traveller. It needs to be considered in the febrile returning traveller with a characteristic rash: a black eschar. We describe a 51-year-old man returning from South Africa who presented to our emergency department with fever, headache, myalgia, and chills. On careful history and skin examination, a black eschar was found on the patient's left lateral shoulder, pointing toward a diagnosis of African tick-bite fever. The patient was treated with doxycycline and rapidly improved. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: In the emergency department, the diagnosis of African tick-bite fever is often overlooked in the pursuit of ruling out other travel-related illnesses, such as malaria. A thorough history, a complete physical examination, and a high level of suspicion are essential to the timely diagnosis and treatment of African tick-bite fever in the returning traveller. An increasing number of travelers from western countries visit tropical regions, questioning western physicians on the prophylaxis, the diagnosis and the therapeutic management of patients with travel-associated infection. In July 2014, a French couple stayed for an adventure-travel in Columbia without malaria prophylaxis. A week after their return the woman presented with fever, myalgia, and retro-orbital pain. Three days later, her husband presented similar symptoms. In both patients, testing for malaria, arboviruses and blood cultures remained negative. An empirical treatment with doxycycline and ceftriaxone was initiated for both patients. Serum collected from the female patient yielded positive IgM for leptospirosis but was negative for her husband. Positive Real-Time PCR were observed in blood and urine from both patients, confirming leptospirosis. Three lessons are noteworthy from this case report. First, after exclusion of malaria, as enteric fever, leptospirosis and rickettsial infection are the most prevalent travel-associated infections, empirical treatment with doxycycline and third generation cephalosporin should be considered. In addition, the diagnosis of leptospirosis requires both serology and PCR performed in both urine and blood samples. Finally, prophylaxis using doxycycline, also effective against leptospirosis, rickettsial infections or travellers' diarrhea should be recommended for adventure travelers in malaria endemic areas.  Severe leptospirosis rarely presents with primary pulmonary manifestations, without any associated jaundice or renal dysfunction. The authors report a nine-year-old boy who presented with complaints of abrupt onset of high fever; with myalgia, headache, and pain in right chest region, productive cough with hemoptysis and vomiting developing over the past 72 hours. Chest radiograph showed consolidation in the right upper lobe with air bronchogram. A history of contact with sewage water and presence of conjunctival suffusion in a child with pneumonia made us suspect leptospirosis. Following prompt initiation of parenteral penicillin therapy the child's complaints resolved over the next five days. Dri-Dot test to detect anti-Leptospira antibodies was positive. The diagnosis of leptospirosis was confirmed by a positive microagglutination test to Leptospira interrogans serovar Australis by a fourfold rise in antibody titer in paired sera collected during convalescence. Leptospirosis presenting with pulmonary hemorrhage has been associated with significant mortality but it can be successfully treated with early clinical suspicion of alveolar hemorrhage and prompt therapy. Fever in a traveller returning from an area endemic with malaria is a medical emergency. Although malaria is rare in Canada, it is one of the commonest communicable diseases in the world. A history of prophylaxis is no guarantee that malaria has not been contracted. This case history details an example of failed prophylaxis, emergency room presentation, and emergency treatment for Plasmodium falciparum. Clinical manifestations of the disease can occur up to six months after return from a malarial region, especially if chemoprophylaxis delays initial presentation. Symptoms include the sudden onset of chills, rigor, fever, profuse sweating, prostration, malaise, myalgia, headache, anorexia, nausea, vomiting and diarrhea. A single negative blood film does not exclude the diagnosis. Physicians in areas not endemic for schistosomiasis face considerable diagnostic challenges. In the most common clinical presentation, a traveler returns with symptoms and signs of acute syndromes of schistosomiasis—namely, cercarial dermatitis or Katayama syndrome. Central to a correct diagnosis is a thorough inquiry into the patient’s history of travel and exposure to freshwater bodies—whether slowor fast-running—in an endemic area. Differential diagnosis of fever in returned travelers includes a spectrum of infections whose etiologies are viral (e.g., dengue fever), bacterial (e.g., enteric fever, leptospirosis), rickettsial, or protozoal (e.g., malaria). In cases of Katayama syndrome, prompt diagnosis is essential and is based on clinical presentation, high-level peripheral-blood eosinophilia, and a positive serologic assay for schistosomal antibodies. Two tests are available at the CDC: the Falcon assay screening test/enzyme-linked immunosorbent assay (FAST-ELISA) and the The differential diagnosis for Leptospirosis is extremely large and varies from benign processes like viral upper respiratory tract infections, other viral flu-like illnesses, to severe infections from rarer \"travel\" conditions including Dengue Fever, malaria, Hantavirus, hemorrhagic fevers, and typhoid fever. Also consider other more common conditions (which one would be likely to consider unless specific exposure history is known) like cholecystitis, mononucleosis, primary HIV, or if unvaccinated measles or rubella. A 23 year old university student comes to see you with a febrile illness and a rash. She has just returned from a 6 week holiday in South East Asia having visited Thailand, Vietnam, Hong Kong and the Philippines. Prior to going away she went to a travel clinic, was appropriately immunised and given malaria prophylaxis which she has taken assiduously. Her symptoms have been present for about 3 days and consist of severe retro-orbital headache, diffuse myalgias, fevers and chills, and anorexia. The rash appeared the day before on her trunk and is now beginning to involve her arms with a slight papular element. She also has conjunctival haemorrhages and is febrile with a temperature of 38.9 degrees C. A full blood count done urgently does not show any malaria parasites but does reveal a low platelet count of 85,000 x 10(6)/L. Mild Leptospirosis Most patients are asymptomatic or only mildly ill and do not seek medical attention. Serologic evidence of past inapparent infection is frequently found in persons who have been exposed but have not become ill. Mild symptomatic leptospirosis usually presents as a flu-like illness of sudden onset, with fever, chills, headache, nausea, vomiting, abdominal pain, conjunctival suffusion (redness without exudate), and myalgia. Muscle pain is intense and especially affects the calves, back, and abdomen. The headache is intense, localized to the frontal or retroorbital region (resembling that occurring in dengue), and sometimes accompanied by photophobia. Aseptic meningitis may be present and is more common among children than among adults. Although Leptospira can be cultured from the cerebrospinal fluid (CSF) in the early phase, the majority of cases follow a benign course with regard to the central nervous system; symptoms disappear within a few days but may persist for The delayed onset of symptoms of leptospirosis can make it difficult to detect and distinguish. After an incubation period of typically 5 to 10 days, but potentially as early as 2 days and up to 30 days after infection, people infected with leptospira bacteria can develop flu-like symptoms including fever, chills, headache, myalgia (muscle pain), cough, vomiting, and diarrhea. The early signs are vague and often too general to be able to make a confident presumptive diagnosis of leptospirosis. In some cases, patients may present with only febrile illness with other differentials considered including meningitis, influenza, sepsis and many others. Other patients will present with the fulminant infection exhibiting signs of end stage liver failure, acute renal failure or severe pulmonary hemorrhage syndrome (SPHS). The test considered to be the gold standard for leptospirosis diagnosis by the WHO is one that is not very sensitive in the early stages of the disease, before the body The differential diagnosis of leptospirosis is broad, reflecting the diverse clinical presentations of the disease. Although leptospirosis transmission is more common in tropical and subtropical regions, the absence of a travel history does not exclude the diagnosis. When fever, headache, and myalgia predominate, influenza and other common and less common (e.g., dengue and chikungunya) viral infections should be considered. Malaria, typhoid fever, ehrlichiosis, viral hepatitis, and acute HIV infection may mimic the early stages of leptospirosis and are important to recognize. Rickettsial diseases, hantavirus infections (hemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome), and dengue share epidemiologic and clinical features with leptospirosis. Dual infections have been reported. In this light, it is advisable to conduct serologic testing for hantavirus, rickettsiae, and dengue virus when leptospirosis is suspected. When bleeding is detected, dengue Malaria is a very common cause of fever in tropical countries. The first symptoms of malaria are nonspecific; the lack of a sense of wellbeing, headache, fatigue, abdominal discomfort, and muscle aches followed by fever are all similar to the symptoms of a minor viral illness. In some instances, a prominence of headache, chest pain, abdominal pain, cough, arthralgia, myalgia, or diarrhea may suggest another diagnosis. Although headache may be severe in malaria, the neck stiffness and photophobia seen in meningitis do not occur. While myalgia may be prominent, it is not usually as severe as in dengue fever, and the muscles are not tender as in leptospirosis or typhus. Nausea, vomiting, and orthostatic hypotension are common. The classic malarial paroxysms, in which fever spikes, chills, and rigors occur at regular intervals, are relatively unusual and suggest infection with P. vivax or P. ovale. The fever is usually irregular at first (that of falciparum malaria may never become To the best of our knowledge, there are no reports of serological evidence of human leptospirosis from Uttarakhand state in India. The aim of this study was to screen for serological evidence of leptospirosis in patients with acute undifferentiated febrile illness at a tertiary care teaching hospital in Uttarakhand. A pilot study was conducted from March to November 2017. Fifty-three adult patients who presented in Medicine outpatient Department with a history of fever of ≥7 up to 14 days duration with or without other associated symptoms such as a headache, rashes, myalgia, arthralgia, and conjunctival suffusion were enrolled in the study using convenience sampling technique. Blood samples of these patients were collected and subjected to peripheral smear examination for malaria parasites, dengue immunoglobulin M (IgM) immunochromatographic card test, IgM Typhidot, Leptospira and Scrub typhus IgM ELISA, respectively. Aerobic blood culture was performed in 24 cases. Relevant clinico-epidemiological details were obtained as per the pro forma formulated in accordance with the modified Faine's criteria. Descriptive statistics. The study population consisted of 50.94% of males and 49.06% of females with a mean age ± standard deviation of 34.2 ± 15.2 years. Fifty febrile patients had additional symptoms of which myalgia was the most common (81.1%) followed by arthralgia (22.6%). Peripheral smears of all patients were negative for malaria parasites. Dengue and Typhidot IgM positivity was observed in two and eight patients, respectively. Six and five patients were tested positive by leptospira and scrub typhus IgM ELISA, respectively. <iSalmonella</i Typhi was isolated from blood sample of only one patient. Serum samples of two patients showed dual positivity. All six leptospira seropositive patients satisfied modified Faine's criteria. Leptospirosis is a seemingly unexplored infection in Uttarakhand and should be considered as a differential diagnosis in patients with acute undifferentiated febrile illness. Leptospirosis is a zoonotic infection that typically presents with fever, myalgias, nausea, and vomiting after contact with contaminated waters or infected animals (typically rodents); and their excrements. Conditions favorable to the transmission of leptospirosis are common in LA and, without treatment, leptospirosis can lead to both liver and renal failure, meningitis, pulmonary hemorrhage and ultimately death. A 56 year old woman with no past medical history presented to the Emergency Department with weakness, myalgias, jaundice and decreased urine output for one week. On arrival, she appeared septic with a heart rate of 130 and fever. Her exam was significant for significant jaundice and diffuse abdominal pain. Laboratory studies were notable for WBC 14, hemoglobin of 12 and platelet count of 63. Creatinine was 8.5mg/dL with a blood-urea nitrogen of 96mg/dl. Total bilirubin was 19.4mg/dL and direct bilirubin was 13.7mg/dL. AST/ALT were 69/38 U/L, respectively and the alkaline phosphate was 160U/L. The patient was admitted to the hospital medicine wards for sepsis and multi-organ failure. She was started on broad spectrum antibiotics but her clinical condition continued to worsen with progressive decline in her hemoglobin and thrombocytopenia and worsening liver failure. She quickly became anuric necessitating dialysis and developed respiratory distress with bilateral pulmonary infiltrates and hemoptysis. Additional history was obtained from her employer that she works at a local New Orleans bar and had been cleaning out rats from the kitchen. Leptospirosis antibody was sent, which returned as positive. Her antibiotics were de-escalated to IV Ceftriaxone. She made a slow recovery over the next two-week period. Since 1987, there has been an average of 3 cases of Leptospirosis diagnosed per year, most of which have been from southeast LA. This case illustrates the importance of considering the diagnosis of Leptospirosis and Weil's Disease in patients in the southeast region of LA who present with multi-organ failure. In addition, our patient's occupational exposure was key to her diagnosis which emphasizes the importance of a detailed history in clinical decision making and patient outcomes. The main symptom of O. tsutsugamushi infection is high (febrile) fever; however, the symptom is similar to other vector-borne tropical diseases such as malaria, leptospirosis, typhoid, murine typhus, chikungunya, and dengue fever. This makes precise clinical diagnosis difficult, which often leads to misdiagnosis. The initial indications are fever with chills, associated with headache, muscle pain (myalgia), sweating and vomiting. The appearance of symptoms (the incubation period) takes between 6 and 21 days. A simple visual diagnosis is the presence of an inflamed scar-like scab called eschar, which is regarded as \"the most useful diagnostic clue in patients with acute febrile illness\". Eschar is formed on the skin where an infected mite bit, usually seen in the armpit, groin or any abdominal area (Figure 7). In rare cases, it can be seen on the cheek, ear lobe and dorsum of the feet. But, the problem is that eschar is not always present; at the highest record, only 55% of scrub FIGuRE 211-2 Eschar at the site of the mite bite in a patient with rickettsialpox. (Reprinted from A Krusell et al: Emerg Infect Dis 8:727, 2002. Photo obtained by Dr. Kenneth Kaye.) FIGuRE 211-3 Top: Papulovesicular lesions on the trunk of the patient with rickettsialpox shown in Fig. 211-2. Bottom: Close-up of lesions from the same patient. (Reprinted from A Krusell et al: Emerg Infect Dis 8:727, 2002. Photos obtained by Dr. Kenneth Kaye.) 10–17 days, during which the eschar and regional lymphadenopathy frequently go unnoticed, disease onset is marked by malaise, chills, fever, headache, and myalgia. A macular rash appears 2–6 days after onset and usually evolves sequentially into papules, vesicles, and crusts that heal without scarring (Fig. 211-3); in some cases, the rash remains macular or maculopapular. Some patients develop nausea, vomiting, abdominal pain, cough, conjunctivitis, or photophobia. Without treatment, fever lasts 6–10 days. Since the initial discovery of Plasmodium knowlesi in Malaysia, cases have been reported from several neighbouring countries. Tourism has also resulted in an increasing number of cases diagnosed in Europe, America, and Oceania. In this review we focus on the risk of the travel-associated acquisition of P. knowlesi malaria. A search of the literature in PubMed was carried out to identify articles and literature on the distribution of P. knowlesi infections in Southeast Asia and details of its acquisition and importation by travellers to other continents. The cut-off date for the search was December 1, 2013. Search words used were: \"Plasmodium knowlesi\", \"Plasmodium knowlesi infections\", \"Plasmodium knowlesi travellers\", \"Plasmodium knowlesi prevalence\", \"Plasmodium knowlesi host\", \"Plasmodium knowlesi vector\" \"Plasmodium knowlesi RDT\", and \"Plasmodium knowlesi Malaysia\". Traveller numbers to Malaysia were obtained from the Tourism Malaysia website. A total of 103 articles were found. Using a selection of these and others identified from the reference lists of the papers, we based our review on a total of 66 articles. P. knowlesi malaria appears to be the most common malaria species in Malaysian Borneo and is also widely distributed on the Malaysian mainland. Furthermore, locally transmitted cases of P. knowlesi malaria have been reported in Thailand, the Philippines, Vietnam, Singapore, Myanmar, Indonesian Borneo, and Cambodia. Two cases have been reported from non-endemic countries in Asia (Japan and Taiwan) in people with a history of travel to Malaysia and the Philippines. Twelve cases were imported to their home countries by travellers from other continents: two from the USA, two from the Netherlands, two from Germany, and one each from Spain, France, Sweden, Finland, Australia, and New Zealand. In most cases, the infection was associated with a trip to or near forested areas. The symptoms were fever (n=12), headache (n=6), chills (n=6), nausea (n=4), myalgia (n=3), back pain (n=3), abdominal problems (n=1), anorexia (n=2), fatigue (n=2), malaise (n=1), arthralgia (n=1), sore throat (n=1) vomiting (n=2), and jaundice (n=1). All patients were treated successfully with currently available antimalaria treatments. The identification of the pathogen by microscopy can be problematic due to the morphological similarity of P. knowlesi to Plasmodium malariae. P. knowlesi appears to be a threat not only to the local population in Malaysia, but also to the estimated 25 million annual tourists and occupational travellers to Malaysia, especially those who visit rural, forested areas of the country. The P. knowlesi risk is not limited to Malaysia, and travellers from Southeast Asia presenting with possible malaria should be considered for a diagnostic work-up that includes P. knowlesi. We report 79 cases of acute schistosomiasis. Most of these cases were young, male travelers who acquired their infection in Lake Malawi. Twelve had a normal eosinophil count at presentation and 11 had negative serology, although two had neither eosinophilia nor positive serology when first seen. Acute schistosomiasis should be considered in any febrile traveler with a history of fresh water exposure in an endemic area once malaria has been excluded. Three unrelated patients presented within three months at the Central Hospital of Augsburg, Southern Germany, with jaundice of initially unknown etiology. Patient (Pt.) 1, a 51-year old man was admitted with a history of nausea, vomiting, diarrhea, jaundice and anuria. Pt. 2 was a 58-year-old man who had fever and shivering, and had developed jaundice after a fishing-trip to Canada. Pt. 3 was a 66-year-old woman who presented at the Emergency Unit with recently developed jaundice and pain in the right lateral epigastric area. Laboratory results showed elevated levels for bilirubin, CK, BUN, creatinine and low thrombocytes in patients 1 and 2. An elevated lipase level was found in Pt 1, while Pt 3 had an elevated bilirubin and thrombocytopenia. In Pt 1 and 2 active leptospirosis was diagnosed by serological tests. The third patient showed a subsided leptospirosis, the jaundice having been due to a histologically confirmed drug-associated hepatitis. Patients 1 and 2, who had active disease, showed the full-blown clinical picture of Weil's disease with jaundice, renal failure and thrombocytopenia. After administration of penicillin G and a third generation cephalosporin (ceftriaxone), respectively, all symptoms disappeared. The 66-year-old woman (Pt 3) developed pneumonia and died of multiple organ failure. Leptospirosis is an important differential diagnosis in patients with recent onset of jaundice and acute renal failure. A detailed history may offer the crucial hint and serological tests provide proof. The clinical outcome mainly depends on starting antimicrobial therapy with penicillin G or a third generation cephalosporin as soon as practicable. Following the Bataan Death March, Brown endured a three-year imprisonment in a Japanese POW camp from 1942 until he was liberated in the middle of September 1945. He ate nothing but rice while in the camp. Brown became afflicted with more than twelve diseases while in the camp, including dengue fever, malaria and dysentery. He also suffered a broken neck and back. He was released from the camp when he was 40 years old. He was nearly blind from maltreatment and had lost more than eighty pounds, then weighing less than one hundred pounds. A doctor told Brown that he would not live to be 50 years old due to the extent of his injuries. However, he lived to be 105 years old. Leptospirosis is a widespread zoonosis, which is diagnosed less frequently in children than might be expected from the level of exposure to hazards, especially in tropical areas. A 15 1/2-year-old Gabonese boy was admitted following five days of fever, headache, myalgia, abdominal pain, diarrhea, intestinal bleeding, jaundice and conjunctival suffusion. Laboratory data showed abnormal liver and renal function tests, and diagnosis of Plasmodium falciparum malaria was confirmed by thin blood smear. The patient did not clinically improve despite antimalarial treatment and then leptospirosis was suspected. Serologic tests were performed and leptospirosis was later confirmed. Antibiotic treatment (cefuroxim) was given. The outcome was good, liver and renal tests returned to normal in a few days. In tropical area, leptospirosis should be considered in children who are diagnosed with either an unexplained fever, a pseudo-influenza syndrome, or jaundice with hepatorenal involvement and gastrointestinal bleeding. The most important cause of fever in the returned traveler is malaria. All febrile patients in which malaria is epidemiologically possible require urgent evaluation for P. falciparum malaria, which can be rapidly fatal in the nonimmune patient. Early diagnosis and therapy can prevent severe morbidity and mortality. Other less common causes of undifferentiated fever include acute schistosomiasis, the enteric fevers, rickettsial diseases, leptospirosis, and dengue fever. Early empiric therapy for suspected leptospirosis and the rickettsial infections is encouraged to decrease morbidity and mortality. About a quarter of febrile patients do not have an etiologic agent determined for their illness but recover without sequelae. Patients with fever and hemorrhagic manifestations within 3 weeks of their return need to be isolated for the remote possibility of a highly transmissible agent. Although the febrile traveler is always a challenge, the real world differential diagnosis is limited and a systematic approach via the history, physical examination, and selected laboratory tests is usually sufficient to confirm the diagnosis or eliminate potentially serious infections.\nHere is the question:\nINFECTIOUS DISEASES: A 25-year-old man with no past history of interest presents to the emergency department with fever, headache, myalgia, nausea, vomiting, abdominal pain, jaundice and conjunctival injection, 2 weeks after traveling to Thailand to participate in a freshwater regatta. What is the most likely diagnosis?\nHere are the potential choices:\n1. Malaria.\n2. Schistosomiasis.\n3. Leptospirosis.\n4. Rabies.\nThe correct answer is: 3. Leptospirosis."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Invasive pulmonary aspergillosis generally occurs in immunocompromised hosts such as patients with leukemia, and other malignancies, who are receiving anti-cancer chemotherapy. In this report, two non-immunocompromised patients who developed invasive pulmonary aspergillosis are presented. Case 1: A 63-year-old man complained of productive cough and fever. He received antibiotic therapy from his personal physician. This symptoms did not respond, however, and dyspnea developed. He was then transferred to our hospital, about one month after the onset. The chest X-ray showed a meniscus shadow suggesting an aspergilloma in the right upper lung field and an infiltrative shadow in the remaining right lung field. Case 2: A 78-year-old man was admitted because of dyspnea, productive cough and appetite loss over the previous three months. The chest X-ray showed a meniscus shadow in the left upper field, an infiltrative shadow in the left lower field and a right pleural effusion sign was also observed. Both cases were diagnosed as having aspergillosis, early in their illness, by the detection of aspergillus antigen in their sera and histopathological and cultural studies of specimens obtained by TBLB. Both improved with intravenous amphotericin B (30 mg/day) and intravenous ulinastatin (200000 IU/day) administration. On the examinations conducted during hospitalization, there was no evidence of any immunosuppressive diseases or immunoincompetent conditions such as leukemia, and other malignancies human immunodeficiency virus infection, diabetes or alcoholism. Bone metastases presenting with pain and body-ache may be the first presentation of carcinoma in about a fourth of patients with cancer. Radiologically majority of the metastases are osteolytic and multiple. Sometimes these may be confused with infective or inflammatory conditions, particularly in young individuals, and degenerative conditions of the spine and hip in elderly, which may delay the diagnosis and treatment leading to poor outcomes. A 30 year old non-smoking male teetotaller presented with intermittent, high-grade nocturnal fever with night sweats of one year. He also had low back ache over his right hip. We found him febrile, pale and his long bones, ribs and pelvis were tender. He had a 3 x 4 cm tender and hard swelling over the upper part of his sternum. Another firm, non-tender swelling about 4 x 5 cm was seen in the right iliac region. Radiographs of the skull, spine and pelvis revealed multiple variable sized lytic lesions. A metastatic malignancy or disseminated tuberculosis was considered. His anti-tubercular therapy was intensified Fine needle aspiration from sternal lesion showed inflammatory cells. A bone marrow biopsy showed infiltration by tumor cells suggestive of metastatic adenocarcinoma. Patient's condition continued to deteriorate and he died within a fortnight of his hospitalization. Although masquerading as tuberculosis lytic lesions might be an evidence of malignant metastatic. Although, treatment is ineffective in this stage palliative efforts to improve quality of life should be made. An elderly man without history of travel presented with complaints of intermittent fever for 2 months, cough with scanty expectoration for 15 days and history of weight loss of 5 kg in 1 year. The chest X-ray and CT scan of the thorax showed dispersed centrilobular nodules and patchy subpleural consolidation in both lungs with mediastinal lymphadenopathy. He underwent bronchoscopy and bronchoalveolar lavage culture grew <iPseudomonas aeruginosa</i He was prescribed antibiotics based on culture sensitivity; however, patient continued to have symptoms. All relevant blood investigations were within normal limits. He underwent CT-guided biopsy of the right lung lesion during which clearing of the radio-opacities present in the initial CT scan and appearance of fresh lesions in different locations were observed. Migratory shadows were suspected. Fine-needle aspiration cytology showed features suggestive of coccidioidomycosis for which antifungals were started. After 1 month, he improved symptomatically and chest X-ray showed clearance of shadows. CLINICAL MANIFESTATIONS Respiratory Tract Disease Pneumonia, the most common form of nocardial disease in the respiratory tract, is typically subacute; symptoms have usually been present for days or weeks at presentation. The onset is occasionally more acute in immunosuppressed patients. Cough is prominent and produces small amounts of thick, purulent sputum that is not malodorous. Fever, anorexia, weight loss, and malaise are common; dyspnea, pleuritic pain, and hemoptysis are less common. Remissions and exacerbations over several weeks are frequent. Roentgenographic patterns vary, but some are highly suggestive of nocardial pneumonia. Infiltrates vary in size and are typically dense. Single or multiple nodules are common (Figs. 199-1 and 199-2), sometimes suggesting tumors or metastases. Infiltrates and nodules tend to cavitate (Fig. 199-2). Empyema is present in one-quarter of cases. Co-infection with Nocardia and Mycobacterium tuberculosis has been reported from regions where Acute pulmonary infection is often diagnosed in association with point-source outbreaks. Typical symptoms include the abrupt onset of fever, chills, pleuritic chest pain, arthralgias, and myalgias. Cough is initially nonproductive but frequently becomes purulent as disease progresses. Chest radiographs usually reveal alveolar infiltrates with consolidation. Pleural effusions and hilar adenopathy are uncommon. Most patients diagnosed with pulmonary blastomycosis have chronic indolent pneumonia with signs and symptoms of fever, weight loss, productive cough, and hemoptysis. The most common radiologic findings are alveolar infiltrates with or without cavitation, mass lesions that mimic bronchogenic carcinoma, and fibronodular infiltrates. Hematogenous dissemination to the skin, bones, and genitourinary tract occurs most often in association with chronic pulmonary disease. Although blastomycosis is not considered an opportunistic infection, immunosuppression has been recognized as a risk Symptoms appear seven to 21 days post-exposure. Fever, cough, shortness of breath (SOB), and chest pain are most frequent. The clinical presentation may be acute or sub-acute based on the inoculum size. A headache, weight loss, and rash are often seen. The rash is faint, maculopapular, transient, occurs early during disease, and is, therefore, often missed. Erythema nodosum or erythema multiforme occurs more frequently in women. Migratory arthralgias are also common. The triad of fever, erythema nodosum, and arthralgias (especially of the knees and ankles) has been termed desert rheumatism. Laboratory findings include elevated erythrocyte sedimentation rate (ESR) and eosinophilia. Chest x-ray (CXR) shows unilateral infiltrates. Hilar and peritracheal adenopathy suggests the extrathoracic spread of the disease. Lung cavities are present in only 8% of adults but are more frequent in children. a flu-like illness with fever, chills, arthralgia (joint pain), myalgia (muscle pain), headache, and a nonproductive cough which resolves within days. an acute illness resembling bacterial pneumonia, with symptoms of high fever, chills, a productive cough, and pleuritic chest pain. a chronic illness that mimics tuberculosis or lung cancer, with symptoms of low-grade fever, a productive cough, night sweats, and weight loss. a fast, progressive, and severe disease that manifests as ARDS, with fever, shortness of breath, tachypnea, hypoxemia, and diffuse pulmonary infiltrates. skin lesions, usually asymptomatic, can be verrucous (wart-like) or ulcerated with small pustules at the margins. bone lytic lesions can cause bone or joint pain. prostatitis may be asymptomatic or may cause pain on urinating. laryngeal involvement causes hoarseness. 40% immunocompromised individuals have CNS involvement and present as brain abscess, epidural abscess or meningitis. To report the treatment of the first imported Middle East respiratory syndrome ( MERS ) in China, and to investigate the clinical features and treatment of the patient. On May 28th, 2015, the first patient of imported MERS to China was admitted to Department of Critical Care Medicine of Huizhou Municipal Central Hospital. The clinical features and treatments of this patient were analyzed. (1) A 43 years old male of South Korean nationality was admitted with the complaint of back ache for 7 days and fever 2 days with the following characteristics: back ache 7 days ago, without fever or cough or expectoration. He had been suspected to suffer from infection of Middle East respiratory syndrome coronavirus ( MERS-CoV ) by the Disease Control Department of South Korea, but no specific treatment was given. He had fever for 2 days with maximum body temperature of 39.7 centigrade. He had no chills, cough, expectoration, short of breath, abdominal pain, diarrhea, frequent micturition, or urgency or pain of urination, and no sore throat. The patient had a history of exposure to MERS-CoV patient. He was considered to be a patient of the second batch of South Korean epidemic. (2) Auxiliary examination: 3 copies of throat swab specimens for virus nucleic acid detection were performed by the Disease Prevention Control Center of China ( China CDC ), and they were positive on May 29th, 2015, and also for serum, sputum and stool. Based on the results of whole genome sequence analysis, the virus strains were implicated to be derived from Riyahh and Jeddah regions of Saudi Arabia. On admission, the patient's blood test showed that the white blood cell count was low ( 3.22×10(9)/L ), the proportion of the neutrophils was high ( 0.73 ), and that of the platelet was low ( 81×10(9)/L ). On admission, the patient's chest X-ray showed that a small amount of infiltration in the lung. (3) TREATMENT: a high-flow nasal cannula ( HFNC ) with oxygen concentration of 0.50-0.80 was given, with a flow rate was set at 60 L/min if tolerated. It was changed to a low flow oxygen inhalation nasal cannula on the 20th day, and oxygen treatment was stopped on the 24th day. Ribavirin 2.0 g was given as the first dose, and was switched to 600 mg every 8 h ( q8h ), and it was reduced to 600 mg q12h after 10 days, and extenuated since the 13th day. Ceftriaxone was added on the 4th day with 2.0 g a day , and it was changed to meropenem 2.0 g, q8h on the 7th day for 2 weeks. Gamma globulin was given for 7 days ( 20 g, qd ). Thymosin-α1 was given on the 8th day for 2 weeks. Interferon was given once a week, but only one dose was used. At the same time symptomatic treatment such as methimazole and liver protection therapy were given. (4) Patient began to cough at admission, and it disappeared on the 18th day. There was no sputum at first, then a small amount of sputum with a little blood appeared after the admission. Then there was cough without sputum. Mild shortness of breath and diarrhea after exertion were noticed. He had no chest pain, difficulty in breathing or other symptoms. There was dullness on percussion in both sides of chest, and it disappeared gradually. Fine moist rales were detectable in scapular area and interscapular area on the 5th day, and they disappeared after 3 days. Breath sounds on both sides was weak, and it became more obvious in the right lung after 5 days, and returned to normal after 18 days. He had a sustaining fever for 1 week with the maximum temperature of 39.5 centigrade, then the body temperature returned to normal. The viral nucleic acid test as performed by the Center for Disease Control of Guangdong ( CDC, Guangdong ) showed that the pharyngeal swab cultured turned negative on the 3rd day, that of serum specimens turned negative on the 8th day, that of stool specimen after 2 weeks, and it was persistently positive for sputum culture until 5 days before discharge. The oxygenation index gradually increased, and it was over 300 mmHg ( 1 mmHg = 0.133 kPa ) after 15 days. Pleural effusion was rapidly increased during the first week as shown by chest X-ray films, and it began to be absorbed gradually in the second week, but it was not completely absorbed until discharge. The disease course of the reported patient was short, with an acute onset, with fever as the chief complaint, but there were no respiratory symptoms, though there were high fever, cough, shortness of breath, diarrhea and other clinical symptoms after admission. Virus in sputum disappeared after treatment, but pleural effusion was not completely absorbed. Negative test for virus in sputum was late, indicating that clearance of virus was slow from the lungs. It is the first case of MERS in China, therefore, the clinical manifestations and the treatment strategy need to be further explored. A 71-year-old woman presented with suspected tuberculosis. She reported having productive coughs, unwanted weight loss and subfebrile temperature in the preceding 3 months. She was known to have chronic obstructive pulmonary disease treated with corticoids given systemically and by inhalation. She was a heavy smoker. Computed tomography revealed a left apical lung abscess. In the further course of the disease magnetic resonance imaging of the head demonstrated multiple abscesses in both cerebral hemispheres and an abscess, 3.4 cm in diameter, in the right side of the cerebellum, as well as a intra-orbital tumor on the right. Needle aspirate of the eyeball grew Nocardia farcinica. Over 3 weeks antimicrobial treatment was given with imipenem and amikacin, followed by oral cotrimoxazole for 12 months. The abscesses completely regressed and after 12 months no recurrence was demonstrated either radiologically or clinically. Although nocardiasis is rare in Germany it must be included in the differential diagnosis of pneumonia with abscesses. This is especially so if acid-fast bacilli are found. As the resistance pattern of N. farcinica to antibiotics varies, early treatment is essential with antibiotics to which it is sensitive. Invasive pulmonary aspergillosis (IPA) occurs predominantly in immunocompromised hosts, however increasing numbers of cases of IPA have been reported among basically immunocompetent patients who have some pulmonary abnormalities such as lung cancer and chronic obstructive pulmonary disease (COPD). Case 1. A 67-year-old man was admitted because of hemoptysis and purpura. He had COPD and small cell lung cancer and had finished chemotherapy 5 years previously. Chest X-ray showed pneumonia-like infiltration in his right lower lung field, and marked thrombocytopenia was pointed out. We started antibiotics and corticosteroids for community-acquired pneumonia (CAP) and idiopathic thrombocytopenic purpura. During treatment, we found Aspergillus fumigatus in his sputum culture and therefore added antifungal agents to his treatment. Despite intensive care, he died due to multi-organ dysfunction. Case 2. An 80-year-old man was admitted with fever and productive cough. He had COPD and non-small cell lung cancer and finished chemotherapy 2 months previously. Chest X-ray showed pneumonia-like infiltration in his right upper lung field. We started antibiotics and corticosteroids for acute exacerbation of COPD because of CAP. Several weeks later, after we observed initial improvement of his condition, pneumonia-like infiltration re-developed and Aspergillus fumigatus was detected in his sputum. We started antifungal agents and the treatment of IPA was successful, but he died because of idiopathic perforation of the sigmoid colon. In patients without myelosuppression, IPA could develop pneumonia-like pulmonary infiltrations. Pulmonary nocardiosis is an infrequent infection whose incidence seems to be increasing due to a higher degree of clinical suspicion and the increasing number of immunosuppressive factors. To study the predisposing factors, clinical characteristics, diagnostic procedures, treatment and progress of pulmonary nocardiosis (PN). Review of 10 patients (9 male, 1 female, mean age 61) with PN in a 600-bed teaching hospital, diagnosed from 1992 to 1999. Associated diseases observed were chronic obstructive pulmonary disease (COPD) in 6 patients, human immunodeficiency virus (HIV) infection in 3 and polymyalgia rheumatica in 1. Four patients had received oral corticotherapy for COPD for over a year (mean dose 13 mg/day of prednisone or equivalent). The main reason for consultation was an increase in dyspnea in the patients with COPD (6/6) and fever in those with HIV (3/3). Mean time between onset of symptoms and diagnosis was 5 weeks. In 8 patients, the infection occurred outside the hospital setting. The infection was restricted to the lung in 9/10; in the remaining case, the central nervous system (CNS) and subcutaneous tissue were affected. Lobar or multilobar consolidation was the most frequent radiographic pattern found (6/10). Sputum culture was positive when performed (8 cases). Diagnosis was made or confirmed by bronchoscopy (bronchoaspirate or protected specimen brush) in 5 patients. Germs isolated were: Nocardia asteroides (8/10), Nocardia farcinica (1/10), Nocardia otitidiscaviarum (1/10). Cotrimoxazole was the most used empirical treatment (6/10). Resolution was achieved in 5 cases. Four subjects died: 1 HIV patient with disseminated nocardiosis, and 3 COPD patients, 2 of whom had received long-term corticotherapy. Illness recurred in only 1 case, due to failure to comply with treatment. (1) In our geographical setting Nocardia presents as a subacute or chronic pulmonary infection, mainly outside the hospital. (2) It tends to affect only the lung. (3) Diagnosis requires a high clinical suspicion, and can be made on the basis of a sputum culture. (4) Nocardia tends to attack patients with underlying COPD, or immunodepressed patients treated with glucocorticoids, or patients with HIV infection. (5) Mortality is high in both COPD and HIV patients. (6) In our area, cotrimoxazole seems to be the most commonly prescribed treatment. Individuals with tuberculosis (TB) who are being treated with anti-tumor necrosis factor α (anti-TNFα) for coexisting conditions may experience unexpected exacerbations of TB after the initiation of antituberculous therapy, so-called anti-TNFα-induced TB-immune reconstitution inflammatory syndrome (anti-TNFα-induced TB-IRIS). Anti-TNFα-induced TB-IRIS is often treated empirically with corticosteroids; however, the evidence of the effectiveness of corticosteroids is lacking and the management can be a challenge. A 32-year-old man on long-term infliximab therapy for Crohn disease visited a clinic complaining of persistent fever and cough that had started 1 week previously. His most recent infliximab injection had been administered 14 days before the visit. A chest X-ray revealed a left pleural effusion, and he was admitted to a local hospital. A chest computed tomography (CT) scan revealed miliary pulmonary nodules; acid-fast bacilli were found in a sputum smear and a urine sediment sample; and polymerase chain reaction confirmed the presence of Mycobacterium tuberculosis in both his sputum and the pleural effusion. He was diagnosed with miliary TB. Antituberculous therapy was started and he was transferred to our hospital for further management. His symptoms initially improved after the initiation of antituberculous therapy, but 2 weeks later, his symptoms recurred and shadows on chest X-ray worsened. A repeat chest CT scan revealed enlarged miliary pulmonary nodules, extensive ground-glass opacities, and an increased volume of his pleural effusion. This paradoxical exacerbation was diagnosed as TB-IRIS associated with infliximab. A moderate-dose of systemic corticosteroid was initiated [prednisolone 25 mg/day (0.5 mg/kg/day)]. After starting corticosteroid treatment, his radiological findings improved immediately, and his fever and cough disappeared within a few days. After discharge, prednisolone was tapered off over the course of 10 weeks, and he completed a 9-month course of antituberculous therapy uneventfully. He had not restarted infliximab at his most recent follow-up 14 months later. We successfully managed a patient with anti-TNFα-induced TB-IRIS using moderate-dose corticosteroids. Due to the limited evidence currently available, physicians should consider the necessity, dosage, and duration of corticosteroids for each case of anti-TNFα-induced TB-IRIS on an individual patient-by-patient basis. We compared the clinical-radiographic presentations of bacteriologically proven tuberculosis in 72 elderly (mean age: 71 yr) and 73 younger patients (mean age: 39 yrs). The tuberculin test (2 TU PPD) was positive in 55% and 92%, respectively. The prevalence of cough, dyspnea, anorexia, and weight loss was higher in the elderly (p less than .05), and night sweats were more prevalent in the younger patients (p less than .01). The radiographic pattern was not different between both groups (p greater than .10): \"usual\" apicoposterior lesions (with or without other abnormalities) were found in more than 70% of both groups; isolated \"unusual\" lesions consisted in both groups mainly of anterobasal infiltrations and sometimes of pleural effusions, rounded nodules, or miliary patterns. Yet, initially a wrong diagnosis was made more often in the elderly (p = .05). Malignancy, chronic pulmonary disease, and immunosuppression were more frequently encountered in the elderly (p less than .05), whereas alcoholism and smoking were more frequent in the younger patients (p less than .001). Tuberculosis-related mortality occurred in 6 elderly and 1 younger patient. Pulmonary nocardiosis is a rare disorder that mainly affects immune-compromised patients. We report a 37-year-old male who presented with persistent fever associated with productive cough. During this course of therapy, he had recurrent admissions for empyema thoracic. Clinically, his vital signs were normal. Blood investigations show leukocytosis with a significantly raised erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Sputum acid-fast bacilli (AFB) was scanty 1+ and sputum mycobacterium culture was negative. Chest X-ray (CXR) showed consolidative changes with mild to moderate pleural effusion on the right side. Skin biopsy was taken and showed Paecilomyces species. A computed tomography scan (CT thorax) was performed and revealed a multiloculated collection within the right hemithorax with a split pleura sign. Decortications were performed and tissue culture and sensitivity (C+S) growth of <iNocardia</i species. And it is sensitive to sulfamethoxazole-trimethoprim and completed treatment for 4 months. This case highlights that pulmonary nocardiosis should be kept in mind in also immune-competent patients, especially in suspected cases of tuberculosis not responding to antitubercular therapy. Nocardiosis is known as an opportunistic infection in immunocompromised hosts, but it occasionally has been reported in immunocompetent patient. The Nocardia exalbida is first-reported in 2006 from Japan, and a few cases of have been reported in only immunocompromised host, and the characteristic is still unclear. We herein describe the first case of pulmonary nocardiosis caused by N. exalbida in an immunocompetent patient. A77 -year-old Japanese man was admitted to our hospital on November 2, 2018. He was a lifelong non-smoker with no childhood history of respiratory disease. He had a medical history of dyslipidemia. One month before this admission fevers, sputum, mild cough were developed and he was evaluated in a clinic near our hospital. His diagnosis was community acquired pneumonia within his right middle lobe. He was treated with ceftriaxone 1 g/day intravenously for a week, however his symptoms relapsed a few days later. So, the physician retried ceftriaxone for another 3 days, but his symptoms did not improve. He was referred to our hospital. He was treated with sitafloxacin as an outpatient for a week, however his symptoms got worse. The chest CT showed consolidation and atelectasis in his right middle lobe. Low density area was scattered in consolidation, and right pleural effusion was observed. The patient was diagnosed with pulmonary abscess and he was admitted. Administration of piperacillin/tazobactam improved his condition. We switched antibiotics to amoxicillin/clavulanate, and he was discharged. After 2 weeks, he relapsed and was admitted again. After administration of piperacillin/tazobactam for 3 weeks, we perform bronchoscopy and Nocardia species were cultured from samples of the bronchial wash. The isolates were identified as N. exalbida using 16S rRNA gene sequencing. We prescribed Trimethoprim / Sulfamethoxazole (TMP/SMX) for 4 months. Then we switched to minocycline for renal dysfunction caused from TMP-SMX for 1 more month. After 5 months therapy, Consolidation on CT disappeared, and Nocardiosis was cured. we reported the first case of pulmonary nocardiosis caused by N. exalbida in an immunocompetent patient. N. exalbida infection might be associated with a good response to treatment. A 49-year-old man presented with 3 months of persistent fever, cough, shortness of breath, and chest tightness. He had no response to treatment with antibiotics. He had been treated with an empiric 2-week course of steroids approximately 2 months before presentation, with mild and transient improvement. He did not use tobacco and had not experienced any weight loss, hemoptysis, arthralgia, or myalgia, and was otherwise in good health. He denied contact with anyone with pulmonary TB or other respiratory illnesses. Chronic Pulmonary Aspergillosis The hallmark of chronic cavitary pulmonary aspergillosis (also called semi-invasive aspergillosis, chronic necrotizing aspergillosis, or complex aspergilloma) (Fig. 241-1) is one or more pulmonary cavities expanding over a period of months or years in association with pulmonary symptoms and systemic manifestations such as fatigue and weight loss. (Pulmonary aspergillosis developing over <3 months is better classified as subacute invasive aspergillosis.) Often mistaken initially for tuberculosis, almost all cases occur in patients with prior pulmonary disease (e.g., tuberculosis, atypical mycobacterial infection, sarcoidosis, rheumatoid lung disease, pneumothorax, bullae) or lung surgery. The onset is insidious, and systemic features may be more prominent than pulmonary symptoms. Cavities may have a fluid level or a well-formed fungal ball, but pericavitary infiltrates and multiple cavities—with or without pleural thickening—are typical. An irregular\nHere is the question:\nPNEUMOLOGY AND THORACIC SURGERY: A 64-year-old patient, farmer, former smoker (5 years), COPD and afflicted with rheumatoid arthritis on corticosteroid therapy. He consults the emergency department for presenting intense headache of 2 days of evolution with deviation of the oral commissure. As background, he reports that after a month of influenza, he persists with cough, purulent and occasionally hemoptotic expectoration, febrile fever, anorexia, asthenia and weight loss. On arrival, the patient had a fever of 38.2ºC, multiple skin abscesses on the hands, back and buttocks (some with fistulous tracts) and right central facial paralysis, apical infiltrates with small associated pleural effusion on chest X-ray and leukocytosis with neutrophilia. Among the following suspected diagnoses I would consider MOST likely:\nHere are the potential choices:\n1. Lung neoplasm with brain metastases.\n2. Disseminated tuberculosis.\n3. Nocardiosis.\n4. Aspergillosis.\nThe correct answer is: ",
        "gold_answer": "4 Aspergillosis.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Invasive pulmonary aspergillosis generally occurs in immunocompromised hosts such as patients with leukemia, and other malignancies, who are receiving anti-cancer chemotherapy. In this report, two non-immunocompromised patients who developed invasive pulmonary aspergillosis are presented. Case 1: A 63-year-old man complained of productive cough and fever. He received antibiotic therapy from his personal physician. This symptoms did not respond, however, and dyspnea developed. He was then transferred to our hospital, about one month after the onset. The chest X-ray showed a meniscus shadow suggesting an aspergilloma in the right upper lung field and an infiltrative shadow in the remaining right lung field. Case 2: A 78-year-old man was admitted because of dyspnea, productive cough and appetite loss over the previous three months. The chest X-ray showed a meniscus shadow in the left upper field, an infiltrative shadow in the left lower field and a right pleural effusion sign was also observed. Both cases were diagnosed as having aspergillosis, early in their illness, by the detection of aspergillus antigen in their sera and histopathological and cultural studies of specimens obtained by TBLB. Both improved with intravenous amphotericin B (30 mg/day) and intravenous ulinastatin (200000 IU/day) administration. On the examinations conducted during hospitalization, there was no evidence of any immunosuppressive diseases or immunoincompetent conditions such as leukemia, and other malignancies human immunodeficiency virus infection, diabetes or alcoholism. Bone metastases presenting with pain and body-ache may be the first presentation of carcinoma in about a fourth of patients with cancer. Radiologically majority of the metastases are osteolytic and multiple. Sometimes these may be confused with infective or inflammatory conditions, particularly in young individuals, and degenerative conditions of the spine and hip in elderly, which may delay the diagnosis and treatment leading to poor outcomes. A 30 year old non-smoking male teetotaller presented with intermittent, high-grade nocturnal fever with night sweats of one year. He also had low back ache over his right hip. We found him febrile, pale and his long bones, ribs and pelvis were tender. He had a 3 x 4 cm tender and hard swelling over the upper part of his sternum. Another firm, non-tender swelling about 4 x 5 cm was seen in the right iliac region. Radiographs of the skull, spine and pelvis revealed multiple variable sized lytic lesions. A metastatic malignancy or disseminated tuberculosis was considered. His anti-tubercular therapy was intensified Fine needle aspiration from sternal lesion showed inflammatory cells. A bone marrow biopsy showed infiltration by tumor cells suggestive of metastatic adenocarcinoma. Patient's condition continued to deteriorate and he died within a fortnight of his hospitalization. Although masquerading as tuberculosis lytic lesions might be an evidence of malignant metastatic. Although, treatment is ineffective in this stage palliative efforts to improve quality of life should be made. An elderly man without history of travel presented with complaints of intermittent fever for 2 months, cough with scanty expectoration for 15 days and history of weight loss of 5 kg in 1 year. The chest X-ray and CT scan of the thorax showed dispersed centrilobular nodules and patchy subpleural consolidation in both lungs with mediastinal lymphadenopathy. He underwent bronchoscopy and bronchoalveolar lavage culture grew <iPseudomonas aeruginosa</i He was prescribed antibiotics based on culture sensitivity; however, patient continued to have symptoms. All relevant blood investigations were within normal limits. He underwent CT-guided biopsy of the right lung lesion during which clearing of the radio-opacities present in the initial CT scan and appearance of fresh lesions in different locations were observed. Migratory shadows were suspected. Fine-needle aspiration cytology showed features suggestive of coccidioidomycosis for which antifungals were started. After 1 month, he improved symptomatically and chest X-ray showed clearance of shadows. CLINICAL MANIFESTATIONS Respiratory Tract Disease Pneumonia, the most common form of nocardial disease in the respiratory tract, is typically subacute; symptoms have usually been present for days or weeks at presentation. The onset is occasionally more acute in immunosuppressed patients. Cough is prominent and produces small amounts of thick, purulent sputum that is not malodorous. Fever, anorexia, weight loss, and malaise are common; dyspnea, pleuritic pain, and hemoptysis are less common. Remissions and exacerbations over several weeks are frequent. Roentgenographic patterns vary, but some are highly suggestive of nocardial pneumonia. Infiltrates vary in size and are typically dense. Single or multiple nodules are common (Figs. 199-1 and 199-2), sometimes suggesting tumors or metastases. Infiltrates and nodules tend to cavitate (Fig. 199-2). Empyema is present in one-quarter of cases. Co-infection with Nocardia and Mycobacterium tuberculosis has been reported from regions where Acute pulmonary infection is often diagnosed in association with point-source outbreaks. Typical symptoms include the abrupt onset of fever, chills, pleuritic chest pain, arthralgias, and myalgias. Cough is initially nonproductive but frequently becomes purulent as disease progresses. Chest radiographs usually reveal alveolar infiltrates with consolidation. Pleural effusions and hilar adenopathy are uncommon. Most patients diagnosed with pulmonary blastomycosis have chronic indolent pneumonia with signs and symptoms of fever, weight loss, productive cough, and hemoptysis. The most common radiologic findings are alveolar infiltrates with or without cavitation, mass lesions that mimic bronchogenic carcinoma, and fibronodular infiltrates. Hematogenous dissemination to the skin, bones, and genitourinary tract occurs most often in association with chronic pulmonary disease. Although blastomycosis is not considered an opportunistic infection, immunosuppression has been recognized as a risk Symptoms appear seven to 21 days post-exposure. Fever, cough, shortness of breath (SOB), and chest pain are most frequent. The clinical presentation may be acute or sub-acute based on the inoculum size. A headache, weight loss, and rash are often seen. The rash is faint, maculopapular, transient, occurs early during disease, and is, therefore, often missed. Erythema nodosum or erythema multiforme occurs more frequently in women. Migratory arthralgias are also common. The triad of fever, erythema nodosum, and arthralgias (especially of the knees and ankles) has been termed desert rheumatism. Laboratory findings include elevated erythrocyte sedimentation rate (ESR) and eosinophilia. Chest x-ray (CXR) shows unilateral infiltrates. Hilar and peritracheal adenopathy suggests the extrathoracic spread of the disease. Lung cavities are present in only 8% of adults but are more frequent in children. a flu-like illness with fever, chills, arthralgia (joint pain), myalgia (muscle pain), headache, and a nonproductive cough which resolves within days. an acute illness resembling bacterial pneumonia, with symptoms of high fever, chills, a productive cough, and pleuritic chest pain. a chronic illness that mimics tuberculosis or lung cancer, with symptoms of low-grade fever, a productive cough, night sweats, and weight loss. a fast, progressive, and severe disease that manifests as ARDS, with fever, shortness of breath, tachypnea, hypoxemia, and diffuse pulmonary infiltrates. skin lesions, usually asymptomatic, can be verrucous (wart-like) or ulcerated with small pustules at the margins. bone lytic lesions can cause bone or joint pain. prostatitis may be asymptomatic or may cause pain on urinating. laryngeal involvement causes hoarseness. 40% immunocompromised individuals have CNS involvement and present as brain abscess, epidural abscess or meningitis. To report the treatment of the first imported Middle East respiratory syndrome ( MERS ) in China, and to investigate the clinical features and treatment of the patient. On May 28th, 2015, the first patient of imported MERS to China was admitted to Department of Critical Care Medicine of Huizhou Municipal Central Hospital. The clinical features and treatments of this patient were analyzed. (1) A 43 years old male of South Korean nationality was admitted with the complaint of back ache for 7 days and fever 2 days with the following characteristics: back ache 7 days ago, without fever or cough or expectoration. He had been suspected to suffer from infection of Middle East respiratory syndrome coronavirus ( MERS-CoV ) by the Disease Control Department of South Korea, but no specific treatment was given. He had fever for 2 days with maximum body temperature of 39.7 centigrade. He had no chills, cough, expectoration, short of breath, abdominal pain, diarrhea, frequent micturition, or urgency or pain of urination, and no sore throat. The patient had a history of exposure to MERS-CoV patient. He was considered to be a patient of the second batch of South Korean epidemic. (2) Auxiliary examination: 3 copies of throat swab specimens for virus nucleic acid detection were performed by the Disease Prevention Control Center of China ( China CDC ), and they were positive on May 29th, 2015, and also for serum, sputum and stool. Based on the results of whole genome sequence analysis, the virus strains were implicated to be derived from Riyahh and Jeddah regions of Saudi Arabia. On admission, the patient's blood test showed that the white blood cell count was low ( 3.22×10(9)/L ), the proportion of the neutrophils was high ( 0.73 ), and that of the platelet was low ( 81×10(9)/L ). On admission, the patient's chest X-ray showed that a small amount of infiltration in the lung. (3) TREATMENT: a high-flow nasal cannula ( HFNC ) with oxygen concentration of 0.50-0.80 was given, with a flow rate was set at 60 L/min if tolerated. It was changed to a low flow oxygen inhalation nasal cannula on the 20th day, and oxygen treatment was stopped on the 24th day. Ribavirin 2.0 g was given as the first dose, and was switched to 600 mg every 8 h ( q8h ), and it was reduced to 600 mg q12h after 10 days, and extenuated since the 13th day. Ceftriaxone was added on the 4th day with 2.0 g a day , and it was changed to meropenem 2.0 g, q8h on the 7th day for 2 weeks. Gamma globulin was given for 7 days ( 20 g, qd ). Thymosin-α1 was given on the 8th day for 2 weeks. Interferon was given once a week, but only one dose was used. At the same time symptomatic treatment such as methimazole and liver protection therapy were given. (4) Patient began to cough at admission, and it disappeared on the 18th day. There was no sputum at first, then a small amount of sputum with a little blood appeared after the admission. Then there was cough without sputum. Mild shortness of breath and diarrhea after exertion were noticed. He had no chest pain, difficulty in breathing or other symptoms. There was dullness on percussion in both sides of chest, and it disappeared gradually. Fine moist rales were detectable in scapular area and interscapular area on the 5th day, and they disappeared after 3 days. Breath sounds on both sides was weak, and it became more obvious in the right lung after 5 days, and returned to normal after 18 days. He had a sustaining fever for 1 week with the maximum temperature of 39.5 centigrade, then the body temperature returned to normal. The viral nucleic acid test as performed by the Center for Disease Control of Guangdong ( CDC, Guangdong ) showed that the pharyngeal swab cultured turned negative on the 3rd day, that of serum specimens turned negative on the 8th day, that of stool specimen after 2 weeks, and it was persistently positive for sputum culture until 5 days before discharge. The oxygenation index gradually increased, and it was over 300 mmHg ( 1 mmHg = 0.133 kPa ) after 15 days. Pleural effusion was rapidly increased during the first week as shown by chest X-ray films, and it began to be absorbed gradually in the second week, but it was not completely absorbed until discharge. The disease course of the reported patient was short, with an acute onset, with fever as the chief complaint, but there were no respiratory symptoms, though there were high fever, cough, shortness of breath, diarrhea and other clinical symptoms after admission. Virus in sputum disappeared after treatment, but pleural effusion was not completely absorbed. Negative test for virus in sputum was late, indicating that clearance of virus was slow from the lungs. It is the first case of MERS in China, therefore, the clinical manifestations and the treatment strategy need to be further explored. A 71-year-old woman presented with suspected tuberculosis. She reported having productive coughs, unwanted weight loss and subfebrile temperature in the preceding 3 months. She was known to have chronic obstructive pulmonary disease treated with corticoids given systemically and by inhalation. She was a heavy smoker. Computed tomography revealed a left apical lung abscess. In the further course of the disease magnetic resonance imaging of the head demonstrated multiple abscesses in both cerebral hemispheres and an abscess, 3.4 cm in diameter, in the right side of the cerebellum, as well as a intra-orbital tumor on the right. Needle aspirate of the eyeball grew Nocardia farcinica. Over 3 weeks antimicrobial treatment was given with imipenem and amikacin, followed by oral cotrimoxazole for 12 months. The abscesses completely regressed and after 12 months no recurrence was demonstrated either radiologically or clinically. Although nocardiasis is rare in Germany it must be included in the differential diagnosis of pneumonia with abscesses. This is especially so if acid-fast bacilli are found. As the resistance pattern of N. farcinica to antibiotics varies, early treatment is essential with antibiotics to which it is sensitive. Invasive pulmonary aspergillosis (IPA) occurs predominantly in immunocompromised hosts, however increasing numbers of cases of IPA have been reported among basically immunocompetent patients who have some pulmonary abnormalities such as lung cancer and chronic obstructive pulmonary disease (COPD). Case 1. A 67-year-old man was admitted because of hemoptysis and purpura. He had COPD and small cell lung cancer and had finished chemotherapy 5 years previously. Chest X-ray showed pneumonia-like infiltration in his right lower lung field, and marked thrombocytopenia was pointed out. We started antibiotics and corticosteroids for community-acquired pneumonia (CAP) and idiopathic thrombocytopenic purpura. During treatment, we found Aspergillus fumigatus in his sputum culture and therefore added antifungal agents to his treatment. Despite intensive care, he died due to multi-organ dysfunction. Case 2. An 80-year-old man was admitted with fever and productive cough. He had COPD and non-small cell lung cancer and finished chemotherapy 2 months previously. Chest X-ray showed pneumonia-like infiltration in his right upper lung field. We started antibiotics and corticosteroids for acute exacerbation of COPD because of CAP. Several weeks later, after we observed initial improvement of his condition, pneumonia-like infiltration re-developed and Aspergillus fumigatus was detected in his sputum. We started antifungal agents and the treatment of IPA was successful, but he died because of idiopathic perforation of the sigmoid colon. In patients without myelosuppression, IPA could develop pneumonia-like pulmonary infiltrations. Pulmonary nocardiosis is an infrequent infection whose incidence seems to be increasing due to a higher degree of clinical suspicion and the increasing number of immunosuppressive factors. To study the predisposing factors, clinical characteristics, diagnostic procedures, treatment and progress of pulmonary nocardiosis (PN). Review of 10 patients (9 male, 1 female, mean age 61) with PN in a 600-bed teaching hospital, diagnosed from 1992 to 1999. Associated diseases observed were chronic obstructive pulmonary disease (COPD) in 6 patients, human immunodeficiency virus (HIV) infection in 3 and polymyalgia rheumatica in 1. Four patients had received oral corticotherapy for COPD for over a year (mean dose 13 mg/day of prednisone or equivalent). The main reason for consultation was an increase in dyspnea in the patients with COPD (6/6) and fever in those with HIV (3/3). Mean time between onset of symptoms and diagnosis was 5 weeks. In 8 patients, the infection occurred outside the hospital setting. The infection was restricted to the lung in 9/10; in the remaining case, the central nervous system (CNS) and subcutaneous tissue were affected. Lobar or multilobar consolidation was the most frequent radiographic pattern found (6/10). Sputum culture was positive when performed (8 cases). Diagnosis was made or confirmed by bronchoscopy (bronchoaspirate or protected specimen brush) in 5 patients. Germs isolated were: Nocardia asteroides (8/10), Nocardia farcinica (1/10), Nocardia otitidiscaviarum (1/10). Cotrimoxazole was the most used empirical treatment (6/10). Resolution was achieved in 5 cases. Four subjects died: 1 HIV patient with disseminated nocardiosis, and 3 COPD patients, 2 of whom had received long-term corticotherapy. Illness recurred in only 1 case, due to failure to comply with treatment. (1) In our geographical setting Nocardia presents as a subacute or chronic pulmonary infection, mainly outside the hospital. (2) It tends to affect only the lung. (3) Diagnosis requires a high clinical suspicion, and can be made on the basis of a sputum culture. (4) Nocardia tends to attack patients with underlying COPD, or immunodepressed patients treated with glucocorticoids, or patients with HIV infection. (5) Mortality is high in both COPD and HIV patients. (6) In our area, cotrimoxazole seems to be the most commonly prescribed treatment. Individuals with tuberculosis (TB) who are being treated with anti-tumor necrosis factor α (anti-TNFα) for coexisting conditions may experience unexpected exacerbations of TB after the initiation of antituberculous therapy, so-called anti-TNFα-induced TB-immune reconstitution inflammatory syndrome (anti-TNFα-induced TB-IRIS). Anti-TNFα-induced TB-IRIS is often treated empirically with corticosteroids; however, the evidence of the effectiveness of corticosteroids is lacking and the management can be a challenge. A 32-year-old man on long-term infliximab therapy for Crohn disease visited a clinic complaining of persistent fever and cough that had started 1 week previously. His most recent infliximab injection had been administered 14 days before the visit. A chest X-ray revealed a left pleural effusion, and he was admitted to a local hospital. A chest computed tomography (CT) scan revealed miliary pulmonary nodules; acid-fast bacilli were found in a sputum smear and a urine sediment sample; and polymerase chain reaction confirmed the presence of Mycobacterium tuberculosis in both his sputum and the pleural effusion. He was diagnosed with miliary TB. Antituberculous therapy was started and he was transferred to our hospital for further management. His symptoms initially improved after the initiation of antituberculous therapy, but 2 weeks later, his symptoms recurred and shadows on chest X-ray worsened. A repeat chest CT scan revealed enlarged miliary pulmonary nodules, extensive ground-glass opacities, and an increased volume of his pleural effusion. This paradoxical exacerbation was diagnosed as TB-IRIS associated with infliximab. A moderate-dose of systemic corticosteroid was initiated [prednisolone 25 mg/day (0.5 mg/kg/day)]. After starting corticosteroid treatment, his radiological findings improved immediately, and his fever and cough disappeared within a few days. After discharge, prednisolone was tapered off over the course of 10 weeks, and he completed a 9-month course of antituberculous therapy uneventfully. He had not restarted infliximab at his most recent follow-up 14 months later. We successfully managed a patient with anti-TNFα-induced TB-IRIS using moderate-dose corticosteroids. Due to the limited evidence currently available, physicians should consider the necessity, dosage, and duration of corticosteroids for each case of anti-TNFα-induced TB-IRIS on an individual patient-by-patient basis. We compared the clinical-radiographic presentations of bacteriologically proven tuberculosis in 72 elderly (mean age: 71 yr) and 73 younger patients (mean age: 39 yrs). The tuberculin test (2 TU PPD) was positive in 55% and 92%, respectively. The prevalence of cough, dyspnea, anorexia, and weight loss was higher in the elderly (p less than .05), and night sweats were more prevalent in the younger patients (p less than .01). The radiographic pattern was not different between both groups (p greater than .10): \"usual\" apicoposterior lesions (with or without other abnormalities) were found in more than 70% of both groups; isolated \"unusual\" lesions consisted in both groups mainly of anterobasal infiltrations and sometimes of pleural effusions, rounded nodules, or miliary patterns. Yet, initially a wrong diagnosis was made more often in the elderly (p = .05). Malignancy, chronic pulmonary disease, and immunosuppression were more frequently encountered in the elderly (p less than .05), whereas alcoholism and smoking were more frequent in the younger patients (p less than .001). Tuberculosis-related mortality occurred in 6 elderly and 1 younger patient. Pulmonary nocardiosis is a rare disorder that mainly affects immune-compromised patients. We report a 37-year-old male who presented with persistent fever associated with productive cough. During this course of therapy, he had recurrent admissions for empyema thoracic. Clinically, his vital signs were normal. Blood investigations show leukocytosis with a significantly raised erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Sputum acid-fast bacilli (AFB) was scanty 1+ and sputum mycobacterium culture was negative. Chest X-ray (CXR) showed consolidative changes with mild to moderate pleural effusion on the right side. Skin biopsy was taken and showed Paecilomyces species. A computed tomography scan (CT thorax) was performed and revealed a multiloculated collection within the right hemithorax with a split pleura sign. Decortications were performed and tissue culture and sensitivity (C+S) growth of <iNocardia</i species. And it is sensitive to sulfamethoxazole-trimethoprim and completed treatment for 4 months. This case highlights that pulmonary nocardiosis should be kept in mind in also immune-competent patients, especially in suspected cases of tuberculosis not responding to antitubercular therapy. Nocardiosis is known as an opportunistic infection in immunocompromised hosts, but it occasionally has been reported in immunocompetent patient. The Nocardia exalbida is first-reported in 2006 from Japan, and a few cases of have been reported in only immunocompromised host, and the characteristic is still unclear. We herein describe the first case of pulmonary nocardiosis caused by N. exalbida in an immunocompetent patient. A77 -year-old Japanese man was admitted to our hospital on November 2, 2018. He was a lifelong non-smoker with no childhood history of respiratory disease. He had a medical history of dyslipidemia. One month before this admission fevers, sputum, mild cough were developed and he was evaluated in a clinic near our hospital. His diagnosis was community acquired pneumonia within his right middle lobe. He was treated with ceftriaxone 1 g/day intravenously for a week, however his symptoms relapsed a few days later. So, the physician retried ceftriaxone for another 3 days, but his symptoms did not improve. He was referred to our hospital. He was treated with sitafloxacin as an outpatient for a week, however his symptoms got worse. The chest CT showed consolidation and atelectasis in his right middle lobe. Low density area was scattered in consolidation, and right pleural effusion was observed. The patient was diagnosed with pulmonary abscess and he was admitted. Administration of piperacillin/tazobactam improved his condition. We switched antibiotics to amoxicillin/clavulanate, and he was discharged. After 2 weeks, he relapsed and was admitted again. After administration of piperacillin/tazobactam for 3 weeks, we perform bronchoscopy and Nocardia species were cultured from samples of the bronchial wash. The isolates were identified as N. exalbida using 16S rRNA gene sequencing. We prescribed Trimethoprim / Sulfamethoxazole (TMP/SMX) for 4 months. Then we switched to minocycline for renal dysfunction caused from TMP-SMX for 1 more month. After 5 months therapy, Consolidation on CT disappeared, and Nocardiosis was cured. we reported the first case of pulmonary nocardiosis caused by N. exalbida in an immunocompetent patient. N. exalbida infection might be associated with a good response to treatment. A 49-year-old man presented with 3 months of persistent fever, cough, shortness of breath, and chest tightness. He had no response to treatment with antibiotics. He had been treated with an empiric 2-week course of steroids approximately 2 months before presentation, with mild and transient improvement. He did not use tobacco and had not experienced any weight loss, hemoptysis, arthralgia, or myalgia, and was otherwise in good health. He denied contact with anyone with pulmonary TB or other respiratory illnesses. Chronic Pulmonary Aspergillosis The hallmark of chronic cavitary pulmonary aspergillosis (also called semi-invasive aspergillosis, chronic necrotizing aspergillosis, or complex aspergilloma) (Fig. 241-1) is one or more pulmonary cavities expanding over a period of months or years in association with pulmonary symptoms and systemic manifestations such as fatigue and weight loss. (Pulmonary aspergillosis developing over <3 months is better classified as subacute invasive aspergillosis.) Often mistaken initially for tuberculosis, almost all cases occur in patients with prior pulmonary disease (e.g., tuberculosis, atypical mycobacterial infection, sarcoidosis, rheumatoid lung disease, pneumothorax, bullae) or lung surgery. The onset is insidious, and systemic features may be more prominent than pulmonary symptoms. Cavities may have a fluid level or a well-formed fungal ball, but pericavitary infiltrates and multiple cavities—with or without pleural thickening—are typical. An irregular\nHere is the question:\nPNEUMOLOGY AND THORACIC SURGERY: A 64-year-old patient, farmer, former smoker (5 years), COPD and afflicted with rheumatoid arthritis on corticosteroid therapy. He consults the emergency department for presenting intense headache of 2 days of evolution with deviation of the oral commissure. As background, he reports that after a month of influenza, he persists with cough, purulent and occasionally hemoptotic expectoration, febrile fever, anorexia, asthenia and weight loss. On arrival, the patient had a fever of 38.2ºC, multiple skin abscesses on the hands, back and buttocks (some with fistulous tracts) and right central facial paralysis, apical infiltrates with small associated pleural effusion on chest X-ray and leukocytosis with neutrophilia. Among the following suspected diagnoses I would consider MOST likely:\nHere are the potential choices:\n1. Lung neoplasm with brain metastases.\n2. Disseminated tuberculosis.\n3. Nocardiosis.\n4. Aspergillosis.\nThe correct answer is: 3. Nocardiosis."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n This single case study reports on a 74-year-old woman with 48-hour cycles of mood disturbance for 2 years. Every other day she awakened feeling sad with low energy, decreased appetite, fatigue, diminished enjoyment of normal activities, increased irritability, occasional self-deprecatory thoughts, and difficulty concentrating. On alternative days she was active, outgoing, energetic, and cheerful. Her past history was marked by mild postpartum depressions, not requiring treatment, with each of her six pregnancies, and a more severe depression at age 57, which seemed to respond to Premarin. During the recent 2-year period of mood swings, the patient was given trials of several heterocyclic antidepressant medications, but side effects precluded the use of therapeutic doses or durations of treatment. Reluctantly, the patient agreed to a trial of lithium carbonate. After the second week of lithium treatment, at a level of 0.4 mEq/ml, she reported marked improvement, feeling fine every day without mood fluctuations. After almost 1 year at this blood level, she remains asymptomatic. Thus, the patient's cyclic 48-hour unipolar depression responded dramatically and completely to low doses of lithium carbonate. Saul asks Adri to pretend they are both doctors when his young daughter visits, as her stepfather disapproves of his disorder. While posing as a doctor, Adri bails an uncomfortable Carla out of a visit from her parents. However, she still treats him coldly. Adri finally convinces Martha to seduce Victor with a pickup line, which fails until Carla steps in and tells her to admit her feelings bluntly, which goes well. Carla reveals to Adri that she is bipolar. She has episodes of extreme euphoria where she does things for fun without thinking of the consequences, like the night they met. She also has episodes of severe depression and frequent mood swings. We report the case of a female in her 40s diagnosed with depression. She was raised by an eccentric father, suspected of having pervasive developmental disorder, and a dominant mother. After graduating from high school, she worked as a clerk in a company for twenty years or so; however, a change in her work environment made her fall into a depressive state. Her worsening depression caused her impulsive resignation and disappearance for about four months. She spent the duration of her disappearance traveling the country, with no dissociative episodes. After returning, she received treatment for depression as an inpatient for about four months. During the first month of hospitalization, she mainly complained of a depressive mood and anxiety over the prognosis of her disorder, while she made scarcely any progress in introspection. In the second month, she gradually advanced with introspective work, but, as her introspection progressed, her depressive mood became aggravated. The therapist avoided intervention to modify her cognition, and told her the following: \"it is better not to persist in managing your depressive mood itself because curing depression does not mean resolving the superficial depressive mood, but to achieve a condition not directly influenced by mood.\" Then, at the beginning of the third month, she became aware of \"the presence of God\" and, at the same time, her depressive mood greatly improved. She extended her sympathy to her mother with her unfortunate life history, and expected her mother to change as she herself had experienced, but, disappointed by her mother, she experienced anxiety attacks and came to realize her own internal rage against significant persons in her life including her mother. After \"the Great being\" experience, she, who had formerly attended Christian church for a short time, started to read the Bible, but she still hesitated about committing herself to \"religious following.\" One day during the last month of hospitalization, as she prayed to God for healing when she read a part in the Bible about a woman suffering from a hemorrhage for twelve years who touched the hem of Jesus' garment and was healed immediately (Matthew 9:20-22 and Luke 8:43-48), the patient suddenly experienced \"the salvation of God\" and realized what trust really meant. Through the experience, her clinical problems became totally cured, and the therapy concluded with her discharge from hospital. Several months later, she sent the therapist a letter including the following message: \"I am grateful to the Lord for salvation from anxiety and irritation, but to the therapist for helping me realize it.\" This clinical course can be understood based on the patient's clinical problems (e.g., despair, anxiety, and depression), arising from the breakdown of her efforts to maintain stability by founding her psychological base on her feelings of omnipotence, avoiding facing her internal negative psychological factors (e.g., rage), and these were automatically resolved when her psychological base was switched to the transcendent level through \"the Great being\" experience and \"the salvation of God.\" Such a sudden, marked improvement resembles what Miller and C'de Baca reported as \"quantum change,\" of which the characteristics are vividness, surprise, benevolence, and permanence. The therapist paid attention to maintain a constant psychological distance from the patient, not persisting in modifying her cognition, with the transcendent level being the basis for the entire therapy. This stance of the therapist itself was considered to prompt her transcendence and bring about her eventual cure. This clinical course seemed to be highly suggestive of a psychotherapeutic mechanism, indicating the close relationship between the transcendent level and basic trust. psychic acceleration, however, (as seen in mania or hypomania) the thoughts move in a rapid progression, with many themes, rather than a singular one, being touched upon. Even when such experiences are accounted for on the basis of depression, the possibility does still exist, however, that the depressive episode may be complicated by other manic or hypomanic symptoms, in which case it is often prudent to attend to the patient's personal and family history (e.g., family history of bipolar disorder, early age of onset) to determine whether or not the patient has bipolar disorder. DEPRESSIVE DISORDERS Clinical Manifestations Major depression is defined as depressed mood on a daily basis for a minimum duration of 2 weeks (Table 466-7). An episode may be characterized by sadness, indifference, apathy, or irritability and is usually associated with changes in sleep patterns, appetite, and weight; motor agitation or retardation; fatigue; impaired concentration and decision making; feelings of shame or guilt; and thoughts of death or dying. Patients with depression have a profound loss of pleasure in all enjoyable activities, exhibit early morning awakening, feel that the dysphoric mood state is qualitatively different from sadness, and often notice a diurnal variation in mood (worse in morning hours). Patients experiencing bereavement or grief may exhibit many of the same signs and symptoms of major depression, although the emphasis is usually on feelings of emptiness and loss, rather than Depressive episodes in BP-II can present similarly to those experienced in unipolar depressive disorders. Patients characteristically experience a depressed mood and may describe themselves as feeling sad, gloomy, down in the dumps, hopeless, or for most of the day, nearly every day. In children, this can present with an irritable mood. Most patients report significant fatigue, loss of energy, or tiredness. Patients or their family members may note diminished interest in usual activities such as sex, hobbies, or daily routines. Many patients report a change in appetite along with associated weight change. Sleep disturbances may be present, and can manifest as problems falling or staying asleep, frequent awakenings, excessive sleep, or difficulties getting up in the morning. Around half of depressed patients develop changes in psychomotor activity, described as slowness in thinking, speaking, or movement. Conversely, they may also present with agitation, with inability to sit still or The World Health Organization reported a lifetime prevalence of 2.4% for BD-I, BD-II and sub-threshold types of bipolar disorder (BD). Depressive episodes are more common than manic episodes for many BD patients. Studies show that depressive mood persists in 2/3 of life, even if they are under treatment. It may be difficult to diagnose BD in the event of depression in the first episode. The correct diagnosis and the treatment can be delayed for 6-8 years, and even longer if disorder starts in adolescence. It is reported that 40% of the patients who were initially diagnosed as unipolar were later diagnosed as BD. The features that enable us to diagnose BD depressive episode: 1) family history of BD or psychosis 2) early onset with depression 3) cyclothymic temperament characteristics 4) four or more depressive episodes in 10 years 5) agitation, anger, insomnia, irritability, excessive talkativeness or other 'mixed' or hypomanic features or psychotic symptoms during depressive episode, 6) clinical 'worsening' caused by the appearance of mixed symptoms after AD treatment 7) suicidal thoughts and attempts 8) substance abuse 9) hypersomnia in the depressive episode or sleeping too much during the day, overeating, psychomotor agitation. The number of studies conducted on BD depressive treatment is limited, the information was obtained by excluding this group from the studies or by compiling the information obtained from the treatment of unipolar depression. In this review, acute and maintenance treatment of the depressive episodes of BD will be discussed according to the treatment algorithms. Beth, whom you have cared for in your primary care practice since she was born, is a 15-year-old adolescent girl with no prior psychiatric history who developed significant symptoms of clinical depression, associated with self-injurious behavior (cutting on wrists, arms, and thighs). She denied any known precipitant for her depression.She is a ninth grade honors student in the gifted program at a local high school and is described as a talented musician, playing multiple musical instruments as well as soccer and basketball. She has good family support, was sociable, and had several close friends. She denied any history of trauma and denied ever using recreational drugs or other mood-altering substances.At this visit, she reported feeling \"sad and anxious.\" Family history was significant for maternal depression, which persisted through her teens and twenties. Her older sister had been diagnosed with Social Anxiety Disorder. Beth reported anhedonia, fatigue and irritable mood, lack of motivation, impaired concentration, and anxiety related to failing grades.You decide to begin medication because of the severity of her symptoms, and 1 week after starting fluoxetine 10 mg, she reportedly overdosed on an unknown quantity of acetaminophen. Within a few days of switching to escitalopram (due to persistent gastrointestinal complaints while taking fluoxetine), she developed homicidal ideation. She reported feeling grandiose, empowered, invincible, elated, and \"crazy,\" although she never demonstrated or endorsed psychotic symptoms. She became fixated upon the idea that she could kill someone and \"get away with it.\" At the time she tried to suffocate a peer with her hands, she was described as having \"a glazed over look in her eyes.\" Moods were now described as alternating between depressed and elated, with mood shifts occurring every few days. These symptoms did not improve after the antidepressant medication was discontinued.Subsequently, patient was admitted for acute psychiatric care, at which time she was described as depressed, but with an \"expansive and irritable\" mood, and with obsessive suicidal ideation. She had developed a plan to hang herself in the home. She started to believe that her mother was trying to give her \"poison.\" She reported panic attacks and said that she wanted to be in the hospital where she could feel \"safe.\" She claimed to have an \"entity inside of her body who was a bully\" and who was \"taking over her body\" and stated that he put her hand over her peer's mouth, as she watched.Psychological testing included the Minnesota Multiphasic Personality Inventory-Adolescent, showed significant paranoia, bizarre mentation, and poor reality testing. Along with interview and observation, it was determined that patient met criteria for the DSM-IV-TR clinical diagnosis of Other Specified Bipolar Disorder, with psychotic features.Aripiprazole was initiated at a dosage of 2 mg; however, moods were still described as fluctuating between extremes every few hours. It was discontinued after reaching 5 mg due to affective blunting. Risperidone 0.5 mg twice daily helped patient to feel and act \"more like herself\"; however, she continued to report significant depression. The addition of lamotrigine 25 mg daily, in addition to individual Dialectical Behavior Therapy, finally led to improvement of mood and a gradual return of her normal baseline, with reportedly stable emotional, social, and academic functioning.The patient's mother remained convinced that this adolescent's mood instability was caused by underlying hormonal problems so you refer her to endocrinology. Beth developed puberty at age 8, with menses occurring on average of twice yearly. She was found to have elevated free testosterone level of 8.6 (reference range, 1.2-7.5). She was of normal weight (body mass index = 21.85 kg/m) and did not manifest acne, male pattern hair thinning, or hirsutism. Thyroid functions, 17-OH progesterone, follicle-stimulating hormone/luteinizing hormone, and estradiol were within normal limits. Prolactin elevation (46.3) was assumed to be due to Risperidone. Patient refused ovarian ultrasound.After starting oral contraceptives to establish monthly menses, patient's emotional and behavioral symptoms continue to remain stable. After Beth decided on her own to discontinue psychotropic medications, she continued for 17 months following her initial visit to remain free of neuropsychiatric symptoms.Now that her symptoms seem resolved; you wonder what the medical diagnosis for Beth was? You wonder if \"hormones\" may have caused or contributed to her psychiatric presentation. \"Tell Her About It\" is a 1983 hit song written and performed by Billy Joel, from the album An Innocent Man. The song was number 1 on the Billboard Hot 100 charts for one week on September 24, 1983, replacing \"Maniac\" by Michael Sembello. The single was certified Gold by the RIAA for US sales of over 500,000 copies. Single A 'special version' mixed by John \"Jellybean\" Benitez was also released as a 12-inch maxi single. The cover art varied depending on the country of release. The remixed version was longer, approximately five-and-a-half minutes. On the B-side featured Billy Joel's song \"Easy Money\" from the same album, and a live recording of the song \"You Got Me Hummin'\" written by Isaac Hayes and David Porter. In the lyrics of the song, the singer exhorts a young man to tell the woman he loves how he feels about her before he misses his chance. Arbus experienced \"depressive episodes\" during her life, similar to those experienced by her mother; the episodes may have been made worse by symptoms of hepatitis. In 1968, Arbus wrote a letter to a personal friend, Carlotta Marshall, that says: \"I go up and down a lot. Maybe I’ve always been like that. Partly what happens though is I get filled with energy and joy and I begin lots of things or think about what I want to do and get all breathless with excitement and then quite suddenly either through tiredness or a disappointment or something more mysterious the energy vanishes, leaving me harassed, swamped, distraught, frightened by the very things I thought I was so eager for! I’m sure this is quite classic.\" Her ex-husband once noted that she had \"violent changes of mood\". On July 26, 1971, while living at Westbeth Artists Community in New York City, Arbus died by suicide by ingesting barbiturates and cutting her wrists with a razor. She wrote the words \"Last Supper\" in her diary Dienogest is a type of progestin used for the treatment of endometriosis (EM). However, a significant adverse effect of dienogest is depression; therefore, assessing for a history of mood disorders is recommended before prescribing the drug. Herein, we present the case of a patient with no history of psychiatric disorders who was diagnosed with dienogest-induced major depressive disorder. This case emphasizes the importance of close monitoring for negative mood changes in patients taking dienogest. A 41-year-old woman underwent surgery for EM. Postoperatively, her gynecologist prescribed dienogest (2 mg/d) to control EM symptoms. Two months after the initiation of dienogest, she manifested insomnia almost daily, gradually became depressed, lost interest in all activities, had incessant cries, and repeatedly thought of death. She had no history of major physical or psychiatric disorders. Major depressive disorder, single episode, severe. A psychiatric consultation was recommended, an antidepressant was prescribed, and dienogest was discontinued. Two weeks later, there was significant improvement in the symptoms, and after 4 weeks, she remained in a stable mood with no suicidal thoughts. She was followed up for 13 months with a maintenance dose of escitalopram (5 -10mg/d), until the psychiatrist recommended treatment discontinuation, with a confirmed state of remission. This was a case of dienogest-induced depression in a patient with no history of mood disorders. Clinicians should be aware of the possibility of the occurrence of severe depression in progestin users regardless of their previous history. Part 2: A Not So Fine Madness Jamison describes her episodes of mania and how they related to her personal and professional life. Her heightened energy and emotions make her a social at work and very efficient with her responsibilities, but irritable and restless in her marriage, which leads her to separating from her husband. She describes periods of reckless spending as characteristic of her mania, and how her brother helped her fix her financial situation. Jamison describes how, in her mania, her brain couldn't focus to read a single paragraph or listen to a song. Shortly after this she seeks treatment for the first time, and a colleague confronts her with her need to take lithium for her disease. Around this time Jamison starts seeing a psychiatrist with whom she starts psychotherapy sessions that would become a part of her routine for the rest of her life. Restless legs syndrome (RLS) is a sensorimotor disorder characterized by distressing sensations deep inside the limbs, typically occurring at bedtime or rest. These paresthesias involve an irresistible urge to move the limb, which provides temporary relief but at the expense of sleep and quality of life. The pathophysiology of RLS has been related to dopaminergic pathway dysfunction, thereby aligning it closely with depression from both pathophysiologic and treatment perspectives. Certain antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), may induce or exacerbate RLS. We describe the case of a 34-year-old woman with no history of RLS who came to the emergency department with acute decompensated heart failure. After 7 days of hospitalization, she was waitlisted to receive a heart transplant. Her mood became depressed, and she requested a psychiatric consultation; escitalopram 10 mg at bedtime was started. Within 2 days of starting therapy, she developed very severe (determined by a score based on an RLS symptom rating scale) RLS symptoms, warranting the discontinuation of escitalopram. Within 2 days of stopping therapy, her RLS symptoms improved considerably (rated as mild). One week later, the patient was rechallenged with a lower dose of escitalopram, and her very severe RLS symptoms reappeared. Within 2 days of stopping escitalopram, her RLS symptoms again improved, with complete resolution 1 week later. Using the Naranjo adverse drug reaction probability scale, which assesses the probability of a drug causing an adverse event, the patient's score was 9, indicating a definite adverse drug reaction. Although published case reports have linked fluoxetine, sertraline, citalopram, paroxetine, and mirtazapine to RLS, this is the first report, to our knowledge, of escitalopram as a cause of RLS. Based on this case and additional data published with other SSRIs and SNRIs, we believe that escitalopram should be added to the list of agents that can induce RLS. Single release and impact Overview Similar in style to the Different Light lead single \"Manic Monday\", \"If She Knew What She Wants\" was issued as a follow-up single in April 1986 while \"Manic Monday\" was still cresting (its Hot 100 peak was no. 2). \"If She Knew What She Wants\" debuted at no. 80 on the Hot 100 dated 10 May 1986, which ranked \"Manic Monday\" at no. 18. \"If She Knew What She Wants\" would begin to lose momentum after reaching no. 50 in its third charting week, stalling at no. 29 on the Hot 100 dated 12 July 1986 in the final week of a five-week Top 40 tenure. \"If She Knew What She Wants\" would spend a total of ten weeks on the Hot 100. \"If She Knew What She Wants\" peaked at no. 31 on the UK Singles, which had afforded \"Manic Monday\" a no. 2 peak. \"If She Knew What She Wants\" also became a moderate chart success in Australia at no. 31 on the Kent Music Report, and in Canada where it peaked in its 10th week on the RPM 100 Singles chart at no. 29 on 26 July 1986.\nHere is the question:\nPSYCHIATRY: 68-year-old woman, with a history of 2 major depressive episodes in her lifetime, who consults for symptoms of sadness, depressed mood, anhedonia, asthenia and anorexia compatible with a new depressive episode. She was prescribed 10 mg of escitalopram and was evaluated 2 weeks later. In this review the patient reports feeling very well, she wakes up early very hyperactive and with 'a lot of desire to do things', she says she has a lot of energy and is more talkative than usual. She does not report being irritable and is able to sleep for 6 hours continuously. Given this situation, what would you think the patient has?\nHere are the potential choices:\n1. Bipolar disorder type I.\n2. Drug-induced hypomania.\n3. Normal response to escitalopram.\n4. Frontal dementia.\nThe correct answer is: ",
        "gold_answer": "3 Normal response to escitalopram.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n This single case study reports on a 74-year-old woman with 48-hour cycles of mood disturbance for 2 years. Every other day she awakened feeling sad with low energy, decreased appetite, fatigue, diminished enjoyment of normal activities, increased irritability, occasional self-deprecatory thoughts, and difficulty concentrating. On alternative days she was active, outgoing, energetic, and cheerful. Her past history was marked by mild postpartum depressions, not requiring treatment, with each of her six pregnancies, and a more severe depression at age 57, which seemed to respond to Premarin. During the recent 2-year period of mood swings, the patient was given trials of several heterocyclic antidepressant medications, but side effects precluded the use of therapeutic doses or durations of treatment. Reluctantly, the patient agreed to a trial of lithium carbonate. After the second week of lithium treatment, at a level of 0.4 mEq/ml, she reported marked improvement, feeling fine every day without mood fluctuations. After almost 1 year at this blood level, she remains asymptomatic. Thus, the patient's cyclic 48-hour unipolar depression responded dramatically and completely to low doses of lithium carbonate. Saul asks Adri to pretend they are both doctors when his young daughter visits, as her stepfather disapproves of his disorder. While posing as a doctor, Adri bails an uncomfortable Carla out of a visit from her parents. However, she still treats him coldly. Adri finally convinces Martha to seduce Victor with a pickup line, which fails until Carla steps in and tells her to admit her feelings bluntly, which goes well. Carla reveals to Adri that she is bipolar. She has episodes of extreme euphoria where she does things for fun without thinking of the consequences, like the night they met. She also has episodes of severe depression and frequent mood swings. We report the case of a female in her 40s diagnosed with depression. She was raised by an eccentric father, suspected of having pervasive developmental disorder, and a dominant mother. After graduating from high school, she worked as a clerk in a company for twenty years or so; however, a change in her work environment made her fall into a depressive state. Her worsening depression caused her impulsive resignation and disappearance for about four months. She spent the duration of her disappearance traveling the country, with no dissociative episodes. After returning, she received treatment for depression as an inpatient for about four months. During the first month of hospitalization, she mainly complained of a depressive mood and anxiety over the prognosis of her disorder, while she made scarcely any progress in introspection. In the second month, she gradually advanced with introspective work, but, as her introspection progressed, her depressive mood became aggravated. The therapist avoided intervention to modify her cognition, and told her the following: \"it is better not to persist in managing your depressive mood itself because curing depression does not mean resolving the superficial depressive mood, but to achieve a condition not directly influenced by mood.\" Then, at the beginning of the third month, she became aware of \"the presence of God\" and, at the same time, her depressive mood greatly improved. She extended her sympathy to her mother with her unfortunate life history, and expected her mother to change as she herself had experienced, but, disappointed by her mother, she experienced anxiety attacks and came to realize her own internal rage against significant persons in her life including her mother. After \"the Great being\" experience, she, who had formerly attended Christian church for a short time, started to read the Bible, but she still hesitated about committing herself to \"religious following.\" One day during the last month of hospitalization, as she prayed to God for healing when she read a part in the Bible about a woman suffering from a hemorrhage for twelve years who touched the hem of Jesus' garment and was healed immediately (Matthew 9:20-22 and Luke 8:43-48), the patient suddenly experienced \"the salvation of God\" and realized what trust really meant. Through the experience, her clinical problems became totally cured, and the therapy concluded with her discharge from hospital. Several months later, she sent the therapist a letter including the following message: \"I am grateful to the Lord for salvation from anxiety and irritation, but to the therapist for helping me realize it.\" This clinical course can be understood based on the patient's clinical problems (e.g., despair, anxiety, and depression), arising from the breakdown of her efforts to maintain stability by founding her psychological base on her feelings of omnipotence, avoiding facing her internal negative psychological factors (e.g., rage), and these were automatically resolved when her psychological base was switched to the transcendent level through \"the Great being\" experience and \"the salvation of God.\" Such a sudden, marked improvement resembles what Miller and C'de Baca reported as \"quantum change,\" of which the characteristics are vividness, surprise, benevolence, and permanence. The therapist paid attention to maintain a constant psychological distance from the patient, not persisting in modifying her cognition, with the transcendent level being the basis for the entire therapy. This stance of the therapist itself was considered to prompt her transcendence and bring about her eventual cure. This clinical course seemed to be highly suggestive of a psychotherapeutic mechanism, indicating the close relationship between the transcendent level and basic trust. psychic acceleration, however, (as seen in mania or hypomania) the thoughts move in a rapid progression, with many themes, rather than a singular one, being touched upon. Even when such experiences are accounted for on the basis of depression, the possibility does still exist, however, that the depressive episode may be complicated by other manic or hypomanic symptoms, in which case it is often prudent to attend to the patient's personal and family history (e.g., family history of bipolar disorder, early age of onset) to determine whether or not the patient has bipolar disorder. DEPRESSIVE DISORDERS Clinical Manifestations Major depression is defined as depressed mood on a daily basis for a minimum duration of 2 weeks (Table 466-7). An episode may be characterized by sadness, indifference, apathy, or irritability and is usually associated with changes in sleep patterns, appetite, and weight; motor agitation or retardation; fatigue; impaired concentration and decision making; feelings of shame or guilt; and thoughts of death or dying. Patients with depression have a profound loss of pleasure in all enjoyable activities, exhibit early morning awakening, feel that the dysphoric mood state is qualitatively different from sadness, and often notice a diurnal variation in mood (worse in morning hours). Patients experiencing bereavement or grief may exhibit many of the same signs and symptoms of major depression, although the emphasis is usually on feelings of emptiness and loss, rather than Depressive episodes in BP-II can present similarly to those experienced in unipolar depressive disorders. Patients characteristically experience a depressed mood and may describe themselves as feeling sad, gloomy, down in the dumps, hopeless, or for most of the day, nearly every day. In children, this can present with an irritable mood. Most patients report significant fatigue, loss of energy, or tiredness. Patients or their family members may note diminished interest in usual activities such as sex, hobbies, or daily routines. Many patients report a change in appetite along with associated weight change. Sleep disturbances may be present, and can manifest as problems falling or staying asleep, frequent awakenings, excessive sleep, or difficulties getting up in the morning. Around half of depressed patients develop changes in psychomotor activity, described as slowness in thinking, speaking, or movement. Conversely, they may also present with agitation, with inability to sit still or The World Health Organization reported a lifetime prevalence of 2.4% for BD-I, BD-II and sub-threshold types of bipolar disorder (BD). Depressive episodes are more common than manic episodes for many BD patients. Studies show that depressive mood persists in 2/3 of life, even if they are under treatment. It may be difficult to diagnose BD in the event of depression in the first episode. The correct diagnosis and the treatment can be delayed for 6-8 years, and even longer if disorder starts in adolescence. It is reported that 40% of the patients who were initially diagnosed as unipolar were later diagnosed as BD. The features that enable us to diagnose BD depressive episode: 1) family history of BD or psychosis 2) early onset with depression 3) cyclothymic temperament characteristics 4) four or more depressive episodes in 10 years 5) agitation, anger, insomnia, irritability, excessive talkativeness or other 'mixed' or hypomanic features or psychotic symptoms during depressive episode, 6) clinical 'worsening' caused by the appearance of mixed symptoms after AD treatment 7) suicidal thoughts and attempts 8) substance abuse 9) hypersomnia in the depressive episode or sleeping too much during the day, overeating, psychomotor agitation. The number of studies conducted on BD depressive treatment is limited, the information was obtained by excluding this group from the studies or by compiling the information obtained from the treatment of unipolar depression. In this review, acute and maintenance treatment of the depressive episodes of BD will be discussed according to the treatment algorithms. Beth, whom you have cared for in your primary care practice since she was born, is a 15-year-old adolescent girl with no prior psychiatric history who developed significant symptoms of clinical depression, associated with self-injurious behavior (cutting on wrists, arms, and thighs). She denied any known precipitant for her depression.She is a ninth grade honors student in the gifted program at a local high school and is described as a talented musician, playing multiple musical instruments as well as soccer and basketball. She has good family support, was sociable, and had several close friends. She denied any history of trauma and denied ever using recreational drugs or other mood-altering substances.At this visit, she reported feeling \"sad and anxious.\" Family history was significant for maternal depression, which persisted through her teens and twenties. Her older sister had been diagnosed with Social Anxiety Disorder. Beth reported anhedonia, fatigue and irritable mood, lack of motivation, impaired concentration, and anxiety related to failing grades.You decide to begin medication because of the severity of her symptoms, and 1 week after starting fluoxetine 10 mg, she reportedly overdosed on an unknown quantity of acetaminophen. Within a few days of switching to escitalopram (due to persistent gastrointestinal complaints while taking fluoxetine), she developed homicidal ideation. She reported feeling grandiose, empowered, invincible, elated, and \"crazy,\" although she never demonstrated or endorsed psychotic symptoms. She became fixated upon the idea that she could kill someone and \"get away with it.\" At the time she tried to suffocate a peer with her hands, she was described as having \"a glazed over look in her eyes.\" Moods were now described as alternating between depressed and elated, with mood shifts occurring every few days. These symptoms did not improve after the antidepressant medication was discontinued.Subsequently, patient was admitted for acute psychiatric care, at which time she was described as depressed, but with an \"expansive and irritable\" mood, and with obsessive suicidal ideation. She had developed a plan to hang herself in the home. She started to believe that her mother was trying to give her \"poison.\" She reported panic attacks and said that she wanted to be in the hospital where she could feel \"safe.\" She claimed to have an \"entity inside of her body who was a bully\" and who was \"taking over her body\" and stated that he put her hand over her peer's mouth, as she watched.Psychological testing included the Minnesota Multiphasic Personality Inventory-Adolescent, showed significant paranoia, bizarre mentation, and poor reality testing. Along with interview and observation, it was determined that patient met criteria for the DSM-IV-TR clinical diagnosis of Other Specified Bipolar Disorder, with psychotic features.Aripiprazole was initiated at a dosage of 2 mg; however, moods were still described as fluctuating between extremes every few hours. It was discontinued after reaching 5 mg due to affective blunting. Risperidone 0.5 mg twice daily helped patient to feel and act \"more like herself\"; however, she continued to report significant depression. The addition of lamotrigine 25 mg daily, in addition to individual Dialectical Behavior Therapy, finally led to improvement of mood and a gradual return of her normal baseline, with reportedly stable emotional, social, and academic functioning.The patient's mother remained convinced that this adolescent's mood instability was caused by underlying hormonal problems so you refer her to endocrinology. Beth developed puberty at age 8, with menses occurring on average of twice yearly. She was found to have elevated free testosterone level of 8.6 (reference range, 1.2-7.5). She was of normal weight (body mass index = 21.85 kg/m) and did not manifest acne, male pattern hair thinning, or hirsutism. Thyroid functions, 17-OH progesterone, follicle-stimulating hormone/luteinizing hormone, and estradiol were within normal limits. Prolactin elevation (46.3) was assumed to be due to Risperidone. Patient refused ovarian ultrasound.After starting oral contraceptives to establish monthly menses, patient's emotional and behavioral symptoms continue to remain stable. After Beth decided on her own to discontinue psychotropic medications, she continued for 17 months following her initial visit to remain free of neuropsychiatric symptoms.Now that her symptoms seem resolved; you wonder what the medical diagnosis for Beth was? You wonder if \"hormones\" may have caused or contributed to her psychiatric presentation. \"Tell Her About It\" is a 1983 hit song written and performed by Billy Joel, from the album An Innocent Man. The song was number 1 on the Billboard Hot 100 charts for one week on September 24, 1983, replacing \"Maniac\" by Michael Sembello. The single was certified Gold by the RIAA for US sales of over 500,000 copies. Single A 'special version' mixed by John \"Jellybean\" Benitez was also released as a 12-inch maxi single. The cover art varied depending on the country of release. The remixed version was longer, approximately five-and-a-half minutes. On the B-side featured Billy Joel's song \"Easy Money\" from the same album, and a live recording of the song \"You Got Me Hummin'\" written by Isaac Hayes and David Porter. In the lyrics of the song, the singer exhorts a young man to tell the woman he loves how he feels about her before he misses his chance. Arbus experienced \"depressive episodes\" during her life, similar to those experienced by her mother; the episodes may have been made worse by symptoms of hepatitis. In 1968, Arbus wrote a letter to a personal friend, Carlotta Marshall, that says: \"I go up and down a lot. Maybe I’ve always been like that. Partly what happens though is I get filled with energy and joy and I begin lots of things or think about what I want to do and get all breathless with excitement and then quite suddenly either through tiredness or a disappointment or something more mysterious the energy vanishes, leaving me harassed, swamped, distraught, frightened by the very things I thought I was so eager for! I’m sure this is quite classic.\" Her ex-husband once noted that she had \"violent changes of mood\". On July 26, 1971, while living at Westbeth Artists Community in New York City, Arbus died by suicide by ingesting barbiturates and cutting her wrists with a razor. She wrote the words \"Last Supper\" in her diary Dienogest is a type of progestin used for the treatment of endometriosis (EM). However, a significant adverse effect of dienogest is depression; therefore, assessing for a history of mood disorders is recommended before prescribing the drug. Herein, we present the case of a patient with no history of psychiatric disorders who was diagnosed with dienogest-induced major depressive disorder. This case emphasizes the importance of close monitoring for negative mood changes in patients taking dienogest. A 41-year-old woman underwent surgery for EM. Postoperatively, her gynecologist prescribed dienogest (2 mg/d) to control EM symptoms. Two months after the initiation of dienogest, she manifested insomnia almost daily, gradually became depressed, lost interest in all activities, had incessant cries, and repeatedly thought of death. She had no history of major physical or psychiatric disorders. Major depressive disorder, single episode, severe. A psychiatric consultation was recommended, an antidepressant was prescribed, and dienogest was discontinued. Two weeks later, there was significant improvement in the symptoms, and after 4 weeks, she remained in a stable mood with no suicidal thoughts. She was followed up for 13 months with a maintenance dose of escitalopram (5 -10mg/d), until the psychiatrist recommended treatment discontinuation, with a confirmed state of remission. This was a case of dienogest-induced depression in a patient with no history of mood disorders. Clinicians should be aware of the possibility of the occurrence of severe depression in progestin users regardless of their previous history. Part 2: A Not So Fine Madness Jamison describes her episodes of mania and how they related to her personal and professional life. Her heightened energy and emotions make her a social at work and very efficient with her responsibilities, but irritable and restless in her marriage, which leads her to separating from her husband. She describes periods of reckless spending as characteristic of her mania, and how her brother helped her fix her financial situation. Jamison describes how, in her mania, her brain couldn't focus to read a single paragraph or listen to a song. Shortly after this she seeks treatment for the first time, and a colleague confronts her with her need to take lithium for her disease. Around this time Jamison starts seeing a psychiatrist with whom she starts psychotherapy sessions that would become a part of her routine for the rest of her life. Restless legs syndrome (RLS) is a sensorimotor disorder characterized by distressing sensations deep inside the limbs, typically occurring at bedtime or rest. These paresthesias involve an irresistible urge to move the limb, which provides temporary relief but at the expense of sleep and quality of life. The pathophysiology of RLS has been related to dopaminergic pathway dysfunction, thereby aligning it closely with depression from both pathophysiologic and treatment perspectives. Certain antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), may induce or exacerbate RLS. We describe the case of a 34-year-old woman with no history of RLS who came to the emergency department with acute decompensated heart failure. After 7 days of hospitalization, she was waitlisted to receive a heart transplant. Her mood became depressed, and she requested a psychiatric consultation; escitalopram 10 mg at bedtime was started. Within 2 days of starting therapy, she developed very severe (determined by a score based on an RLS symptom rating scale) RLS symptoms, warranting the discontinuation of escitalopram. Within 2 days of stopping therapy, her RLS symptoms improved considerably (rated as mild). One week later, the patient was rechallenged with a lower dose of escitalopram, and her very severe RLS symptoms reappeared. Within 2 days of stopping escitalopram, her RLS symptoms again improved, with complete resolution 1 week later. Using the Naranjo adverse drug reaction probability scale, which assesses the probability of a drug causing an adverse event, the patient's score was 9, indicating a definite adverse drug reaction. Although published case reports have linked fluoxetine, sertraline, citalopram, paroxetine, and mirtazapine to RLS, this is the first report, to our knowledge, of escitalopram as a cause of RLS. Based on this case and additional data published with other SSRIs and SNRIs, we believe that escitalopram should be added to the list of agents that can induce RLS. Single release and impact Overview Similar in style to the Different Light lead single \"Manic Monday\", \"If She Knew What She Wants\" was issued as a follow-up single in April 1986 while \"Manic Monday\" was still cresting (its Hot 100 peak was no. 2). \"If She Knew What She Wants\" debuted at no. 80 on the Hot 100 dated 10 May 1986, which ranked \"Manic Monday\" at no. 18. \"If She Knew What She Wants\" would begin to lose momentum after reaching no. 50 in its third charting week, stalling at no. 29 on the Hot 100 dated 12 July 1986 in the final week of a five-week Top 40 tenure. \"If She Knew What She Wants\" would spend a total of ten weeks on the Hot 100. \"If She Knew What She Wants\" peaked at no. 31 on the UK Singles, which had afforded \"Manic Monday\" a no. 2 peak. \"If She Knew What She Wants\" also became a moderate chart success in Australia at no. 31 on the Kent Music Report, and in Canada where it peaked in its 10th week on the RPM 100 Singles chart at no. 29 on 26 July 1986.\nHere is the question:\nPSYCHIATRY: 68-year-old woman, with a history of 2 major depressive episodes in her lifetime, who consults for symptoms of sadness, depressed mood, anhedonia, asthenia and anorexia compatible with a new depressive episode. She was prescribed 10 mg of escitalopram and was evaluated 2 weeks later. In this review the patient reports feeling very well, she wakes up early very hyperactive and with 'a lot of desire to do things', she says she has a lot of energy and is more talkative than usual. She does not report being irritable and is able to sleep for 6 hours continuously. Given this situation, what would you think the patient has?\nHere are the potential choices:\n1. Bipolar disorder type I.\n2. Drug-induced hypomania.\n3. Normal response to escitalopram.\n4. Frontal dementia.\nThe correct answer is: 2. Drug-induced hypomania."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Diuretics have been accepted as first-line treatment in refractory congestive heart failure (CHF), but a lack of response to them is a frequent event. A randomized, single-blind study was performed to evaluate the effects of the combination of high-dose furosemide and small-volume hypertonic saline solution (HSS) infusion in the treatment of refractory New York Heart Association (NYHA) class IV CHF and a normosodic diet during follow-up. Materials and Methods One hundred seven patients (39 women and 68 men, age range 65-90 years) with refractory CHF (NYHA class IV) of different etiologies, who were unresponsive to high oral doses of furosemide, angiotensin-converting enzyme inhibitors, digitalis, and nitrates, were enrolled. Inclusion criteria included an ejection fraction (EF) &lt;35%, serum creatinine level &lt;2 mg/dL, blood urea nitrogen level &lt; or =60 mg/dL, reduced urinary volume, and low natriuresis. The patients were randomized in 2 groups (single-blind). Patients in group 1 (20 women and 33 men) received an intravenous (IV) infusion of furosemide (500-1000 mg) plus HSS (150 mL of 1.4%-4.6% NACl) twice a day in 30 minutes. Patients in group 2 (19 women and 35 men) received an IV bolus of furosemide (500-1000 mg) twice a day, without HSS, during a period lasting 6 to 12 days. Both groups received IV KCl (20-40 mEq) to prevent hypokalemia. At study entry, all patients underwent a physical examination and measurement of body weight (BW), blood pressure (BP), and heart rate (HR), an evaluation of signs of CHF, and measurement of control levels of serum Na, K, Cl, bicarbonate, albumin, uric acid, creatinine, urea, and glycemia daily during hospitalization, and measurements of the daily output of urine for Na, K, and Cl. A chest radiograph, electrocardiogram, and echocardiogram were obtained at study entry, during hospitalization, and at the time of discharge from the hospital. During the treatment and after discharge, the daily dietary Na intake was 120 mmol in group 1 versus 80 mmol in group 2, with a fluid intake of 1000 mL daily in both groups. An assessment of BW and 24-hour urinary volume, serum, and urinary laboratory parameters were performed daily until patients reached a compensated state, when IV furosemide was replaced with oral administration (250-500 mg/d). After discharge from the hospital, patients were observed as outpatients weekly for the first 3 months and, subsequently, once a month. The groups were similar in age, sex, EF, risk factors, treatment, and etiology of CHF. All patients showed a clinical improvement. Ten patients in both groups had hyponatremia at entry. A significant increase in daily diuresis and natriuresis was observed in both groups, but it was more significant in the group receiving HSS (P &lt;.05). The serum Na level increased in group 1 and decreased in group 2 (P &lt;.05). The serum K level was decreased in both groups (P &lt;.05). BW was reduced in both groups (P &lt;.05). Group 2 had an increase in serum creatinine level. Serum uric acid levels increased in both groups. BP values decreased and HR was corrected to normal values in both groups. In the follow-up period (31 +/- 14 months), 25 patients from group 1 were readmitted to the hospital for heart failure. In group 2, 43 patients were readmitted to the hospital at a higher class than at discharge. Twenty-four patients in group 1 died during follow-up, versus 47 patients in group 2 (P &lt;.001). This treatment is effective and well tolerated, improves the quality of life through the relief of signs and symptoms of congestion, and may delay more aggressive treatments. The effects were also beneficial in a long period for mortality reduction (55% vs 13% survival rate) and for clinical improvement. Pulmonary edema - Slow intravenous bolus dose of 40 to 80 mg furosemide at 4 mg per minute is indicated for patients with fluid overload and pulmonary odema. Such dose can be repeated after 20 minutes. After the bolus, a continuous intravenous infusion can be given at 5 to 10 mg per hour. For those with underlying renal impairment or severe heart failure, up to 160 to 200 mg bolus dose can be given. The effectiveness and safety of once-daily administration of drugs in the treatment of moderate to severe hypertension was studied. Forty men taking diuretics were randomized to atenolol (A, n = 18), 50 mg/day, or betaxolol (B, n = 22), a new B1-blocker, 20 mg/day, if their SDAP was 105 to 125 mm Hg at baseline (weeks 2 to 4). At week 6, if SDAP was greater than 95 mm Hg, minoxidil (M), 5.5 mg/day, was added. The patients were seen every two weeks to week 16 (end of drug titration) and then every four weeks to week 32. The dosages were increased to 200 mg/day for A, 80 mg/day for B, and 20 mg/day for M as needed. Physical examinations, chest x-ray films, ECGs, echocardiograms, spirometric studies, 24-h ambulatory arterial pressures (AAP), and blood chemistry analyses were done at baseline and during treatment. A and B combined with a diuretic (furosemide, F) and M decreased the arterial pressures and heart rates equally well by both clinical and AAP measurements (p less than .001). The IVS was decreased (p less than .05), whereas LVIDd, RVIDd, and cardiothoracic ratios were increased by both A and B (p less than .05, p less than .01). No changes were noted in LVPW, LVM, EF, FS, spirometric values, or blood chemistry analyses. Common side effects were weight gain, edema, and hypertrichosis. Once-daily administration of A or B in combination with F and M were effective in the treatment of moderate to severe hypertension. Although effective, prolonged use of M may lead to volume overload and cardiomegaly. The significance of these latter findings is not yet known. Nitrates and furosemide, commonly administered in the treatment of pulmonary oedema, have not been compared in a prospective clinical trial. We compared the efficacy and safety of these drugs in a randomised trial of patients with severe pulmonary oedema and oxygen saturation below 90%. Patients presenting to mobile emergency units with signs of congestive heart failure were treated with oxygen 10 L/min, intravenous furosemide 40 mg, and morphine 3 mg bolus. 110 patients were randomly assigned either to group A, who received isosorbide dinitrate (3 mg bolus administered intravenously every 5 min; n=56) or to group B, who received furosemide (80 mg bolus administered intravenously every 15 min, as well as isosorbide dinitrate 1 mg/h, increased every 10 min by 1 mg/h; n=54). Six patients were withdrawn on the basis of chest radiography results. Treatment was continued until oxygen saturation was above 96% or mean arterial blood pressure had decreased by 30% or to below 90 mm Hg. The main endpoints were death, need for mechanical ventilation, and myocardial infarction. The analyses were by intention to treat. Mechanical ventilation was required in seven (13%) of 52 group-A patients and 21 (40%) of 52 group-B patients (p=0.0041). Myocardial infarction occurred in nine (17%) and 19 (37%) patients, respectively (p=0.047). One patient in group A and three in group B died (p=0.61). One or more of these endpoints occurred in 13 (25%) and 24 (46%) patients, respectively (p=0.041). High-dose isosorbide dinitrate, given as repeated intravenous boluses after low-dose intravenous furosemide, is safe and effective in controlling severe pulmonary oedema. This treatment regimen is more effective than high-dose furosemide with low-dose isosorbide nitrate in terms of need for mechanical ventilation and frequency of myocardial infarction. The hemodynamic response of isosorbide-5-mononitrate (IS-5-MN) to the addition of the widely used therapy of diuretic drugs and the maximally tolerated dose of enalapril for heart failure was assessed in 8 patients with congestive heart failure (CHF) (New York Heart Association class II and III). The diuretic therapy was furosemide, 40 to 80 mg/day, with or without amiloride, 5 to 10 mg/day. The dose of enalapril was 5 to 20 mg/day. Four hours after the administration of the morning dose of enalapril, a Swan-Ganz catheter was positioned in the pulmonary artery. Patients received increasing doses of IS-5-MN to produce a satisfactory decrease in pulmonary capillary wedge pressure. Two of the first 3 patients studied had a large reduction in blood pressure when given 10 mg of IS-5-MN. Subsequent patients were therefore given an initial dose of 5 mg, the total dose being 5 to 20 mg over 2 hours. Results at baseline and 1 hour after the final dose of IS-5-MN are expressed as mean +/- standard deviation. Both pulmonary artery systolic and diastolic pressures decreased significantly (p less than 0.05) by 12.2 +/- 8.9/4.2 +/- 5.2 mm Hg, from 47.2 +/- 16.0/21.6 +/- 6.0 mm Hg to 35.0 +/- 15.2/17.4 +/- 9.3 mm Hg. Pulmonary capillary wedge pressure decreased by 8.6 +/- 4.4 mm Hg, from 22.1 +/- 5.4 to 13.6 +/- 7.5 mm Hg (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) A recent 8-week, double-masked, placebo-controlled, 3 x 4 factorial-design study demonstrated that enalapril-felodipine extended-release (ER) combinations had statistically significant additive effects for reducing both sitting systolic blood pressure (SiSBP) and sitting diastolic blood pressure (SiDBP) and were generally well tolerated in hypertensive patients with SiDBPs ranging from 95 to 115 mm Hg. The present open-label study was undertaken to assess the long-term efficacy, tolerability, and safety of such combinations. Patients from the factorial study were eligible for the 1-year, open-label extension. Initially, all patients received enalapril 5 mg-felodipine ER 2.5 mg once daily; if SiDBP was not controlled (&lt; 90 mm Hg) after 4 weeks of treatment, the dose was titrated upward at 2- to 4-week intervals to a maximum of enalapril 10 mg-felodipine ER 10 mg. Hydrochlorothiazide (HCTZ) 12.5 mg was added to the regimen of patients whose hypertension was not controlled at the highest enalapril-felodipine ER dose. A total of 507 patients were enrolled, of whom 502 were assessable. At their last study visit, 391 (78%) of the assessable patients were receiving only an enalapril-felodipine ER combination. The enalapril-felodipine ER combinations resulted in mean trough SiDBPs of 85 to 89 mm Hg (decreases of 13 to 16 mm Hg from baseline) and SiSBPs of 137 to 140 mm Hg (decreases of 13 to 21 mm Hg). Overall, 407 (81%) of the 502 assessable patients achieved an SiDBP &lt; 90 mm Hg or a reduction from baseline &gt; or = 10 mm Hg (responders); such a response was recorded in 331 patients (66%) taking a combination of enalapril-felodipine ER alone and 76 patients (15%) taking the combination with the addition of HCTZ 12.5 mg. Blood pressure reductions were maintained throughout the treatment period. Drug-related adverse events were relatively infrequent, often transient, usually mild, and apparently not dose related. The most frequently reported drug-related adverse events were edema/swelling, asthenia/fatigue, dizziness, cough, and headache. These results suggest that combination therapy with enalapril-felodipine ER is effective for long-term blood pressure reduction, has an excellent safety profile, and is generally well tolerated. Addition of low-dose HCTZ to the enalapril-felodipine ER combination appears to provide further blood pressure control without increasing drug-related adverse events. Monitoring diuresis: Diuresis can be monitored by weighing the person daily. The goal is weight loss of no more than 1.0 kg/day for people with both ascites and peripheral edema and no more than 0.5 kg/day for people with ascites alone. If daily weights cannot be obtained, diuretics can also be guided by the urinary sodium concentration. Dosage is increased until a negative sodium balance occurs. A random urine sodium-to-potassium ratio of > 1 is 90% sensitivity in predicting negative balance (> 78-mmol/day sodium excretion). Diuretic resistance: Diuretic resistance can be predicted by giving 80 mg intravenous furosemide after 3 days without diuretics and on an 80 mEq sodium/day diet. The urinary sodium excretion over 8 hours < 50 mEq/8 hours predicts resistance. Clinical use Loop diuretics are principally used in the following indications: Heart failure - Giving 2.5 times of previous oral dose twice daily for those with acute decompensated heart failure is a reasonable strategy. However, daily assessment of clinical response is needed to adjust the subsequent doses. Edema associated with liver cirrhosis, and nephrotic syndrome Cerebral edema - intravenous furosemide can be combined with mannitol to initiate rapid diuresis. However, the optimum duration of such treatment remains unknown. Frequent fluid status monitoring is required to prevent intravascular volume depletion which leads to reduced cerebral perfusion. A bolus intravenous dose of 10 or 20 mg of furosemide can be administered and then followed by intravenous bolus of 2 or 3% hypertonic saline to increase the serum sodium level. Felodipine (Plendil), a new drug, has been used in the treatment of five patients with refractory essential hypertension (WHO II-III). Their mean blood pressure at the last outpatient visit before the study was opened was 195 +/- 25/129 +/- 21 mmHg (mean +/- s.d.) (range 175-235/110-165 mmHg), despite treatment with combinations of diuretics, beta-blockers and vasodilators, including minoxidil and captopril. Felodipin is a dihydropyridine derivative, a calcium antagonist that exerts a relaxant effect on resistance vessels. The first period of the study consisted of a 5-day stay in hospital followed by 3 months during which observations were carried out at the Outpatients' Department. After the first days in hospital felodipine therapy was introduced at a dose of 25 mg three times daily, given together with diuretics, beta-blockers and, in one case, captopril. At 8.00 immediately before the first dose was given, the blood pressure was 178 +/- 19/118 +/- 19 mmHg (mean +/- s.d.); 2 h later it was 144 +/- 18/85 +/- 4 mmHg, at which level it remained throughout the rest of the study. At the 3-month follow-up the mean pressure (recorded at the Outpatients' Department) was 138 +/- 20/89 +/- 14 mmHg. Side-effects included headache, flushing, palpitations and ankle oedema (in two patients during the second part of the study); they were of a mild to moderate degree and did not interfere with the treatment. There was no evidence of general fluid retention, and the body weight remained constant.(ABSTRACT TRUNCATED AT 250 WORDS) Placebo-controlled trials have found that angiotensin-converting enzyme inhibitors (ACEIs) decrease proteinuria and slow the progression of nondiabetic nephropathies. However, head-to-head comparisons of ACEIs and calcium channel blockers (CCBs) have shown conflicting results. Indeed, a recent metaanalysis concluded that there is still uncertainty about the greater renoprotection seen with ACEIs or angiotensin II receptor blockers in nondiabetic patients with renal disease, particularly when using true glomerular filtration rate (GFR) as the primary outcome. The objective of this 3-year, randomized, multicenter, double-blind, placebo-controlled study was to compare true GFR decline (measured by yearly 51Cr-EDTA blood clearance) in nondiabetic, nonnephrotic adult hypertensive patients with estimated creatinine clearance of 20 to 60 mL/min.1.73 m(2), when randomized to a CCB (amlodipine, 5-10 mg/d) or an ACEI (enalapril, 5-20 mg/d). Patients (aged 18-80 years) entered a 4-week placebo run-in washout period and previous antihypertensive drugs were tapered off over 2 weeks. Add-on treatments were atenolol (50-100 mg/d), loop diuretics (furosemide, 20-500 mg/d or torsemide, 5-200 mg/d), alpha-blockers (prazosin, 2.5-5 mg/d or doxazosin, 1-16 mg/d), and centrally acting drugs (rilmenidine, 1-2 mg/d or methyldopa, 250-500 mg/d). The primary end point was true GFR measured by yearly (51)Cr-EDTA blood clearance. Secondary end points included a clinical composite of renal events and tolerability collected by a full clinical and laboratory evaluation at each study visit. Post hoc analyses for the change in GFR, proteinuria, and time to clinical events were also planned on baseline proteinuria subgroups (&lt;1 and &gt;or=1 g/d) before unblinding the database. Three hundred eighteen patients entered the run-in period and 263 patients (156 men/107 women; mean age, 58 years) were randomized to receive either amlodipine (5 mg/d, n=132) or enalapril (5 mg/d, n=131). Blood pressure declined from 165/102 mm Hg to 138/84 mm Hg and 138/85 mm Hg with amlodipine and enalapril, respectively (no between-group significance). Only 20.8% of the patients randomized to ACEI treatment received diuretics at the last observation. No statistically significant difference was found between amlodipine and enalapril in GFR decline (-4.92 and -3.98 mL/min.1.73 m(2), respectively, at last observation) and composite secondary end point after a median follow-up of 2.9 years, including in the subgroup of patients with proteinuria &gt;1 g/d at baseline. Protein excretion rate decreased significantly from baseline in patients taking enalapril plus diuretics (median -270 mg/d; P&lt;0.001) but not in patients taking amlodipine plus diuretics (-25 mg/d at last observation). In this cohort of nondiabetic, nonnephrotic hypertensive patients, no statistically significant difference in true GFR decline was found over 3 years between amlodipine-treated patients and enalapril-treated patients with main add-on treatment with ss-blockers, including in the subgroup of patients with proteinuria &gt;1 g/d. The international, prospective, randomized HOT study was aimed at determining the influence of a targeted BP reduction on cardiovascular morbidity and mortality. Patients were randomly allocated to 3 DBP targets (&lt; 80, &lt; 85, &lt; 90 mmHg). In addition, the impact of a coprescription of aspirin was studied. The BP target had to be reached within 3 months, according to a well-defined strategy : felodipine 5 mg o.d. as a 1st intention drug, 1, 2 or 3 additional drugs, if necessary, on the following steps. BP measurements were made, using an oscillometric automatic device (Hestia). From April 1992 to October 1994, 18,790 patients with an age range 50-80 years, coming from 26 countries, entered the study. The data collected on the 36th month were in agreement with those obtained on the 12th and the 24th months. Baseline DBP was reduced by 21, 23 and 25 mmHg in the 90, 85 and 80 mmHg target groups, respectively. The rate of patients whose DBP reached the target, obviously increased from the 3rd to the 12th month: from 43 to 56%, 60 to 70%, 74 to 83% in the 90, 85 and 80 mmHg, target groups, respectively. From the 2nd to the 3rd year, BP control was further improved, with a slightly higher rate of controlled patients in the elderly (age &gt; 60 y), especially in the 80 mmHg target group. From inclusion to the 3rd month, one-drug treated patients decreased, whereas 2- or 3-drug treated patients increased. Felodipine-treated patients decreased on the 36th month, but remained over 80%. From the 6th to the 36th month, additional prescription of a betablocker or an ACE-inhibitor increased from 36 to 39%, and from 23 to 28%, respectively; moreover, the side-effects rate decreased from 10.5 to 3.6%, with a special decline in ankle edema from 4 to 1%. In conclusion, the BP reduction observed on the 36th month was of the same extent as that observed in the first months. It seems obviously possible to reach a targeted DBP and to maintain it over time, along with a good acceptability of the treatment. Targeted DBP could be more easily achieved in elderly patients, possibly due to a better drug compliance. Ephedrine has previously been described as a causative factor of vasculitis but myocarditis has not yet been associated with either ephedrine or its plant derivative ephedra. A 39-year-old African American male with hypertension presented to Rush Presbyterian St. Luke's Medical Center with a 1-month history of progressive dyspnea on exertion, orthopnea, and dependent edema. He was taking Ma Huang (Herbalife) 1-3 tablets twice daily for 3 months along with other vitamin supplements, pravastatin, and furosemide. Physical examination revealed a male in mild respiratory distress. The lung fields had rales at both bases without audible wheezes. Internal jugular venous pulsations were 5 cm above the sternal notch. Medical therapy with intravenous furosemide and oral enalapril was initiated upon admission. Cardiac catheterization with coronary angiography revealed normal coronary arteries, a dilated left ventricle, moderate pulmonary hypertension, and a pulmonary capillary wedge pressure of 34 mm Hg. The patient had right ventricular biopsy performed demonstrating mild myocyte hypertrophy and an infiltrate consisting predominantly of lymphocytes with eosinophils present in significantly increased numbers. Treatment for myocarditis was initiated with azothioprine 200 mg daily and prednisone 60 mg per day with a tapering course over 6 months. Anticoagulation with warfarin and diuretics was initiated and angiotensin-converting enzyme inhibition was continued. Hydralazine was added later. One month into therapy, an echocardiogram demonstrated improved left ventricular function with only mild global hypokinesis. A repeat right ventricular biopsy 2 months after the first admission showed no evidence of myocarditis. At 6 months, left ventricular ejection fraction was normal (EFN 50%) and the patient asymptomatic. Ephedra (Ma Huang) is the suspected cause of hypersensitivity myocarditis in this patient due to the temporal course of disease and its propensity to induce vasculitis. Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), is a well-tolerated and highly effective treatment for erectile dysfunction. The mechanism of action of sildenafil depends on activation of the nitric oxide (NO)-cGMP pathway during sexual stimulation, which results in corpus cavernosal smooth muscle relaxation and penile erection. Endogenously derived NO is also involved in blood pressure regulation through its effect on basal vascular tone, which is mediated by cGMP levels. Organic nitrates and NO donors exert their therapeutic effects on blood pressure and vascular smooth muscle by the same mechanism as endogenous NO. Since both sildenafil and organic nitrates exert their pharmacologic effects via increases in cGMP concentrations, a double-blind, placebo-controlled, crossover study was undertaken to investigate the effects of sildenafil coadministered with glyceryl trinitrate on blood pressure and heart rate in healthy male subjects. The hemodynamic effects of sildenafil were also evaluated in a second placebo-controlled crossover study in men with hypertension who were taking the calcium antagonist amlodipine, which has a mechanism of action that does not involve the cGMP pathway. In the first crossover study, subjects were treated with oral sildenafil (25 mg, 3 times a day for 4 days) or placebo and then challenged on day 4 with a 40-minute, stepwise, intravenous infusion of glyceryl trinitrate (0.5 mg/mL in 5% dextrose at an initial infusion rate of 2.5 microg/min and doubling every 5 minutes to a maximum rate of 40 microg/min) 1 hour after taking sildenafil or placebo. On day 5, subjects received a sublingual glyceryl trinitrate tablet (500 microg) 1 hour after taking 25 mg of sildenafil or placebo. During sildenafil treatment, the subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo treatment, based on the occurrence of a &gt;25 mm Hg decrease in blood pressure or the incidence of symptomatic hypotension (p &lt;0.01). When a sublingual glyceryl trinitrate tablet was administered on day 5, a 4-fold greater decrease in systolic blood pressure was observed for the subjects during the sildenafil treatment period than during the placebo treatment period. The changes in heart rate were negligible during both glyceryl trinitrate challenges. In conclusion, sildenafil potentiated the hypotensive effects of glyceryl trinitrate, an organic nitrate. Thus, sildenafil administration to patients who are using organic nitrates, either regularly and/or intermittently, in any form is contraindicated. In the second crossover study, men with hypertension, who were taking 5 or 10 mg/day of amlodipine, received a single oral dose of 100 mg sildenafil or placebo. Coadministration of sildenafil did not significantly affect the pharmacokinetics of amlodipine. In the 4 hours after dosing, differences in the mean maximum change from baseline in supine systolic and diastolic blood pressures between the sildenafil plus amlodipine and the placebo plus amlodipine treatment periods were -8 mm Hg and -7 mm Hg, respectively (p &lt; or =0.002). The mean maximum supine heart rate increased 2.1 beats/min during sildenafil plus amlodipine treatment and decreased 1.5 beats/min during placebo plus amlodipine treatment (p &lt;0.02). The adverse events in this study were predominantly mild or moderate and did not cause discontinuation of treatment. Adverse events considered to be related to sildenafil treatment included headache, nausea, and dyspepsia. In patients with hypertension who were taking amlodipine therapy, sildenafil produced additive, but not synergistic, reductions in blood pressure. The difference in the mean maximum change from baseline in blood pressure between sildenafil plus amlodipine and placebo plus amlodipine was comparable to the decrease in blood pressure reported for healthy men taking sildenafil alone. (ABSTRACT TRUNCATED)\nHere is the question:\nCARDIOLOGY AND VASCULAR SURGERY: A 73-year-old woman is admitted with progressive dyspnea until she becomes at rest, orthopnea and weight gain of 4 kg. Physical examination showed blood pressure of 150/84 mm Hg, heart rate 100 beats/minute, increased jugular venous pressure, crepitant in both bases and malleolar edema. Usual treatment: enalapril 5 mg every 12 hours, furosemide 80 mg per day. What is the most appropriate treatment at this time?\nHere are the potential choices:\n1. Administer fiirosemide intravenously.\n2. Increase enalapril dose according to tolerance and administer intravenous furosemide.\n3. Start a beta-blocker.\n4. Add treatment with amlodipine.\nThe correct answer is: ",
        "gold_answer": "2 Increase enalapril dose according to tolerance and administer intravenous furosemide.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Diuretics have been accepted as first-line treatment in refractory congestive heart failure (CHF), but a lack of response to them is a frequent event. A randomized, single-blind study was performed to evaluate the effects of the combination of high-dose furosemide and small-volume hypertonic saline solution (HSS) infusion in the treatment of refractory New York Heart Association (NYHA) class IV CHF and a normosodic diet during follow-up. Materials and Methods One hundred seven patients (39 women and 68 men, age range 65-90 years) with refractory CHF (NYHA class IV) of different etiologies, who were unresponsive to high oral doses of furosemide, angiotensin-converting enzyme inhibitors, digitalis, and nitrates, were enrolled. Inclusion criteria included an ejection fraction (EF) &lt;35%, serum creatinine level &lt;2 mg/dL, blood urea nitrogen level &lt; or =60 mg/dL, reduced urinary volume, and low natriuresis. The patients were randomized in 2 groups (single-blind). Patients in group 1 (20 women and 33 men) received an intravenous (IV) infusion of furosemide (500-1000 mg) plus HSS (150 mL of 1.4%-4.6% NACl) twice a day in 30 minutes. Patients in group 2 (19 women and 35 men) received an IV bolus of furosemide (500-1000 mg) twice a day, without HSS, during a period lasting 6 to 12 days. Both groups received IV KCl (20-40 mEq) to prevent hypokalemia. At study entry, all patients underwent a physical examination and measurement of body weight (BW), blood pressure (BP), and heart rate (HR), an evaluation of signs of CHF, and measurement of control levels of serum Na, K, Cl, bicarbonate, albumin, uric acid, creatinine, urea, and glycemia daily during hospitalization, and measurements of the daily output of urine for Na, K, and Cl. A chest radiograph, electrocardiogram, and echocardiogram were obtained at study entry, during hospitalization, and at the time of discharge from the hospital. During the treatment and after discharge, the daily dietary Na intake was 120 mmol in group 1 versus 80 mmol in group 2, with a fluid intake of 1000 mL daily in both groups. An assessment of BW and 24-hour urinary volume, serum, and urinary laboratory parameters were performed daily until patients reached a compensated state, when IV furosemide was replaced with oral administration (250-500 mg/d). After discharge from the hospital, patients were observed as outpatients weekly for the first 3 months and, subsequently, once a month. The groups were similar in age, sex, EF, risk factors, treatment, and etiology of CHF. All patients showed a clinical improvement. Ten patients in both groups had hyponatremia at entry. A significant increase in daily diuresis and natriuresis was observed in both groups, but it was more significant in the group receiving HSS (P &lt;.05). The serum Na level increased in group 1 and decreased in group 2 (P &lt;.05). The serum K level was decreased in both groups (P &lt;.05). BW was reduced in both groups (P &lt;.05). Group 2 had an increase in serum creatinine level. Serum uric acid levels increased in both groups. BP values decreased and HR was corrected to normal values in both groups. In the follow-up period (31 +/- 14 months), 25 patients from group 1 were readmitted to the hospital for heart failure. In group 2, 43 patients were readmitted to the hospital at a higher class than at discharge. Twenty-four patients in group 1 died during follow-up, versus 47 patients in group 2 (P &lt;.001). This treatment is effective and well tolerated, improves the quality of life through the relief of signs and symptoms of congestion, and may delay more aggressive treatments. The effects were also beneficial in a long period for mortality reduction (55% vs 13% survival rate) and for clinical improvement. Pulmonary edema - Slow intravenous bolus dose of 40 to 80 mg furosemide at 4 mg per minute is indicated for patients with fluid overload and pulmonary odema. Such dose can be repeated after 20 minutes. After the bolus, a continuous intravenous infusion can be given at 5 to 10 mg per hour. For those with underlying renal impairment or severe heart failure, up to 160 to 200 mg bolus dose can be given. The effectiveness and safety of once-daily administration of drugs in the treatment of moderate to severe hypertension was studied. Forty men taking diuretics were randomized to atenolol (A, n = 18), 50 mg/day, or betaxolol (B, n = 22), a new B1-blocker, 20 mg/day, if their SDAP was 105 to 125 mm Hg at baseline (weeks 2 to 4). At week 6, if SDAP was greater than 95 mm Hg, minoxidil (M), 5.5 mg/day, was added. The patients were seen every two weeks to week 16 (end of drug titration) and then every four weeks to week 32. The dosages were increased to 200 mg/day for A, 80 mg/day for B, and 20 mg/day for M as needed. Physical examinations, chest x-ray films, ECGs, echocardiograms, spirometric studies, 24-h ambulatory arterial pressures (AAP), and blood chemistry analyses were done at baseline and during treatment. A and B combined with a diuretic (furosemide, F) and M decreased the arterial pressures and heart rates equally well by both clinical and AAP measurements (p less than .001). The IVS was decreased (p less than .05), whereas LVIDd, RVIDd, and cardiothoracic ratios were increased by both A and B (p less than .05, p less than .01). No changes were noted in LVPW, LVM, EF, FS, spirometric values, or blood chemistry analyses. Common side effects were weight gain, edema, and hypertrichosis. Once-daily administration of A or B in combination with F and M were effective in the treatment of moderate to severe hypertension. Although effective, prolonged use of M may lead to volume overload and cardiomegaly. The significance of these latter findings is not yet known. Nitrates and furosemide, commonly administered in the treatment of pulmonary oedema, have not been compared in a prospective clinical trial. We compared the efficacy and safety of these drugs in a randomised trial of patients with severe pulmonary oedema and oxygen saturation below 90%. Patients presenting to mobile emergency units with signs of congestive heart failure were treated with oxygen 10 L/min, intravenous furosemide 40 mg, and morphine 3 mg bolus. 110 patients were randomly assigned either to group A, who received isosorbide dinitrate (3 mg bolus administered intravenously every 5 min; n=56) or to group B, who received furosemide (80 mg bolus administered intravenously every 15 min, as well as isosorbide dinitrate 1 mg/h, increased every 10 min by 1 mg/h; n=54). Six patients were withdrawn on the basis of chest radiography results. Treatment was continued until oxygen saturation was above 96% or mean arterial blood pressure had decreased by 30% or to below 90 mm Hg. The main endpoints were death, need for mechanical ventilation, and myocardial infarction. The analyses were by intention to treat. Mechanical ventilation was required in seven (13%) of 52 group-A patients and 21 (40%) of 52 group-B patients (p=0.0041). Myocardial infarction occurred in nine (17%) and 19 (37%) patients, respectively (p=0.047). One patient in group A and three in group B died (p=0.61). One or more of these endpoints occurred in 13 (25%) and 24 (46%) patients, respectively (p=0.041). High-dose isosorbide dinitrate, given as repeated intravenous boluses after low-dose intravenous furosemide, is safe and effective in controlling severe pulmonary oedema. This treatment regimen is more effective than high-dose furosemide with low-dose isosorbide nitrate in terms of need for mechanical ventilation and frequency of myocardial infarction. The hemodynamic response of isosorbide-5-mononitrate (IS-5-MN) to the addition of the widely used therapy of diuretic drugs and the maximally tolerated dose of enalapril for heart failure was assessed in 8 patients with congestive heart failure (CHF) (New York Heart Association class II and III). The diuretic therapy was furosemide, 40 to 80 mg/day, with or without amiloride, 5 to 10 mg/day. The dose of enalapril was 5 to 20 mg/day. Four hours after the administration of the morning dose of enalapril, a Swan-Ganz catheter was positioned in the pulmonary artery. Patients received increasing doses of IS-5-MN to produce a satisfactory decrease in pulmonary capillary wedge pressure. Two of the first 3 patients studied had a large reduction in blood pressure when given 10 mg of IS-5-MN. Subsequent patients were therefore given an initial dose of 5 mg, the total dose being 5 to 20 mg over 2 hours. Results at baseline and 1 hour after the final dose of IS-5-MN are expressed as mean +/- standard deviation. Both pulmonary artery systolic and diastolic pressures decreased significantly (p less than 0.05) by 12.2 +/- 8.9/4.2 +/- 5.2 mm Hg, from 47.2 +/- 16.0/21.6 +/- 6.0 mm Hg to 35.0 +/- 15.2/17.4 +/- 9.3 mm Hg. Pulmonary capillary wedge pressure decreased by 8.6 +/- 4.4 mm Hg, from 22.1 +/- 5.4 to 13.6 +/- 7.5 mm Hg (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) A recent 8-week, double-masked, placebo-controlled, 3 x 4 factorial-design study demonstrated that enalapril-felodipine extended-release (ER) combinations had statistically significant additive effects for reducing both sitting systolic blood pressure (SiSBP) and sitting diastolic blood pressure (SiDBP) and were generally well tolerated in hypertensive patients with SiDBPs ranging from 95 to 115 mm Hg. The present open-label study was undertaken to assess the long-term efficacy, tolerability, and safety of such combinations. Patients from the factorial study were eligible for the 1-year, open-label extension. Initially, all patients received enalapril 5 mg-felodipine ER 2.5 mg once daily; if SiDBP was not controlled (&lt; 90 mm Hg) after 4 weeks of treatment, the dose was titrated upward at 2- to 4-week intervals to a maximum of enalapril 10 mg-felodipine ER 10 mg. Hydrochlorothiazide (HCTZ) 12.5 mg was added to the regimen of patients whose hypertension was not controlled at the highest enalapril-felodipine ER dose. A total of 507 patients were enrolled, of whom 502 were assessable. At their last study visit, 391 (78%) of the assessable patients were receiving only an enalapril-felodipine ER combination. The enalapril-felodipine ER combinations resulted in mean trough SiDBPs of 85 to 89 mm Hg (decreases of 13 to 16 mm Hg from baseline) and SiSBPs of 137 to 140 mm Hg (decreases of 13 to 21 mm Hg). Overall, 407 (81%) of the 502 assessable patients achieved an SiDBP &lt; 90 mm Hg or a reduction from baseline &gt; or = 10 mm Hg (responders); such a response was recorded in 331 patients (66%) taking a combination of enalapril-felodipine ER alone and 76 patients (15%) taking the combination with the addition of HCTZ 12.5 mg. Blood pressure reductions were maintained throughout the treatment period. Drug-related adverse events were relatively infrequent, often transient, usually mild, and apparently not dose related. The most frequently reported drug-related adverse events were edema/swelling, asthenia/fatigue, dizziness, cough, and headache. These results suggest that combination therapy with enalapril-felodipine ER is effective for long-term blood pressure reduction, has an excellent safety profile, and is generally well tolerated. Addition of low-dose HCTZ to the enalapril-felodipine ER combination appears to provide further blood pressure control without increasing drug-related adverse events. Monitoring diuresis: Diuresis can be monitored by weighing the person daily. The goal is weight loss of no more than 1.0 kg/day for people with both ascites and peripheral edema and no more than 0.5 kg/day for people with ascites alone. If daily weights cannot be obtained, diuretics can also be guided by the urinary sodium concentration. Dosage is increased until a negative sodium balance occurs. A random urine sodium-to-potassium ratio of > 1 is 90% sensitivity in predicting negative balance (> 78-mmol/day sodium excretion). Diuretic resistance: Diuretic resistance can be predicted by giving 80 mg intravenous furosemide after 3 days without diuretics and on an 80 mEq sodium/day diet. The urinary sodium excretion over 8 hours < 50 mEq/8 hours predicts resistance. Clinical use Loop diuretics are principally used in the following indications: Heart failure - Giving 2.5 times of previous oral dose twice daily for those with acute decompensated heart failure is a reasonable strategy. However, daily assessment of clinical response is needed to adjust the subsequent doses. Edema associated with liver cirrhosis, and nephrotic syndrome Cerebral edema - intravenous furosemide can be combined with mannitol to initiate rapid diuresis. However, the optimum duration of such treatment remains unknown. Frequent fluid status monitoring is required to prevent intravascular volume depletion which leads to reduced cerebral perfusion. A bolus intravenous dose of 10 or 20 mg of furosemide can be administered and then followed by intravenous bolus of 2 or 3% hypertonic saline to increase the serum sodium level. Felodipine (Plendil), a new drug, has been used in the treatment of five patients with refractory essential hypertension (WHO II-III). Their mean blood pressure at the last outpatient visit before the study was opened was 195 +/- 25/129 +/- 21 mmHg (mean +/- s.d.) (range 175-235/110-165 mmHg), despite treatment with combinations of diuretics, beta-blockers and vasodilators, including minoxidil and captopril. Felodipin is a dihydropyridine derivative, a calcium antagonist that exerts a relaxant effect on resistance vessels. The first period of the study consisted of a 5-day stay in hospital followed by 3 months during which observations were carried out at the Outpatients' Department. After the first days in hospital felodipine therapy was introduced at a dose of 25 mg three times daily, given together with diuretics, beta-blockers and, in one case, captopril. At 8.00 immediately before the first dose was given, the blood pressure was 178 +/- 19/118 +/- 19 mmHg (mean +/- s.d.); 2 h later it was 144 +/- 18/85 +/- 4 mmHg, at which level it remained throughout the rest of the study. At the 3-month follow-up the mean pressure (recorded at the Outpatients' Department) was 138 +/- 20/89 +/- 14 mmHg. Side-effects included headache, flushing, palpitations and ankle oedema (in two patients during the second part of the study); they were of a mild to moderate degree and did not interfere with the treatment. There was no evidence of general fluid retention, and the body weight remained constant.(ABSTRACT TRUNCATED AT 250 WORDS) Placebo-controlled trials have found that angiotensin-converting enzyme inhibitors (ACEIs) decrease proteinuria and slow the progression of nondiabetic nephropathies. However, head-to-head comparisons of ACEIs and calcium channel blockers (CCBs) have shown conflicting results. Indeed, a recent metaanalysis concluded that there is still uncertainty about the greater renoprotection seen with ACEIs or angiotensin II receptor blockers in nondiabetic patients with renal disease, particularly when using true glomerular filtration rate (GFR) as the primary outcome. The objective of this 3-year, randomized, multicenter, double-blind, placebo-controlled study was to compare true GFR decline (measured by yearly 51Cr-EDTA blood clearance) in nondiabetic, nonnephrotic adult hypertensive patients with estimated creatinine clearance of 20 to 60 mL/min.1.73 m(2), when randomized to a CCB (amlodipine, 5-10 mg/d) or an ACEI (enalapril, 5-20 mg/d). Patients (aged 18-80 years) entered a 4-week placebo run-in washout period and previous antihypertensive drugs were tapered off over 2 weeks. Add-on treatments were atenolol (50-100 mg/d), loop diuretics (furosemide, 20-500 mg/d or torsemide, 5-200 mg/d), alpha-blockers (prazosin, 2.5-5 mg/d or doxazosin, 1-16 mg/d), and centrally acting drugs (rilmenidine, 1-2 mg/d or methyldopa, 250-500 mg/d). The primary end point was true GFR measured by yearly (51)Cr-EDTA blood clearance. Secondary end points included a clinical composite of renal events and tolerability collected by a full clinical and laboratory evaluation at each study visit. Post hoc analyses for the change in GFR, proteinuria, and time to clinical events were also planned on baseline proteinuria subgroups (&lt;1 and &gt;or=1 g/d) before unblinding the database. Three hundred eighteen patients entered the run-in period and 263 patients (156 men/107 women; mean age, 58 years) were randomized to receive either amlodipine (5 mg/d, n=132) or enalapril (5 mg/d, n=131). Blood pressure declined from 165/102 mm Hg to 138/84 mm Hg and 138/85 mm Hg with amlodipine and enalapril, respectively (no between-group significance). Only 20.8% of the patients randomized to ACEI treatment received diuretics at the last observation. No statistically significant difference was found between amlodipine and enalapril in GFR decline (-4.92 and -3.98 mL/min.1.73 m(2), respectively, at last observation) and composite secondary end point after a median follow-up of 2.9 years, including in the subgroup of patients with proteinuria &gt;1 g/d at baseline. Protein excretion rate decreased significantly from baseline in patients taking enalapril plus diuretics (median -270 mg/d; P&lt;0.001) but not in patients taking amlodipine plus diuretics (-25 mg/d at last observation). In this cohort of nondiabetic, nonnephrotic hypertensive patients, no statistically significant difference in true GFR decline was found over 3 years between amlodipine-treated patients and enalapril-treated patients with main add-on treatment with ss-blockers, including in the subgroup of patients with proteinuria &gt;1 g/d. The international, prospective, randomized HOT study was aimed at determining the influence of a targeted BP reduction on cardiovascular morbidity and mortality. Patients were randomly allocated to 3 DBP targets (&lt; 80, &lt; 85, &lt; 90 mmHg). In addition, the impact of a coprescription of aspirin was studied. The BP target had to be reached within 3 months, according to a well-defined strategy : felodipine 5 mg o.d. as a 1st intention drug, 1, 2 or 3 additional drugs, if necessary, on the following steps. BP measurements were made, using an oscillometric automatic device (Hestia). From April 1992 to October 1994, 18,790 patients with an age range 50-80 years, coming from 26 countries, entered the study. The data collected on the 36th month were in agreement with those obtained on the 12th and the 24th months. Baseline DBP was reduced by 21, 23 and 25 mmHg in the 90, 85 and 80 mmHg target groups, respectively. The rate of patients whose DBP reached the target, obviously increased from the 3rd to the 12th month: from 43 to 56%, 60 to 70%, 74 to 83% in the 90, 85 and 80 mmHg, target groups, respectively. From the 2nd to the 3rd year, BP control was further improved, with a slightly higher rate of controlled patients in the elderly (age &gt; 60 y), especially in the 80 mmHg target group. From inclusion to the 3rd month, one-drug treated patients decreased, whereas 2- or 3-drug treated patients increased. Felodipine-treated patients decreased on the 36th month, but remained over 80%. From the 6th to the 36th month, additional prescription of a betablocker or an ACE-inhibitor increased from 36 to 39%, and from 23 to 28%, respectively; moreover, the side-effects rate decreased from 10.5 to 3.6%, with a special decline in ankle edema from 4 to 1%. In conclusion, the BP reduction observed on the 36th month was of the same extent as that observed in the first months. It seems obviously possible to reach a targeted DBP and to maintain it over time, along with a good acceptability of the treatment. Targeted DBP could be more easily achieved in elderly patients, possibly due to a better drug compliance. Ephedrine has previously been described as a causative factor of vasculitis but myocarditis has not yet been associated with either ephedrine or its plant derivative ephedra. A 39-year-old African American male with hypertension presented to Rush Presbyterian St. Luke's Medical Center with a 1-month history of progressive dyspnea on exertion, orthopnea, and dependent edema. He was taking Ma Huang (Herbalife) 1-3 tablets twice daily for 3 months along with other vitamin supplements, pravastatin, and furosemide. Physical examination revealed a male in mild respiratory distress. The lung fields had rales at both bases without audible wheezes. Internal jugular venous pulsations were 5 cm above the sternal notch. Medical therapy with intravenous furosemide and oral enalapril was initiated upon admission. Cardiac catheterization with coronary angiography revealed normal coronary arteries, a dilated left ventricle, moderate pulmonary hypertension, and a pulmonary capillary wedge pressure of 34 mm Hg. The patient had right ventricular biopsy performed demonstrating mild myocyte hypertrophy and an infiltrate consisting predominantly of lymphocytes with eosinophils present in significantly increased numbers. Treatment for myocarditis was initiated with azothioprine 200 mg daily and prednisone 60 mg per day with a tapering course over 6 months. Anticoagulation with warfarin and diuretics was initiated and angiotensin-converting enzyme inhibition was continued. Hydralazine was added later. One month into therapy, an echocardiogram demonstrated improved left ventricular function with only mild global hypokinesis. A repeat right ventricular biopsy 2 months after the first admission showed no evidence of myocarditis. At 6 months, left ventricular ejection fraction was normal (EFN 50%) and the patient asymptomatic. Ephedra (Ma Huang) is the suspected cause of hypersensitivity myocarditis in this patient due to the temporal course of disease and its propensity to induce vasculitis. Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), is a well-tolerated and highly effective treatment for erectile dysfunction. The mechanism of action of sildenafil depends on activation of the nitric oxide (NO)-cGMP pathway during sexual stimulation, which results in corpus cavernosal smooth muscle relaxation and penile erection. Endogenously derived NO is also involved in blood pressure regulation through its effect on basal vascular tone, which is mediated by cGMP levels. Organic nitrates and NO donors exert their therapeutic effects on blood pressure and vascular smooth muscle by the same mechanism as endogenous NO. Since both sildenafil and organic nitrates exert their pharmacologic effects via increases in cGMP concentrations, a double-blind, placebo-controlled, crossover study was undertaken to investigate the effects of sildenafil coadministered with glyceryl trinitrate on blood pressure and heart rate in healthy male subjects. The hemodynamic effects of sildenafil were also evaluated in a second placebo-controlled crossover study in men with hypertension who were taking the calcium antagonist amlodipine, which has a mechanism of action that does not involve the cGMP pathway. In the first crossover study, subjects were treated with oral sildenafil (25 mg, 3 times a day for 4 days) or placebo and then challenged on day 4 with a 40-minute, stepwise, intravenous infusion of glyceryl trinitrate (0.5 mg/mL in 5% dextrose at an initial infusion rate of 2.5 microg/min and doubling every 5 minutes to a maximum rate of 40 microg/min) 1 hour after taking sildenafil or placebo. On day 5, subjects received a sublingual glyceryl trinitrate tablet (500 microg) 1 hour after taking 25 mg of sildenafil or placebo. During sildenafil treatment, the subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo treatment, based on the occurrence of a &gt;25 mm Hg decrease in blood pressure or the incidence of symptomatic hypotension (p &lt;0.01). When a sublingual glyceryl trinitrate tablet was administered on day 5, a 4-fold greater decrease in systolic blood pressure was observed for the subjects during the sildenafil treatment period than during the placebo treatment period. The changes in heart rate were negligible during both glyceryl trinitrate challenges. In conclusion, sildenafil potentiated the hypotensive effects of glyceryl trinitrate, an organic nitrate. Thus, sildenafil administration to patients who are using organic nitrates, either regularly and/or intermittently, in any form is contraindicated. In the second crossover study, men with hypertension, who were taking 5 or 10 mg/day of amlodipine, received a single oral dose of 100 mg sildenafil or placebo. Coadministration of sildenafil did not significantly affect the pharmacokinetics of amlodipine. In the 4 hours after dosing, differences in the mean maximum change from baseline in supine systolic and diastolic blood pressures between the sildenafil plus amlodipine and the placebo plus amlodipine treatment periods were -8 mm Hg and -7 mm Hg, respectively (p &lt; or =0.002). The mean maximum supine heart rate increased 2.1 beats/min during sildenafil plus amlodipine treatment and decreased 1.5 beats/min during placebo plus amlodipine treatment (p &lt;0.02). The adverse events in this study were predominantly mild or moderate and did not cause discontinuation of treatment. Adverse events considered to be related to sildenafil treatment included headache, nausea, and dyspepsia. In patients with hypertension who were taking amlodipine therapy, sildenafil produced additive, but not synergistic, reductions in blood pressure. The difference in the mean maximum change from baseline in blood pressure between sildenafil plus amlodipine and placebo plus amlodipine was comparable to the decrease in blood pressure reported for healthy men taking sildenafil alone. (ABSTRACT TRUNCATED)\nHere is the question:\nCARDIOLOGY AND VASCULAR SURGERY: A 73-year-old woman is admitted with progressive dyspnea until she becomes at rest, orthopnea and weight gain of 4 kg. Physical examination showed blood pressure of 150/84 mm Hg, heart rate 100 beats/minute, increased jugular venous pressure, crepitant in both bases and malleolar edema. Usual treatment: enalapril 5 mg every 12 hours, furosemide 80 mg per day. What is the most appropriate treatment at this time?\nHere are the potential choices:\n1. Administer fiirosemide intravenously.\n2. Increase enalapril dose according to tolerance and administer intravenous furosemide.\n3. Start a beta-blocker.\n4. Add treatment with amlodipine.\nThe correct answer is: 2. Increase enalapril dose according to tolerance and administer intravenous furosemide."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Inguinal lymphadenopathy causes swollen lymph nodes in the groin area. It can be a symptom of infective or neoplastic processes. Infective aetiologies include Tuberculosis, HIV, non-specific or reactive lymphadenopathy to recent lower limb infection or groin infections. Another notable infectious cause is Lymphogranuloma venereum, which is a sexually transmitted infection of the lymphatic system. Neoplastic aetiologies include lymphoma, leukaemia and metastatic disease from primary tumours in the lower limb, external genitalia or perianal region and melanoma. References Further reading Inflammations Diseases of veins, lymphatic vessels and lymph nodes Overview A genital ulcer may be located on the vulva, penis, perianal region, or anus. Globally, the incidence of genital ulcers is estimated to be approximately 20 million cases annually. The most likely cause of a genital ulcer varies depending on the characteristics of a population and location. The most common cause of genital ulcers in the United States is herpes simplex infections, with syphilis the second most common cause, and chancroid the third. These common causes of genital ulcer disease (HSV-1, HSV-2 and treponema pallidum) can all be efficiently transmitted through oral sex. Important signs associated with genital ulcers that may assist in the diagnosis of the cause of the genital ulcer may include the presence of tender or non-tender enlarged lymph nodes in the groin area, a painful or non-painful genital ulcer, or the presence of vesicular lesions, which are small, painful, elevated blisters. Syphilis (lues) is a sexually transmitted infection caused by the spirochete Treponema pallidum. In adolescents, the diagnosis of primary syphilis can be made promptly by taking a sexual medical history and inspecting the glans penis. A 17-year-old male was referred to the paediatric oncology centre for additional diagnostics due to inguinal lymphadenopathy, with a strong suspicion of a malignant lymphoma. None of the physicians took a sexual medical history or investigated the glans penis, as a result of which essential information was lacking. The combination of inguinal lymphadenopathy and the ultrasound findings for the inguinal region made the physicians only consider a malignancy. However, it actually concerned a reactive lymphadenopathy associated with primary syphilis. This case demonstrates that a full medical history and thorough physical examination can prevent the need for costly and invasive diagnostics. Clinical significance The presence of swollen inguinal lymph nodes is an important clinical sign because lymphadenopathy (swelling) may indicate an infection, or spread as a metastasis from cancers, such as anal cancer and vulvar cancer. Inguinal lymph nodes may normally be up to 2 cm. The cut-off value for normal sized inguinal nodes is up to 10 mm. Additional images References Lymphatic organ anatomy Swollen lymph nodes usually indicate infection from bacteria or viruses. Swollen inguinal lymph nodes could indicate an infection of areas of the lower body. One of the more concerning causes of inguinal lymphadenopathy is sexually transmitted infections. Sexually transmitted infections that commonly presents with inguinal lymphadenopathy are lymphogranuloma venereum, secondary syphilis, and chancroid caused by Chlamydia trachomatis (L1-L3), Treponema pallidum , and Haemophilus ducreyi , respectively. Lymphogranuloma venereum Diagnosis Although most genital ulcerations cannot be diagnosed confidently on clinical grounds alone, clinical findings (Table 163-7) FIGURE 163-5 Chancroid: multiple, painful, punched-out ulcers with undermined borders on the labia occurring after autoinoculation. Sexually Transmitted Infections: Overview and Clinical Approach FIGURE 163-6 Genital herpes. A relatively mild, superficial ulcer is typically seen in episodic outbreaks. (Courtesy of Michael Remington, University of Washington Virology Research Clinic.) FIGURE 163-7 Lymphogranuloma venereum (LGV): striking ten-der lymphadenopathy occurring at the femoral and inguinal lymph nodes, separated by a groove made by Poupart’s ligament. This “sign-of-the-groove” is not considered specific for LGV; for example, lym-phomas may present with this sign. InITIAL MAnAgEMEnT of gEnITAL oR PERIAnAL uLCER The secondary stage most often occurs 10–30 days later, but can present up to six months later. The infection spreads to the lymph nodes through lymphatic drainage pathways. The most frequent presenting clinical manifestation of LGV among males whose primary exposure was genital is unilateral (in two-thirds of cases) lymphadenitis and lymphangitis, often with tender inguinal and/or femoral lymphadenopathy because of the drainage pathway for their likely infected areas. Lymphangitis of the dorsal penis may also occur and resembles a string or cord. If the route was anal sex, the infected person may experience lymphadenitis and lymphangitis noted above. They may instead develop proctitis, inflammation limited to the rectum (the distal 10–12 cm) that may be associated with anorectal pain, tenesmus, and rectal discharge, or proctocolitis, inflammation of the colonic mucosa extending to 12 cm above the anus and associated with symptoms of proctitis plus diarrhea or abdominal cramps. Several clinical presentations are highly suggestive of specific diagnoses: 1. A painless and minimally tender ulcer, not accompanied by inguinal lymphadenopathy, is likely to be syphilis, especially if the ulcer is indurated. A nontreponemal rapid plasma reagin (RPR) test, or venereal disease research laboratory (VDRL) test, and a confirmatory treponemal test—fluorescent treponemal antibody absorption (FTA ABS) or microhemagglutinin–T. pallidum (MHA TP)—should be used to diagnose syphilis presumptively. Some laboratories screen samples with treponemal enzyme immunoassay (EIA) tests, the results of which should be confirmed with nontreponemal tests. The results of nontreponemal tests usually correlate with disease activity and should be reported quantitatively. 2. Treponema pallidum : Syphilis infections result from Treponema pallidum . This infection usually manifests as a painless chancre in the primary stage. If the disease is left untreated, it will progress to the secondary stage. In the secondary stage, it manifests as fever, widespread maculopapular skin rashes involving the palms and soles,  widespread lymphadenopathy (epitrochlear node is pathognomic), and genital lesions similar to genital warts (condylomata lata- has a rounder surface when compared with condylomata acuminata). If there is still no treatment during the secondary stage, the infection will progress into the tertiary stage. The tertiary stage causes necrotic lesions called Gummas, neurological symptoms such as tabes dorsalis, Argyll Robertson pupils, and general paresis, cardiac symptoms such as aortitis. The treatment of syphilis is with the use of penicillin. Source: From RM Ballard, in KK Holmes et al (eds): Sexually Transmitted Diseases, 4th ed. New York, McGraw-Hill, 2008. HSV-1 from HSV-2 has prognostic implications, because the latter causes more frequent genital recurrences. Painless, nontender, indurated ulcers with firm, nontender inguinal adenopathy suggest primary syphilis. If results of dark-field examination and a rapid serologic test for syphilis are initially negative, presumptive therapy should be provided on the basis of the individual’s risk. For example, with increasing rates of syphilis among MSM in the United States, most experts would not withhold therapy for this infection pending watchful waiting and/or subsequent detection of seroconversion. Repeated serologic testing for syphilis 1 or 2 weeks after treatment of seronegative primary syphilis usually demonstrates seroconversion. Diagnosis The diagnosis usually is made serologically (through complement fixation) and by exclusion of other causes of inguinal lymphadenopathy or genital ulcers. Serologic testing has a sensitivity of 80% after two weeks. Serologic testing may not be specific for serotype (has some cross reactivity with other chlamydia species) and can suggest LGV from other forms because of their difference in dilution, 1:64 more likely to be LGV and lower than 1:16 is likely to be other chlamydia forms (emedicine). For identification of serotypes, culture is often used. Culture is difficult. Requiring a special medium, cycloheximide-treated McCoy or HeLa cells, and yields are still only 30-50%. DFA, or direct fluorescent antibody test, PCR of likely infected areas and pus, are also sometimes used. DFA test for the L-type serovar of C. trachomatis is the most sensitive and specific test, but is not readily available. Demonstration of H. ducreyi by culture (or by PCR, where available) is most useful when ulcers are painful and purulent, especially if inguinal lymphadenopathy with fluctuance or overlying erythema is noted; if chancroid is prevalent in the community; or if the patient has recently had a sexual exposure elsewhere in a chancroid-endemic area (e.g., a developing country). Enlarged, fluctuant lymph nodes should be aspirated for culture or PCR to detect H. ducreyi as well as for Gram’s staining and culture to rule out the presence of other pyogenic bacteria. Syphilis is a bacterial infection caused by the spirochete Treponema pallidum. Clinical presentation of secondary syphilis can present with diffuse lymphadenopathy along with fever, skin rashes, and condylomata lata. [7] Chancroid Lymphadenopathy may be an incidental finding in patients being examined for various reasons, or it may be a presenting sign or symptom of the patient’s illness. The physician must eventually decide whether the lymphadenopathy is a normal finding or one that requires further study, up to and including biopsy. Soft, flat, submandibular nodes (<1 cm) are often palpable in healthy children and young adults; healthy adults may have palpable inguinal nodes of up to 2 cm, which are considered normal. Further evaluation of these normal nodes is not warranted. In contrast, if the physician believes the node(s) to be abnormal, then pursuit of a more precise diagnosis is needed. APPROACH TO THE PATIENT: Approach to the Patient with an Infectious Disease regions (e.g., popliteal, inguinal, epitrochlear, axillary, multiple cervical regions), with notation of the location, size (normal, <1 cm), presence or absence of tenderness, and consistency (soft, firm, or shotty) and of whether the nodes are matted (i.e., connected and moving together). Of note, palpable epitrochlear nodes are always pathologic. Of patients presenting with lymphadenopathy, 75% have localized findings, and the remaining 25% have generalized lymphadenopathy (i.e., that involving more than one anatomic region). Localized lymphadenopathy in the head and neck region is found in 55% of patients, inguinal lymphadenopathy in 14%, and axillary lymphadenopathy in 5%. Determining whether the patient has generalized versus localized lymphadenopathy can help narrow the differential diagnosis, as various infections present differently. Females and males: Signs and symptoms: Patients will present with highly vascularized lesions over the genitals and perineum that tend to be painless. [37] [38] It can cause severe scarring. Physical Exam: Typical findings include ulcer-like lesions that are beefy red, consistent with high vascularization that bleeds easily with manipulation. Subcutaneous granulomas may be present, but lymphadenopathy is uncommon. The lesions tend to be relatively large and irregular. It is often found to be associated with secondary infections. Four main lesions can be seen on examination: 1. Ulcerovegetative: large painless ulcer on the patient's physical exam. 2. Nodular: soft and erythematous that tend to ulcerate throughout the infectious process. 3. Cicatricial: dry ulcerations that tend to transition into plaques. 4. Hypertrophic: lesions are thick and painless. [37] [39] node is an enlarged left supraclavicular node infiltrated with metastatic cancer from a gastrointestinal primary. Metastases to supraclavicular nodes also occur from lung, breast, testis, or ovarian cancers. Tuberculosis, sarcoidosis, and toxoplasmosis are nonneoplastic causes of supraclavicular adenopathy. Axillary adenopathy is usually due to injuries or localized infections of the ipsilateral upper extremity. Malignant causes include melanoma or lymphoma and, in women, breast cancer. Inguinal lymphadenopathy is usually secondary to infections or trauma of the lower extremities and may accompany sexually transmitted diseases such as lymphogranuloma venereum, primary syphilis, genital herpes, or chancroid. These nodes may also be involved by lymphomas and metastatic cancer from primary lesions of the rectum, genitalia, or lower extremities (melanoma). Serological tests cannot distinguish yaws from the closely related syphilis; no test distinguishing yaws from syphilis is widely available. The two genomes differ by about 0.2%. PCR and DNA sequencing can distinguish the two. There are also no common blood tests which distinguish among the four treponematoses: syphilis (Treponema pallidum pallidum), yaws (Treponema pallidum pertenue), bejel (Treponema pallidum endemicum), and pinta (Treponema carateum). Haemophilus ducreyi infections can cause skin conditions that mimic primary yaws. People infected with Haemophilus ducreyi lesions may or may not also have latent yaws, and thus may or may not test positive on serological tests. This was discovered in the mid 2010s. It seems that a recently diverged strain of Haemophilus ducreyi has evolved from being a sexually transmitted infection to being a skin ulcer pathogen that looks like yaws. Yaws has been reported in nonendemic countries. Females and males: Signs and symptoms: Patients will present with painful lymphadenopathy localized to the inguinal area. Patients may note the initial presentation of a pustule that gradually progresses to large painful ulceration. [41] Men tend to present with early or acute stages, while women typically present much later. [19] Physical Exam: Lymphogranuloma venereum presents with two stages: Primary phase is a small painless papule/pustule that will ulcerate and can be visualized throughout the affected genital area. During the secondary phase, patients present with unilateral lymphadenopathy that is fluctuant with palpation or may be suppurative in a presentation known as buboes. [38] Buboes tend to rupture in the acute phase and progress to a thickened mass. [42] A 36-year-old male sustained fracture of first lumbar vertebra, splenic tear and paraplegia in a motorcycle accident in 2001; splenectomy was performed. In 2008, he presented with temperature and feeling rough. With a diagnosis of urine infection, he was prescribed ciprofloxacin, followed by trimethoprim, amoxicillin, and gentamicin, as temperature did not subside. White cell count was 21.2 x 109/L; lymphocytes were 13.05 x 109/L (1.00 - 4.00). Therefore, computerised tomography (CT) of chest and abdomen was performed. Thrombus was present in pulmonary arteries bilaterally involving the lobar and segmental branches. Enlarged lymph nodes were seen in axillae, chest, abdomen and inguinal regions. Radiological diagnosis was lymphoma. Cell marker showed an excess of large granular lymphocytes and activated lymphocytes. The Glandular Fever Slide Test was positive. Subsequently, Paul Bunnell test was also positive. Epstein Barr virus serology was consistent with recent Epstein Barr virus infection. Antibiotic was omitted; enoxaparin was prescribed for pulmonary artery thrombosis. Learning points from this case: (1) Although routine administration of antibiotic to a spinal cord injury patient with pyrexia may be acceptable in outpatient setting, other possibilities such as infection by multi-drug resistant organism, viral infection, venous or, arterial thrombosis should be considered if a patient does not respond promptly to antibacterial therapy. (2) When full blood count showed lymphocytosis (comprising &gt; 50% of white blood cells) with atypical morphology, lymphocyte surface markers, Paul Bunnell test, and Epstein Barr virus serology should be performed. These tests would have led to a diagnosis of infectious mononucleosis, and abdominal imaging studies could have been avoided. (3) Lymphoid hyperplasia is the hallmark of infectious mononucleosis; therefore, we should have suspected glandular fever rather than lymphoma when CT scan revealed enlarged lymph nodes in abdomen, mediastinum, axillae and inguinal regions in this patient, who had lymphocytosis with atypical morphology. (4) A soft tissue mass, situated inferior to left hemidiaphragm in this asplenic patient, was misinterpreted as lymph nodes; review of CT led to the correct diagnosis of splenunculus. (5) Acute infection with Epstein Barr virus may lead to transient induction of anti-phospholipid antibodies, which can cause vascular thrombosis. (6) This case illustrates the value of reviewing test results and discussion with senior doctors, as these measures help to recognize medical errors and improve patient care. In a private room or space, the patient will partially undress. The clinician may inspect the patient's: Throat and lymph nodes of the neck for inflammation Pubic hair for lice Lymph nodes of the groin for swelling Genitals, anus, and surrounding areas for sores and warts The clinician may swab the patient's: Throat to test for gonorrhea and possibly chlamydia Cheek, inside, to diagnose HIV Sores of the genitals, anus, and surrounding areas to test for herpes Urethra to test for gonorrhea and possibly chlamydia Vagina to test for chlamydia and possibly gonorrhea Cervix to test for cervical intraepithelial neoplasia (a Pap test) Rectum to test for gonorrhea and possibly chlamydia The clinician may take small blood samples by pricking a finger or from a vein to test for HIV, syphilis, and possibly herpes and hepatitis C. Dear Editor, Syphilis is an infection caused by Treponema pallidum. Without treatment, it goes through the following stages: primary, secondary, latent, and tertiary (1). The clinical picture of secondary syphilis is very variable (2,3). We present two rare cases of secondary syphilis, one with nodular lesions initially considered to be lymphoma and second with periostitis, which was initially interpreted as an osteoma. To date, only 15 cases with nodular lesions and 10 cases with periostitis in secondary syphilis have been reported in the literature. The first patient was a 59 year old man who presented in a private practice with nodular lesions on the face and axillary and inguinal folds (Figure 1, a, b). The initial diagnostic consideration was lymphoma. A biopsy specimen was taken, and the histopathological features revealed epidermal hyperplasia with papillomatosis, minimal spongiosis with many neutrophils and with a marked inflammatory infiltrate in dermis, consisting of lymphocytes, plasma cells, and neutrophils; the diagnosis of interfaced dermatitis was established (Figure 1, d, e). After one month, the patient presented to our clinic with numerous nodular lesions, some of them painful, located on the trunk and intertriginous folds, including the intergluteal cleft - the lesions in this area being suggestive of condylomata lata (Figure 1, c). The diagnosis of secondary syphilis was taken into consideration, and screening serum tests were performed and found reactive: a Venereal Diseases Research Laboratory (VDRL) titer of 1:64 and Treponema pallidum Hemaglutination Assay (TPHA) titer of 1:80. Hepatitis and anti-human immunodeficiency virus (HIV) antibodies serology was negative. The biopsy was repeated and showed the same histopathological changes. In addition, Warthin-Starry staining was performed, revealing the presence of some spiral micro-organisms in the dermis corresponding to Treponema pallidum (Figure 1, f). A diagnosis of secondary syphilis was established, and the patient was treated with benzathine penicillin G 2.4 million units by intramuscular injection once a week for 2 consecutive weeks. The skin lesions regressed within 1 month, and serological tests showed a VDRL titer of 1:8 3 months after treatment. The second patient was a homosexual male, 35 years old, diagnosed with HIV infection, stage B2. He presented with bone pain in the calves and forearms, with insidious onset. He also presented with an associated erythematous maculo-papular rash on the trunk and limbs and generalized lymphadenopathy (Figure 2, a, b). The tibial crest and radius were sensitive to palpation. A right leg radiography was performed, raising suspicion of osteoid osteoma. The CT scan excluded the diagnosis of osteoma; taking into account the epidemiological context, the diagnosis of syphilis was suspected. The diagnosis was confirmed by leg ultrasound examination (2D US) which showed thickening of the compact tibial bone associated with subperiosteal destructive and proliferative changes (Figure 2, c, d) and by serology for syphilis: the VDRL titer was 1:32 and the TPHA titer was 1:80. The patient was treated with benzathine penicillin 2.4 million units, once a week, for 2 consecutive weeks, with clinical improvement. Syphilis continues to be a serious public health problem worldwide, even if it is a controllable disease due to diagnostic tests and effective and accessible treatment. According to the World Health Organization in 2008, the estimated number of new cases of sexually transmitted diseases in adults with syphilis is 10.6 million cases (4). The cases presented in this paper were characterized by unusual manifestations, requiring good collaboration between the dermatologist and other specialties. In the first case, the diagnosis of secondary syphilis was confirmed by positive serological, clinical, and histopathological findings. The main differential diagnosis of nodular syphilis includes lymphoma, sarcoidosis, Kaposi's sarcoma, atypical mycobacteriosis, deep fungal infections, leprosy, tuberculosis, leishmaniasis, and lymphomatoid papulosis (5). Another important differential diagnosis is between secondary and tertiary syphilis, especially when ulcerating nodules are present. Tertiary syphilis is characterized by unilateral, deep ulcerating nodules with necrotizing granulomas (6). Bone involvement during syphilis is mainly represented by polyarthritis, synovitis, osteitis, and periostitis (7,8). Syphilitic periostitis is characterized by localized or diffuse pain, particularly during the night, which is relieved by movement. The skull, the shoulder girdle, and the long bones are the most common sites of involvement (9). In conclusion, we presented two different cases of secondary syphilis that contribute to the clinical experience of rare cases presented in the literature, raising the awareness of dermatologists and other specialists about less specific clinical aspects of syphilis. adenopathy that is sometimes mistaken for malignancy; syphilis, LGV, HSV infection, and chancroid involving the anus can produce inguinal adenopathy because anal lymphatics drain to inguinal lymph nodes. Cervical lymphadenopathy is a sign or a symptom, not a diagnosis. The causes are varied, and may be inflammatory, degenerative, or neoplastic. In adults, healthy lymph nodes can be palpable (able to be felt), in the axilla, neck and groin. In children up to the age of 12 cervical nodes up to 1 cm in size may be palpable and this may not signify any disease. If nodes heal by resolution or scarring after being inflamed, they may remain palpable thereafter. In children, most palpable cervical lymphadenopathy is reactive or infective. In individuals over the age of 50, metastatic enlargement from cancers (most commonly squamous cell carcinomas) of the aerodigestive tract should be considered. Classification Cervical lymphadenopathy can be thought of as local where only the cervical lymph nodes are affected, or general where all the lymph nodes of the body are affected. Causes Sexually transmitted infections are the first to consider in the differential diagnosis of LGV. The exclusion of diseases which cause genital ulceration and inguinal adenopathy including herpes simplex, syphilis, chancroid, herpes, and granuloma inguinale will help narrow the diagnosis. HIV and lymphoma can also cause generalized lymphadenopathy. Dermatological conditions and trauma which can cause genital ulcerations should also be in the differential diagnosis. Lymph node enlargement is recognized as a common sign of infectious, autoimmune, or malignant disease. Examples may include: Reactive: acute infection (e.g., bacterial, or viral), or chronic infections (tuberculous lymphadenitis, cat-scratch disease). The most distinctive sign of bubonic plague is extreme swelling of one or more lymph nodes that bulge out of the skin as \"buboes.\" The buboes often become necrotic and may even rupture. Infectious mononucleosis is an acute viral infection usually caused by Epstein-Barr virus and may be characterized by a marked enlargement of the cervical lymph nodes. It is also a sign of cutaneous anthrax and Human African trypanosomiasis Toxoplasmosis, a parasitic disease, gives a generalized lymphadenopathy (Piringer-Kuchinka lymphadenopathy). Plasma cell variant of Castleman's disease - associated with HHV-8 infection and HIV infection A 38-year-old man who had sex with men, presented at the outpatient department for Sexually Transmitted Diseases in Amsterdam with a painful, red, fluctuating swelling in the left groin and general discomfort. He had been sexually active in the population of men who have sex with men, in which an anorectal lymphogranuloma venereum (LGV) epidemic has recently been discovered. Unlike other cases where there was anorectal involvement, this patient was the first case of LGV with the classical inguinal presentation although he had not visited the tropics where the inguinal form of LGV occurs as an STD. Routine investigation using PCR on material from urethra and rectum and from the urine, repeatedly failed to detect LGV. However, PCR on pus aspirated from the enlarged lymph node demonstrated Chlamydia trachomatis serovar type L2. Treatment with doxycycline 100 mg twice daily was started. This case illustrates that routine analysis from urethra and rectum and of urine may fail to detect LGV. Furthermore, this case of a patient who probably had LGV initially in the urethra may be the missing link in explaining the route of transmission of the anorectal LGV epidemic. The presentation of chancroid does not usually include all of the typical clinical features and is sometimes atypical. Multiple ulcers can coalesce to form giant ulcers. Ulcers can appear and then resolve, with inguinal adenitis (Fig. 182-2) and suppuration following 1–3 weeks later; this clinical picture can be confused with that of lymphogranuloma venereum (Chap. 213). Multiple small ulcers can resemble folliculitis. Other differential diagnostic considerations include the various infections causing genital ulceration, such as primary syphilis, secondary syphilis (condyloma latum), genital herpes, and donovanosis. In rare cases, chancroid lesions become secondarily infected with bacteria; the result is extensive inflammation. FIGURE 182-2 Chancroid with characteristic penile ulcers and associated left inguinal adenitis (bubo). A 33-year-old man presented with a two-week history of an asymptomatic ulcer of the oropharynx and submandibular lymph nodes swelling. Laboratory examinations were normal, but serological tests revealed positivity for rapid plasma reagin, Treponema pallidum haemagglutination assay and anti-T. pallidum IgM antibodies. Since the patient denied any homosexual relationship, a biopsy of the lesion was performed, which confirmed primary syphilis. The patient received an intramuscular injection of Benzathine Penicillin G (2.4 MU) with complete resolution of the lesion. Extragenital chancres occur in at least 5% of patients with primary syphilis, and the oral mucosa is the most frequent location as a consequence of orogenital/oroanal contact with an infectious lesion. Because of their transient nature, these oral ulcerations are often underestimated by the patient or by any unsuspecting clinician. Health professionals should consider the recent sexual history of their patients and should be prepared to recognise oral and systemic manifestations of sexually transmitted infections. \nHere is the question:\nINFECTIOUS DISEASES: A 24-year-old woman consults after noticing inguinal lymphadenopathy. The interrogation does not reveal the presence of any local discomfort or data suggestive of sexually transmitted infection. The examination revealed two lymphadenopathies, one in each groin, 1 cm in diameter, soft, mobile, non-painful. There are no skin lesions on the lower limbs, anus or perineum. Which test do you consider essential?\nHere are the potential choices:\n1. A lues serology since it is most likely a Treponema pallidum infection.\n2. A gynecological examination to rule out ovarian cancer.\n3. By the clinical characteristics it seems to be normal lymph nodes and complementary explorations should not be done.\n4. A Paul-Bunnell test should be performed in order to rule out infectious mononucleosis.\nThe correct answer is: ",
        "gold_answer": "3 By the clinical characteristics it seems to be normal lymph nodes and complementary explorations should not be done.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Inguinal lymphadenopathy causes swollen lymph nodes in the groin area. It can be a symptom of infective or neoplastic processes. Infective aetiologies include Tuberculosis, HIV, non-specific or reactive lymphadenopathy to recent lower limb infection or groin infections. Another notable infectious cause is Lymphogranuloma venereum, which is a sexually transmitted infection of the lymphatic system. Neoplastic aetiologies include lymphoma, leukaemia and metastatic disease from primary tumours in the lower limb, external genitalia or perianal region and melanoma. References Further reading Inflammations Diseases of veins, lymphatic vessels and lymph nodes Overview A genital ulcer may be located on the vulva, penis, perianal region, or anus. Globally, the incidence of genital ulcers is estimated to be approximately 20 million cases annually. The most likely cause of a genital ulcer varies depending on the characteristics of a population and location. The most common cause of genital ulcers in the United States is herpes simplex infections, with syphilis the second most common cause, and chancroid the third. These common causes of genital ulcer disease (HSV-1, HSV-2 and treponema pallidum) can all be efficiently transmitted through oral sex. Important signs associated with genital ulcers that may assist in the diagnosis of the cause of the genital ulcer may include the presence of tender or non-tender enlarged lymph nodes in the groin area, a painful or non-painful genital ulcer, or the presence of vesicular lesions, which are small, painful, elevated blisters. Syphilis (lues) is a sexually transmitted infection caused by the spirochete Treponema pallidum. In adolescents, the diagnosis of primary syphilis can be made promptly by taking a sexual medical history and inspecting the glans penis. A 17-year-old male was referred to the paediatric oncology centre for additional diagnostics due to inguinal lymphadenopathy, with a strong suspicion of a malignant lymphoma. None of the physicians took a sexual medical history or investigated the glans penis, as a result of which essential information was lacking. The combination of inguinal lymphadenopathy and the ultrasound findings for the inguinal region made the physicians only consider a malignancy. However, it actually concerned a reactive lymphadenopathy associated with primary syphilis. This case demonstrates that a full medical history and thorough physical examination can prevent the need for costly and invasive diagnostics. Clinical significance The presence of swollen inguinal lymph nodes is an important clinical sign because lymphadenopathy (swelling) may indicate an infection, or spread as a metastasis from cancers, such as anal cancer and vulvar cancer. Inguinal lymph nodes may normally be up to 2 cm. The cut-off value for normal sized inguinal nodes is up to 10 mm. Additional images References Lymphatic organ anatomy Swollen lymph nodes usually indicate infection from bacteria or viruses. Swollen inguinal lymph nodes could indicate an infection of areas of the lower body. One of the more concerning causes of inguinal lymphadenopathy is sexually transmitted infections. Sexually transmitted infections that commonly presents with inguinal lymphadenopathy are lymphogranuloma venereum, secondary syphilis, and chancroid caused by Chlamydia trachomatis (L1-L3), Treponema pallidum , and Haemophilus ducreyi , respectively. Lymphogranuloma venereum Diagnosis Although most genital ulcerations cannot be diagnosed confidently on clinical grounds alone, clinical findings (Table 163-7) FIGURE 163-5 Chancroid: multiple, painful, punched-out ulcers with undermined borders on the labia occurring after autoinoculation. Sexually Transmitted Infections: Overview and Clinical Approach FIGURE 163-6 Genital herpes. A relatively mild, superficial ulcer is typically seen in episodic outbreaks. (Courtesy of Michael Remington, University of Washington Virology Research Clinic.) FIGURE 163-7 Lymphogranuloma venereum (LGV): striking ten-der lymphadenopathy occurring at the femoral and inguinal lymph nodes, separated by a groove made by Poupart’s ligament. This “sign-of-the-groove” is not considered specific for LGV; for example, lym-phomas may present with this sign. InITIAL MAnAgEMEnT of gEnITAL oR PERIAnAL uLCER The secondary stage most often occurs 10–30 days later, but can present up to six months later. The infection spreads to the lymph nodes through lymphatic drainage pathways. The most frequent presenting clinical manifestation of LGV among males whose primary exposure was genital is unilateral (in two-thirds of cases) lymphadenitis and lymphangitis, often with tender inguinal and/or femoral lymphadenopathy because of the drainage pathway for their likely infected areas. Lymphangitis of the dorsal penis may also occur and resembles a string or cord. If the route was anal sex, the infected person may experience lymphadenitis and lymphangitis noted above. They may instead develop proctitis, inflammation limited to the rectum (the distal 10–12 cm) that may be associated with anorectal pain, tenesmus, and rectal discharge, or proctocolitis, inflammation of the colonic mucosa extending to 12 cm above the anus and associated with symptoms of proctitis plus diarrhea or abdominal cramps. Several clinical presentations are highly suggestive of specific diagnoses: 1. A painless and minimally tender ulcer, not accompanied by inguinal lymphadenopathy, is likely to be syphilis, especially if the ulcer is indurated. A nontreponemal rapid plasma reagin (RPR) test, or venereal disease research laboratory (VDRL) test, and a confirmatory treponemal test—fluorescent treponemal antibody absorption (FTA ABS) or microhemagglutinin–T. pallidum (MHA TP)—should be used to diagnose syphilis presumptively. Some laboratories screen samples with treponemal enzyme immunoassay (EIA) tests, the results of which should be confirmed with nontreponemal tests. The results of nontreponemal tests usually correlate with disease activity and should be reported quantitatively. 2. Treponema pallidum : Syphilis infections result from Treponema pallidum . This infection usually manifests as a painless chancre in the primary stage. If the disease is left untreated, it will progress to the secondary stage. In the secondary stage, it manifests as fever, widespread maculopapular skin rashes involving the palms and soles,  widespread lymphadenopathy (epitrochlear node is pathognomic), and genital lesions similar to genital warts (condylomata lata- has a rounder surface when compared with condylomata acuminata). If there is still no treatment during the secondary stage, the infection will progress into the tertiary stage. The tertiary stage causes necrotic lesions called Gummas, neurological symptoms such as tabes dorsalis, Argyll Robertson pupils, and general paresis, cardiac symptoms such as aortitis. The treatment of syphilis is with the use of penicillin. Source: From RM Ballard, in KK Holmes et al (eds): Sexually Transmitted Diseases, 4th ed. New York, McGraw-Hill, 2008. HSV-1 from HSV-2 has prognostic implications, because the latter causes more frequent genital recurrences. Painless, nontender, indurated ulcers with firm, nontender inguinal adenopathy suggest primary syphilis. If results of dark-field examination and a rapid serologic test for syphilis are initially negative, presumptive therapy should be provided on the basis of the individual’s risk. For example, with increasing rates of syphilis among MSM in the United States, most experts would not withhold therapy for this infection pending watchful waiting and/or subsequent detection of seroconversion. Repeated serologic testing for syphilis 1 or 2 weeks after treatment of seronegative primary syphilis usually demonstrates seroconversion. Diagnosis The diagnosis usually is made serologically (through complement fixation) and by exclusion of other causes of inguinal lymphadenopathy or genital ulcers. Serologic testing has a sensitivity of 80% after two weeks. Serologic testing may not be specific for serotype (has some cross reactivity with other chlamydia species) and can suggest LGV from other forms because of their difference in dilution, 1:64 more likely to be LGV and lower than 1:16 is likely to be other chlamydia forms (emedicine). For identification of serotypes, culture is often used. Culture is difficult. Requiring a special medium, cycloheximide-treated McCoy or HeLa cells, and yields are still only 30-50%. DFA, or direct fluorescent antibody test, PCR of likely infected areas and pus, are also sometimes used. DFA test for the L-type serovar of C. trachomatis is the most sensitive and specific test, but is not readily available. Demonstration of H. ducreyi by culture (or by PCR, where available) is most useful when ulcers are painful and purulent, especially if inguinal lymphadenopathy with fluctuance or overlying erythema is noted; if chancroid is prevalent in the community; or if the patient has recently had a sexual exposure elsewhere in a chancroid-endemic area (e.g., a developing country). Enlarged, fluctuant lymph nodes should be aspirated for culture or PCR to detect H. ducreyi as well as for Gram’s staining and culture to rule out the presence of other pyogenic bacteria. Syphilis is a bacterial infection caused by the spirochete Treponema pallidum. Clinical presentation of secondary syphilis can present with diffuse lymphadenopathy along with fever, skin rashes, and condylomata lata. [7] Chancroid Lymphadenopathy may be an incidental finding in patients being examined for various reasons, or it may be a presenting sign or symptom of the patient’s illness. The physician must eventually decide whether the lymphadenopathy is a normal finding or one that requires further study, up to and including biopsy. Soft, flat, submandibular nodes (<1 cm) are often palpable in healthy children and young adults; healthy adults may have palpable inguinal nodes of up to 2 cm, which are considered normal. Further evaluation of these normal nodes is not warranted. In contrast, if the physician believes the node(s) to be abnormal, then pursuit of a more precise diagnosis is needed. APPROACH TO THE PATIENT: Approach to the Patient with an Infectious Disease regions (e.g., popliteal, inguinal, epitrochlear, axillary, multiple cervical regions), with notation of the location, size (normal, <1 cm), presence or absence of tenderness, and consistency (soft, firm, or shotty) and of whether the nodes are matted (i.e., connected and moving together). Of note, palpable epitrochlear nodes are always pathologic. Of patients presenting with lymphadenopathy, 75% have localized findings, and the remaining 25% have generalized lymphadenopathy (i.e., that involving more than one anatomic region). Localized lymphadenopathy in the head and neck region is found in 55% of patients, inguinal lymphadenopathy in 14%, and axillary lymphadenopathy in 5%. Determining whether the patient has generalized versus localized lymphadenopathy can help narrow the differential diagnosis, as various infections present differently. Females and males: Signs and symptoms: Patients will present with highly vascularized lesions over the genitals and perineum that tend to be painless. [37] [38] It can cause severe scarring. Physical Exam: Typical findings include ulcer-like lesions that are beefy red, consistent with high vascularization that bleeds easily with manipulation. Subcutaneous granulomas may be present, but lymphadenopathy is uncommon. The lesions tend to be relatively large and irregular. It is often found to be associated with secondary infections. Four main lesions can be seen on examination: 1. Ulcerovegetative: large painless ulcer on the patient's physical exam. 2. Nodular: soft and erythematous that tend to ulcerate throughout the infectious process. 3. Cicatricial: dry ulcerations that tend to transition into plaques. 4. Hypertrophic: lesions are thick and painless. [37] [39] node is an enlarged left supraclavicular node infiltrated with metastatic cancer from a gastrointestinal primary. Metastases to supraclavicular nodes also occur from lung, breast, testis, or ovarian cancers. Tuberculosis, sarcoidosis, and toxoplasmosis are nonneoplastic causes of supraclavicular adenopathy. Axillary adenopathy is usually due to injuries or localized infections of the ipsilateral upper extremity. Malignant causes include melanoma or lymphoma and, in women, breast cancer. Inguinal lymphadenopathy is usually secondary to infections or trauma of the lower extremities and may accompany sexually transmitted diseases such as lymphogranuloma venereum, primary syphilis, genital herpes, or chancroid. These nodes may also be involved by lymphomas and metastatic cancer from primary lesions of the rectum, genitalia, or lower extremities (melanoma). Serological tests cannot distinguish yaws from the closely related syphilis; no test distinguishing yaws from syphilis is widely available. The two genomes differ by about 0.2%. PCR and DNA sequencing can distinguish the two. There are also no common blood tests which distinguish among the four treponematoses: syphilis (Treponema pallidum pallidum), yaws (Treponema pallidum pertenue), bejel (Treponema pallidum endemicum), and pinta (Treponema carateum). Haemophilus ducreyi infections can cause skin conditions that mimic primary yaws. People infected with Haemophilus ducreyi lesions may or may not also have latent yaws, and thus may or may not test positive on serological tests. This was discovered in the mid 2010s. It seems that a recently diverged strain of Haemophilus ducreyi has evolved from being a sexually transmitted infection to being a skin ulcer pathogen that looks like yaws. Yaws has been reported in nonendemic countries. Females and males: Signs and symptoms: Patients will present with painful lymphadenopathy localized to the inguinal area. Patients may note the initial presentation of a pustule that gradually progresses to large painful ulceration. [41] Men tend to present with early or acute stages, while women typically present much later. [19] Physical Exam: Lymphogranuloma venereum presents with two stages: Primary phase is a small painless papule/pustule that will ulcerate and can be visualized throughout the affected genital area. During the secondary phase, patients present with unilateral lymphadenopathy that is fluctuant with palpation or may be suppurative in a presentation known as buboes. [38] Buboes tend to rupture in the acute phase and progress to a thickened mass. [42] A 36-year-old male sustained fracture of first lumbar vertebra, splenic tear and paraplegia in a motorcycle accident in 2001; splenectomy was performed. In 2008, he presented with temperature and feeling rough. With a diagnosis of urine infection, he was prescribed ciprofloxacin, followed by trimethoprim, amoxicillin, and gentamicin, as temperature did not subside. White cell count was 21.2 x 109/L; lymphocytes were 13.05 x 109/L (1.00 - 4.00). Therefore, computerised tomography (CT) of chest and abdomen was performed. Thrombus was present in pulmonary arteries bilaterally involving the lobar and segmental branches. Enlarged lymph nodes were seen in axillae, chest, abdomen and inguinal regions. Radiological diagnosis was lymphoma. Cell marker showed an excess of large granular lymphocytes and activated lymphocytes. The Glandular Fever Slide Test was positive. Subsequently, Paul Bunnell test was also positive. Epstein Barr virus serology was consistent with recent Epstein Barr virus infection. Antibiotic was omitted; enoxaparin was prescribed for pulmonary artery thrombosis. Learning points from this case: (1) Although routine administration of antibiotic to a spinal cord injury patient with pyrexia may be acceptable in outpatient setting, other possibilities such as infection by multi-drug resistant organism, viral infection, venous or, arterial thrombosis should be considered if a patient does not respond promptly to antibacterial therapy. (2) When full blood count showed lymphocytosis (comprising &gt; 50% of white blood cells) with atypical morphology, lymphocyte surface markers, Paul Bunnell test, and Epstein Barr virus serology should be performed. These tests would have led to a diagnosis of infectious mononucleosis, and abdominal imaging studies could have been avoided. (3) Lymphoid hyperplasia is the hallmark of infectious mononucleosis; therefore, we should have suspected glandular fever rather than lymphoma when CT scan revealed enlarged lymph nodes in abdomen, mediastinum, axillae and inguinal regions in this patient, who had lymphocytosis with atypical morphology. (4) A soft tissue mass, situated inferior to left hemidiaphragm in this asplenic patient, was misinterpreted as lymph nodes; review of CT led to the correct diagnosis of splenunculus. (5) Acute infection with Epstein Barr virus may lead to transient induction of anti-phospholipid antibodies, which can cause vascular thrombosis. (6) This case illustrates the value of reviewing test results and discussion with senior doctors, as these measures help to recognize medical errors and improve patient care. In a private room or space, the patient will partially undress. The clinician may inspect the patient's: Throat and lymph nodes of the neck for inflammation Pubic hair for lice Lymph nodes of the groin for swelling Genitals, anus, and surrounding areas for sores and warts The clinician may swab the patient's: Throat to test for gonorrhea and possibly chlamydia Cheek, inside, to diagnose HIV Sores of the genitals, anus, and surrounding areas to test for herpes Urethra to test for gonorrhea and possibly chlamydia Vagina to test for chlamydia and possibly gonorrhea Cervix to test for cervical intraepithelial neoplasia (a Pap test) Rectum to test for gonorrhea and possibly chlamydia The clinician may take small blood samples by pricking a finger or from a vein to test for HIV, syphilis, and possibly herpes and hepatitis C. Dear Editor, Syphilis is an infection caused by Treponema pallidum. Without treatment, it goes through the following stages: primary, secondary, latent, and tertiary (1). The clinical picture of secondary syphilis is very variable (2,3). We present two rare cases of secondary syphilis, one with nodular lesions initially considered to be lymphoma and second with periostitis, which was initially interpreted as an osteoma. To date, only 15 cases with nodular lesions and 10 cases with periostitis in secondary syphilis have been reported in the literature. The first patient was a 59 year old man who presented in a private practice with nodular lesions on the face and axillary and inguinal folds (Figure 1, a, b). The initial diagnostic consideration was lymphoma. A biopsy specimen was taken, and the histopathological features revealed epidermal hyperplasia with papillomatosis, minimal spongiosis with many neutrophils and with a marked inflammatory infiltrate in dermis, consisting of lymphocytes, plasma cells, and neutrophils; the diagnosis of interfaced dermatitis was established (Figure 1, d, e). After one month, the patient presented to our clinic with numerous nodular lesions, some of them painful, located on the trunk and intertriginous folds, including the intergluteal cleft - the lesions in this area being suggestive of condylomata lata (Figure 1, c). The diagnosis of secondary syphilis was taken into consideration, and screening serum tests were performed and found reactive: a Venereal Diseases Research Laboratory (VDRL) titer of 1:64 and Treponema pallidum Hemaglutination Assay (TPHA) titer of 1:80. Hepatitis and anti-human immunodeficiency virus (HIV) antibodies serology was negative. The biopsy was repeated and showed the same histopathological changes. In addition, Warthin-Starry staining was performed, revealing the presence of some spiral micro-organisms in the dermis corresponding to Treponema pallidum (Figure 1, f). A diagnosis of secondary syphilis was established, and the patient was treated with benzathine penicillin G 2.4 million units by intramuscular injection once a week for 2 consecutive weeks. The skin lesions regressed within 1 month, and serological tests showed a VDRL titer of 1:8 3 months after treatment. The second patient was a homosexual male, 35 years old, diagnosed with HIV infection, stage B2. He presented with bone pain in the calves and forearms, with insidious onset. He also presented with an associated erythematous maculo-papular rash on the trunk and limbs and generalized lymphadenopathy (Figure 2, a, b). The tibial crest and radius were sensitive to palpation. A right leg radiography was performed, raising suspicion of osteoid osteoma. The CT scan excluded the diagnosis of osteoma; taking into account the epidemiological context, the diagnosis of syphilis was suspected. The diagnosis was confirmed by leg ultrasound examination (2D US) which showed thickening of the compact tibial bone associated with subperiosteal destructive and proliferative changes (Figure 2, c, d) and by serology for syphilis: the VDRL titer was 1:32 and the TPHA titer was 1:80. The patient was treated with benzathine penicillin 2.4 million units, once a week, for 2 consecutive weeks, with clinical improvement. Syphilis continues to be a serious public health problem worldwide, even if it is a controllable disease due to diagnostic tests and effective and accessible treatment. According to the World Health Organization in 2008, the estimated number of new cases of sexually transmitted diseases in adults with syphilis is 10.6 million cases (4). The cases presented in this paper were characterized by unusual manifestations, requiring good collaboration between the dermatologist and other specialties. In the first case, the diagnosis of secondary syphilis was confirmed by positive serological, clinical, and histopathological findings. The main differential diagnosis of nodular syphilis includes lymphoma, sarcoidosis, Kaposi's sarcoma, atypical mycobacteriosis, deep fungal infections, leprosy, tuberculosis, leishmaniasis, and lymphomatoid papulosis (5). Another important differential diagnosis is between secondary and tertiary syphilis, especially when ulcerating nodules are present. Tertiary syphilis is characterized by unilateral, deep ulcerating nodules with necrotizing granulomas (6). Bone involvement during syphilis is mainly represented by polyarthritis, synovitis, osteitis, and periostitis (7,8). Syphilitic periostitis is characterized by localized or diffuse pain, particularly during the night, which is relieved by movement. The skull, the shoulder girdle, and the long bones are the most common sites of involvement (9). In conclusion, we presented two different cases of secondary syphilis that contribute to the clinical experience of rare cases presented in the literature, raising the awareness of dermatologists and other specialists about less specific clinical aspects of syphilis. adenopathy that is sometimes mistaken for malignancy; syphilis, LGV, HSV infection, and chancroid involving the anus can produce inguinal adenopathy because anal lymphatics drain to inguinal lymph nodes. Cervical lymphadenopathy is a sign or a symptom, not a diagnosis. The causes are varied, and may be inflammatory, degenerative, or neoplastic. In adults, healthy lymph nodes can be palpable (able to be felt), in the axilla, neck and groin. In children up to the age of 12 cervical nodes up to 1 cm in size may be palpable and this may not signify any disease. If nodes heal by resolution or scarring after being inflamed, they may remain palpable thereafter. In children, most palpable cervical lymphadenopathy is reactive or infective. In individuals over the age of 50, metastatic enlargement from cancers (most commonly squamous cell carcinomas) of the aerodigestive tract should be considered. Classification Cervical lymphadenopathy can be thought of as local where only the cervical lymph nodes are affected, or general where all the lymph nodes of the body are affected. Causes Sexually transmitted infections are the first to consider in the differential diagnosis of LGV. The exclusion of diseases which cause genital ulceration and inguinal adenopathy including herpes simplex, syphilis, chancroid, herpes, and granuloma inguinale will help narrow the diagnosis. HIV and lymphoma can also cause generalized lymphadenopathy. Dermatological conditions and trauma which can cause genital ulcerations should also be in the differential diagnosis. Lymph node enlargement is recognized as a common sign of infectious, autoimmune, or malignant disease. Examples may include: Reactive: acute infection (e.g., bacterial, or viral), or chronic infections (tuberculous lymphadenitis, cat-scratch disease). The most distinctive sign of bubonic plague is extreme swelling of one or more lymph nodes that bulge out of the skin as \"buboes.\" The buboes often become necrotic and may even rupture. Infectious mononucleosis is an acute viral infection usually caused by Epstein-Barr virus and may be characterized by a marked enlargement of the cervical lymph nodes. It is also a sign of cutaneous anthrax and Human African trypanosomiasis Toxoplasmosis, a parasitic disease, gives a generalized lymphadenopathy (Piringer-Kuchinka lymphadenopathy). Plasma cell variant of Castleman's disease - associated with HHV-8 infection and HIV infection A 38-year-old man who had sex with men, presented at the outpatient department for Sexually Transmitted Diseases in Amsterdam with a painful, red, fluctuating swelling in the left groin and general discomfort. He had been sexually active in the population of men who have sex with men, in which an anorectal lymphogranuloma venereum (LGV) epidemic has recently been discovered. Unlike other cases where there was anorectal involvement, this patient was the first case of LGV with the classical inguinal presentation although he had not visited the tropics where the inguinal form of LGV occurs as an STD. Routine investigation using PCR on material from urethra and rectum and from the urine, repeatedly failed to detect LGV. However, PCR on pus aspirated from the enlarged lymph node demonstrated Chlamydia trachomatis serovar type L2. Treatment with doxycycline 100 mg twice daily was started. This case illustrates that routine analysis from urethra and rectum and of urine may fail to detect LGV. Furthermore, this case of a patient who probably had LGV initially in the urethra may be the missing link in explaining the route of transmission of the anorectal LGV epidemic. The presentation of chancroid does not usually include all of the typical clinical features and is sometimes atypical. Multiple ulcers can coalesce to form giant ulcers. Ulcers can appear and then resolve, with inguinal adenitis (Fig. 182-2) and suppuration following 1–3 weeks later; this clinical picture can be confused with that of lymphogranuloma venereum (Chap. 213). Multiple small ulcers can resemble folliculitis. Other differential diagnostic considerations include the various infections causing genital ulceration, such as primary syphilis, secondary syphilis (condyloma latum), genital herpes, and donovanosis. In rare cases, chancroid lesions become secondarily infected with bacteria; the result is extensive inflammation. FIGURE 182-2 Chancroid with characteristic penile ulcers and associated left inguinal adenitis (bubo). A 33-year-old man presented with a two-week history of an asymptomatic ulcer of the oropharynx and submandibular lymph nodes swelling. Laboratory examinations were normal, but serological tests revealed positivity for rapid plasma reagin, Treponema pallidum haemagglutination assay and anti-T. pallidum IgM antibodies. Since the patient denied any homosexual relationship, a biopsy of the lesion was performed, which confirmed primary syphilis. The patient received an intramuscular injection of Benzathine Penicillin G (2.4 MU) with complete resolution of the lesion. Extragenital chancres occur in at least 5% of patients with primary syphilis, and the oral mucosa is the most frequent location as a consequence of orogenital/oroanal contact with an infectious lesion. Because of their transient nature, these oral ulcerations are often underestimated by the patient or by any unsuspecting clinician. Health professionals should consider the recent sexual history of their patients and should be prepared to recognise oral and systemic manifestations of sexually transmitted infections. \nHere is the question:\nINFECTIOUS DISEASES: A 24-year-old woman consults after noticing inguinal lymphadenopathy. The interrogation does not reveal the presence of any local discomfort or data suggestive of sexually transmitted infection. The examination revealed two lymphadenopathies, one in each groin, 1 cm in diameter, soft, mobile, non-painful. There are no skin lesions on the lower limbs, anus or perineum. Which test do you consider essential?\nHere are the potential choices:\n1. A lues serology since it is most likely a Treponema pallidum infection.\n2. A gynecological examination to rule out ovarian cancer.\n3. By the clinical characteristics it seems to be normal lymph nodes and complementary explorations should not be done.\n4. A Paul-Bunnell test should be performed in order to rule out infectious mononucleosis.\nThe correct answer is: 3. By the clinical characteristics it seems to be normal lymph nodes and complementary explorations should not be done."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A systematic review and cost comparison were conducted to determine the optimal treatment of active herpes zoster ophthalmicus (HZO) in immunocompetent adults. A literature search of MEDLINE, EMBASE, CINAHL, Cochrane Library, BIOSIS Previews and Web of Science, ClinicalTrials.gov, International Clinical Trials Registry Platform, Networked Digital Library of Theses and Dissertations, and Canadian Health Research Collection was performed. The search period was from January 1990 to March 2017. Collectively, 516 immunocompetent patients with active HZO treated with oral antivirals were included. Randomized controlled trials (RCTs) investigating treatment of active HZO in immunocompetent adults, with one oral acyclovir monotherapy arm, were included. Studies fulfilling inclusion criteria were subjected to quality assessment and data extraction. Provincial drug formularies were consulted to extrapolate cost comparison for investigated treatment regimens. A total of 1515 titles and abstracts and 9 full-text articles were assessed. Three RCTs met the inclusion criteria. Treatment with oral acyclovir (800 mg 5 times daily for 10 days) was superior to placebo in the prevention of ocular manifestations. Oral famciclovir (500 mg 3 times daily for 7 days) and valacyclovir (1000 mg 3 times daily for 7 days) resulted in comparable rates of ocular manifestations relative to oral acyclovir (800 mg 5 times daily for 7 days). According to provincial drug formulary data, famciclovir and valacyclovir are more affordable across Canada with the recommended dosing schedules. Oral famciclovir and valacyclovir are reasonable alternatives to oral acyclovir for treatment of active HZO in immunocompetent individuals. Their simpler dosing schedules are associated with a cost benefit that is consistent across Canada. Zoster ophthalmicus Treatment for zoster ophthalmicus is similar to standard treatment for shingles at other sites. A trial comparing acyclovir with its prodrug, valacyclovir, demonstrated similar efficacies in treating this form of the disease. The significant advantage of valacyclovir over acyclovir is its dosing of only three times/day (compared with acyclovir's five times/day dosing), which could make it more convenient for people and improve adherence with therapy. Treatment Treatment is usually with antivirals such as acyclovir, valacyclovir, or famcyclovir by mouth. There is uncertainty as to the difference in effect between these three antivirals. Antiviral eye drops have not been found to be useful. These medications work best if started within 3 days of the start of the rash. Cycloplegics prevent synechiae from forming. References External links Varicella zoster virus-associated diseases Ophthalmology Wikipedia medicine articles ready to translate Secondary prevention A 2013 Cochrane meta-analysis of 6 randomized controlled trials (RCTs) investigating oral antiviral medications given within 72 hours after the onset of herpes zoster rash in immunocompetent people for preventing postherpetic neuralgia (PHN) found no significant difference between placebo and acyclovir. Additionally, there was no significant difference in preventing the incidence of PHN found in the one RCT included in the meta-analysis that compared placebo to oral famciclovir treatment within 72 hours of HZ rash onset. Studies using valacyclovir treatment were not included in the meta-analysis. PHN was defined as pain at the site of the dermatomic rash at 120 days after the onset of rash, and incidence was evaluated at 1, 4, and 6 months after rash onset. Patients who are prescribed oral antiviral agents after the onset of rash should be informed that their chances of developing PHN are no different than those not taking oral antiviral agents. Evaluation of evidence-based strategies for managing herpes zoster (HZ) and the pain of postherpetic neuralgia (PHN). Approximately 20% of the world's population suffers from herpes zoster at least once in a lifetime, with 10% to 20% having ophthalmic involvement. Treatment of the acute disease with oral antivirals may reduce the incidence and severity of complications but does not reliably prevent PHN or postherpetic itch (PHI). The acute pain abates as the acute phase resolves; the long-term pain of PHN or PHI may be severe and difficult to manage. Although many therapeutic agents have efficacy in the management of these complications, relief is frequently partial for months to the remainder of the lifetime. Literature review was performed using the resources of the Harvard Medical School/Massachusetts Eye and Ear Infirmary Ophthalmic library as well as the National Library of Medicine and the National Institutes of Health PubMed service searching by pertinent topics, authors, and journals. If started within 72 hours of the onset of the acute HZ rash, the oral antiviral agents acyclovir, valacyclovir, and famciclovir significantly shorten the periods of acute pain, virus shedding, rash, acute and late-onset anterior segment complications, and, in the case of valacyclovir and famciclovir, the incidence and severity of PHN. However, these medications do not prevent PHN, which remains a common and debilitating complication of HZ in older patients, requiring assiduous pain management. Tricyclic antidepressants, antiseizure drugs, opioids, and topical analgesics all offer some pain relief, and may be combined. Options are available to manage HZ and reduce the pain of PHN. However, prevention, now possible with the HZ vaccine, is preferable to treatment. The mutation rate for synonymous and nonsynonymous mutation rates among the herpesviruses have been estimated at 1 × 10−7 and 2.7 × 10−8 mutations/site/year, respectively, based on the highly conserved gB gene. Treatment Within the human body it can be treated by a number of drugs and therapeutic agents including acyclovir for the chicken pox, famciclovir, valaciclovir for the shingles, zoster-immune globulin (ZIG), and vidarabine. Acyclovir is frequently used as the drug of choice in primary VZV infections, and beginning its administration early can significantly shorten the duration of any symptoms. However, reaching an effective serum concentration of acyclovir typically requires intravenous administration, making its use more difficult outside of a hospital. Vaccination Approximately 10 to 30% of the population will suffer from herpes zoster (HZ) during their lifetime. Prompt treatment of acute HZ with acyclovir, valacyclovir or famciclovir is recommend, if patients are over 50 years old or have severe or moderate pain or severe or moderate rash or they are immonocompromised or suffer from herpes zoster ophtalmicus. Zoster lesions contain high concentrations of Varicella zoster virus that can spread, and cause chicken pox. There is no universal recommendations for varicella vaccination. It has been shown that zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults. Antiviral agents: Ideally, treatment with systemic antiviral agents should begin within 72 hours of disease onset. Initiation should not be delayed while awaiting definitive diagnosis or ophthalmology follow-up. Topical antiviral agents may be considered, but there is limited evidence regarding their utility in managing HZO. Immunocompetent adult dosing (choose single agent): Acyclovir 800 mg orally five times per day for at least 7 days Valacyclovir 1000 mg orally every eight hours for at least 7 days (may require renal dosing) Famciclovir 500 mg orally three times per day for at least 7 days (may require renal dosing) Immunocompromised adult dosing (choose a single agent): Acyclovir 10 mg/kg of ideal body weight (IBW) intravenously (IV) every eight hours for at least 7 days Foscarnet 90 mg/kg IV every 12 hours (typically reserved for severe or acyclovir-resistant disease) The objective of this study was to assess the status and trends of antiviral treatment in outpatients with herpes zoster in China. Prescription data on antiviral drugs were extracted from the database of the Hospital Prescription Analysis Program of China according to the inclusion criteria. Yearly prescriptions and costs were calculated, and trends were analyzed. The trends were further stratified by age, sex, and specific drug use. The distribution of defined daily costs (DDCs) of valaciclovir and famciclovir were analyzed, and trends in the median DDCs were identified. A total of 132,911 prescriptions from 49 hospitals located in six major areas of China were included in the analysis. The yearly prescriptions containing antivirals increased from 8,819 in 2010 to 16,361 in 2019. The percentage of prescriptions for patients aged 65 years and above also increased (27.7% in 2010 to 31.0% in 2019), and the number of prescriptions for females was higher than those for males (<iP</i &lt; 0.001). The average cost of antivirals per prescription decreased; thus, the yearly cost showed no increasing trend. The main prescribed antivirals were valaciclovir and famciclovir, which progressively increased in prescriptions. The use of acyclovir decreased during the study period. Prescriptions containing topical formulations, acyclovir and penciclovir, both increased. The DDCs of valaciclovir and famciclovir decreased dramatically. The use of antivirals has increased over the decade, while the cost has not. Antiviral treatments adhere well to recent recommendations, except for the use of topical antivirals. The findings of this study may benefit the healthcare source allocation and management of herpes zoster in China. Treatment of herpes zoster conjunctivitis includes a combination of oral antivirals and topical steroids; however, steroids should only be part of therapy in consultation with ophthalmology. Antiviral doses differ from those used for herpes simplex and consist of acyclovir 800 mg PO 5 times a day, famciclovir 500 mg PO 3 times a day, or valacyclovir 1 g PO 3 times a day, each for 7 to 10 days. Treatment Herpes outbreaks should be treated with antiviral medications like Acyclovir, Valacyclovir, or Famcyclovir, each of which is available in tablet form. Oral antiviral medication is often used as a prophylactic to suppress or prevent outbreaks from occurring. The recommended dosage for suppression therapy for recurrent outbreaks is 1,000 mg of valacyclovir once a day or 400 mg Acyclovir taken twice a day. In addition to preventing outbreaks, these medications greatly reduce the chance of infecting someone while the patient is not having an outbreak. In adults, it is more common for the primary source to be the genital region, with a corresponding preponderance of HSV-2. It is also seen in adult health care workers such as dentists because of increased exposure to the herpes virus. Contact sports are also a potential source of infection with herpetic whitlows. Treatment Although it is a self-limited illness, oral or intravenous antiviral treatments, particularly acyclovir, have been used in the management of immunocompromised or severely infected patients. It is usually given when the condition fails to improve on its own. Topical acyclovir has not been shown to be effective in management of herpetic whitlow. Famciclovir has been demonstrated to effectively treat and prevent recurrent episodes. Lancing or surgically debriding the lesion may make it worse by causing a superinfection or encephalitis. Over the years, acyclovir has been the oral antiviral agent approved for the treatment of patients with acute herpes zoster,Its effectiveness in lessening the acute signs and symptoms of herpes zoster has been established but the effects on post herpetic neuralgia are less clear cut. Famciclovir is a new member of guanine nucleoside family of drugs. It is a well absorbed oral form of penciclovir with longer half life. This was a open comparative randomized study carried out to compare the safety and efficacy of famciclovir administered at 250mg thrice daily with acyclovir 800mg five times daily for the treatment of acute uncomplicated herpes zoster in immunocompetent individuals aged above 40 years. To assess the clinical profile of Herpes zoster, compare the efficacy and safety of acyclovir and famciclovir in the treatment of herpes zoster and to describe the effectiveness of acyclovir and famciclovir preventing post herpetic neuralgia. A total of 100 newly zoster were randomized in 1:1 ratio into acyclovir and famciclovir groups after inclusion criteria were satisfied.Treatment was initiated within 72 hrs of onset of symptoms and was continued for 7 days and evaluated at the end of each week up to six weeks period for full crusting of the lesions, complete healing of the lesion and loss of acute pain. It was observed that famciclovir was as effective as acyclovir with no significant difference in time taken for full crusting, complete healing of lesions or loss of acute pain. Famciclovir was well tolerated with a better safety profile comparable to that of acyclovir. Constipation, headache, nausea and vomiting were the most commonly reported adverse effects, but constipation was considered to have a possible relationship to treatment. In conclusion, oral famciclovir administered three times daily for 7 days during acute zoster infection is as effective as acyclovir, administered 800mg five times daily.In addition it offers significant benefit by providing a well tolerated, cost effective, convenient dosage regime and accelerated rate of lesion resolution and a reduced duration of PHN. Treatment Medication Currently treatment of ARN consists of antiviral therapy administered orally. Typical antiviral agents used include famciclovir, valganciclovir, and valacyclovir. While on these medications, a patient's kidney function should be watched. Some physician's also may administer the antiviral agents via intravitreal delivery. Though controversial, some physicians administer steroids (prednisone) and antithrombotic therapy (aspirin). Some commonly administered antiviral agents are as follows: Acyclovir Famciclovir Valacyclovir Gancicilovir Valganciclovir Research In a study done published by the British Journal of Ophthalmology, the cases of ARN/BARN reported in 2001-2002 in the UK, Varicella Zoster Virus was the most common culprit for the disease and presented mostly in men than in women. Differential diagnosis CMV, VZV as well as HIV infections of the esophagus can have a similar presentation. Tissue culture is the most accurate means of distinguishing between the different viral causes. Caustic esophagitis, pill-induced esophagitis as well as yeast esophagitis can have a similar clinical presentation. Prevention Herpes simplex virus is commonly found in humans, yet uncommonly results in systemic manifestations. Suppression of HIV with antiretroviral medications, careful monitoring of immunosuppressive medications are important means of prevention. Antiviral prophylaxis such as daily acyclovir in immunocompromised individuals may be considered. Treatment Antivirals such as acyclovir, famciclovir, or valacyclovir may be used. Intravenous acyclovir is reserved for individuals who cannot swallow due to the pain, individuals with other systemic manifestations of herpes or severely immunocompromised individuals. References lymphoproliferative malignancies), both chickenpox and herpes zoster (including disseminated disease) should be treated, at least at the outset, with IV acyclovir, which reduces the occurrence of visceral complications but has no effect on healing of skin lesions or pain. The dose is 10 mg/kg every 8 h for 7 days. For low-risk immunocompromised hosts, oral therapy with valacyclovir or famciclovir appears beneficial. If medically feasible, it is desirable to decrease immunosuppressive treatment concomitant with the administration of IV acyclovir. Patients with varicella pneumonia often require ventilatory support. Persons with zoster ophthalmicus should be referred immediately to an ophthalmologist. Therapy for this condition consists of the administration of analgesics for severe pain and the use of atropine. Acyclovir, valacyclovir, and famciclovir all accelerate healing. Decisions about the use of glucocorticoids should be made by the ophthalmologist. The management of acute Herpes zoster ophthalmicus affects the eye and vision, and is caused by the reactivation of the varicella zoster virus in the distribution of the first division of the trigeminal nerve. An aggressive management of acute herpes zoster ophthalmicus with systemic antiviral medication is generally recommended as the standard first-line treatment for herpes zoster ophthalmicus infections. Both acyclovir and its prodrug valacyclovir are medications that are approved for the systemic treatment of herpes zoster. Although it is known that valacyclovir has an improved bioavailability and steadier plasma concentration, it is currently unclear as to whether this leads to better treatment results and less ocular complications. To assess the effects of valacyclovir versus acyclovir for the systemic antiviral treatment of herpes zoster ophthalmicus in immunocompetent patients. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register; 2016, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2016), Embase (January 1980 to June 2016), Web of Science Conference Proceedings Citation Index-Science (CPCI-S; January 1990 to June 2016), BIOSIS Previews (January 1969 to June 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 13 June 2016. We considered all randomised controlled trials (RCTs) in which systemic valacyclovir was compared to systemic acyclovir medication for treatment of herpes zoster ophthalmicus. There were no language restrictions. Two review authors independently selected trials, evaluated the risk of bias in included trials, and extracted and analysed data. We did not conduct a meta-analysis, as only one study was included. We assessed the certainty of the evidence for the selected outcomes using the GRADE approach. One study fulfilled the inclusion criteria. In this multicentre, randomised double-masked study carried out in France, 110 immunocompetent people with herpes zoster ophthalmicus, diagnosed within 72 hours of skin eruption, were treated, with 56 participants allocated to the valacyclovir group and 54 to the acyclovir group. The study was poorly reported and we judged it to be unclear risk of bias for most domains.Persistent ocular lesions after 6 months were observed in 2/56 people in the valacyclovir group compared with 1/54 people in the acyclovir group (risk ratio (RR) 1.93 (95% CI 0.18 to 20.65); very low certainty evidence. Dendritic ulcer appeared in 3/56 patients treated with valacyclovir, while 1/54 suffered in the acyclovir group (RR 2.89; 95% confidence interval (CI) 0.31 to 26.96); very low certainty evidence), uveitis in 7/56 people in the valacyclovir group compared with 9/54 in the acyclovir group (RR 0.96; 95% CI 0.36 to 2.57); very low certainty evidence). Similarly, there was uncertainty as to the comparative effects of these two treatments on post-herpetic pain, and side effects (vomiting, eyelid or facial edema, disseminated zoster). Due to concerns about imprecision (small number of events and large confidence intervals) and study limitations, the certainty of evidence using the GRADE approach was rated as low to very low for the use of valacyclovir compared to acyclovir. This review included data from only one study, which had methodological limitations. As such, our results indicated uncertainty of the relative benefits and harms of valacyclovir over acyclovir in herpes zoster ophthalmicus, despite its widespread use for this condition. Further well-designed and adequately powered trials are needed. These trials should include outcomes important to patients, including compliance. In people experiencing their first episode of genital herpes oral acyclovir may reduce the duration of symptoms and lesions but the risk of adverse effects is not certain. There may also be little or no difference between topical acyclovir and placebo in terms of duration of symptoms and lesions and the risk of adverse effects. Valacyclovir is a prodrug that is converted to acyclovir once in the body. It helps relieve the pain and discomfort and speeds healing of sores. It only comes in caplets and its advantage is that it has a longer duration of action than acyclovir. An example usage is by mouth twice per day for ten days for primary lesion, and twice per day for three days for a recurrent episode. Famciclovir is another antiviral drug that belongs to the same class. Famciclovir is a prodrug that is converted to penciclovir in the body. The latter is the one active against the viruses. It has a longer duration of action than acyclovir and it only comes in tablets. Application at initial symptoms reduces healing time by 1 d. Therapy should be undertaken in consultation with an ophthalmologist. Valacyclovir may be more effective than acyclovir for pain relief; otherwise, it has a similar effect on cutaneous lesions and should be given within 72 h of rash onset. The duration of postherpetic neuralgia is shorter than with placebo. Famciclovir showed overall efficacy similar to that of acyclovir in a comparative trial. It should be given ≤72 h after rash onset. Acyclovir causes faster resolution of skin lesions than placebo and provides some relief of acute symptoms if given within 72 h of rash onset. Combined with tapering doses of prednisone, acyclovir improves quality-of-life outcomes. Antiviral Chemotherapy, Excluding Antiretroviral Drugs Treatments for Ramsay Hunt Syndrome Type 2 are used to reduce further damage causes by the viral infection. These medications will not reverse any damage that has already occurred at the time that they are prescribed. Initial treatment with a corticosteroid such as prednisone and the antiviral drug such as acyclovir (500 milligrams five times a day), valacyclovir (1000 mg three times a day) or famciclovir (500 mg three times a day) for 5 to 7 days is standard, however some studies have shown later damage to the facial nerve and recommend 21 days of antivirals. Studies indicate that treatment started within 72 hours of the onset of facial paralysis improves the chances of the patient experiencing significant recovery. Chances of recovery appear to decrease when treatment is delayed. Delay of treatment may result in permanent facial nerve paralysis. However, some studies demonstrate that even when steroids are started promptly, only 22% of all patient achieve full recovery of facial Because VZV is generally less sensitive to acyclovir than is HSV, higher doses of acyclovir must be used to treat VZV infections. In immunocompromised patients with herpes zoster, IV acyclovir reduces the frequency of cutaneous dissemination and visceral complications and—in one comparative trial—was more effective than vidarabine. Acyclovir, administered at oral doses of 800 mg five times a day, had a modest beneficial effect on localized herpes zoster lesions in both immunocompromised and immunocompetent patients. Combination of acyclovir with a tapering regimen of prednisone appeared to be more effective than acyclovir alone in terms of quality-of-life outcomes in immunocompetent patients over age 50 with herpes zoster. A comparative study of acyclovir (800 mg PO five times daily) and valacyclovir (1 g PO three times daily) in immunocompetent patients with herpes zoster indicated that the latter drug may be more effective in eliciting the resolution of zoster-associated pain. Although vidarabine was the first systemic antiviral drug for the treatment of acute herpes zoster, the agent now used most frequently is acyclovir, a far safer drug that became available a decade ago. However, even with widespread use of acyclovir, postherpetic neuralgia (PHN) remains a principal cause of postinfectious morbidity. Newer antiviral agents, such as famciclovir and valacyclovir, have recently been introduced for the treatment of uncomplicated herpes zoster. In a double-blind, randomized study, 500 mg of famciclovir three times daily for 7 days was compared with placebo; in a second study, 500 mg of famciclovir three times daily for 7 days was compared with 800 mg of acyclovir five times daily for 7 days. Famciclovir significantly reduced duration of viral shedding (P = 0.0001) and accelerated lesion resolution compared with placebo. Famciclovir was comparable to acyclovir for these acute parameters. Most importantly, famciclovir recipients lost PHN two times faster than those receiving placebo (P = 0.02 all patients; P = 0.004 patients &gt; or = 50 years) resulting in a reduction in the median duration of PHN (56 days all patients; 100 days patients &gt; or = 50 years). This reduction translated to a 3.5-month reduction in the median duration of PHN for patients 50 years or older, those at greatest risk for developing the most common complication of herpes zoster. Famciclovir 500 mg administered three times a day for 7 days is an effective and well-tolerated treatment for acute herpes zoster, and is the only oral antiviral agent proven to reduce the duration of PHN when administered during acute zoster infection. Women with a history of genital herpes, can be treated with antiviral drugs to prevent symptomatic lesions and viral shedding that could infect the infant at birth. The antiviral medications used include acyclovir, penciclovir, valacyclovir, and famciclovir. Only very small amounts of the drug can be detected in the fetus. There are no increases in drug-related abnormalities in the infant that could be attributed to acyclovir. Long-term effects of antiviral medications have not been evaluated for their effects after growth and development of the child occurs. Neutropenia can be a complication of acyclovir treatment of neonatal HSV infection, but is usually transient. Treatment with immunoglobulin therapy has not been proven to be effective and is not recommended. Epidemiology A related prodrug form, valaciclovir came into medical use in 1995. It is converted to aciclovir in the body after absorption. In 2009, acyclovir in combination with hydrocortisone cream, marketed as Xerese, was approved in the United States for the early treatment of recurrent herpes labialis (cold sores) to reduce the likelihood of ulcerative cold sores and to shorten the lesion healing time in adults and children (six years of age and older). Society and culture Names Aciclovir is the International Nonproprietary Name (INN) and British Approved Name (BAN) while acyclovir is the United States Adopted Name (USAN) and former British Approved Name. It was originally marketed as Zovirax; patents expired in the 1990s and since then it is generic and is marketed under many brand names worldwide. Notes References Despite the long-term use of acyclovir to treat HSV encephalitis, there has not been a systematic review regarding the efficacy of this disease/treatment combination. Current systematic reviews addressing its safety and efficacy are ongoing, with the primary outcome being the mortality rate. A secondary outcome measure is the quality of life. [4] HSV keratitis has been shown to respond to oral acyclovir and topical steroids in pediatric patients. [5] The objective was to evaluate the efficacy of antiviral agent valacyclovir compared with famciclovir in the treatment of herpes zoster. A comparative study was conducted over a period of 1 year. Data relevant to the study were collected from 60 patients, with active herpes zoster presenting to the outpatient department within 72 hr of the first occurrence of zoster rash. They were divided in to two groups of 30 patients each. The first group of patients received valacyclovir tablet 1000 mg thrice daily, whereas those in the second group were given famciclovir tablet 500 mg thrice daily. Both the drugs were given for 7 days. Periodic follow-up till 29<supth</sup day was done for assessment of the effects of given drugs. Significant decrease was observed on comparison of pain scores between the two groups using the visual analog scale, with the drug valacyclovir, than in the famciclovir group at day 29. Furthermore, valacyclovir treatment accelerated the resolution of zoster associated pain in more number of patients compared with famciclovir. Oral valacyclovir administered during acute zoster infection for a period of 7 days offers significant benefit compared to famciclovir by providing a well tolerated and greater resolution of pain while maintaining the favorable safety profile, making valacyclovir more efficacious and a better drug in management of Herpes Zoster in comparison to famciclovir.\nHere is the question:\nINFECTIOUS: A 71-year-old woman with a history of rheumatoid arthritis on sulfasalazine, prednisone and etanercept. She goes to the emergency room for 72 hours of clinical manifestations compatible with facial herpes zoster affecting the right hemiface, auricular pavilion, respecting the forehead and conjunctival chemosis. What would be the appropriate treatment?\nHere are the potential choices:\n1. Symptomatic treatment of pain only.\n2. Topical treatment with acyclovir.\n3. Outpatient treatment with acyclovir, valacyclovir or oral famciclovir.\n4. Hospital admission and treatment with acyclovir or famciclovir iv.\n5. Parenteral Ig and vaccination.\nThe correct answer is: ",
        "gold_answer": "4 Hospital admission and treatment with acyclovir or famciclovir iv.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A systematic review and cost comparison were conducted to determine the optimal treatment of active herpes zoster ophthalmicus (HZO) in immunocompetent adults. A literature search of MEDLINE, EMBASE, CINAHL, Cochrane Library, BIOSIS Previews and Web of Science, ClinicalTrials.gov, International Clinical Trials Registry Platform, Networked Digital Library of Theses and Dissertations, and Canadian Health Research Collection was performed. The search period was from January 1990 to March 2017. Collectively, 516 immunocompetent patients with active HZO treated with oral antivirals were included. Randomized controlled trials (RCTs) investigating treatment of active HZO in immunocompetent adults, with one oral acyclovir monotherapy arm, were included. Studies fulfilling inclusion criteria were subjected to quality assessment and data extraction. Provincial drug formularies were consulted to extrapolate cost comparison for investigated treatment regimens. A total of 1515 titles and abstracts and 9 full-text articles were assessed. Three RCTs met the inclusion criteria. Treatment with oral acyclovir (800 mg 5 times daily for 10 days) was superior to placebo in the prevention of ocular manifestations. Oral famciclovir (500 mg 3 times daily for 7 days) and valacyclovir (1000 mg 3 times daily for 7 days) resulted in comparable rates of ocular manifestations relative to oral acyclovir (800 mg 5 times daily for 7 days). According to provincial drug formulary data, famciclovir and valacyclovir are more affordable across Canada with the recommended dosing schedules. Oral famciclovir and valacyclovir are reasonable alternatives to oral acyclovir for treatment of active HZO in immunocompetent individuals. Their simpler dosing schedules are associated with a cost benefit that is consistent across Canada. Zoster ophthalmicus Treatment for zoster ophthalmicus is similar to standard treatment for shingles at other sites. A trial comparing acyclovir with its prodrug, valacyclovir, demonstrated similar efficacies in treating this form of the disease. The significant advantage of valacyclovir over acyclovir is its dosing of only three times/day (compared with acyclovir's five times/day dosing), which could make it more convenient for people and improve adherence with therapy. Treatment Treatment is usually with antivirals such as acyclovir, valacyclovir, or famcyclovir by mouth. There is uncertainty as to the difference in effect between these three antivirals. Antiviral eye drops have not been found to be useful. These medications work best if started within 3 days of the start of the rash. Cycloplegics prevent synechiae from forming. References External links Varicella zoster virus-associated diseases Ophthalmology Wikipedia medicine articles ready to translate Secondary prevention A 2013 Cochrane meta-analysis of 6 randomized controlled trials (RCTs) investigating oral antiviral medications given within 72 hours after the onset of herpes zoster rash in immunocompetent people for preventing postherpetic neuralgia (PHN) found no significant difference between placebo and acyclovir. Additionally, there was no significant difference in preventing the incidence of PHN found in the one RCT included in the meta-analysis that compared placebo to oral famciclovir treatment within 72 hours of HZ rash onset. Studies using valacyclovir treatment were not included in the meta-analysis. PHN was defined as pain at the site of the dermatomic rash at 120 days after the onset of rash, and incidence was evaluated at 1, 4, and 6 months after rash onset. Patients who are prescribed oral antiviral agents after the onset of rash should be informed that their chances of developing PHN are no different than those not taking oral antiviral agents. Evaluation of evidence-based strategies for managing herpes zoster (HZ) and the pain of postherpetic neuralgia (PHN). Approximately 20% of the world's population suffers from herpes zoster at least once in a lifetime, with 10% to 20% having ophthalmic involvement. Treatment of the acute disease with oral antivirals may reduce the incidence and severity of complications but does not reliably prevent PHN or postherpetic itch (PHI). The acute pain abates as the acute phase resolves; the long-term pain of PHN or PHI may be severe and difficult to manage. Although many therapeutic agents have efficacy in the management of these complications, relief is frequently partial for months to the remainder of the lifetime. Literature review was performed using the resources of the Harvard Medical School/Massachusetts Eye and Ear Infirmary Ophthalmic library as well as the National Library of Medicine and the National Institutes of Health PubMed service searching by pertinent topics, authors, and journals. If started within 72 hours of the onset of the acute HZ rash, the oral antiviral agents acyclovir, valacyclovir, and famciclovir significantly shorten the periods of acute pain, virus shedding, rash, acute and late-onset anterior segment complications, and, in the case of valacyclovir and famciclovir, the incidence and severity of PHN. However, these medications do not prevent PHN, which remains a common and debilitating complication of HZ in older patients, requiring assiduous pain management. Tricyclic antidepressants, antiseizure drugs, opioids, and topical analgesics all offer some pain relief, and may be combined. Options are available to manage HZ and reduce the pain of PHN. However, prevention, now possible with the HZ vaccine, is preferable to treatment. The mutation rate for synonymous and nonsynonymous mutation rates among the herpesviruses have been estimated at 1 × 10−7 and 2.7 × 10−8 mutations/site/year, respectively, based on the highly conserved gB gene. Treatment Within the human body it can be treated by a number of drugs and therapeutic agents including acyclovir for the chicken pox, famciclovir, valaciclovir for the shingles, zoster-immune globulin (ZIG), and vidarabine. Acyclovir is frequently used as the drug of choice in primary VZV infections, and beginning its administration early can significantly shorten the duration of any symptoms. However, reaching an effective serum concentration of acyclovir typically requires intravenous administration, making its use more difficult outside of a hospital. Vaccination Approximately 10 to 30% of the population will suffer from herpes zoster (HZ) during their lifetime. Prompt treatment of acute HZ with acyclovir, valacyclovir or famciclovir is recommend, if patients are over 50 years old or have severe or moderate pain or severe or moderate rash or they are immonocompromised or suffer from herpes zoster ophtalmicus. Zoster lesions contain high concentrations of Varicella zoster virus that can spread, and cause chicken pox. There is no universal recommendations for varicella vaccination. It has been shown that zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults. Antiviral agents: Ideally, treatment with systemic antiviral agents should begin within 72 hours of disease onset. Initiation should not be delayed while awaiting definitive diagnosis or ophthalmology follow-up. Topical antiviral agents may be considered, but there is limited evidence regarding their utility in managing HZO. Immunocompetent adult dosing (choose single agent): Acyclovir 800 mg orally five times per day for at least 7 days Valacyclovir 1000 mg orally every eight hours for at least 7 days (may require renal dosing) Famciclovir 500 mg orally three times per day for at least 7 days (may require renal dosing) Immunocompromised adult dosing (choose a single agent): Acyclovir 10 mg/kg of ideal body weight (IBW) intravenously (IV) every eight hours for at least 7 days Foscarnet 90 mg/kg IV every 12 hours (typically reserved for severe or acyclovir-resistant disease) The objective of this study was to assess the status and trends of antiviral treatment in outpatients with herpes zoster in China. Prescription data on antiviral drugs were extracted from the database of the Hospital Prescription Analysis Program of China according to the inclusion criteria. Yearly prescriptions and costs were calculated, and trends were analyzed. The trends were further stratified by age, sex, and specific drug use. The distribution of defined daily costs (DDCs) of valaciclovir and famciclovir were analyzed, and trends in the median DDCs were identified. A total of 132,911 prescriptions from 49 hospitals located in six major areas of China were included in the analysis. The yearly prescriptions containing antivirals increased from 8,819 in 2010 to 16,361 in 2019. The percentage of prescriptions for patients aged 65 years and above also increased (27.7% in 2010 to 31.0% in 2019), and the number of prescriptions for females was higher than those for males (<iP</i &lt; 0.001). The average cost of antivirals per prescription decreased; thus, the yearly cost showed no increasing trend. The main prescribed antivirals were valaciclovir and famciclovir, which progressively increased in prescriptions. The use of acyclovir decreased during the study period. Prescriptions containing topical formulations, acyclovir and penciclovir, both increased. The DDCs of valaciclovir and famciclovir decreased dramatically. The use of antivirals has increased over the decade, while the cost has not. Antiviral treatments adhere well to recent recommendations, except for the use of topical antivirals. The findings of this study may benefit the healthcare source allocation and management of herpes zoster in China. Treatment of herpes zoster conjunctivitis includes a combination of oral antivirals and topical steroids; however, steroids should only be part of therapy in consultation with ophthalmology. Antiviral doses differ from those used for herpes simplex and consist of acyclovir 800 mg PO 5 times a day, famciclovir 500 mg PO 3 times a day, or valacyclovir 1 g PO 3 times a day, each for 7 to 10 days. Treatment Herpes outbreaks should be treated with antiviral medications like Acyclovir, Valacyclovir, or Famcyclovir, each of which is available in tablet form. Oral antiviral medication is often used as a prophylactic to suppress or prevent outbreaks from occurring. The recommended dosage for suppression therapy for recurrent outbreaks is 1,000 mg of valacyclovir once a day or 400 mg Acyclovir taken twice a day. In addition to preventing outbreaks, these medications greatly reduce the chance of infecting someone while the patient is not having an outbreak. In adults, it is more common for the primary source to be the genital region, with a corresponding preponderance of HSV-2. It is also seen in adult health care workers such as dentists because of increased exposure to the herpes virus. Contact sports are also a potential source of infection with herpetic whitlows. Treatment Although it is a self-limited illness, oral or intravenous antiviral treatments, particularly acyclovir, have been used in the management of immunocompromised or severely infected patients. It is usually given when the condition fails to improve on its own. Topical acyclovir has not been shown to be effective in management of herpetic whitlow. Famciclovir has been demonstrated to effectively treat and prevent recurrent episodes. Lancing or surgically debriding the lesion may make it worse by causing a superinfection or encephalitis. Over the years, acyclovir has been the oral antiviral agent approved for the treatment of patients with acute herpes zoster,Its effectiveness in lessening the acute signs and symptoms of herpes zoster has been established but the effects on post herpetic neuralgia are less clear cut. Famciclovir is a new member of guanine nucleoside family of drugs. It is a well absorbed oral form of penciclovir with longer half life. This was a open comparative randomized study carried out to compare the safety and efficacy of famciclovir administered at 250mg thrice daily with acyclovir 800mg five times daily for the treatment of acute uncomplicated herpes zoster in immunocompetent individuals aged above 40 years. To assess the clinical profile of Herpes zoster, compare the efficacy and safety of acyclovir and famciclovir in the treatment of herpes zoster and to describe the effectiveness of acyclovir and famciclovir preventing post herpetic neuralgia. A total of 100 newly zoster were randomized in 1:1 ratio into acyclovir and famciclovir groups after inclusion criteria were satisfied.Treatment was initiated within 72 hrs of onset of symptoms and was continued for 7 days and evaluated at the end of each week up to six weeks period for full crusting of the lesions, complete healing of the lesion and loss of acute pain. It was observed that famciclovir was as effective as acyclovir with no significant difference in time taken for full crusting, complete healing of lesions or loss of acute pain. Famciclovir was well tolerated with a better safety profile comparable to that of acyclovir. Constipation, headache, nausea and vomiting were the most commonly reported adverse effects, but constipation was considered to have a possible relationship to treatment. In conclusion, oral famciclovir administered three times daily for 7 days during acute zoster infection is as effective as acyclovir, administered 800mg five times daily.In addition it offers significant benefit by providing a well tolerated, cost effective, convenient dosage regime and accelerated rate of lesion resolution and a reduced duration of PHN. Treatment Medication Currently treatment of ARN consists of antiviral therapy administered orally. Typical antiviral agents used include famciclovir, valganciclovir, and valacyclovir. While on these medications, a patient's kidney function should be watched. Some physician's also may administer the antiviral agents via intravitreal delivery. Though controversial, some physicians administer steroids (prednisone) and antithrombotic therapy (aspirin). Some commonly administered antiviral agents are as follows: Acyclovir Famciclovir Valacyclovir Gancicilovir Valganciclovir Research In a study done published by the British Journal of Ophthalmology, the cases of ARN/BARN reported in 2001-2002 in the UK, Varicella Zoster Virus was the most common culprit for the disease and presented mostly in men than in women. Differential diagnosis CMV, VZV as well as HIV infections of the esophagus can have a similar presentation. Tissue culture is the most accurate means of distinguishing between the different viral causes. Caustic esophagitis, pill-induced esophagitis as well as yeast esophagitis can have a similar clinical presentation. Prevention Herpes simplex virus is commonly found in humans, yet uncommonly results in systemic manifestations. Suppression of HIV with antiretroviral medications, careful monitoring of immunosuppressive medications are important means of prevention. Antiviral prophylaxis such as daily acyclovir in immunocompromised individuals may be considered. Treatment Antivirals such as acyclovir, famciclovir, or valacyclovir may be used. Intravenous acyclovir is reserved for individuals who cannot swallow due to the pain, individuals with other systemic manifestations of herpes or severely immunocompromised individuals. References lymphoproliferative malignancies), both chickenpox and herpes zoster (including disseminated disease) should be treated, at least at the outset, with IV acyclovir, which reduces the occurrence of visceral complications but has no effect on healing of skin lesions or pain. The dose is 10 mg/kg every 8 h for 7 days. For low-risk immunocompromised hosts, oral therapy with valacyclovir or famciclovir appears beneficial. If medically feasible, it is desirable to decrease immunosuppressive treatment concomitant with the administration of IV acyclovir. Patients with varicella pneumonia often require ventilatory support. Persons with zoster ophthalmicus should be referred immediately to an ophthalmologist. Therapy for this condition consists of the administration of analgesics for severe pain and the use of atropine. Acyclovir, valacyclovir, and famciclovir all accelerate healing. Decisions about the use of glucocorticoids should be made by the ophthalmologist. The management of acute Herpes zoster ophthalmicus affects the eye and vision, and is caused by the reactivation of the varicella zoster virus in the distribution of the first division of the trigeminal nerve. An aggressive management of acute herpes zoster ophthalmicus with systemic antiviral medication is generally recommended as the standard first-line treatment for herpes zoster ophthalmicus infections. Both acyclovir and its prodrug valacyclovir are medications that are approved for the systemic treatment of herpes zoster. Although it is known that valacyclovir has an improved bioavailability and steadier plasma concentration, it is currently unclear as to whether this leads to better treatment results and less ocular complications. To assess the effects of valacyclovir versus acyclovir for the systemic antiviral treatment of herpes zoster ophthalmicus in immunocompetent patients. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register; 2016, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2016), Embase (January 1980 to June 2016), Web of Science Conference Proceedings Citation Index-Science (CPCI-S; January 1990 to June 2016), BIOSIS Previews (January 1969 to June 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 13 June 2016. We considered all randomised controlled trials (RCTs) in which systemic valacyclovir was compared to systemic acyclovir medication for treatment of herpes zoster ophthalmicus. There were no language restrictions. Two review authors independently selected trials, evaluated the risk of bias in included trials, and extracted and analysed data. We did not conduct a meta-analysis, as only one study was included. We assessed the certainty of the evidence for the selected outcomes using the GRADE approach. One study fulfilled the inclusion criteria. In this multicentre, randomised double-masked study carried out in France, 110 immunocompetent people with herpes zoster ophthalmicus, diagnosed within 72 hours of skin eruption, were treated, with 56 participants allocated to the valacyclovir group and 54 to the acyclovir group. The study was poorly reported and we judged it to be unclear risk of bias for most domains.Persistent ocular lesions after 6 months were observed in 2/56 people in the valacyclovir group compared with 1/54 people in the acyclovir group (risk ratio (RR) 1.93 (95% CI 0.18 to 20.65); very low certainty evidence. Dendritic ulcer appeared in 3/56 patients treated with valacyclovir, while 1/54 suffered in the acyclovir group (RR 2.89; 95% confidence interval (CI) 0.31 to 26.96); very low certainty evidence), uveitis in 7/56 people in the valacyclovir group compared with 9/54 in the acyclovir group (RR 0.96; 95% CI 0.36 to 2.57); very low certainty evidence). Similarly, there was uncertainty as to the comparative effects of these two treatments on post-herpetic pain, and side effects (vomiting, eyelid or facial edema, disseminated zoster). Due to concerns about imprecision (small number of events and large confidence intervals) and study limitations, the certainty of evidence using the GRADE approach was rated as low to very low for the use of valacyclovir compared to acyclovir. This review included data from only one study, which had methodological limitations. As such, our results indicated uncertainty of the relative benefits and harms of valacyclovir over acyclovir in herpes zoster ophthalmicus, despite its widespread use for this condition. Further well-designed and adequately powered trials are needed. These trials should include outcomes important to patients, including compliance. In people experiencing their first episode of genital herpes oral acyclovir may reduce the duration of symptoms and lesions but the risk of adverse effects is not certain. There may also be little or no difference between topical acyclovir and placebo in terms of duration of symptoms and lesions and the risk of adverse effects. Valacyclovir is a prodrug that is converted to acyclovir once in the body. It helps relieve the pain and discomfort and speeds healing of sores. It only comes in caplets and its advantage is that it has a longer duration of action than acyclovir. An example usage is by mouth twice per day for ten days for primary lesion, and twice per day for three days for a recurrent episode. Famciclovir is another antiviral drug that belongs to the same class. Famciclovir is a prodrug that is converted to penciclovir in the body. The latter is the one active against the viruses. It has a longer duration of action than acyclovir and it only comes in tablets. Application at initial symptoms reduces healing time by 1 d. Therapy should be undertaken in consultation with an ophthalmologist. Valacyclovir may be more effective than acyclovir for pain relief; otherwise, it has a similar effect on cutaneous lesions and should be given within 72 h of rash onset. The duration of postherpetic neuralgia is shorter than with placebo. Famciclovir showed overall efficacy similar to that of acyclovir in a comparative trial. It should be given ≤72 h after rash onset. Acyclovir causes faster resolution of skin lesions than placebo and provides some relief of acute symptoms if given within 72 h of rash onset. Combined with tapering doses of prednisone, acyclovir improves quality-of-life outcomes. Antiviral Chemotherapy, Excluding Antiretroviral Drugs Treatments for Ramsay Hunt Syndrome Type 2 are used to reduce further damage causes by the viral infection. These medications will not reverse any damage that has already occurred at the time that they are prescribed. Initial treatment with a corticosteroid such as prednisone and the antiviral drug such as acyclovir (500 milligrams five times a day), valacyclovir (1000 mg three times a day) or famciclovir (500 mg three times a day) for 5 to 7 days is standard, however some studies have shown later damage to the facial nerve and recommend 21 days of antivirals. Studies indicate that treatment started within 72 hours of the onset of facial paralysis improves the chances of the patient experiencing significant recovery. Chances of recovery appear to decrease when treatment is delayed. Delay of treatment may result in permanent facial nerve paralysis. However, some studies demonstrate that even when steroids are started promptly, only 22% of all patient achieve full recovery of facial Because VZV is generally less sensitive to acyclovir than is HSV, higher doses of acyclovir must be used to treat VZV infections. In immunocompromised patients with herpes zoster, IV acyclovir reduces the frequency of cutaneous dissemination and visceral complications and—in one comparative trial—was more effective than vidarabine. Acyclovir, administered at oral doses of 800 mg five times a day, had a modest beneficial effect on localized herpes zoster lesions in both immunocompromised and immunocompetent patients. Combination of acyclovir with a tapering regimen of prednisone appeared to be more effective than acyclovir alone in terms of quality-of-life outcomes in immunocompetent patients over age 50 with herpes zoster. A comparative study of acyclovir (800 mg PO five times daily) and valacyclovir (1 g PO three times daily) in immunocompetent patients with herpes zoster indicated that the latter drug may be more effective in eliciting the resolution of zoster-associated pain. Although vidarabine was the first systemic antiviral drug for the treatment of acute herpes zoster, the agent now used most frequently is acyclovir, a far safer drug that became available a decade ago. However, even with widespread use of acyclovir, postherpetic neuralgia (PHN) remains a principal cause of postinfectious morbidity. Newer antiviral agents, such as famciclovir and valacyclovir, have recently been introduced for the treatment of uncomplicated herpes zoster. In a double-blind, randomized study, 500 mg of famciclovir three times daily for 7 days was compared with placebo; in a second study, 500 mg of famciclovir three times daily for 7 days was compared with 800 mg of acyclovir five times daily for 7 days. Famciclovir significantly reduced duration of viral shedding (P = 0.0001) and accelerated lesion resolution compared with placebo. Famciclovir was comparable to acyclovir for these acute parameters. Most importantly, famciclovir recipients lost PHN two times faster than those receiving placebo (P = 0.02 all patients; P = 0.004 patients &gt; or = 50 years) resulting in a reduction in the median duration of PHN (56 days all patients; 100 days patients &gt; or = 50 years). This reduction translated to a 3.5-month reduction in the median duration of PHN for patients 50 years or older, those at greatest risk for developing the most common complication of herpes zoster. Famciclovir 500 mg administered three times a day for 7 days is an effective and well-tolerated treatment for acute herpes zoster, and is the only oral antiviral agent proven to reduce the duration of PHN when administered during acute zoster infection. Women with a history of genital herpes, can be treated with antiviral drugs to prevent symptomatic lesions and viral shedding that could infect the infant at birth. The antiviral medications used include acyclovir, penciclovir, valacyclovir, and famciclovir. Only very small amounts of the drug can be detected in the fetus. There are no increases in drug-related abnormalities in the infant that could be attributed to acyclovir. Long-term effects of antiviral medications have not been evaluated for their effects after growth and development of the child occurs. Neutropenia can be a complication of acyclovir treatment of neonatal HSV infection, but is usually transient. Treatment with immunoglobulin therapy has not been proven to be effective and is not recommended. Epidemiology A related prodrug form, valaciclovir came into medical use in 1995. It is converted to aciclovir in the body after absorption. In 2009, acyclovir in combination with hydrocortisone cream, marketed as Xerese, was approved in the United States for the early treatment of recurrent herpes labialis (cold sores) to reduce the likelihood of ulcerative cold sores and to shorten the lesion healing time in adults and children (six years of age and older). Society and culture Names Aciclovir is the International Nonproprietary Name (INN) and British Approved Name (BAN) while acyclovir is the United States Adopted Name (USAN) and former British Approved Name. It was originally marketed as Zovirax; patents expired in the 1990s and since then it is generic and is marketed under many brand names worldwide. Notes References Despite the long-term use of acyclovir to treat HSV encephalitis, there has not been a systematic review regarding the efficacy of this disease/treatment combination. Current systematic reviews addressing its safety and efficacy are ongoing, with the primary outcome being the mortality rate. A secondary outcome measure is the quality of life. [4] HSV keratitis has been shown to respond to oral acyclovir and topical steroids in pediatric patients. [5] The objective was to evaluate the efficacy of antiviral agent valacyclovir compared with famciclovir in the treatment of herpes zoster. A comparative study was conducted over a period of 1 year. Data relevant to the study were collected from 60 patients, with active herpes zoster presenting to the outpatient department within 72 hr of the first occurrence of zoster rash. They were divided in to two groups of 30 patients each. The first group of patients received valacyclovir tablet 1000 mg thrice daily, whereas those in the second group were given famciclovir tablet 500 mg thrice daily. Both the drugs were given for 7 days. Periodic follow-up till 29<supth</sup day was done for assessment of the effects of given drugs. Significant decrease was observed on comparison of pain scores between the two groups using the visual analog scale, with the drug valacyclovir, than in the famciclovir group at day 29. Furthermore, valacyclovir treatment accelerated the resolution of zoster associated pain in more number of patients compared with famciclovir. Oral valacyclovir administered during acute zoster infection for a period of 7 days offers significant benefit compared to famciclovir by providing a well tolerated and greater resolution of pain while maintaining the favorable safety profile, making valacyclovir more efficacious and a better drug in management of Herpes Zoster in comparison to famciclovir.\nHere is the question:\nINFECTIOUS: A 71-year-old woman with a history of rheumatoid arthritis on sulfasalazine, prednisone and etanercept. She goes to the emergency room for 72 hours of clinical manifestations compatible with facial herpes zoster affecting the right hemiface, auricular pavilion, respecting the forehead and conjunctival chemosis. What would be the appropriate treatment?\nHere are the potential choices:\n1. Symptomatic treatment of pain only.\n2. Topical treatment with acyclovir.\n3. Outpatient treatment with acyclovir, valacyclovir or oral famciclovir.\n4. Hospital admission and treatment with acyclovir or famciclovir iv.\n5. Parenteral Ig and vaccination.\nThe correct answer is: 3. Outpatient treatment with acyclovir, valacyclovir or oral famciclovir."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Primary hyperaldosteronism is only rarely caused by unilateral adrenal hyperplasia. A 73-year-old hypertensive Greek man (on 10 mg amlodipine for the last ten years) presented in the emergency department with severe muscle weakness of all limbs. The initial physical and laboratory examination revealed normal blood pressure, muscle weakness, severe hypokalemia, sinus rhythm and U wave, rhabdomyolysis and metabolic alkalosis. The patient was immediately treated with intravenous administration of potassium-rich solutions, 25 mg spironolactone with progressive dose titration up to 100 mg. Because of high arterial blood pressure, irbesartan was added. On day 6, muscle weakness was completely restored with decrease of arterial blood pressure and further improvement of laboratory tests. The combination of hypokalemia with arterial hypertension raised the suspicion of primary hyperaldosteronism; therefore, we performed abdomen computed tomography scan, which revealed a nodular mass (15 mm in diameter) in the left adrenal gland. Plasma renin activity was in the lower normal range with a three-fold increase of plasma aldosterone concentration. We performed total resection of the left adrenal gland and the histopathological examination revealed hyperplasia of the left adrenal gland. This report presents a rare case of an elderly patient under antihypertensive treatment the last ten years for essential hypertension, who admitted to our emergency department with hypokalemia - induced myopathy as first manifestation of primary hyperaldosteronism due to unilateral adrenal hyperplasia. Primary aldosteronism occurs in 1-10% of hypertensive patients and is classified in adenomas or bilateral adrenal hyperplasia. Computed tomography (CT) or magnetic resonance imaging can be used to discriminate these subtypes and in guiding treatment selection. This case report describes a 65-year-old man with hypertension and hypokalaemia during 25 years. Bilateral adrenal hyperplasia was diagnosed based on a CT, and an oral sodium-loading test with measurement of renin and aldosterone confirmed the diagnosis. Blood pressure and potassium in plasma was normalized during treatment with the mineralocorticoid receptor antagonist eplerenon.  Primary aldosteronism (PA) is the most common form of secondary hypertension (HTN), with an estimated prevalence of 4% of hypertensive patients in primary care and around 10% of referred patients. Patients with PA have higher cardiovascular morbidity and mortality than age- and sex-matched patients with essential HTN and the same degree of blood pressure elevation. PA is characterized by an autonomous aldosterone production causing sodium retention, plasma renin supression, HTN, cardiovascular damage, and increased potassium excretion, leading to variable degrees of hypokalemia. Aldosterone-producing adenomas (APAs) account for around 40% and idiopathic hyperaldosteronism for around 60% of PA cases. The aldosterone-to-renin ratio is the most sensitive screening test for PA. There are several confirmatory tests and the current literature does not identify a \"gold standard\" confirmatory test for PA. In our institution, we recommend starting case confirmation with the furosemide test. After case confirmation, all patients with PA should undergo adrenal CT as the initial study in subtype testing to exclude adrenocortical carcinoma. Bilateral adrenal vein sampling (AVS) is the gold standard method to define the PA subtype, but it is not indicated in all cases. An experienced radiologist must perform AVS. Unilateral laparoscopic adrenalectomy is the preferential treatment for patients with APAs, and bilateral hyperplasia should be treated with mineralocorticoid antagonist (spironolactone or eplerenone). Cardiovascular morbidity caused by aldosterone excess can be decreased by either unilateral adrenalectomy or mineralocorticoid antagonist. In this review, we address the most relevant issues regarding PA screening, case confirmation, subtype classification, and treatment. Based on two patients, we discuss the difficulties in diagnosing and managing primary aldosteronism in pregnancy, which derive from changes of the renin-angiotensin-aldosterone axis, from the uncertainty regarding blood pressure control along gestation and postpartum, and from the contraindication to the use of spironolactone. The first case is a 27 years old woman with a long standing refractory hypertension, a hemorrhagic stroke with left brachial hemiplegia and crural hemiparesia, two miscarriages, one stillbirth and one offspring with intrauterine growth retardation. Due to hypokalemia, a plasma aldosterone/renin activity ratio of 91, and a negative genetic screening for glucocorticoid remediable aldosteronism (GRA), a primary hyperaldosteronism with normal adrenals in CT scan was diagnosed, and good blood pressure control was attained with spironolactone. After two and a half years of normotension, a fifth pregnancy, managed with methyldopa evolved with satisfactory blood pressures, plasma potassium, fetal growth, uterine and umbilical arterial resistance indexes, and maternal endothelial function. At 37 1/2 weeks of pregnancy the patient delivered a healthy newborn weighing 2,960 g. Blood pressure rose during the 48 hours of postpartum in the absence of proteinuria and required i.v. hydralazine. The second patient is a 37 years old woman, with known refractory hypertension for 7 years, hypokalemia, plasma aldosterone/renin activity ratio greater than 40, normal adrenals in the CAT scan, and a negative genetic screening for GRA. She had normotensive pregnancies 5 and 3 years prior to the detection of hypertension, with hypertensive crisis in both postpartum periods, retrospectively considered as expressions of primary hyperaldosteronism. The prevalence of primary hyperaldosteronism is 5-10% of all hypertensive patients, and clearly above the estimated prevalence in the past. In nearly 30% of patients with therapy resistant hypertension, primary hyperaldosteronism is detected if they are investigated thoroughly. This will result in 1.5 to 2.5 million people in Germany suffering from primary hyperaldosteronism. Besides efficient diagnostic procedures, an effective treatment is of increasing importance. The aldosterone-producing adenoma (Conn's syndrome) is primarily cured by operation, in most cases performed endoscopically. Bilateral hyperplasia, which is found in two-thirds of primary hyperaldosteronism, is treated primarily by mineralocorticoid receptor antagonist: 12.5-50 mg/day spironolactone (in case of anti-androgenic side-effects alternatively by 50-100 mg/day eplerenone). If the blood pressure can not be lowered by this first-line treatment, an additional treatment with potassium-sparing diuretics, calcium-antagonists, ACE-inhibitors or angiotensin-2-antagonists is necessary. The start of medication should be closely monitored by serum electrolyte and creatinine controls. We report a case of a renin secreting tumor, which is a very rare cause of secondary high blood pressure. A 22-year-old woman was hospitalised for exploration of high blood pressure (160/110 mmHg) with severe hypokaliemia (2,7 mmol/l) and secondary hyperaldosteronism. Physical examination was normal except the high blood pressure. Bioassays show increased kaliuresis (66 mmol/24h), plasma renin (89 pg/ml in clinostastism--108 pg/ml in orthostatism), pro-renin (1207 pg/ml in clinostastism--1412 pg/ml in orthostatism) and aldosterone (210 pg/ml in clinostastism--566 pg/ml in orthostatism). The rest of the endocrine tests were normal (cortisol and ACTH at 8:00 am, urinary free cortisol, overnight 1 mg dexamethasone suppression test). Doppler ultrasound method, performed by an experienced radiologist, did not show renal artery stenosis. Abdominal computerized tomography showed a nodular formation at the upper pole of the right kidney, isodense to renal medullary. The size tumor was 15 mm. The renal vein sampling shows high values of renin on both sides whereas, for the pro-renin, the values were higher on the tumor side. In spite of treatment with CEI (Converting Enzyme Inhibitors) and calcium antagonists, the blood pressure was not controlled. Hypokaliemia persisted (3 mmol/l) in spite of high daily potassium intake (64 mmol/l of potassium chloride). After tumor resection, reninoma was diagnosed by the pathology examination and blood pressure, plasma rennin, plasma aldosterone level returned to normal. Diagnosis Other conditions such as Liddle's Syndrome can mimic the clinical features of AME, so diagnosis can be made by calculating the ratio of free urinary cortisol to free urinary cortisone. Since AME patients create less cortisone, the ratio will much be higher than non-affected patients. Alternatively, one could differentiate between the two syndromes by administering a potassium-sparing diuretic. Patients with Liddle's syndrome will only respond to a diuretic that binds the ENaC channel, whereas those with AME will respond to a diuretic that binds to ENaC or the mineralcorticoid receptor. Treatment The treatment for AME is based on the blood pressure control with Aldosterone antagonist like Spironolactone which also reverses the hypokalemic metabolic alkalosis and other anti-hypertensives. Renal transplant is found curative in almost all clinical cases.AME is exceedingly rare, with fewer than 100 cases recorded worldwide. Primary hyperaldosteronism (PHA) represents less than 1 to 2% of all causes of hypertension (HT). We report 2 cases of primary hyperaldosteronism which emphasize the difficulty of distinguishing neoplastic PHA from idiopathic PHA, observed in a 60-year-old woman and a 42-year old woman, respectively. In both cases, the diagnosis of PHA was suggested by marked hypokalaemia with inappropriate potassium excretion and was confirmed by hyperaldosteronaemia and low and poorly stimulated renin activity. In the first case, computed tomography showed nodular hyperplasia of the 2 adrenal glands. The patient was treated with spironolactone and calcium channel blockers which controlled blood pressure and serum potassium. In the second case, computed tomography and magnetic resonance imaging revealed an adrenocortical adenoma confirmed by pathological examination after the operation. The diagnosis of primary hyperaldosteronism is based on three steps: detection, positive diagnosis and aetiological diagnosis. Detection is essentially based on demonstration of hypokalaemia. Positive diagnosis is based on demonstration of elevated aldosterone secretion with inhibited renin secretion. The aetiological diagnosis is dominated by the differentiation between Conn's adenoma and bilateral adrenal hyperplasia, which has therapeutic implications. To investigate the clinical characteristics, differential diagnosis, and surgery outcome of unilateral nodular adrenal hyperplasia (UNAH). The clinical data of 145 patients with primary aldosteronism, 67 males and 78 females, aged 37.9 (19-60), including 78 cases of aldosterone-producing adenoma (APA), 14 cases of UNAH, and 55 cases of idiopathic bilateral adrenal hyperplasia (BAH), were collected. Radioimmunoassay was used to examine the blood and urine aldosterone and plasma rennin activity. Automatic biochemical apparatus was used to examine the blood and urine electrolytes, renal functions, and urine microalbumin. Twelve-lead electrocardiography, echocardiography, and plain scanning of enhanced CT scanning of the bilateral adrenals were conducted. Adrenal venous sampling (AVS) was conducted in 62 patients to collect blood samples from vena cava and bilateral suprarenal veins to detect the levels of aldosterone and cortisol. All UNAH patients and 3 BAH patients underwent unilateral adrenalectomy and three APA patients underwent unilateral adrenalectomy or adenoma resection. Then the patients were followed up for 39.2 months. The incidence of UNAH is 9.7% in the primary aldosteronism patients. There were no significant differences in age, gender, duration of hypertension, blood pressure (SBP, DBP), and indexes indicating damages in target organs of hypertension (left ventricular hypertrophy rate, blood creatinine, urine microalbumin, etc) among these three groups. The level of serum potassium of the APA group was significantly lower than that of the BAH group (P &lt; 0.01), and the levels of plasma and urine aldosterone of the APA group were significantly higher than those of the BAH group (P &lt; 0.05 and P &lt; 0.01). The serum potassium of the UNAH group was higher than that of the APA group and lower than that of the BAH group, and the levels of plasma and urine aldosterone of the UNAH group were both higher than those of the APA group and lower than those of the BAH group, however all not significantly (all P &gt; 0.05). The coincidence rate of CT was 50% (7/14) in the UNAH group. The accuracy of AVS for diagnosis of UNAH was 85.7% (12/14). After operation, the serum potassium and plasma aldosterone concentrations returned normal in all the UNAH patients. Blood pressure returned to normal in 50% (7/14) of the UNAH patients, and was improved in the other 50% (7/14) patients. UNAH can be cured by adrenal surgery. The diagnostic values of clinical examination and adrenal CT are limited. AVS is essential in diagnosing UNAH patients. Pseudohyperaldosteronism (also pseudoaldosteronism) is a medical condition which mimics the effects of elevated aldosterone (hyperaldosteronism) by presenting with high blood pressure (hypertension), low blood potassium levels (hypokalemia), metabolic alkalosis, and low levels of plasma renin activity (PRA). However, unlike hyperaldosteronism, this conditions exhibits low or normal levels of aldosterone in the blood. Causes include genetic disorders (e.g. Apparent mineralocorticoid excess syndrome, Liddle's syndrome, and types of Congenital adrenal hyperplasia), acquired conditions (e.g. Cushing's syndrome and mineralocorticoid-producing adrenal tumors), metabolic disorders, and dietary imbalances including excessive consumption of licorice. Confirmatory diagnosis depends on the specific root cause and may involve blood tests, urine tests, or genetic testing; however, all forms of this condition exhibit abnormally low concentrations of both plasma renin activity (PRA) and plasma Primary hyperaldosteronism (PHA) is characterized by an increased Aldosterone synthesis which is independent of the Renin-Angiotensin-Aldosterone-System (RAAS). The prevalence of PHA in patients who present in specialized hypertension centers is approx. 10 %. Besides patients with the classical symptoms known as \"Conn-Trias\" (hypertension, hypokalemia, metabolic alkalosis), the more frequent normokalemic patients with PHA also show a worse outcome compared to patients with essential hypertension. Identifying these patients is an important task in the evaluation of hypertension since targeted treatment options are available. Screening for PHA using the Aldosterone-Renin-Ratio (ARR) should be performed in patients with hypokalemic, severe or resistant hypertension. In addition, young patients with early onset of severe hypertension and/or positive family history should be screened. A positive screening result should be followed by a confirmatory test. The saline infusion test is the preferred clinical test for confirming a suspected PHA since it is accessible and time efficient. Other confirmatory tests are not used on a regular basis. After any confirmatory test, CT- or MRI-imaging and adrenal vein sampling (AVS) is used in order to differentiate between a unilateral adenoma, a bilateral hyperplasia or another cause of PHA. CT or MRI usually cannot discriminate smaller tumors form hyperplasia. Therefore AVS is used to detect lateralization of autonomous aldosterone production. Lateralization of aldosterone production indicates a unilateral adenoma. In these cases, laparoscopic adrenalectomy is the therapeutic option of choice with a hypertension cure rate of up to 60 %. If no lateralization is detectable, bilateral hyperplasia as the underlying cause of PHA is likely. Pharmacological inhibition of the mineralocorticoid receptor is the preferred treatment option in these cases. If Spironolactone is not well tolerated, Eplerenone and potassium-sparing diuretics should be prescribed. Often, however, in order to fully control hypertension, additional antihypertensive therapy is necessary. Great strides have been made in our understanding of the pathophysiology of primary aldosteronism syndrome since Conn's description of the clinical presentation of a patient with an aldosterone-producing adenoma (APA) more than 50 years ago. It is now recognized that the APA is just one of the seven subtypes of primary aldosteronism. APA and bilateral idiopathic hyperaldosteronism (IHA) are the most common subtypes of primary aldosteronism. Although most clinicians had thought primary aldosteronism to be a rare form of hypertension for more than three decades, it is now recognized to be the most common form of secondary hypertension. Using the plasma aldosterone to plasma renin activity ratio as a case-finding test, followed by aldosterone suppression confirmatory testing, has resulted in much higher prevalence estimates of 5-13% of all patients with hypertension. In addition, there has been a new recognition of the aldosterone-specific cardiovascular morbidity and mortality associated with aldosterone excess. Although thought to be daunting and complex in the past, the diagnostic approach to primary aldosteronism is straightforward and can be considered in three phases: case-finding tests, confirmatory tests and subtype evaluation tests. Patients with hypertension and hypokalaemia (regardless of presumed cause), treatment-resistant hypertension (three antihypertensive drugs and poor control), severe hypertension (&gt;or= 160 mmHg systolic or &gt;or= 100 mmHg diastolic), hypertension and an incidental adrenal mass, onset of hypertension at a young age or patients being evaluated for other forms of secondary hypertension should undergo screening for primary aldosteronism. In patients with suspected primary aldosteronism, screening can be accomplished by measuring a morning (preferably between 0800 and 1000 h) ambulatory paired random plasma aldosterone concentration (PAC) and plasma renin activity (PRA). An increased PAC:PRA ratio is not diagnostic by itself, and primary aldosteronism must be confirmed by demonstrating inappropriate aldosterone secretion. Aldosterone suppression testing can be performed with orally administered sodium chloride and measurement of urinary aldosterone or with intravenous sodium chloride loading and measurement of PAC. Unilateral adrenalectomy in patients with APA or unilateral adrenal hyperplasia results in normalization of hypokalaemia in all these patients; hypertension is improved in all and is cured in approximately 30-60% of them. In bilateral adrenal forms of primary aldosteronism, unilateral or bilateral adrenalectomy seldom corrects the hypertension and they should be treated medically with a mineralocorticoid receptor antagonist. Primary Primary aldosteronism (hyporeninemic hyperaldosteronism) was previously thought to be most commonly caused by an adrenal adenoma, termed Conn's syndrome. However, recent studies have shown that bilateral idiopathic adrenal hyperplasia is the cause in up to 70% of cases. Differentiating between the two is important, as this determines treatment. Also, see congenital adrenal hyperplasia. Adrenal carcinoma is an extremely rare cause of primary hyperaldosteronism. Two familial forms have been identified: type I (dexamethasone suppressible), and type II, which has been linked to the 7p22 gene. Features Hypertension Hypokalemia (e.g., may cause muscle weakness) Alkalosis Investigations High serum aldosterone Low serum renin High-resolution CT abdomen Management Adrenal adenoma: surgery Bilateral adrenocortical hyperplasia: aldosterone antagonist, e.g., spironolactone To show clinical, biochemical, and morphological data of 12 patients with primary hyperaldosteronism: eight with an aldosterone-producing adenoma and four with adrenal hyperplasia. To compare clinical and biochemical parameters of the patients with adenoma and hyperplasia. For those with adenoma, to verify clinical and biochemical modifications after adrenalectomy. In the 12 patients with hyperaldosteronism, retrospective analysis of clinical (age, sex, blood pressure), biochemical (plasmatic and urinary potassium, plasmatic aldosterone, plasma renin activity, and plasmatic aldosterone/renin activity ratio), and morphological (computed tomography, magnetic resonance, and norcholesterol scintigraphy) data was performed. 1--In the 12 patients with hyperaldosteronism (seven female), the age was 51.0 +/- 10.2 years (mean +/- standard deviation), the systolic pressure 200.9 +/- 34.5 mm Hg and the diastolic pressure 120.0 +/- 12.3 mm Hg. Hypertension was diagnosed 12.0 +/- 10.1 years before. As biochemical evidence, we found kalaemia of 3.06 +/- 0.28 and urinary potassium of 63.4 +/- 16.5 mEq/l, renin activity 0.98 +/- 1.02 ng/ml/h, plasmatic aldosterone of 49.4 +/- 36.0 ng/dl, aldosterone/renin activity &gt; 30 in 83% of the cases. As morphological evidence, computed tomography allowed diagnosis in nine patients, suggested it in two, being doubtful in one. Performed on four patients, resonance confirmed the tomography in three and was not contributive in one. The scintigraphy performed in four patients visualized two adenomas, was negative in one adenoma and in one hyperplasia. 2--In the eight patients with adenoma (six female), the youngest age and the highest diastolic pressure compared with patients with hyperplasia were statistically significant (p &lt; 0.01 and 0.05). In the adenomas, the biochemical changes were more pronounced, but not statistically significant. The plasmatic aldosterone/renin activity ratio was also higher in the adenoma cases. 3--After the adrenalectomy, blood pressure became normal in five patients and was more easily therapeutically controlled in three. The average systolic and diastolic pressures decreased and the biochemical parameters became normal in all patients. The pre/post surgical modification of these parameters had statistical significance (systolic pressure decrease, p &lt; 0.01; diastolic pressure decrease, p &lt; 0.01; kalaemia increase, p &lt; 0.001; renin activity increase, p &lt; 0.01; aldosterone decrease, p &lt; 0.02). The plasmatic aldosterone/renine activity ratio normalized in all patients. In diagnosing primary hyperaldosteronism, biochemical (kalaemia, urinary potassium, plasmatic aldosterone, renin activity, aldosterone plasmatic/renin activity) and tomography studies were important. On comparing the patients with hyperplasia with those with adenoma, we found that the latter are younger and exhibit higher diastolic pressure, both findings with statistical significance. After adenoma surgery, blood pressure became normal in five patients and improved in three, these findings, and the improvement of the kalaemia, plasmatic aldosterone, and renin activity parameters were statistically significant. In patients with normal adrenal morphology and family history of early-onset, severe hypertension, a diagnosis of GRA should be Disorders of the Adrenal Cortex Clinical suspicion of mineralocorticoid excess Patients with hypertension and Severe hypertension (>3 BP drugs, drug-resistant) or Family history of early-onset hypertension or cerebrovascular events at < 40 years of age Measurement of aldosterone-renin ratio (ARR) on current blood pressure medication (stop spironolactone for 4 wks) and with hypokalemia corrected (ARR screen positive if ARR >750 pmol/L: ng/ml/h and aldosterone >450 pmol/L) (consider repeat off ˜-blockers for 2 wks if results are equivocal) Negative E.g., saline infusion test (2 liters physiologic saline over 4 h IV), oral sodium loading, fludrocortisone suppression Confirmation of diagnosis Rare: Both renin and Aldo suppressed The diagnosis of primary hyperaldosteronism (PHPA) has progressively increased over the last years and some authors consider it as the main cause of secondary hypertension. We studied the prevalence of PHPA in hypertensive patients followed at the Hypertension Unit from July 1999 to July 2017. A total of 2500 patients were included and diagnosis of PHPA was done in 79 of them (3.2%). It was more frequent in women (55.7%) with an increased incidence in the elderly, as compared to previous studies (27.8%). Initial diagnosis was suspected upon the presence of inappropriate kaliuria and metabolic alkalosis, associated to an aldosterone/plasma renin activity ratio &gt; 30 (ng/dl)/(ng/ml/h). After confirmation of the presence of PA, imaging techniques to determine the etiology were performed. In this way, 29 cases (36.8%) of aldosterone-producing adenoma and 5 cases of bilateral adrenal hyperplasia with nodules were identified. Computed tomography identified the adenomas and hyperplasias with bilateral cortical nodules in all patients. Adrenalectomy and/or antialdosteronics were efficient in controlling blood pressure in 69.9% of cases. Of note in this series was the remission of stage 3 chronic renal failure in two cases, the high prevalence of hypercalciuric urinary lithiasis and a case of breast carcinoma after prolonged treatment with spironolactone. Primary hyperaldosteronism has a number of causes. About 33% of cases are due to an adrenal adenoma that produces aldosterone, and 66% of cases are due to an enlargement of both adrenal glands. Other uncommon causes include adrenal cancer and an inherited disorder called familial hyperaldosteronism. Some recommend screening people with high blood pressure who are at increased risk, while others recommend screening all people with high blood pressure for the disease. Screening is usually done by measuring the aldosterone-to-renin ratio in the blood (ARR) whilst off interfering medications and a serum potassium over 4, with further testing used to confirm positive results. While low blood potassium is classically described in primary hyperaldosteronism, this is only present in about a quarter of people. To determine the underlying cause, medical imaging is carried out.\nHere is the question:\nNEPHROLOGY: A 58-year-old man with a 6-year history of hypertension consults for poor blood pressure control despite treatment with an angiotensin-converting enzyme inhibitor, a diuretic and a calcium antagonist. On consultation she presented with blood pressure of 149/100 mmHg. Laboratory tests: creatinine 1.2 mg/dl, potassium 2.2 mEq/l and compensated metabolic alkalosis; the rest of the biochemical study, blood count, coagulation and urinary sediment were normal. Point out the correct statement:\nHere are the potential choices:\n1. The origin of hypertension in this case is excessive secretion of aldosterone caused by autonomic hyperfunction of the adrenal medulla.\n2. In most cases the anatomical substrate is a bilateral hyperplasia of the adrenal cortex.\n3. CT scan is part of the diagnostic study in case of biochemical confirmation.\n4. Spironolactone is contraindicated in the management of this pathology.\nThe correct answer is: ",
        "gold_answer": "3 CT scan is part of the diagnostic study in case of biochemical confirmation.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Primary hyperaldosteronism is only rarely caused by unilateral adrenal hyperplasia. A 73-year-old hypertensive Greek man (on 10 mg amlodipine for the last ten years) presented in the emergency department with severe muscle weakness of all limbs. The initial physical and laboratory examination revealed normal blood pressure, muscle weakness, severe hypokalemia, sinus rhythm and U wave, rhabdomyolysis and metabolic alkalosis. The patient was immediately treated with intravenous administration of potassium-rich solutions, 25 mg spironolactone with progressive dose titration up to 100 mg. Because of high arterial blood pressure, irbesartan was added. On day 6, muscle weakness was completely restored with decrease of arterial blood pressure and further improvement of laboratory tests. The combination of hypokalemia with arterial hypertension raised the suspicion of primary hyperaldosteronism; therefore, we performed abdomen computed tomography scan, which revealed a nodular mass (15 mm in diameter) in the left adrenal gland. Plasma renin activity was in the lower normal range with a three-fold increase of plasma aldosterone concentration. We performed total resection of the left adrenal gland and the histopathological examination revealed hyperplasia of the left adrenal gland. This report presents a rare case of an elderly patient under antihypertensive treatment the last ten years for essential hypertension, who admitted to our emergency department with hypokalemia - induced myopathy as first manifestation of primary hyperaldosteronism due to unilateral adrenal hyperplasia. Primary aldosteronism occurs in 1-10% of hypertensive patients and is classified in adenomas or bilateral adrenal hyperplasia. Computed tomography (CT) or magnetic resonance imaging can be used to discriminate these subtypes and in guiding treatment selection. This case report describes a 65-year-old man with hypertension and hypokalaemia during 25 years. Bilateral adrenal hyperplasia was diagnosed based on a CT, and an oral sodium-loading test with measurement of renin and aldosterone confirmed the diagnosis. Blood pressure and potassium in plasma was normalized during treatment with the mineralocorticoid receptor antagonist eplerenon.  Primary aldosteronism (PA) is the most common form of secondary hypertension (HTN), with an estimated prevalence of 4% of hypertensive patients in primary care and around 10% of referred patients. Patients with PA have higher cardiovascular morbidity and mortality than age- and sex-matched patients with essential HTN and the same degree of blood pressure elevation. PA is characterized by an autonomous aldosterone production causing sodium retention, plasma renin supression, HTN, cardiovascular damage, and increased potassium excretion, leading to variable degrees of hypokalemia. Aldosterone-producing adenomas (APAs) account for around 40% and idiopathic hyperaldosteronism for around 60% of PA cases. The aldosterone-to-renin ratio is the most sensitive screening test for PA. There are several confirmatory tests and the current literature does not identify a \"gold standard\" confirmatory test for PA. In our institution, we recommend starting case confirmation with the furosemide test. After case confirmation, all patients with PA should undergo adrenal CT as the initial study in subtype testing to exclude adrenocortical carcinoma. Bilateral adrenal vein sampling (AVS) is the gold standard method to define the PA subtype, but it is not indicated in all cases. An experienced radiologist must perform AVS. Unilateral laparoscopic adrenalectomy is the preferential treatment for patients with APAs, and bilateral hyperplasia should be treated with mineralocorticoid antagonist (spironolactone or eplerenone). Cardiovascular morbidity caused by aldosterone excess can be decreased by either unilateral adrenalectomy or mineralocorticoid antagonist. In this review, we address the most relevant issues regarding PA screening, case confirmation, subtype classification, and treatment. Based on two patients, we discuss the difficulties in diagnosing and managing primary aldosteronism in pregnancy, which derive from changes of the renin-angiotensin-aldosterone axis, from the uncertainty regarding blood pressure control along gestation and postpartum, and from the contraindication to the use of spironolactone. The first case is a 27 years old woman with a long standing refractory hypertension, a hemorrhagic stroke with left brachial hemiplegia and crural hemiparesia, two miscarriages, one stillbirth and one offspring with intrauterine growth retardation. Due to hypokalemia, a plasma aldosterone/renin activity ratio of 91, and a negative genetic screening for glucocorticoid remediable aldosteronism (GRA), a primary hyperaldosteronism with normal adrenals in CT scan was diagnosed, and good blood pressure control was attained with spironolactone. After two and a half years of normotension, a fifth pregnancy, managed with methyldopa evolved with satisfactory blood pressures, plasma potassium, fetal growth, uterine and umbilical arterial resistance indexes, and maternal endothelial function. At 37 1/2 weeks of pregnancy the patient delivered a healthy newborn weighing 2,960 g. Blood pressure rose during the 48 hours of postpartum in the absence of proteinuria and required i.v. hydralazine. The second patient is a 37 years old woman, with known refractory hypertension for 7 years, hypokalemia, plasma aldosterone/renin activity ratio greater than 40, normal adrenals in the CAT scan, and a negative genetic screening for GRA. She had normotensive pregnancies 5 and 3 years prior to the detection of hypertension, with hypertensive crisis in both postpartum periods, retrospectively considered as expressions of primary hyperaldosteronism. The prevalence of primary hyperaldosteronism is 5-10% of all hypertensive patients, and clearly above the estimated prevalence in the past. In nearly 30% of patients with therapy resistant hypertension, primary hyperaldosteronism is detected if they are investigated thoroughly. This will result in 1.5 to 2.5 million people in Germany suffering from primary hyperaldosteronism. Besides efficient diagnostic procedures, an effective treatment is of increasing importance. The aldosterone-producing adenoma (Conn's syndrome) is primarily cured by operation, in most cases performed endoscopically. Bilateral hyperplasia, which is found in two-thirds of primary hyperaldosteronism, is treated primarily by mineralocorticoid receptor antagonist: 12.5-50 mg/day spironolactone (in case of anti-androgenic side-effects alternatively by 50-100 mg/day eplerenone). If the blood pressure can not be lowered by this first-line treatment, an additional treatment with potassium-sparing diuretics, calcium-antagonists, ACE-inhibitors or angiotensin-2-antagonists is necessary. The start of medication should be closely monitored by serum electrolyte and creatinine controls. We report a case of a renin secreting tumor, which is a very rare cause of secondary high blood pressure. A 22-year-old woman was hospitalised for exploration of high blood pressure (160/110 mmHg) with severe hypokaliemia (2,7 mmol/l) and secondary hyperaldosteronism. Physical examination was normal except the high blood pressure. Bioassays show increased kaliuresis (66 mmol/24h), plasma renin (89 pg/ml in clinostastism--108 pg/ml in orthostatism), pro-renin (1207 pg/ml in clinostastism--1412 pg/ml in orthostatism) and aldosterone (210 pg/ml in clinostastism--566 pg/ml in orthostatism). The rest of the endocrine tests were normal (cortisol and ACTH at 8:00 am, urinary free cortisol, overnight 1 mg dexamethasone suppression test). Doppler ultrasound method, performed by an experienced radiologist, did not show renal artery stenosis. Abdominal computerized tomography showed a nodular formation at the upper pole of the right kidney, isodense to renal medullary. The size tumor was 15 mm. The renal vein sampling shows high values of renin on both sides whereas, for the pro-renin, the values were higher on the tumor side. In spite of treatment with CEI (Converting Enzyme Inhibitors) and calcium antagonists, the blood pressure was not controlled. Hypokaliemia persisted (3 mmol/l) in spite of high daily potassium intake (64 mmol/l of potassium chloride). After tumor resection, reninoma was diagnosed by the pathology examination and blood pressure, plasma rennin, plasma aldosterone level returned to normal. Diagnosis Other conditions such as Liddle's Syndrome can mimic the clinical features of AME, so diagnosis can be made by calculating the ratio of free urinary cortisol to free urinary cortisone. Since AME patients create less cortisone, the ratio will much be higher than non-affected patients. Alternatively, one could differentiate between the two syndromes by administering a potassium-sparing diuretic. Patients with Liddle's syndrome will only respond to a diuretic that binds the ENaC channel, whereas those with AME will respond to a diuretic that binds to ENaC or the mineralcorticoid receptor. Treatment The treatment for AME is based on the blood pressure control with Aldosterone antagonist like Spironolactone which also reverses the hypokalemic metabolic alkalosis and other anti-hypertensives. Renal transplant is found curative in almost all clinical cases.AME is exceedingly rare, with fewer than 100 cases recorded worldwide. Primary hyperaldosteronism (PHA) represents less than 1 to 2% of all causes of hypertension (HT). We report 2 cases of primary hyperaldosteronism which emphasize the difficulty of distinguishing neoplastic PHA from idiopathic PHA, observed in a 60-year-old woman and a 42-year old woman, respectively. In both cases, the diagnosis of PHA was suggested by marked hypokalaemia with inappropriate potassium excretion and was confirmed by hyperaldosteronaemia and low and poorly stimulated renin activity. In the first case, computed tomography showed nodular hyperplasia of the 2 adrenal glands. The patient was treated with spironolactone and calcium channel blockers which controlled blood pressure and serum potassium. In the second case, computed tomography and magnetic resonance imaging revealed an adrenocortical adenoma confirmed by pathological examination after the operation. The diagnosis of primary hyperaldosteronism is based on three steps: detection, positive diagnosis and aetiological diagnosis. Detection is essentially based on demonstration of hypokalaemia. Positive diagnosis is based on demonstration of elevated aldosterone secretion with inhibited renin secretion. The aetiological diagnosis is dominated by the differentiation between Conn's adenoma and bilateral adrenal hyperplasia, which has therapeutic implications. To investigate the clinical characteristics, differential diagnosis, and surgery outcome of unilateral nodular adrenal hyperplasia (UNAH). The clinical data of 145 patients with primary aldosteronism, 67 males and 78 females, aged 37.9 (19-60), including 78 cases of aldosterone-producing adenoma (APA), 14 cases of UNAH, and 55 cases of idiopathic bilateral adrenal hyperplasia (BAH), were collected. Radioimmunoassay was used to examine the blood and urine aldosterone and plasma rennin activity. Automatic biochemical apparatus was used to examine the blood and urine electrolytes, renal functions, and urine microalbumin. Twelve-lead electrocardiography, echocardiography, and plain scanning of enhanced CT scanning of the bilateral adrenals were conducted. Adrenal venous sampling (AVS) was conducted in 62 patients to collect blood samples from vena cava and bilateral suprarenal veins to detect the levels of aldosterone and cortisol. All UNAH patients and 3 BAH patients underwent unilateral adrenalectomy and three APA patients underwent unilateral adrenalectomy or adenoma resection. Then the patients were followed up for 39.2 months. The incidence of UNAH is 9.7% in the primary aldosteronism patients. There were no significant differences in age, gender, duration of hypertension, blood pressure (SBP, DBP), and indexes indicating damages in target organs of hypertension (left ventricular hypertrophy rate, blood creatinine, urine microalbumin, etc) among these three groups. The level of serum potassium of the APA group was significantly lower than that of the BAH group (P &lt; 0.01), and the levels of plasma and urine aldosterone of the APA group were significantly higher than those of the BAH group (P &lt; 0.05 and P &lt; 0.01). The serum potassium of the UNAH group was higher than that of the APA group and lower than that of the BAH group, and the levels of plasma and urine aldosterone of the UNAH group were both higher than those of the APA group and lower than those of the BAH group, however all not significantly (all P &gt; 0.05). The coincidence rate of CT was 50% (7/14) in the UNAH group. The accuracy of AVS for diagnosis of UNAH was 85.7% (12/14). After operation, the serum potassium and plasma aldosterone concentrations returned normal in all the UNAH patients. Blood pressure returned to normal in 50% (7/14) of the UNAH patients, and was improved in the other 50% (7/14) patients. UNAH can be cured by adrenal surgery. The diagnostic values of clinical examination and adrenal CT are limited. AVS is essential in diagnosing UNAH patients. Pseudohyperaldosteronism (also pseudoaldosteronism) is a medical condition which mimics the effects of elevated aldosterone (hyperaldosteronism) by presenting with high blood pressure (hypertension), low blood potassium levels (hypokalemia), metabolic alkalosis, and low levels of plasma renin activity (PRA). However, unlike hyperaldosteronism, this conditions exhibits low or normal levels of aldosterone in the blood. Causes include genetic disorders (e.g. Apparent mineralocorticoid excess syndrome, Liddle's syndrome, and types of Congenital adrenal hyperplasia), acquired conditions (e.g. Cushing's syndrome and mineralocorticoid-producing adrenal tumors), metabolic disorders, and dietary imbalances including excessive consumption of licorice. Confirmatory diagnosis depends on the specific root cause and may involve blood tests, urine tests, or genetic testing; however, all forms of this condition exhibit abnormally low concentrations of both plasma renin activity (PRA) and plasma Primary hyperaldosteronism (PHA) is characterized by an increased Aldosterone synthesis which is independent of the Renin-Angiotensin-Aldosterone-System (RAAS). The prevalence of PHA in patients who present in specialized hypertension centers is approx. 10 %. Besides patients with the classical symptoms known as \"Conn-Trias\" (hypertension, hypokalemia, metabolic alkalosis), the more frequent normokalemic patients with PHA also show a worse outcome compared to patients with essential hypertension. Identifying these patients is an important task in the evaluation of hypertension since targeted treatment options are available. Screening for PHA using the Aldosterone-Renin-Ratio (ARR) should be performed in patients with hypokalemic, severe or resistant hypertension. In addition, young patients with early onset of severe hypertension and/or positive family history should be screened. A positive screening result should be followed by a confirmatory test. The saline infusion test is the preferred clinical test for confirming a suspected PHA since it is accessible and time efficient. Other confirmatory tests are not used on a regular basis. After any confirmatory test, CT- or MRI-imaging and adrenal vein sampling (AVS) is used in order to differentiate between a unilateral adenoma, a bilateral hyperplasia or another cause of PHA. CT or MRI usually cannot discriminate smaller tumors form hyperplasia. Therefore AVS is used to detect lateralization of autonomous aldosterone production. Lateralization of aldosterone production indicates a unilateral adenoma. In these cases, laparoscopic adrenalectomy is the therapeutic option of choice with a hypertension cure rate of up to 60 %. If no lateralization is detectable, bilateral hyperplasia as the underlying cause of PHA is likely. Pharmacological inhibition of the mineralocorticoid receptor is the preferred treatment option in these cases. If Spironolactone is not well tolerated, Eplerenone and potassium-sparing diuretics should be prescribed. Often, however, in order to fully control hypertension, additional antihypertensive therapy is necessary. Great strides have been made in our understanding of the pathophysiology of primary aldosteronism syndrome since Conn's description of the clinical presentation of a patient with an aldosterone-producing adenoma (APA) more than 50 years ago. It is now recognized that the APA is just one of the seven subtypes of primary aldosteronism. APA and bilateral idiopathic hyperaldosteronism (IHA) are the most common subtypes of primary aldosteronism. Although most clinicians had thought primary aldosteronism to be a rare form of hypertension for more than three decades, it is now recognized to be the most common form of secondary hypertension. Using the plasma aldosterone to plasma renin activity ratio as a case-finding test, followed by aldosterone suppression confirmatory testing, has resulted in much higher prevalence estimates of 5-13% of all patients with hypertension. In addition, there has been a new recognition of the aldosterone-specific cardiovascular morbidity and mortality associated with aldosterone excess. Although thought to be daunting and complex in the past, the diagnostic approach to primary aldosteronism is straightforward and can be considered in three phases: case-finding tests, confirmatory tests and subtype evaluation tests. Patients with hypertension and hypokalaemia (regardless of presumed cause), treatment-resistant hypertension (three antihypertensive drugs and poor control), severe hypertension (&gt;or= 160 mmHg systolic or &gt;or= 100 mmHg diastolic), hypertension and an incidental adrenal mass, onset of hypertension at a young age or patients being evaluated for other forms of secondary hypertension should undergo screening for primary aldosteronism. In patients with suspected primary aldosteronism, screening can be accomplished by measuring a morning (preferably between 0800 and 1000 h) ambulatory paired random plasma aldosterone concentration (PAC) and plasma renin activity (PRA). An increased PAC:PRA ratio is not diagnostic by itself, and primary aldosteronism must be confirmed by demonstrating inappropriate aldosterone secretion. Aldosterone suppression testing can be performed with orally administered sodium chloride and measurement of urinary aldosterone or with intravenous sodium chloride loading and measurement of PAC. Unilateral adrenalectomy in patients with APA or unilateral adrenal hyperplasia results in normalization of hypokalaemia in all these patients; hypertension is improved in all and is cured in approximately 30-60% of them. In bilateral adrenal forms of primary aldosteronism, unilateral or bilateral adrenalectomy seldom corrects the hypertension and they should be treated medically with a mineralocorticoid receptor antagonist. Primary Primary aldosteronism (hyporeninemic hyperaldosteronism) was previously thought to be most commonly caused by an adrenal adenoma, termed Conn's syndrome. However, recent studies have shown that bilateral idiopathic adrenal hyperplasia is the cause in up to 70% of cases. Differentiating between the two is important, as this determines treatment. Also, see congenital adrenal hyperplasia. Adrenal carcinoma is an extremely rare cause of primary hyperaldosteronism. Two familial forms have been identified: type I (dexamethasone suppressible), and type II, which has been linked to the 7p22 gene. Features Hypertension Hypokalemia (e.g., may cause muscle weakness) Alkalosis Investigations High serum aldosterone Low serum renin High-resolution CT abdomen Management Adrenal adenoma: surgery Bilateral adrenocortical hyperplasia: aldosterone antagonist, e.g., spironolactone To show clinical, biochemical, and morphological data of 12 patients with primary hyperaldosteronism: eight with an aldosterone-producing adenoma and four with adrenal hyperplasia. To compare clinical and biochemical parameters of the patients with adenoma and hyperplasia. For those with adenoma, to verify clinical and biochemical modifications after adrenalectomy. In the 12 patients with hyperaldosteronism, retrospective analysis of clinical (age, sex, blood pressure), biochemical (plasmatic and urinary potassium, plasmatic aldosterone, plasma renin activity, and plasmatic aldosterone/renin activity ratio), and morphological (computed tomography, magnetic resonance, and norcholesterol scintigraphy) data was performed. 1--In the 12 patients with hyperaldosteronism (seven female), the age was 51.0 +/- 10.2 years (mean +/- standard deviation), the systolic pressure 200.9 +/- 34.5 mm Hg and the diastolic pressure 120.0 +/- 12.3 mm Hg. Hypertension was diagnosed 12.0 +/- 10.1 years before. As biochemical evidence, we found kalaemia of 3.06 +/- 0.28 and urinary potassium of 63.4 +/- 16.5 mEq/l, renin activity 0.98 +/- 1.02 ng/ml/h, plasmatic aldosterone of 49.4 +/- 36.0 ng/dl, aldosterone/renin activity &gt; 30 in 83% of the cases. As morphological evidence, computed tomography allowed diagnosis in nine patients, suggested it in two, being doubtful in one. Performed on four patients, resonance confirmed the tomography in three and was not contributive in one. The scintigraphy performed in four patients visualized two adenomas, was negative in one adenoma and in one hyperplasia. 2--In the eight patients with adenoma (six female), the youngest age and the highest diastolic pressure compared with patients with hyperplasia were statistically significant (p &lt; 0.01 and 0.05). In the adenomas, the biochemical changes were more pronounced, but not statistically significant. The plasmatic aldosterone/renin activity ratio was also higher in the adenoma cases. 3--After the adrenalectomy, blood pressure became normal in five patients and was more easily therapeutically controlled in three. The average systolic and diastolic pressures decreased and the biochemical parameters became normal in all patients. The pre/post surgical modification of these parameters had statistical significance (systolic pressure decrease, p &lt; 0.01; diastolic pressure decrease, p &lt; 0.01; kalaemia increase, p &lt; 0.001; renin activity increase, p &lt; 0.01; aldosterone decrease, p &lt; 0.02). The plasmatic aldosterone/renine activity ratio normalized in all patients. In diagnosing primary hyperaldosteronism, biochemical (kalaemia, urinary potassium, plasmatic aldosterone, renin activity, aldosterone plasmatic/renin activity) and tomography studies were important. On comparing the patients with hyperplasia with those with adenoma, we found that the latter are younger and exhibit higher diastolic pressure, both findings with statistical significance. After adenoma surgery, blood pressure became normal in five patients and improved in three, these findings, and the improvement of the kalaemia, plasmatic aldosterone, and renin activity parameters were statistically significant. In patients with normal adrenal morphology and family history of early-onset, severe hypertension, a diagnosis of GRA should be Disorders of the Adrenal Cortex Clinical suspicion of mineralocorticoid excess Patients with hypertension and Severe hypertension (>3 BP drugs, drug-resistant) or Family history of early-onset hypertension or cerebrovascular events at < 40 years of age Measurement of aldosterone-renin ratio (ARR) on current blood pressure medication (stop spironolactone for 4 wks) and with hypokalemia corrected (ARR screen positive if ARR >750 pmol/L: ng/ml/h and aldosterone >450 pmol/L) (consider repeat off ˜-blockers for 2 wks if results are equivocal) Negative E.g., saline infusion test (2 liters physiologic saline over 4 h IV), oral sodium loading, fludrocortisone suppression Confirmation of diagnosis Rare: Both renin and Aldo suppressed The diagnosis of primary hyperaldosteronism (PHPA) has progressively increased over the last years and some authors consider it as the main cause of secondary hypertension. We studied the prevalence of PHPA in hypertensive patients followed at the Hypertension Unit from July 1999 to July 2017. A total of 2500 patients were included and diagnosis of PHPA was done in 79 of them (3.2%). It was more frequent in women (55.7%) with an increased incidence in the elderly, as compared to previous studies (27.8%). Initial diagnosis was suspected upon the presence of inappropriate kaliuria and metabolic alkalosis, associated to an aldosterone/plasma renin activity ratio &gt; 30 (ng/dl)/(ng/ml/h). After confirmation of the presence of PA, imaging techniques to determine the etiology were performed. In this way, 29 cases (36.8%) of aldosterone-producing adenoma and 5 cases of bilateral adrenal hyperplasia with nodules were identified. Computed tomography identified the adenomas and hyperplasias with bilateral cortical nodules in all patients. Adrenalectomy and/or antialdosteronics were efficient in controlling blood pressure in 69.9% of cases. Of note in this series was the remission of stage 3 chronic renal failure in two cases, the high prevalence of hypercalciuric urinary lithiasis and a case of breast carcinoma after prolonged treatment with spironolactone. Primary hyperaldosteronism has a number of causes. About 33% of cases are due to an adrenal adenoma that produces aldosterone, and 66% of cases are due to an enlargement of both adrenal glands. Other uncommon causes include adrenal cancer and an inherited disorder called familial hyperaldosteronism. Some recommend screening people with high blood pressure who are at increased risk, while others recommend screening all people with high blood pressure for the disease. Screening is usually done by measuring the aldosterone-to-renin ratio in the blood (ARR) whilst off interfering medications and a serum potassium over 4, with further testing used to confirm positive results. While low blood potassium is classically described in primary hyperaldosteronism, this is only present in about a quarter of people. To determine the underlying cause, medical imaging is carried out.\nHere is the question:\nNEPHROLOGY: A 58-year-old man with a 6-year history of hypertension consults for poor blood pressure control despite treatment with an angiotensin-converting enzyme inhibitor, a diuretic and a calcium antagonist. On consultation she presented with blood pressure of 149/100 mmHg. Laboratory tests: creatinine 1.2 mg/dl, potassium 2.2 mEq/l and compensated metabolic alkalosis; the rest of the biochemical study, blood count, coagulation and urinary sediment were normal. Point out the correct statement:\nHere are the potential choices:\n1. The origin of hypertension in this case is excessive secretion of aldosterone caused by autonomic hyperfunction of the adrenal medulla.\n2. In most cases the anatomical substrate is a bilateral hyperplasia of the adrenal cortex.\n3. CT scan is part of the diagnostic study in case of biochemical confirmation.\n4. Spironolactone is contraindicated in the management of this pathology.\nThe correct answer is: 3. CT scan is part of the diagnostic study in case of biochemical confirmation."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Erythematous scaly papules on the palms and soles are a common manifestation of secondary syphilis. We report a case of 19-year-old male who presented with erythematous, scaly, psoriasiform lesions over the palms and glans penis. The papules over the palms showed tenderness on blunt vertical pressure. There was a history of sexual contact and ulcer over the glans around 2 months back, which resolved on its own. Venereal Disease Research Laboratory test was positive in 1:32 dilution. <iTreponema pallidum</i hemagglutination test was also positive. This case highlights the atypical presentation of secondary syphilis. The clinical manifestations of recent syphilis can be variable, with typical and atypical patterns. Several conditions may cause atypical clinical aspects, including human immunodeficiency virus (HIV) co-infection. Besides the clinical features, co-infections may completely alter syphilis serological tests, causing interpretative difficulties and diagnostic delays. Aim of the work is to describe the difficulties encountered during the diagnostic evaluation of atypical skin manifestations and of the serology for syphilis of an HIV-infected patient who had contracted it several times. In 2020, a 52-year old HIV-positive bisexual male patient was admitted to our department with a 4-month history of moderately itchy cutaneous lesions localized at his neck, trunk and arms. In 2013, the patient presented with a classic syphilitic roseola of the trunk and a secondary syphilis was diagnosed, with increased levels of rapid plasma reagin (RPR), Treponema pallidum hemagglutination assay (TPHA), anti-Treponema pallidum IgM and IgG Index. A second episode occurred in 2018, as a primary syphilis with multiple ulcerative lesions of the penis, and increased levels of RPR, IgG and IgM. In 2019, a further episode of secondary syphilis was treated with Doxycycline. In 2020, erythematous and papular lesions with vesicular components and urticarial erythema multiforme (EM)-like lesions were present at the neck, trunk and arms. Serological tests and Nucleic Acid Amplification Test (NAAT) for Treponema Pallidum were performed, as well as a cutaneous biopsy with histological and immunohistochemical evaluation of one lesion. NAAT was negative for T. pallidum. Serological test results were discordant with a new syphilis infection, showing only increased levels of RPR and anti-Treponema IgG. The cutaneous biopsy revealed a non specific histological pattern, while the immunohistochemical evaluation with anti-spirochetal antibodies was mandatory for the diagnosis of recent syphilis, showing clusters of rod-shaped elements, some of which with spiral form, focally present at the epidermis and adnexal structures. Nowadays, syphilis may present with atypical clinical and serological features. Physicians should be aware of these possible alterations and consider syphilis even in case of uncommon clinical aspect and unclear serological tests. Cutaneous biopsy and immunohistochemical exam may be mandatory for the diagnosis. Known as \"the great imitator,\" secondary syphilis may clinically manifest itself in myriad of ways, involving different organs (including the oral cavity), and mimicking, both clinically and histologically, several diseases, thereby making diagnosis a challenge for clinicians. We highlight an interesting case of a 45-year-old man on whose diagnosis of secondary syphilis was based on the presence of unusual oral lesions, consisting of a well delimited, raised, nonhomogeneous, and corrugated white plaque on the right buccal mucosa which mimicked, clinically and histologically, a \"leukoplakia-like\" plaque and several whitish oral mucous patches localized on the lower labial mucosa and the right lateral margin of the tongue. After the oral lesions, the patient developed a symmetric maculopapular cutaneous rash on the palms, soles, and the trunk of the body. Furthermore, during the anamnesis the patient stated an asymptomatic ulcerative lesion on the glans penis, which had appeared 7 months before the onset of the oral lesions and spontaneously disappeared after 2 weeks. The history of these genital and cutaneous lesions suggested performing serologic tests for syphilis, revealing strongly positive titers and leading us to making a diagnosis of secondary syphilis. This case is remarkable because it displays an unusual oral sign, associated with secondary syphilis; in fact, only occasionally does syphilis manifest itself with a \"leukoplakia-like\" plaque. Dentists should consider secondary syphilis in the differential diagnosis of white and/or ulcerative oral lesions, above all in at-risk patients, given the continuing rise of syphilis in western Europe. A 39-year-old man complained about a slightly reddish non-itching rash evolving on his body during the last few weeks without any general symptoms. Physical examination revealed trunk-dominated roseola, papules, a few nodules with haemorrhagic crust on top, and round hyperkeratotic clavus-like lesion on the left plantar foot. In his mouth, he had a few up to 1.5 cm large erosions, and on his capillitium a diffuse alopecia. Serologic testing for syphilis was positive with Treponema-pallidum-particle-agglutination test at 1:163840, VDRL 1:64, positive IgG-FTA-ABS and 19S-IgM-FTA-ABS tests, and a pleocytosis of the liquor. In addition, there were a co-infection with mycoplasma hominis and first diagnosis of HIV infection (CDC-stadium A1). The patient was diagnosed as having secondary syphilis with suspicion of neurologic involvement and was therefore treated with 6x5 Mio. I.E. Penicillin G i.v. per day for 14 days after the initial application of 40 mg methylprednisolone. Under this regimen complete resolution of the skin lesions was noted over a 4 week period as well as slow re-growth of the hair. HIV infection at stadium A1 did not require antiretroviral treatment. A non-pruritic rash should always point to the differential diagnosis of syphilis. If syphilis is diagnosed, any other sexually transmitted disease including HIV should be excluded as possible co-infection. In case of HIV, neurosyphilis can develop at an earlier stage of common syphilis. Neurosyphilis is an infection of the central nervous system by Treponema pallidum, which can occur after the initial syphilis infection. Although commonly associated with late stage disease, patients with early neurosyphilis may present with acute syphilitic meningitis, meningovascular syphilis, or uveitis. A 28 year old man with a past medical history of HIV (CD4 364);, and recent diagnosis of uveitis presented to the Emergency Department with a positive RPR result. His visual acuity had been gradually declining over the past few months. He denied painless or painful ulcerating lesions on his penis, or scrotum, difficulty concentrating, dermatitis on the soles/palms, or difficulty with proprioception. Physical exam was notable for atrophic hyperpigmented polycyclic, annular plaques and patches along the hairline as well as several areas of confluent hyperpigmented polycyclic plaques and nodules on the patient's face, back, left arm, and right posterior leg. Fundoscopic exam revealed bilateral posterior uveitis and chorioretinitis. Evaluation of cerebrospinal fluid revealed a lymphocytic pleocytosis with a positive VDRL and FTA-ABS. Aqueous crystalline penicillin G was initiated for treatment of early neurosyphilis. Within six hours of beginning the infusion, the patient had a documented temperature of 101.8°F, heart rate of 128 beats per minute, blood pressure 142/84, with generalized malaise and headache. Fever and tachycardia resolved over the next 12 hours, with weakness and headache resolving within 1-2 days. His symptom complex was consistent with the Jarisch-Herxheimer reaction. Histopathology of skin biopsy of the back showed perivascular inflammation and rare spirochetes, consistent with secondary syphilis. The patient completed 14 days of aqueous crystalline penicillin G and was discharged after receiving the first of three benzathine penicillin injections. The initial manifestations of syphilis in this patient were posterior uveitis and pruritic skin plaques. His diagnosis should be appropriately classified as secondary syphilis with concomitant symptomatic early neurosyphilis, requiring 14 days of aqueous crystalline penicillin G. This type of presentation is not specific to immunocompromised populations and must be considered even in the general population. Making the diagnosis of early neurosyphilis, regardless of stage, is critical, as it necessitates a longer duration of treatment. Furthermore, clinicians should be reminded of the profound immunologic reaction, Jarisch-Herxheimer, which may occur when treating any treponemal disease. Primary syphilis is typically acquired by direct sexual contact with the infectious lesions of another person. Approximately 2–6 weeks after contact (with a range of 10–90 days) a skin lesion, called a chancre, appears at the site and this contains infectious spirochetes. This is classically (40% of the time) a single, firm, painless, non-itchy skin ulceration with a clean base and sharp borders approximately 0.3–3.0 cm in size. The lesion may take on almost any form. In the classic form, it evolves from a macule to a papule and finally to an erosion or ulcer. Occasionally, multiple lesions may be present (~40%), with multiple lesions being more common when coinfected with HIV. Lesions may be painful or tender (30%), and they may occur in places other than the genitals (2–7%). The most common location in women is the cervix (44%), the penis in heterosexual men (99%), and anally and rectally in men who have sex with men (34%). Lymph node enlargement frequently (80%) occurs around the Syphilis is a sexually transmitted infection by Treponema pallidum. Without antibiotic treatment syphilis lasts for several decades and may develop up to 4 different clinical stages. Usually, the disease begins with a distinct painless and indurated ulcer at the contact site: the primary chancre. An indolent regional lymph node swelling is usually associated with the syphilitic chancre. After spontaneous healing of the primary lesion and several weeks of latency, the clinical symptoms of secondary syphilis occur. Treponema pallidum bacteremia leads to common symptoms like fever and malaise, but also to a generalized lymphadenopathy, and a broad variety of lesions of the skin and mucosal membranes. Non-pruritic transient exanthems often involving palms and soles, condylomata lata, and a specific angina with mucous patches of the oral cavity are prominent signs. After several relapses, which are characterized by a decreasing intensity of clinical symptoms, secondary syphilis then resolves spontaneously. A second period of latency follows, lasting 3-12 years. Then the outcome of untreated syphilis becomes apparent: spontaneous healing by elimination/inactivation of the spirochetes (75%) or transition to tertiary syphilis (25%). Two kinds of granulomatous skin reactions are typical for tertiary syphilis: superficial nodular syphilids and gummas. The bones, as well as the cardiovascular and central nervous system, may also be involved. Finally, metasyphilis with severe and sometimes lethal neurological symptoms (tabes dorsalis, progressive paralysis) occurs 10 to 30 years after primary infection. Except for irreversible tissue destruction which occurs prior to therapy, all stages of syphilis can be cured completely. The incidence of syphilis has historically been cyclical in nature, often in relation to the rise and fall of public health initiatives directed toward eradication along with social attitudes toward sexual practices. The incidence of syphilis has increased by 15% in the last 6 years in the United States, with similar increases worldwide. Herein, we present an atypical case of syphilis presenting with severe septic shock and multiple anogenital lesions in an immunocompetent host. A 22-year-old male with no significant past medical history presented with fevers, chills, sore throat, diaphoresis, and diarrhea. He was febrile, tachycardic, hypotensive, and unresponsive to fluid resuscitation requiring short-term vasopressor support. Physical exam revealed diffuse lymphadenopathy; lower extremity macular rash involving the soles of the feet; papular non-pustular lesions on the scrotum; and a 0.5 cm non-tender irregular, healing lesion on the shaft of the penis. Laboratory analysis was significant for leukocytosis and elevated creatinine. Serum screening rapid plasma reagin was positive, and further testing revealed a titer of 1:32, with confirmation via fluorescent treponemal antibody absorption test. The patient was diagnosed with secondary syphilis, which was determined to be the underlying etiology of the sepsis as all other serological evaluations were negative. He was treated with penicillin G benzathine 2.4 million units intramuscular and supportive management, with improvement of symptoms. The patient engaged in high-risk sexual behaviors, including prior unprotected sexual contact with males. New research indicates that up to one-third of patients may present with atypical cutaneous manifestations, as demonstrated by this patient. It is important for physicians to familiarize themselves with the varied clinical presentations of syphilis, which include multiple anogenital lesions and tender primary lesions in primary or secondary syphilis. A 28-year-old white man presented to the Emergency Department with a 24-hour history of an eruption on his extremities, trunk, and face. The patient was known to be HIV positive with a CD4 count of 527 and a viral load of 20,300. He denied fever, chills, malaise, and headache. His social history was significant for the fact that he was in a monogamous homosexual relationship. He had no recent travel, pet exposures, or sick contacts. Physical examination revealed stable vital signs and no documented fever. A maculopapular eruption was present on his face, trunk, and extremities (Figures 1 and 2). There was no palmar or plantar involvement. He was treated with diphenhydramine and topical 2.5% hydrocortisone and advised to return if his condition did not improve. Twelve days after the initial evaluation, the patient consulted us again due to progression of his dermatitis. He had no additional complaints other than an eruption on both palms but neither sole. (Figure 3). The eruption now demonstrated erythematous pink-red oval macules and papules 1-2 cm in size distributed on his scalp, face, trunk, and arms. A few papules contained fine collarettes of scale. Further questioning revealed that the patient had experienced a tender rectal ulcer 2 months previously. A punch biopsy and rapid plasma reagin were performed. The histopathologic examination revealed interface dermatitis with lymphocytes, plasma cells, occasional neutrophils, and a prominent lymphoplasmacytic perivascular dermatitis with infiltration of the vessel walls. Warthrin-Starry and Steiner methods demonstrated spirochetes at the dermal-epidermal junction and in vessel walls, consistent with Treponema pallidum (Figure 4). Rapid plasma reagin and fluorescent Treponema antibody were both reactive with a Venereal Disease Research Laboratory (VDRL) of 1:16. The patient was diagnosed as having secondary syphilis and treated with 2.4 million units of IM benzathine penicillin for 3 weeks. His eruption resolved after the initial treatment and he did not experience a Jarisch-Herxheimer reaction. Secondary syphilis occurs approximately four to ten weeks after the primary infection. While secondary disease is known for the many different ways it can manifest, symptoms most commonly involve the skin, mucous membranes, and lymph nodes. There may be a symmetrical, reddish-pink, non-itchy rash on the trunk and extremities, including the palms and soles. The rash may become maculopapular or pustular. It may form flat, broad, whitish, wart-like lesions on mucous membranes, known as condyloma latum. All of these lesions harbor bacteria and are infectious. Other symptoms may include fever, sore throat, malaise, weight loss, hair loss, and headache. Rare manifestations include liver inflammation, kidney disease, joint inflammation, periostitis, inflammation of the optic nerve, uveitis, and interstitial keratitis. The acute symptoms usually resolve after three to six weeks; about 25% of people may present with a recurrence of secondary symptoms. Many people who present with secondary Syphilis, caused by Treponema pallidum agent, results in polymorphic and non-specific ocular manifestations. Early diagnosis and institution of individualized treatment play a large role in the prognosis. The increase in syphilis over the past several years requires the ophthalmologist to consider this diagnosis in the setting of any intraocular inflammatory involvement. To describe epidemiological, clinical and paraclinical features and natural history of syphilitic uveitis. Retrospective, descriptive and non-comparative study of a series of patients hospitalized between 2007 and 2013 in our department of ophthalmology for management of ocular inflammation associated with a positive syphilitic serology. Thirteen patients of mean age 52.5 years ± 12.9 (33-82 years) were included. All were male and were followed for six months. Co-infection with human immunodeficiency virus (HIV) was present in four of them. Other risk factors discovered on history were unprotected sexual relations, multiple partners, homosexual relations, co-infection with another sexually transmitted disease (STD) or an occupational risk. Decreased visual acuity (VA) was present in all patients, with an average initial VA of 0.71 ± 0.81 LogMAR, i.e. 2/10. Involvement was bilateral in 38% (n=5) of cases. Papilledema was present in 10 patients. Seven patients exhibited vasculitis, 6 patients a necrotizing retinitis, 2 patients with placoid lesions, 7 patients with panuveitis and 2 patients with macular edema. We did not find any patients with isolated anterior uveitis. Three patients exhibited concomitant extraocular involvement with cutaneous palmoplantar lesions. Spectral domain optical coherence tomography (SD-OCT) found a fragmentation of the external limiting membrane and a disorganization of the ellipsoid line in two patients. Cerebrospinal fluid was studied for all patients. Eight of them exhibited lymphocytic meningitis, and we found the presence of anti-Treponema pallidum hemagglutination assay antibody (TPHA) in 9 patients and anti-veneral disease research laboratory antibody (VDRL) in 1 patient. Syphilis polymerase chain reaction (PCR) in the aqueous humor was positive in 50% (n=6) of studied cases and the PCR for Epstein Barr virus came back positive in four specimens out of eight. False positive reactions were observed for Lyme disease in eight patients. The four HIV-positive patients showed bilateral lesions more frequently, but less severe and with a favorable outcome. Antibiotic treatment with ceftriaxone (2 grams per day intramuscularly for 15 to 21 days) and local treatment (corticoids and mydriatics) in the case of inflammation of the anterior segment, allowed a regression of the inflammation in all of our patients as well as an improvement in VA (average final VA 0.09 ± 0.17 LogMAR, i.e. approximately 8/10). One Jarisch Herxheimer reaction occurred and was resolved with systemic corticosteroid therapy. A change in the retinal pigment epithelium was the main sequela in 44% of cases (n=8 eyes). Every structure of the eye may be involved with syphilis; therefore, syphilis must be systematically sought during the etiologic assessment of ocular inflammation even in the absence of historical risk factors. HIV-positive patients must be handled in the same way as immunocompetent patients. Collaboration with the internist is essential for the diagnosis, monitoring, and staging, especially in search of neurosyphilis. The clinical course is favorable with early treatment. Immune reconstitution inflammatory syndrome (IRIS) is a condition associated with paradoxical worsening and/or new onset of an opportunistic infection in HIV patients following the initiation of anti-retroviral therapy or switching to more potent antiretroviral therapy (ART) regimen. Although IRIS associated with many opportunistic infections (OIs) has been well reported, syphilis has very rarely been mentioned in this regard. A 52-year-old male, diagnosed with AIDS six weeks ago, presented with the disseminated non-pruritic painless skin rash. He denied any fever, cough, shortness of breath, and joint pain or swelling. The patient had no similar symptoms, genital ulcers, or any medical illness in the past. CD4 cell count and viral load were 40 cells/mm<sup3</sup and 280,000 copies/ml, respectively, while screening tests for OIs including rapid plasma reagin test, quantiferon, cryptococcal antigen, and toxoplasma tests were negative at the time of HIV diagnosis. After three days of initiation of anti-retroviral therapy, he developed the above-mentioned skin rash. Repeat rapid plasma regain (RPR) test at this time was also negative. Punch biopsy of the skin lesion demonstrated findings suggestive of secondary syphilitic lesions, which was confirmed by immunostain. The repeat RPR, CD4 cell count, and viral load showed a titer of 1:256, 257 cells/mm<sup3</sup, and 5000 copies/ml, respectively. His skin rashes faded away, and RPR titer trended down on treatment with benzathine penicillin without discontinuation of ART. The presence of an IRIS response does not predict overall HIV or OI treatment responses, and discontinuation of ART is not generally recommended as the benefits of treating HIV infection outweighs the risk associated with IRIS. Syphilis is commonly known as \"the great imitator\" owing to its varied clinical manifestations. Secondary syphilis has a variety of presentations, with the most common manifesting as a diffuse papulosquamous eruption on the palms and soles. Lues maligna praecox is a rare form of secondary syphilis, with severe constitutional symptoms, seen primarily in HIV-positive individuals. We report an atypical case of suspected lues maligna in a 45-year-old male. The patient was HIV-positive with a CD4 count of 441. He presented to our clinic with large painful gummatous ulcers in the groin and lower back. He also reported daily fevers, night sweats, and weight loss consistent with secondary syphilis. Prior to this episode the patient had a history of acute active syphilis (RPR 1:128) in 2012 treated at that time with a single dose of 2.4 million units intramuscular benzathine penicillin; he had no reported exposures since that time. The patient was treated with three weekly doses of benzathine penicillin, 2.4 million units, given intramuscularly. This case demonstrates the importance of recognizing the varied clinical presentation of secondary syphilis and keeping lues maligna in consideration for ulceronodular skin lesions in patients who are HIV-positive. Syphilis is a sexually transmitted infection with various stages of evolution and a myriad of presentations. To avoid a delay in diagnosis, it is important to recognize secondary syphilis presenting with vesicular lesions. A patient presented with maculopapular rash of recent onset with several vesicles and related the eruption to paracetamol taken one day before. The differential diagnoses considered were drug eruption, pityriasis lichenoides et varioliformis acuta, pityriasis rosea and secondary syphilis. HIV, VDRL (1:256) and TPHA tests were positive and histopathology revealed lymphohistiocytic infiltrate and plasma cells. Thus, a diagnosis of secondary syphilis coexisting with HIV was confirmed. The patient was administered benzathine penicillin and anti-retroviral therapy was started. He responded very well to treatment. We report this case because of the rarity of vesicular eruption in secondary syphilis.  Hepatitis is a rare clinical manifestation of syphilis. In this report a 50 years old male patient who was diagnosed as secondary syphilis presenting with hepatitis has been discussed. The patient was admitted to the hospital with high fever and skin rash, and his history revealed a suspected sexual contact. He indicated that he had been admitted to a health center eight months ago because of the presence of a penile wound, however VDRL (Venereal Disease Research Laboratory) test was negative at that time. Fever (39.5 degrees C), jaundice in skin and sclera, generalized macular and maculopapular skin rash including palms and soles, lymphadenopathy and hepatosplenomegaly were detected in physical examination. Laboratory tests yielded elevated erythrocyte sedimantation rate, high CRP levels and elevated liver enzyme levels, however viral hepatitis markers together with VDRL and TPHA (Treponema pallidum hemagglutination) tests were found negative. Ceftriaxone therapy was initiated because of the presence of high fever (40 degrees C) and 30 leukocyte/mm3 in urine, and the absence of bacteria in Gram staining of urine sample. However, the antibiotic therapy was discontinued since fever persisted. As the clinical signs and symptoms strongly indicated syphilis, the serological tests were repeated and VDRL positivity at 1/8 and TPHA positivity at 1/1280 titers were detected. Ceftriaxone therapy was restarted and continued for 14 days with complete cure. Since the spouse of the patient was also found VDRL and TPHA positive, she was treated with penicilin. The presentation of this case emphasized the importance of repeating the serological tests for syphilis since they might be negative in the early stages of infection. The case also indicates that syphilis should be considered in the differential diagnosis of hepatitis. Immune reconstitution inflammatory syndrome (IRIS) is a condition during the clinical course of HIV infection in which there is paradoxical worsening and/or new onset of opportunistic infections in a HIV-positive patient who has recently been started on anti-retroviral therapy (ART). We present a case of AIDS with CD4 count of 20 cells/μl who presented within 6 weeks of starting ART with a CD4 count of 160 cells/μl and a painless solitary genital ulcer along with annular dark-colored plaques over soles. His screening test for syphilis was negative both during baseline evaluation, prior to initiation of ART, and during his clinical presentation. His disease was confirmed based on a positive treponema pallidum hemagglutination test report and a suggestive skin biopsy. He responded well to three doses of Benzathine Penicillin and continuation of ART. There are very few case reports of syphilis presenting as IRIS and this case is all the more unique as he had features of both primary and secondary syphilis occurring together within 6 weeks of starting ART. This report would reiterate the fact that syphilis and HIV co-infection can alter the natural course of both the diseases and a high index of suspicion is required for treating them. Secondary Syphilis The protean manifestations of the secondary stage usually include mucocutaneous lesions and generalized nontender lymphadenopathy. The healing primary chancre may still be present in ∼15% of cases, and the stages may overlap more frequently in persons with concurrent HIV infection. The skin rash consists of macular, papular, papulosquamous, and occasionally pustular syphilides; often more than one form is present simultaneously. The eruption may be very subtle, and 25% of patients with a discernible rash may be unaware that they have dermatologic manifestations. Initial lesions are pale red or pink, nonpruritic, discrete macules distributed on the trunk and proximal extremities; these macules progress to papular lesions that are distributed widely and that frequently involve the palms and soles (Fig. 206-3; see also Figs. 25e-18 and 25e-19). Rarely, severe necrotic lesions (lues maligna) may appear; they are more commonly reported in HIV-infected individuals. We report a case of secondary syphilis mimicking lupus vulgaris in an HIV-infected patient. A 21-year-old Brazilian man presented with a two-month history of asymptomatic cutaneous lesions accompanied by fever and fatigue. Dermatological evaluation revealed an erythematous, crusted, large plaque on the neck with the 'apple jelly' sign on diascopy and two smaller scaly elements on the trunk and left palm. Bacteriological examinations for bacteria and mycobacteria gave negative results. Histology revealed psoriasiform epidermal hyperplasia and dermal lymphoplasmacytic infiltrate. Serology for syphilis was positive, and immunohistochemistry confirmed the presence of Treponema pallidum in lesional skin. A diagnosis of secondary syphilis was made, and the patient was successfully treated with benzathine penicillin G. Cutaneous manifestations of secondary syphilis are protean and skin tuberculosis may be considered in the differential diagnosis, especially in HIV-infected patients. In the current case, clinical examination, and particularly, 'apple jelly' sign positivity, was suggestive of lupus vulgaris, but only typical histopathology and immunohistochemistry led to the correct diagnosis of secondary syphilis.\nHere is the question:\nDERMATOLOGY, VENEREOLOGY AND PLASTIC SURGERY: Gustavo comes to the emergency room with skin lesions and general malaise of several days of evolution. He has psoriasiform lesions on the trunk with involvement of palms and soles. He also presents asymmetric non-suppurative joint inflammation and bilateral ocular redness as well as erosions on the glans penis. In the subsequent anamnesis Gustavo recognizes a risky sexual contact 20 days before. What is his diagnosis?\nHere are the potential choices:\n1. HIV infection.\n2. Secondary syphilis.\n3. Reiter's syndrome.\n4. Erythema multiforme.\nThe correct answer is: ",
        "gold_answer": "3 Reiter's syndrome.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Erythematous scaly papules on the palms and soles are a common manifestation of secondary syphilis. We report a case of 19-year-old male who presented with erythematous, scaly, psoriasiform lesions over the palms and glans penis. The papules over the palms showed tenderness on blunt vertical pressure. There was a history of sexual contact and ulcer over the glans around 2 months back, which resolved on its own. Venereal Disease Research Laboratory test was positive in 1:32 dilution. <iTreponema pallidum</i hemagglutination test was also positive. This case highlights the atypical presentation of secondary syphilis. The clinical manifestations of recent syphilis can be variable, with typical and atypical patterns. Several conditions may cause atypical clinical aspects, including human immunodeficiency virus (HIV) co-infection. Besides the clinical features, co-infections may completely alter syphilis serological tests, causing interpretative difficulties and diagnostic delays. Aim of the work is to describe the difficulties encountered during the diagnostic evaluation of atypical skin manifestations and of the serology for syphilis of an HIV-infected patient who had contracted it several times. In 2020, a 52-year old HIV-positive bisexual male patient was admitted to our department with a 4-month history of moderately itchy cutaneous lesions localized at his neck, trunk and arms. In 2013, the patient presented with a classic syphilitic roseola of the trunk and a secondary syphilis was diagnosed, with increased levels of rapid plasma reagin (RPR), Treponema pallidum hemagglutination assay (TPHA), anti-Treponema pallidum IgM and IgG Index. A second episode occurred in 2018, as a primary syphilis with multiple ulcerative lesions of the penis, and increased levels of RPR, IgG and IgM. In 2019, a further episode of secondary syphilis was treated with Doxycycline. In 2020, erythematous and papular lesions with vesicular components and urticarial erythema multiforme (EM)-like lesions were present at the neck, trunk and arms. Serological tests and Nucleic Acid Amplification Test (NAAT) for Treponema Pallidum were performed, as well as a cutaneous biopsy with histological and immunohistochemical evaluation of one lesion. NAAT was negative for T. pallidum. Serological test results were discordant with a new syphilis infection, showing only increased levels of RPR and anti-Treponema IgG. The cutaneous biopsy revealed a non specific histological pattern, while the immunohistochemical evaluation with anti-spirochetal antibodies was mandatory for the diagnosis of recent syphilis, showing clusters of rod-shaped elements, some of which with spiral form, focally present at the epidermis and adnexal structures. Nowadays, syphilis may present with atypical clinical and serological features. Physicians should be aware of these possible alterations and consider syphilis even in case of uncommon clinical aspect and unclear serological tests. Cutaneous biopsy and immunohistochemical exam may be mandatory for the diagnosis. Known as \"the great imitator,\" secondary syphilis may clinically manifest itself in myriad of ways, involving different organs (including the oral cavity), and mimicking, both clinically and histologically, several diseases, thereby making diagnosis a challenge for clinicians. We highlight an interesting case of a 45-year-old man on whose diagnosis of secondary syphilis was based on the presence of unusual oral lesions, consisting of a well delimited, raised, nonhomogeneous, and corrugated white plaque on the right buccal mucosa which mimicked, clinically and histologically, a \"leukoplakia-like\" plaque and several whitish oral mucous patches localized on the lower labial mucosa and the right lateral margin of the tongue. After the oral lesions, the patient developed a symmetric maculopapular cutaneous rash on the palms, soles, and the trunk of the body. Furthermore, during the anamnesis the patient stated an asymptomatic ulcerative lesion on the glans penis, which had appeared 7 months before the onset of the oral lesions and spontaneously disappeared after 2 weeks. The history of these genital and cutaneous lesions suggested performing serologic tests for syphilis, revealing strongly positive titers and leading us to making a diagnosis of secondary syphilis. This case is remarkable because it displays an unusual oral sign, associated with secondary syphilis; in fact, only occasionally does syphilis manifest itself with a \"leukoplakia-like\" plaque. Dentists should consider secondary syphilis in the differential diagnosis of white and/or ulcerative oral lesions, above all in at-risk patients, given the continuing rise of syphilis in western Europe. A 39-year-old man complained about a slightly reddish non-itching rash evolving on his body during the last few weeks without any general symptoms. Physical examination revealed trunk-dominated roseola, papules, a few nodules with haemorrhagic crust on top, and round hyperkeratotic clavus-like lesion on the left plantar foot. In his mouth, he had a few up to 1.5 cm large erosions, and on his capillitium a diffuse alopecia. Serologic testing for syphilis was positive with Treponema-pallidum-particle-agglutination test at 1:163840, VDRL 1:64, positive IgG-FTA-ABS and 19S-IgM-FTA-ABS tests, and a pleocytosis of the liquor. In addition, there were a co-infection with mycoplasma hominis and first diagnosis of HIV infection (CDC-stadium A1). The patient was diagnosed as having secondary syphilis with suspicion of neurologic involvement and was therefore treated with 6x5 Mio. I.E. Penicillin G i.v. per day for 14 days after the initial application of 40 mg methylprednisolone. Under this regimen complete resolution of the skin lesions was noted over a 4 week period as well as slow re-growth of the hair. HIV infection at stadium A1 did not require antiretroviral treatment. A non-pruritic rash should always point to the differential diagnosis of syphilis. If syphilis is diagnosed, any other sexually transmitted disease including HIV should be excluded as possible co-infection. In case of HIV, neurosyphilis can develop at an earlier stage of common syphilis. Neurosyphilis is an infection of the central nervous system by Treponema pallidum, which can occur after the initial syphilis infection. Although commonly associated with late stage disease, patients with early neurosyphilis may present with acute syphilitic meningitis, meningovascular syphilis, or uveitis. A 28 year old man with a past medical history of HIV (CD4 364);, and recent diagnosis of uveitis presented to the Emergency Department with a positive RPR result. His visual acuity had been gradually declining over the past few months. He denied painless or painful ulcerating lesions on his penis, or scrotum, difficulty concentrating, dermatitis on the soles/palms, or difficulty with proprioception. Physical exam was notable for atrophic hyperpigmented polycyclic, annular plaques and patches along the hairline as well as several areas of confluent hyperpigmented polycyclic plaques and nodules on the patient's face, back, left arm, and right posterior leg. Fundoscopic exam revealed bilateral posterior uveitis and chorioretinitis. Evaluation of cerebrospinal fluid revealed a lymphocytic pleocytosis with a positive VDRL and FTA-ABS. Aqueous crystalline penicillin G was initiated for treatment of early neurosyphilis. Within six hours of beginning the infusion, the patient had a documented temperature of 101.8°F, heart rate of 128 beats per minute, blood pressure 142/84, with generalized malaise and headache. Fever and tachycardia resolved over the next 12 hours, with weakness and headache resolving within 1-2 days. His symptom complex was consistent with the Jarisch-Herxheimer reaction. Histopathology of skin biopsy of the back showed perivascular inflammation and rare spirochetes, consistent with secondary syphilis. The patient completed 14 days of aqueous crystalline penicillin G and was discharged after receiving the first of three benzathine penicillin injections. The initial manifestations of syphilis in this patient were posterior uveitis and pruritic skin plaques. His diagnosis should be appropriately classified as secondary syphilis with concomitant symptomatic early neurosyphilis, requiring 14 days of aqueous crystalline penicillin G. This type of presentation is not specific to immunocompromised populations and must be considered even in the general population. Making the diagnosis of early neurosyphilis, regardless of stage, is critical, as it necessitates a longer duration of treatment. Furthermore, clinicians should be reminded of the profound immunologic reaction, Jarisch-Herxheimer, which may occur when treating any treponemal disease. Primary syphilis is typically acquired by direct sexual contact with the infectious lesions of another person. Approximately 2–6 weeks after contact (with a range of 10–90 days) a skin lesion, called a chancre, appears at the site and this contains infectious spirochetes. This is classically (40% of the time) a single, firm, painless, non-itchy skin ulceration with a clean base and sharp borders approximately 0.3–3.0 cm in size. The lesion may take on almost any form. In the classic form, it evolves from a macule to a papule and finally to an erosion or ulcer. Occasionally, multiple lesions may be present (~40%), with multiple lesions being more common when coinfected with HIV. Lesions may be painful or tender (30%), and they may occur in places other than the genitals (2–7%). The most common location in women is the cervix (44%), the penis in heterosexual men (99%), and anally and rectally in men who have sex with men (34%). Lymph node enlargement frequently (80%) occurs around the Syphilis is a sexually transmitted infection by Treponema pallidum. Without antibiotic treatment syphilis lasts for several decades and may develop up to 4 different clinical stages. Usually, the disease begins with a distinct painless and indurated ulcer at the contact site: the primary chancre. An indolent regional lymph node swelling is usually associated with the syphilitic chancre. After spontaneous healing of the primary lesion and several weeks of latency, the clinical symptoms of secondary syphilis occur. Treponema pallidum bacteremia leads to common symptoms like fever and malaise, but also to a generalized lymphadenopathy, and a broad variety of lesions of the skin and mucosal membranes. Non-pruritic transient exanthems often involving palms and soles, condylomata lata, and a specific angina with mucous patches of the oral cavity are prominent signs. After several relapses, which are characterized by a decreasing intensity of clinical symptoms, secondary syphilis then resolves spontaneously. A second period of latency follows, lasting 3-12 years. Then the outcome of untreated syphilis becomes apparent: spontaneous healing by elimination/inactivation of the spirochetes (75%) or transition to tertiary syphilis (25%). Two kinds of granulomatous skin reactions are typical for tertiary syphilis: superficial nodular syphilids and gummas. The bones, as well as the cardiovascular and central nervous system, may also be involved. Finally, metasyphilis with severe and sometimes lethal neurological symptoms (tabes dorsalis, progressive paralysis) occurs 10 to 30 years after primary infection. Except for irreversible tissue destruction which occurs prior to therapy, all stages of syphilis can be cured completely. The incidence of syphilis has historically been cyclical in nature, often in relation to the rise and fall of public health initiatives directed toward eradication along with social attitudes toward sexual practices. The incidence of syphilis has increased by 15% in the last 6 years in the United States, with similar increases worldwide. Herein, we present an atypical case of syphilis presenting with severe septic shock and multiple anogenital lesions in an immunocompetent host. A 22-year-old male with no significant past medical history presented with fevers, chills, sore throat, diaphoresis, and diarrhea. He was febrile, tachycardic, hypotensive, and unresponsive to fluid resuscitation requiring short-term vasopressor support. Physical exam revealed diffuse lymphadenopathy; lower extremity macular rash involving the soles of the feet; papular non-pustular lesions on the scrotum; and a 0.5 cm non-tender irregular, healing lesion on the shaft of the penis. Laboratory analysis was significant for leukocytosis and elevated creatinine. Serum screening rapid plasma reagin was positive, and further testing revealed a titer of 1:32, with confirmation via fluorescent treponemal antibody absorption test. The patient was diagnosed with secondary syphilis, which was determined to be the underlying etiology of the sepsis as all other serological evaluations were negative. He was treated with penicillin G benzathine 2.4 million units intramuscular and supportive management, with improvement of symptoms. The patient engaged in high-risk sexual behaviors, including prior unprotected sexual contact with males. New research indicates that up to one-third of patients may present with atypical cutaneous manifestations, as demonstrated by this patient. It is important for physicians to familiarize themselves with the varied clinical presentations of syphilis, which include multiple anogenital lesions and tender primary lesions in primary or secondary syphilis. A 28-year-old white man presented to the Emergency Department with a 24-hour history of an eruption on his extremities, trunk, and face. The patient was known to be HIV positive with a CD4 count of 527 and a viral load of 20,300. He denied fever, chills, malaise, and headache. His social history was significant for the fact that he was in a monogamous homosexual relationship. He had no recent travel, pet exposures, or sick contacts. Physical examination revealed stable vital signs and no documented fever. A maculopapular eruption was present on his face, trunk, and extremities (Figures 1 and 2). There was no palmar or plantar involvement. He was treated with diphenhydramine and topical 2.5% hydrocortisone and advised to return if his condition did not improve. Twelve days after the initial evaluation, the patient consulted us again due to progression of his dermatitis. He had no additional complaints other than an eruption on both palms but neither sole. (Figure 3). The eruption now demonstrated erythematous pink-red oval macules and papules 1-2 cm in size distributed on his scalp, face, trunk, and arms. A few papules contained fine collarettes of scale. Further questioning revealed that the patient had experienced a tender rectal ulcer 2 months previously. A punch biopsy and rapid plasma reagin were performed. The histopathologic examination revealed interface dermatitis with lymphocytes, plasma cells, occasional neutrophils, and a prominent lymphoplasmacytic perivascular dermatitis with infiltration of the vessel walls. Warthrin-Starry and Steiner methods demonstrated spirochetes at the dermal-epidermal junction and in vessel walls, consistent with Treponema pallidum (Figure 4). Rapid plasma reagin and fluorescent Treponema antibody were both reactive with a Venereal Disease Research Laboratory (VDRL) of 1:16. The patient was diagnosed as having secondary syphilis and treated with 2.4 million units of IM benzathine penicillin for 3 weeks. His eruption resolved after the initial treatment and he did not experience a Jarisch-Herxheimer reaction. Secondary syphilis occurs approximately four to ten weeks after the primary infection. While secondary disease is known for the many different ways it can manifest, symptoms most commonly involve the skin, mucous membranes, and lymph nodes. There may be a symmetrical, reddish-pink, non-itchy rash on the trunk and extremities, including the palms and soles. The rash may become maculopapular or pustular. It may form flat, broad, whitish, wart-like lesions on mucous membranes, known as condyloma latum. All of these lesions harbor bacteria and are infectious. Other symptoms may include fever, sore throat, malaise, weight loss, hair loss, and headache. Rare manifestations include liver inflammation, kidney disease, joint inflammation, periostitis, inflammation of the optic nerve, uveitis, and interstitial keratitis. The acute symptoms usually resolve after three to six weeks; about 25% of people may present with a recurrence of secondary symptoms. Many people who present with secondary Syphilis, caused by Treponema pallidum agent, results in polymorphic and non-specific ocular manifestations. Early diagnosis and institution of individualized treatment play a large role in the prognosis. The increase in syphilis over the past several years requires the ophthalmologist to consider this diagnosis in the setting of any intraocular inflammatory involvement. To describe epidemiological, clinical and paraclinical features and natural history of syphilitic uveitis. Retrospective, descriptive and non-comparative study of a series of patients hospitalized between 2007 and 2013 in our department of ophthalmology for management of ocular inflammation associated with a positive syphilitic serology. Thirteen patients of mean age 52.5 years ± 12.9 (33-82 years) were included. All were male and were followed for six months. Co-infection with human immunodeficiency virus (HIV) was present in four of them. Other risk factors discovered on history were unprotected sexual relations, multiple partners, homosexual relations, co-infection with another sexually transmitted disease (STD) or an occupational risk. Decreased visual acuity (VA) was present in all patients, with an average initial VA of 0.71 ± 0.81 LogMAR, i.e. 2/10. Involvement was bilateral in 38% (n=5) of cases. Papilledema was present in 10 patients. Seven patients exhibited vasculitis, 6 patients a necrotizing retinitis, 2 patients with placoid lesions, 7 patients with panuveitis and 2 patients with macular edema. We did not find any patients with isolated anterior uveitis. Three patients exhibited concomitant extraocular involvement with cutaneous palmoplantar lesions. Spectral domain optical coherence tomography (SD-OCT) found a fragmentation of the external limiting membrane and a disorganization of the ellipsoid line in two patients. Cerebrospinal fluid was studied for all patients. Eight of them exhibited lymphocytic meningitis, and we found the presence of anti-Treponema pallidum hemagglutination assay antibody (TPHA) in 9 patients and anti-veneral disease research laboratory antibody (VDRL) in 1 patient. Syphilis polymerase chain reaction (PCR) in the aqueous humor was positive in 50% (n=6) of studied cases and the PCR for Epstein Barr virus came back positive in four specimens out of eight. False positive reactions were observed for Lyme disease in eight patients. The four HIV-positive patients showed bilateral lesions more frequently, but less severe and with a favorable outcome. Antibiotic treatment with ceftriaxone (2 grams per day intramuscularly for 15 to 21 days) and local treatment (corticoids and mydriatics) in the case of inflammation of the anterior segment, allowed a regression of the inflammation in all of our patients as well as an improvement in VA (average final VA 0.09 ± 0.17 LogMAR, i.e. approximately 8/10). One Jarisch Herxheimer reaction occurred and was resolved with systemic corticosteroid therapy. A change in the retinal pigment epithelium was the main sequela in 44% of cases (n=8 eyes). Every structure of the eye may be involved with syphilis; therefore, syphilis must be systematically sought during the etiologic assessment of ocular inflammation even in the absence of historical risk factors. HIV-positive patients must be handled in the same way as immunocompetent patients. Collaboration with the internist is essential for the diagnosis, monitoring, and staging, especially in search of neurosyphilis. The clinical course is favorable with early treatment. Immune reconstitution inflammatory syndrome (IRIS) is a condition associated with paradoxical worsening and/or new onset of an opportunistic infection in HIV patients following the initiation of anti-retroviral therapy or switching to more potent antiretroviral therapy (ART) regimen. Although IRIS associated with many opportunistic infections (OIs) has been well reported, syphilis has very rarely been mentioned in this regard. A 52-year-old male, diagnosed with AIDS six weeks ago, presented with the disseminated non-pruritic painless skin rash. He denied any fever, cough, shortness of breath, and joint pain or swelling. The patient had no similar symptoms, genital ulcers, or any medical illness in the past. CD4 cell count and viral load were 40 cells/mm<sup3</sup and 280,000 copies/ml, respectively, while screening tests for OIs including rapid plasma reagin test, quantiferon, cryptococcal antigen, and toxoplasma tests were negative at the time of HIV diagnosis. After three days of initiation of anti-retroviral therapy, he developed the above-mentioned skin rash. Repeat rapid plasma regain (RPR) test at this time was also negative. Punch biopsy of the skin lesion demonstrated findings suggestive of secondary syphilitic lesions, which was confirmed by immunostain. The repeat RPR, CD4 cell count, and viral load showed a titer of 1:256, 257 cells/mm<sup3</sup, and 5000 copies/ml, respectively. His skin rashes faded away, and RPR titer trended down on treatment with benzathine penicillin without discontinuation of ART. The presence of an IRIS response does not predict overall HIV or OI treatment responses, and discontinuation of ART is not generally recommended as the benefits of treating HIV infection outweighs the risk associated with IRIS. Syphilis is commonly known as \"the great imitator\" owing to its varied clinical manifestations. Secondary syphilis has a variety of presentations, with the most common manifesting as a diffuse papulosquamous eruption on the palms and soles. Lues maligna praecox is a rare form of secondary syphilis, with severe constitutional symptoms, seen primarily in HIV-positive individuals. We report an atypical case of suspected lues maligna in a 45-year-old male. The patient was HIV-positive with a CD4 count of 441. He presented to our clinic with large painful gummatous ulcers in the groin and lower back. He also reported daily fevers, night sweats, and weight loss consistent with secondary syphilis. Prior to this episode the patient had a history of acute active syphilis (RPR 1:128) in 2012 treated at that time with a single dose of 2.4 million units intramuscular benzathine penicillin; he had no reported exposures since that time. The patient was treated with three weekly doses of benzathine penicillin, 2.4 million units, given intramuscularly. This case demonstrates the importance of recognizing the varied clinical presentation of secondary syphilis and keeping lues maligna in consideration for ulceronodular skin lesions in patients who are HIV-positive. Syphilis is a sexually transmitted infection with various stages of evolution and a myriad of presentations. To avoid a delay in diagnosis, it is important to recognize secondary syphilis presenting with vesicular lesions. A patient presented with maculopapular rash of recent onset with several vesicles and related the eruption to paracetamol taken one day before. The differential diagnoses considered were drug eruption, pityriasis lichenoides et varioliformis acuta, pityriasis rosea and secondary syphilis. HIV, VDRL (1:256) and TPHA tests were positive and histopathology revealed lymphohistiocytic infiltrate and plasma cells. Thus, a diagnosis of secondary syphilis coexisting with HIV was confirmed. The patient was administered benzathine penicillin and anti-retroviral therapy was started. He responded very well to treatment. We report this case because of the rarity of vesicular eruption in secondary syphilis.  Hepatitis is a rare clinical manifestation of syphilis. In this report a 50 years old male patient who was diagnosed as secondary syphilis presenting with hepatitis has been discussed. The patient was admitted to the hospital with high fever and skin rash, and his history revealed a suspected sexual contact. He indicated that he had been admitted to a health center eight months ago because of the presence of a penile wound, however VDRL (Venereal Disease Research Laboratory) test was negative at that time. Fever (39.5 degrees C), jaundice in skin and sclera, generalized macular and maculopapular skin rash including palms and soles, lymphadenopathy and hepatosplenomegaly were detected in physical examination. Laboratory tests yielded elevated erythrocyte sedimantation rate, high CRP levels and elevated liver enzyme levels, however viral hepatitis markers together with VDRL and TPHA (Treponema pallidum hemagglutination) tests were found negative. Ceftriaxone therapy was initiated because of the presence of high fever (40 degrees C) and 30 leukocyte/mm3 in urine, and the absence of bacteria in Gram staining of urine sample. However, the antibiotic therapy was discontinued since fever persisted. As the clinical signs and symptoms strongly indicated syphilis, the serological tests were repeated and VDRL positivity at 1/8 and TPHA positivity at 1/1280 titers were detected. Ceftriaxone therapy was restarted and continued for 14 days with complete cure. Since the spouse of the patient was also found VDRL and TPHA positive, she was treated with penicilin. The presentation of this case emphasized the importance of repeating the serological tests for syphilis since they might be negative in the early stages of infection. The case also indicates that syphilis should be considered in the differential diagnosis of hepatitis. Immune reconstitution inflammatory syndrome (IRIS) is a condition during the clinical course of HIV infection in which there is paradoxical worsening and/or new onset of opportunistic infections in a HIV-positive patient who has recently been started on anti-retroviral therapy (ART). We present a case of AIDS with CD4 count of 20 cells/μl who presented within 6 weeks of starting ART with a CD4 count of 160 cells/μl and a painless solitary genital ulcer along with annular dark-colored plaques over soles. His screening test for syphilis was negative both during baseline evaluation, prior to initiation of ART, and during his clinical presentation. His disease was confirmed based on a positive treponema pallidum hemagglutination test report and a suggestive skin biopsy. He responded well to three doses of Benzathine Penicillin and continuation of ART. There are very few case reports of syphilis presenting as IRIS and this case is all the more unique as he had features of both primary and secondary syphilis occurring together within 6 weeks of starting ART. This report would reiterate the fact that syphilis and HIV co-infection can alter the natural course of both the diseases and a high index of suspicion is required for treating them. Secondary Syphilis The protean manifestations of the secondary stage usually include mucocutaneous lesions and generalized nontender lymphadenopathy. The healing primary chancre may still be present in ∼15% of cases, and the stages may overlap more frequently in persons with concurrent HIV infection. The skin rash consists of macular, papular, papulosquamous, and occasionally pustular syphilides; often more than one form is present simultaneously. The eruption may be very subtle, and 25% of patients with a discernible rash may be unaware that they have dermatologic manifestations. Initial lesions are pale red or pink, nonpruritic, discrete macules distributed on the trunk and proximal extremities; these macules progress to papular lesions that are distributed widely and that frequently involve the palms and soles (Fig. 206-3; see also Figs. 25e-18 and 25e-19). Rarely, severe necrotic lesions (lues maligna) may appear; they are more commonly reported in HIV-infected individuals. We report a case of secondary syphilis mimicking lupus vulgaris in an HIV-infected patient. A 21-year-old Brazilian man presented with a two-month history of asymptomatic cutaneous lesions accompanied by fever and fatigue. Dermatological evaluation revealed an erythematous, crusted, large plaque on the neck with the 'apple jelly' sign on diascopy and two smaller scaly elements on the trunk and left palm. Bacteriological examinations for bacteria and mycobacteria gave negative results. Histology revealed psoriasiform epidermal hyperplasia and dermal lymphoplasmacytic infiltrate. Serology for syphilis was positive, and immunohistochemistry confirmed the presence of Treponema pallidum in lesional skin. A diagnosis of secondary syphilis was made, and the patient was successfully treated with benzathine penicillin G. Cutaneous manifestations of secondary syphilis are protean and skin tuberculosis may be considered in the differential diagnosis, especially in HIV-infected patients. In the current case, clinical examination, and particularly, 'apple jelly' sign positivity, was suggestive of lupus vulgaris, but only typical histopathology and immunohistochemistry led to the correct diagnosis of secondary syphilis.\nHere is the question:\nDERMATOLOGY, VENEREOLOGY AND PLASTIC SURGERY: Gustavo comes to the emergency room with skin lesions and general malaise of several days of evolution. He has psoriasiform lesions on the trunk with involvement of palms and soles. He also presents asymmetric non-suppurative joint inflammation and bilateral ocular redness as well as erosions on the glans penis. In the subsequent anamnesis Gustavo recognizes a risky sexual contact 20 days before. What is his diagnosis?\nHere are the potential choices:\n1. HIV infection.\n2. Secondary syphilis.\n3. Reiter's syndrome.\n4. Erythema multiforme.\nThe correct answer is: 2. Secondary syphilis."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Blunt chest trauma can cause severe acute pulmonary dysfunction due to hemo/pneumothorax, rib fractures and lung contusion. To study the long-term effects on lung function tests after patients' recovery from severe chest trauma. We investigated the outcome and lung function tests in 13 patients with severe blunt chest trauma and lung contusion. The study group comprised 9 men and 4 women with an average age of 44.6 +/- 13 years (median 45 years). Ten had been injured in motor vehicle accidents and 3 had fallen from a height. In addition to lung contusion most of them had fractures of more than three ribs and hemo/pneumothorax. Ten patients were treated with chest drains. Mean intensive care unit stay was 11 days (range 0-90) and mechanical ventilation 19 (0-60) days. Ten patients had other concomitant injuries. Mean forced expiratory volume in the first second was 81.2 +/- 15.3%, mean forced vital capacity was 85 +/- 13%, residual volume was 143 +/- 33.4%, total lung capacity was 101 +/- 14% and carbon monoxide diffusion capacity 87 +/- 24. Post-exercise oxygen saturation was normal in all patients (97 +/- 1.5%), and mean oxygen consumption max/kg was 18 +/- 4.3 ml/kg/min (60.2 +/- 15%). FEV1 was significantly lower among smokers (71.1 +/- 12.2 vs. 89.2 +/- 13.6%, P = 0.017). There was a non-significant tendency towards lower FEV1 among patients who underwent mechanical ventilation. Late after severe trauma involving lung contusion, substantial recovery was demonstrated with improved pulmonary function tests. These results encourage maximal intensive care in these patients. Further larger studies are required to investigate different factors affecting prognosis. We report the case of a 21-year-old man who developed adult respiratory distress syndrome (ARDS) after severe lung contusion due to a car accident. At the scene of the accident the patient was awake and oriented, but there were signs of hypoxaemia (SaO2 by pulse oximetry: 86%). The trachea was intubated in the emergency room and, after diagnosis of multiple rib fractures on the right side (the patient nos. 4-11) and emergency treatment, was extubated 16 h later. During spontaneous breathing there was no improvement of pulmonary function, and the patient was transferred to the intensive care unit 5 days later and reintubated because of acute respiratory failure. He then developed the signs of severe ARDS. No improvement occurred during conventional ventilatory treatment including inversed-ratio ventilation, high-frequency ventilation, and ventilation via a double-lumen tube. On day 15 a bovine surfactant preparation (38 mg/kg body wt.) was instilled into both lungs. Initially there was deterioration of the pulmonary function, probably due to crusts in the bronchial mucous membrane. After aspiration of the crusts at bronchoscopy, there was progressive respiratory improvement. The inspired oxygen concentration and PEEP level could be reduced, and the ventilatory ratio normalised within 14 days. This therapeutic intervention improved pulmonary function and probably led to the successful outcome after 36 days of ventilatory support. Venovenous extracorporeal membrane oxygenation (VV-ECMO) is indicated for patients with severe respiratory failure who cannot be managed with a ventilator. We report a case of severe chest trauma with an injury severity score of 66, in which hemostasis was achieved after VV-ECMO. A 29-year-old male patient sustained a fall injury from a 4-m cliff. The fall resulted in significant traumatic cerebral hemorrhage, bilateral pulmonary contusion, hemothorax, pelvic fracture, and limb fracture. During transcatheter arterial embolization, the patient continued to bleed from the left lung and showed progressive hypoxemia. In addition, the patient was unable to maintain tidal volume and experienced hypercapnia, and thus, VV-ECMO was introduced, followed by a thoracotomy to stop the bleeding. On the third day of hospitalization, the patient was weaned off VV-ECMO, and on day 35, he was transferred to a rehabilitation hospital for recovery. VV-ECMO may serve as a \"bridge\" until hemostatic maneuvers for severe chest trauma are completed and may contribute to help ensure adequate respiration. Massive pulmonary haemorrhage can spoil the entire lung and block the airway in a short period of time due to severe bleeding, which quickly leads to death. Alveolar lavage is an effective method for haemostasis and airway maintenance. However, patients often cannot tolerate alveolar lavage due to severe hypoxia. We used extracorporeal membrane oxygenation (ECMO) to overcome this limitation in a patient with massive pulmonary haemorrhage due to severe trauma and succeeded in saving the life by repeated alveolar lavage. A 22-year-old man sustained multiple injuries in a motor vehicle accident and was transferred to our emergency department. On admission, he had a slight cough and a small amount of bloody sputum; computed tomography revealed multiple fractures and mild pulmonary contusion. At 37 h after admission, he developed severe chest tightness, chest pain, dizziness and haemoptysis. His oxygen saturation was 68%. Emergency endotracheal intubation was performed, and a large amount of bloody sputum was suctioned. After transfer to the intensive care unit, he developed refractory hypoxemia and heparin-free venovenous ECMO was initiated. Fibreoptic bronchoscopy revealed diffuse and profuse blood in all bronchopulmonary segment. Bleeding was observed in the trachea and right bronchus, and repeated alveolar lavage was performed. On day 3, the patient's haemoptysis ceased, and ECMO support was terminated 10 d later. Tracheostomy was performed on day 15, and the patient was weaned from the ventilator on day 21. Alveolar lavage combined with ECMO can control bleeding in trauma-induced massive pulmonary haemorrhage, is safe and can be performed bedside. To evaluate the impact on morbidity and mortality of pulmonary contusion in multiple-trauma patients with severe head trauma. Matched-paired, case-control study ICU at a tertiary university hospital. During a 3-year period, 313 consecutive multiple-trauma patients with severe head trauma (Glasgow coma scale [GCS], &lt;/= 8) who were admitted to the ICU. Case-control matching criteria were as follows: (1) age difference within 5 years; (2) sex; (3) GCS in two categories; (4) similar pattern of injury; and (5) simplified acute physiology score II in five categories. A pulmonary contusion, defined by the clinical context and the result of a chest CT scan, was diagnosed in 90 patients. Analysis was performed on 90 pairs who were matched with 100% success. Ninety patients (29%) presented a diagnosis of pulmonary contusion. The presence of pulmonary contusion had an impact on the PaO(2)/fraction of inspired oxygen (FIO(2)) ratio, which was significantly reduced in patients with a pulmonary contusion. The ICU stay, the occurrence of complications such as nosocomial pneumonia or ARDS, the Glasgow outcome scale, and the mortality rate did not significantly differ between case patients and control subjects. Mortality also was not affected when patients were stratified according to the severity of the PaO(2)/FIO(2) ratio. In the study patients, pulmonary contusion alters gas exchange but does not appear to increase the morbidity and mortality of multiple-trauma patients with head trauma. A sample-size effect may limit the interpretation of the study. Polytrauma often results in significant hypoxemia secondary to direct lung contusion or indirectly through atelectasis, systemic inflammatory response, large volume fluid resuscitation and blood product transfusion. In addition to causing hypoxemia, atelectasis and acute lung injury can lead to right ventricular failure through an acute increase in pulmonary vascular resistance. Mechanical ventilation is often applied, accompanied with recruitment maneuvers and positive end-expiratory pressure in order to recruit alveoli and reverse atelectasis, while preventing excessive alveolar damage. This strategy should lead to the reversal of the hypoxemic condition and the detrimental heart-lung interaction that may occur. However, as described in this case report, hemodynamic instability and intractable alveolar atelectasis sometimes do not respond to conventional ventilation strategies. We describe the case of a 21-year-old Caucasian man with severe chest trauma requiring surgical interventions, who developed refractory hypoxemia and overt right ventricular failure. After multiple failed attempts of recruitment using conventional ventilation, the patient was ventilated with high-frequency oscillatory ventilation. This mode of ventilation allowed the reversal of the hemodynamic effects of severe hypoxemia and of the acute cor pulmonale. We use this case report to describe the physiological advantages of high-frequency oscillatory ventilation in patients with chest trauma, and formulate the arguments to explain the positive effect observed in our patient. High-frequency oscillatory ventilation can be used in the context of a blunt chest trauma accompanied by severe hypoxemia due to atelectasis. The positive effect is due to its capacity to recruit the collapsed alveoli and, as a result, the relief of increased pulmonary vascular resistance and subsequently the reversal of acute cor pulmonale. This approach may represent an alternative in case of failure of the conventional ventilation strategy. Ventilation and gas exchange lung functions were studied in 110 patients with severe closed chest trauma. In chest trauma that was not accompanied by intrapulmonary traumatic changes the main pathogenetic mechanism of gas exchange damage was marked pain syndrome. Such patients did not suffer from severe arterial hypoxemia and their intrapulmonary shunting did not exceed 15%. Analgesia and, if necessary, lung decompression improved considerably respiratory parameters and prevented the onset of severe pulmonary failure. Patients with intrapulmonary traumatic changes (lung contusion, intrapulmonary hematomas) were characterized by progressing arterial hypoxemia due to a considerable increase in intrapulmonary shunting. These patients are managed mainly by preventive therapy of pulmonary hyperhydration, thorough tracheobronchial cleansing, cough stimulation, prevention of pneumonia. A large amount of force is required to cause pulmonary contusion; a person injured with such force is likely to have other types of injuries as well. In fact, pulmonary contusion can be used to gauge the severity of trauma. Up to three quarters of cases are accompanied by other chest injuries, the most common of these being hemothorax and pneumothorax. Flail chest is usually associated with significant pulmonary contusion, and the contusion, rather than the chest wall injury, is often the main cause of respiratory failure in people with these injuries. Other indications of thoracic trauma may be associated, including fracture of the sternum and bruising of the chest wall. Over half of fractures of the scapula are associated with pulmonary contusion. The contusion is frequently found underlying fracture sites. When accompanied by a fracture, it is usually concentrated into a specific location—the contusion is more diffuse when there is no fracture. Pulmonary lacerations may Pulmonary contusion is found in 30–75% of severe cases of chest injury, making it the most common serious injury to occur in association with thoracic trauma. Of people who have multiple injuries with an injury severity score of over 15, pulmonary contusion occurs in about 17%. It is difficult to determine the death rate (mortality) because pulmonary contusion rarely occurs by itself. Usually, deaths of people with pulmonary contusion result from other injuries, commonly traumatic brain injury. It is controversial whether pulmonary contusion with flail chest is a major factor in mortality on its own or whether it merely contributes to mortality in people with multiple injuries. The estimated mortality rate of pulmonary contusion ranges from 14–40%, depending on the severity of the contusion itself and on associated injuries. When the contusions are small, they do not normally increase the chance of death or poor outcome for people with blunt chest trauma; however, these chances Signs and symptoms take time to develop, and as many as half of cases are asymptomatic at the initial presentation. The more severe the injury, the more quickly symptoms become apparent. In severe cases, symptoms may occur as quickly as three or four hours after the trauma. Hypoxemia (low oxygen concentration in the arterial blood) typically becomes progressively worse over 24–48 hours after injury. In general, pulmonary contusion tends to worsen slowly over a few days, but it may also cause rapid deterioration or death if untreated. Causes A protocol for treating thoracic trauma is proposed. Severe pulmonary lesion with increased venous admixture (e.g. contusio, atelectasis, aspiration) is treated by mechanical ventilation. Rib fractures with minor pulmonary lesion and therefore with only moderately abnormal gas exchange but with remarkably reduced vital capacity (even with flail chest) are controlled by thoracic epidural analgesia following vital capacity, tidal volume and respiratory rate. If both a severe pulmonary lesion and serial rib fractures are present, the patient is ventilated for 2-3 days and then extubated to breath spontaneously with epidural analgesia. The indication for a mechanical ventilation or for spontaneous breathing with thoracic epidural analgesia is therefore deducted more from functional variables than from morphological facts. The course of a consecutive series of 283 patients is presented. 155 patients were treated with primary ventilation and 112 patients with primary epidural analgesia, while 16 patients could be managed with general analgesia. The duration of treatment morbidity and mortality show this protocol to be very useful. Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a valuable treatment option for chest trauma individuals and some patients required surgery. A 35-year-old female patient with severe chest trauma was admitted to Affiliated Hospital of Zunyi Medical University on February 27, 2020. The patient was hospitalized with chest pain and dyspnea due to fall from a height. Emergency chest CT revealed a right fluid pneumothorax (60% of right lung compression), left hemothorax, little pericardial effusion, and multiple emphysemas in the lower neck, chest, back and mediastinum. Invasive ventilator was difficult to maintain oxygen saturation. After evaluation, the VV-ECMO was established, then, she received a thoracotomy. There was a 1.2 cm trachea rupture observed during operation, and the trachea was repaired. The operation lasted 4 hours with the continuous support of VV-ECMO. When the patient's haemodynamics and oxygenation was stable, ECMO was removed. Sixteen days later, the patient's chest CT showed that, the chest wall subcutaneous emphysema was reduced, and the exudative lesions of both lungs were absorbed, indicating that the patient was treated effectively and reached the discharge standard with no complication. During the treatment of this patient, VV-ECMO was applied rapidly and lasted for a short period, which provided the patient with the opportunity of emergency operation and finally the patient was fully recovered. VV-ECMO can provide support for patients with severe trauma and refractory hypoxemia. The severity ranges from mild to severe: small contusions may have little or no impact on health, yet pulmonary contusion is the most common type of potentially lethal chest trauma. It occurs in 30–75% of severe chest injuries. The risk of death following a pulmonary contusion is between 14–40%. Pulmonary contusion is usually accompanied by other injuries. Although associated injuries are often the cause of death, pulmonary contusion is thought to cause death directly in a quarter to half of cases. Children are at especially high risk for the injury because the relative flexibility of their bones prevents the chest wall from absorbing force from an impact, causing it to be transmitted instead to the lung. Pulmonary contusion is associated with complications including pneumonia and acute respiratory distress syndrome, and it can cause long-term respiratory disability. Classification Causes Pulmonary contusion is the most common injury found in blunt chest trauma, occurring in 25–35% of cases. It is usually caused by the rapid deceleration that results when the moving chest strikes a fixed object. About 70% of cases result from motor vehicle collisions, most often when the chest strikes the inside of the car. Falls, assaults, and sports injuries are other causes. Pulmonary contusion can also be caused by explosions; the organs most vulnerable to blast injuries are those that contain gas, such as the lungs. Blast lung is severe pulmonary contusion, bleeding, or edema with damage to alveoli and blood vessels, or a combination of these. This is the primary cause of death among people who initially survive an explosion. Unlike other mechanisms of injury in which pulmonary contusion is often found alongside other injuries, explosions can cause pulmonary contusion without damage to the chest wall. In the one-year prospective study 71 injured patients were observed (75% male and 25% female). Traffic traumatism was the dominant case (45%). The wounded are divided in the groups with one side fracture of ribs (left/right) and on both sides fracture of ribs considering the side of fracture, and there is consideration about the kind of fracture--there are single fracture of ribs and serial fracture of ribs. The samples of artery blood were followed in PaCO2, %SaO2 and level pH in three points of time: when the patients came, after 24 and after 48 hours. In the group with the both side fracture of the ribs, the fall of worth pH was observed after 48 hours, PaCO2 is increasing to the 6.98 kPa. PaO2 is falling after 48 hours. In %SaO2 there is no considerable difference at any time, but%SaO2 is the highest in the second group. With the serial fracture of ribs wounded are considerate the fall of worth pH which is progressively increasing and is the highest after 48 hours. PaCO2 is increasing in the both groups, but with the serial fracture the worth are considerably higher. PaO2 and %SaO2 are much lower after 48 hours. The authors conclude that the wounded on both sides and wounded with serial fracture along one or several lines of with fracture of all ribs suffer the highest respiratory insufficiency (ARI), so they need artificial ventilation as respiratory support. There are few reports in the literature regarding the use of venoarterial extracorporeal membrane oxygenation (ECMO) for double-dysfunction from both heart and lung contusions in polytrauma patients. This article reports a 48-year-old patient admitted after a traffic accident. He rapidly progressed to shock with low cardiac output due to myocardial contusion and refractory hypoxemia due to pulmonary contusion, an unstable chest wall and bilateral pneumothorax. ECMO was an effective rescue procedure in this dramatic situation and was successfully discontinued on the fourth day after the trauma. The patient also developed an extensive brain infarction and eventually died on the seventh day after admission.  A 53-year-old man was admitted to our trauma center after sustaining thoracoabdominal injuries, secondary to a rear-end motor vehicle collision. As he stepped out of his vehicle, he was struck by a tractor trailer at 55 mph. The following were the initial vital signs on his arrival: heart rate 140 beats/min, blood pressure 142/80 mm Hg, respiratory rate 28 breaths/min, temperature 36.8°C, and oxygen saturation 93%. The Glasgow Coma Scale score was 15 and the Injury Severity Score was 59. He was evaluated and resuscitated per the advanced trauma life support protocols. The focused assessment with sonography for trauma examination was negative. Initial findings included bilateral chest wall and thoracic spine tenderness, subcutaneous emphysema in the chest and neck, and an unstable pelvis. He required bilateral chest tubes and a pelvic binder. CT imaging revealed a left temporal epidural hematoma, multiple facial fractures, a sternal fracture, a left scapula fracture, acromioclavicular fractures, bilateral hemopneumothoraces, pulmonary contusions, extensive pneumomediastinum compressing the right atrium, multiple rib fractures (2-10 on the left with a flail segment and 2-8 on the right) (figure 1), an unstable open-book pelvic fracture which included bilateral superior and inferior pubic rami fractures, sacral and left iliac wing fractures, and symphysis pubis diastasis.Figure 1Three-dimensional CT scan reconstruction demonstrating left-sided flail chest.The patient developed hypotension and severe respiratory distress, and was intubated. ECG revealed no dysrhythmias. Echocardiogram revealed significant left ventricular wall dysfunction consistent with myocardial contusion and right atrial compression. His troponins were also significantly elevated. He required significant resuscitation with crystalloids, blood products and vasopressors. He underwent bronchoscopy, esophagram and upper endoscopy to exclude tracheoesophageal injury, and these were negative. On hospital day 2, the patient was hemodynamically stable, and pressors were discontinued. His pelvic fractures were repaired using external fixation and sacral screws. Given his extensive left flail chest, he underwent reconstruction of his left chest wall on hospital day 5. Open reduction and internal fixation of his left ribs, 3 to 6 anteriorly and 4 to 7 posteriorly, with titanium plates was performed (figure 2). He had an epidural catheter inserted for analgesia. On postoperative day 2 after chest wall reconstruction, the patient was extubated and resumed enteral feeds. Overnight, the output from the left-sided chest tube changed from serosanguinous to milky. A sample was sent for triglycerides and lymphocyte counts confirming the diagnosis of chylothorax. His chest tube output increased to approximately 2000 mL/day. A lymphangiogram was performed with Lipiodol to diagnose the location of the chylous leak. It revealed contrast extravasation at the level of T3 to T4. An MRI was also performed to better define the anatomic course of the thoracic duct.Figure 2Postoperative chest X-ray demonstrating left chest wall reconstruction. Conservative management: placing the patient nulla per os (NPO), and starting total parenteral nutrition (TPN), octreotide and midodrine.Thoracic duct embolization by interventional radiology.CT-guided thoracic duct disruption.Thoracotomy with thoracic duct ligation. Twenty-four patients with severe lung contusion and multiple rib fractures were studied at a mean 4.9 years (range 2-9 years) after injury. All patients had been in good health before the accident. After the accident 15 (63 per cent) patients had respiratory symptoms such as dyspnoea at rest or moderate exercise (4), pain (8), cough or increased expectoration (11) and frequent bronchopulmonary infections (5). Three patients had changed their job because of respiratory disturbance. The average vital capacity, forced expiratory volume in 1 s, maximal voluntary ventilation and CO transfer factor were reduced respectively to 87, 88, 82 and 83 per cent of predicted values (P less than 0.01), while total lung capacity, residual volume and helium mixing time showed no definite changes (P greater than 0.05). Arterial blood gases at rest and at maximum exercise showed slight changes only. Maximal working capacity and ECG, as well as the ventilatory cost of moderate exercise were normal, where as the CO2 recovery time after moderate exercise was slightly increased (P less than 0.05). Overall there was a tendency towards poorer function in patients treated with artificial ventilation. Chest radiographs were normal in 10 patients (42 per cent), and moderate changes were seen in 14 patients. Diaphragmatic movements were essentially normal in all patients. Severe injury to the chest causes frequent respiratory symptoms. However, objective tests were only moderately reduced when compared with normal values. There was no unequivocal association between the subjective symptoms and the pulmonary function. Multiple rib fractures with segmental chest wall instability are caused by high-energy chest trauma and are associated with significant morbidity and mortality. Flail chest injuries are mostly combined with lung injury (contusion, rupture, laceration) and subsequent pneumothorax or haemothorax. Early mechanical ventilation with internal pneumatic splinting is a conservative treatment for flail chest in patients with respiratory insufficiency. The surgical stabilisation of a flail chest is an effective method of treatment and is beneficial for selected patients. It shortens the duration of mechanical ventilation and thus reduces morbidity associated with prolonged ventilatory support. In addition, it decreases long-term pain and the inability of a flail chest to heal due to malunion, non-union or progressive collapse of the flail segment. Surgical stabilisation of a flail chest is indicated when the clinical examination shows progressive respiratory dysfunction confirmed by the results of multiple detector computer tomography (MDCT) of the thorax. Thirty-three consecutive patients who underwent surgical stabilisation of a flail chest at the Trauma Centre between 2010 and 2014 were retrospectively evaluated. This included patient demographics, chest injury extent, results of pre-operative chest imaging (MDCT), surgical stabilisation technique and post-operative outcome. In addition to providing a radiographic finding of respiratory failure, the result of MDCT chest examination was considered an important criterion for surgical intervention. Surgical stabilisation of the chest wall was performed at an interval ranging from 2 hours to 11 days after injury. Intra-thoracic procedures were indicated in patients with lung injury (pulmonary laceration). The surgical procedure was completed by chest tube placement. Surgical stabilisation was carried out using 3 to 8 plates for flail segment fixation involving 3 to 4 ribs. The duration of post- operative mechanical ventilation was 5 days on the average. It was longer in patients with associated injuries such as craniocerebral trauma or severe pulmonary contusion. Tracheostomy was performed in seven patients requiring prolonged mechanical ventilation. Two patients had superficial surgical site infection. No death was recorded in the follow-up period. Surgical stabilisation of the flail chest segment is considered an effective procedure in selected patients, leading to improvement of respiratory function. By allowing for a shorter period of time on mechanical ventilation, it reduces the occurrence of complications due to ventilatory support. The result of MDCT chest examination in patients with fail chest is an important indication criterion for surgical fixation. The body's response to the effects of mechanical injury, taking the form of shock during the first hours and the onset of fat embolism in the subsequent period, is substantially higher in patients with multiple or associated injuries, both as regards the severity of manifestations and prognostic risk. Also the death rate due to this sort of complication is seen rising. Two groups of injured persons with isolated (n = 33) and multiple fractures (n = 33) were used to show that dynamic follow-up of PaO2 in the blood could serve as a criterion of the risk of fat embolism development in the body and, in particular, as a prognostic criterion for the progress of fat embolism. Special point was made of findings demonstrating a time relationship between PaO2 deterioration in the early post-injury period (up to 24-36 hours) as compared with the period of 48-72 hours after the injury. PaO2 is seen dropping rapidly in injured persons showing signs of fat embolism syndrome development. The decrease can be recorded as early as the free interval phase, i.e. prior to the manifestation of the clinical signs of fat embolism. The findings of low PaO2 levels in the blood are in accordance with respiratory ventilation disturbances and impaired diffusion documented in our investigation. The stove-in chest is a rare form of flail chest in which there is collapse of a segment of the chest wall, associated with a high immediate mortality. A 65-year-old male pedestrian was admitted with severe chest pain and dyspnoea, after being struck by a car. The initial chest radiograph demonstrated multiple right-sided rib fractures and pulmonary contusion. His gas exchange was good, and after pain relief via an epidural catheter was achieved, an intercostal drain was inserted into the right hemi-thorax. Clinically apparent deformation of the chest then occurred. A further chest radiograph confirmed the stove-in chest. The patient remained well initially, but on day 5 he deteriorated precipitously with respiratory failure, and signs of systemic sepsis. He died despite maximal ventilatory and inotropic support on the Intensive Care Unit (ICU). Post-mortem examination demonstrated congested, oedematous lungs with a right-sided empyema. The management of complex flail chest injuries requires treatment to be tailored to the individual patient. Early ventilatory support, despite good gas exchange, may have closed down the pleural space prevented the empyema. Prophylactic ventilation and possibly surgical stabilisation of the chest wall should be considered early in the course of admission, even when the conventional parameters to indicate ventilation are not met. One hundred nine patients with the diagnosis of pulmonary contusion were studied retrospectively. Thirteen deaths were respiratory related (12 percent of patients). All of the patients were quickly resuscitated with crystalloid solutions as necessary to restore perfusion to normal. Twenty-eight of the most severely injured patients, all of whom were intubated and ventilated and in whom serial PaO2 and total protein determinations were available, were examined for the relationship between crystalloid induced hemodilution as measured by the plasma colloid oncotic pressure and oxygenation as measured by the PaO2/FiO2 ratio. When survivors and nonsurvivors were analyzed by group, both individually and collectively, no correlation was found between oxygenation and oncotic pressure. Survivors and nonsurvivors exhibited similar post-traumatic courses in the PaO2/FiO2 ratios with differences not becoming significant until the eleventh day after injury. We conclude that contusion is not a progressive lesion unless pneumonia supervenes and that pulmonary dysfunction after contusion is unrelated to hemodilution. Blunt chest trauma is an important cause of morbidity and mortality in traumatized emergency patients. We report the case of a 74-year-old man who suffered a glenohumeral joint dislocation, trans trochanteric femur fracture, multiple rib fractures, diaphragmatic rupture with chest herniation of the spleen and stomach associated with herniation of the lung through an anterior chest wall defect after blunt trauma. Although immediate surgical repair was performed, he developed a delayed complication of multiple rib fracture in the form of large extrapleural hematoma that had to be surgically removed. Due to massive pulmonary contusion and prolonged pulmonary collapse, we used surfactant to facilitate alveolar opening after evacuation of the hematoma.\nHere is the question:\nCRITICAL CARE: 35-year-old man admitted for severe chest trauma with multiple rib fractures. After responding favorably to treatment with analgesics and oxygen, he begins to present severe hypoxemia. Indicate the most probable cause of this deterioration:\nHere are the potential choices:\n1. Chest wall instability due to multiple fractures.\n2. Aspiration respiratory infection.\n3. Alteration of gas exchange due to pulmonary contusion.\n4. Post-traumatic hypovolemia.\nThe correct answer is: ",
        "gold_answer": "3 Alteration of gas exchange due to pulmonary contusion.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Blunt chest trauma can cause severe acute pulmonary dysfunction due to hemo/pneumothorax, rib fractures and lung contusion. To study the long-term effects on lung function tests after patients' recovery from severe chest trauma. We investigated the outcome and lung function tests in 13 patients with severe blunt chest trauma and lung contusion. The study group comprised 9 men and 4 women with an average age of 44.6 +/- 13 years (median 45 years). Ten had been injured in motor vehicle accidents and 3 had fallen from a height. In addition to lung contusion most of them had fractures of more than three ribs and hemo/pneumothorax. Ten patients were treated with chest drains. Mean intensive care unit stay was 11 days (range 0-90) and mechanical ventilation 19 (0-60) days. Ten patients had other concomitant injuries. Mean forced expiratory volume in the first second was 81.2 +/- 15.3%, mean forced vital capacity was 85 +/- 13%, residual volume was 143 +/- 33.4%, total lung capacity was 101 +/- 14% and carbon monoxide diffusion capacity 87 +/- 24. Post-exercise oxygen saturation was normal in all patients (97 +/- 1.5%), and mean oxygen consumption max/kg was 18 +/- 4.3 ml/kg/min (60.2 +/- 15%). FEV1 was significantly lower among smokers (71.1 +/- 12.2 vs. 89.2 +/- 13.6%, P = 0.017). There was a non-significant tendency towards lower FEV1 among patients who underwent mechanical ventilation. Late after severe trauma involving lung contusion, substantial recovery was demonstrated with improved pulmonary function tests. These results encourage maximal intensive care in these patients. Further larger studies are required to investigate different factors affecting prognosis. We report the case of a 21-year-old man who developed adult respiratory distress syndrome (ARDS) after severe lung contusion due to a car accident. At the scene of the accident the patient was awake and oriented, but there were signs of hypoxaemia (SaO2 by pulse oximetry: 86%). The trachea was intubated in the emergency room and, after diagnosis of multiple rib fractures on the right side (the patient nos. 4-11) and emergency treatment, was extubated 16 h later. During spontaneous breathing there was no improvement of pulmonary function, and the patient was transferred to the intensive care unit 5 days later and reintubated because of acute respiratory failure. He then developed the signs of severe ARDS. No improvement occurred during conventional ventilatory treatment including inversed-ratio ventilation, high-frequency ventilation, and ventilation via a double-lumen tube. On day 15 a bovine surfactant preparation (38 mg/kg body wt.) was instilled into both lungs. Initially there was deterioration of the pulmonary function, probably due to crusts in the bronchial mucous membrane. After aspiration of the crusts at bronchoscopy, there was progressive respiratory improvement. The inspired oxygen concentration and PEEP level could be reduced, and the ventilatory ratio normalised within 14 days. This therapeutic intervention improved pulmonary function and probably led to the successful outcome after 36 days of ventilatory support. Venovenous extracorporeal membrane oxygenation (VV-ECMO) is indicated for patients with severe respiratory failure who cannot be managed with a ventilator. We report a case of severe chest trauma with an injury severity score of 66, in which hemostasis was achieved after VV-ECMO. A 29-year-old male patient sustained a fall injury from a 4-m cliff. The fall resulted in significant traumatic cerebral hemorrhage, bilateral pulmonary contusion, hemothorax, pelvic fracture, and limb fracture. During transcatheter arterial embolization, the patient continued to bleed from the left lung and showed progressive hypoxemia. In addition, the patient was unable to maintain tidal volume and experienced hypercapnia, and thus, VV-ECMO was introduced, followed by a thoracotomy to stop the bleeding. On the third day of hospitalization, the patient was weaned off VV-ECMO, and on day 35, he was transferred to a rehabilitation hospital for recovery. VV-ECMO may serve as a \"bridge\" until hemostatic maneuvers for severe chest trauma are completed and may contribute to help ensure adequate respiration. Massive pulmonary haemorrhage can spoil the entire lung and block the airway in a short period of time due to severe bleeding, which quickly leads to death. Alveolar lavage is an effective method for haemostasis and airway maintenance. However, patients often cannot tolerate alveolar lavage due to severe hypoxia. We used extracorporeal membrane oxygenation (ECMO) to overcome this limitation in a patient with massive pulmonary haemorrhage due to severe trauma and succeeded in saving the life by repeated alveolar lavage. A 22-year-old man sustained multiple injuries in a motor vehicle accident and was transferred to our emergency department. On admission, he had a slight cough and a small amount of bloody sputum; computed tomography revealed multiple fractures and mild pulmonary contusion. At 37 h after admission, he developed severe chest tightness, chest pain, dizziness and haemoptysis. His oxygen saturation was 68%. Emergency endotracheal intubation was performed, and a large amount of bloody sputum was suctioned. After transfer to the intensive care unit, he developed refractory hypoxemia and heparin-free venovenous ECMO was initiated. Fibreoptic bronchoscopy revealed diffuse and profuse blood in all bronchopulmonary segment. Bleeding was observed in the trachea and right bronchus, and repeated alveolar lavage was performed. On day 3, the patient's haemoptysis ceased, and ECMO support was terminated 10 d later. Tracheostomy was performed on day 15, and the patient was weaned from the ventilator on day 21. Alveolar lavage combined with ECMO can control bleeding in trauma-induced massive pulmonary haemorrhage, is safe and can be performed bedside. To evaluate the impact on morbidity and mortality of pulmonary contusion in multiple-trauma patients with severe head trauma. Matched-paired, case-control study ICU at a tertiary university hospital. During a 3-year period, 313 consecutive multiple-trauma patients with severe head trauma (Glasgow coma scale [GCS], &lt;/= 8) who were admitted to the ICU. Case-control matching criteria were as follows: (1) age difference within 5 years; (2) sex; (3) GCS in two categories; (4) similar pattern of injury; and (5) simplified acute physiology score II in five categories. A pulmonary contusion, defined by the clinical context and the result of a chest CT scan, was diagnosed in 90 patients. Analysis was performed on 90 pairs who were matched with 100% success. Ninety patients (29%) presented a diagnosis of pulmonary contusion. The presence of pulmonary contusion had an impact on the PaO(2)/fraction of inspired oxygen (FIO(2)) ratio, which was significantly reduced in patients with a pulmonary contusion. The ICU stay, the occurrence of complications such as nosocomial pneumonia or ARDS, the Glasgow outcome scale, and the mortality rate did not significantly differ between case patients and control subjects. Mortality also was not affected when patients were stratified according to the severity of the PaO(2)/FIO(2) ratio. In the study patients, pulmonary contusion alters gas exchange but does not appear to increase the morbidity and mortality of multiple-trauma patients with head trauma. A sample-size effect may limit the interpretation of the study. Polytrauma often results in significant hypoxemia secondary to direct lung contusion or indirectly through atelectasis, systemic inflammatory response, large volume fluid resuscitation and blood product transfusion. In addition to causing hypoxemia, atelectasis and acute lung injury can lead to right ventricular failure through an acute increase in pulmonary vascular resistance. Mechanical ventilation is often applied, accompanied with recruitment maneuvers and positive end-expiratory pressure in order to recruit alveoli and reverse atelectasis, while preventing excessive alveolar damage. This strategy should lead to the reversal of the hypoxemic condition and the detrimental heart-lung interaction that may occur. However, as described in this case report, hemodynamic instability and intractable alveolar atelectasis sometimes do not respond to conventional ventilation strategies. We describe the case of a 21-year-old Caucasian man with severe chest trauma requiring surgical interventions, who developed refractory hypoxemia and overt right ventricular failure. After multiple failed attempts of recruitment using conventional ventilation, the patient was ventilated with high-frequency oscillatory ventilation. This mode of ventilation allowed the reversal of the hemodynamic effects of severe hypoxemia and of the acute cor pulmonale. We use this case report to describe the physiological advantages of high-frequency oscillatory ventilation in patients with chest trauma, and formulate the arguments to explain the positive effect observed in our patient. High-frequency oscillatory ventilation can be used in the context of a blunt chest trauma accompanied by severe hypoxemia due to atelectasis. The positive effect is due to its capacity to recruit the collapsed alveoli and, as a result, the relief of increased pulmonary vascular resistance and subsequently the reversal of acute cor pulmonale. This approach may represent an alternative in case of failure of the conventional ventilation strategy. Ventilation and gas exchange lung functions were studied in 110 patients with severe closed chest trauma. In chest trauma that was not accompanied by intrapulmonary traumatic changes the main pathogenetic mechanism of gas exchange damage was marked pain syndrome. Such patients did not suffer from severe arterial hypoxemia and their intrapulmonary shunting did not exceed 15%. Analgesia and, if necessary, lung decompression improved considerably respiratory parameters and prevented the onset of severe pulmonary failure. Patients with intrapulmonary traumatic changes (lung contusion, intrapulmonary hematomas) were characterized by progressing arterial hypoxemia due to a considerable increase in intrapulmonary shunting. These patients are managed mainly by preventive therapy of pulmonary hyperhydration, thorough tracheobronchial cleansing, cough stimulation, prevention of pneumonia. A large amount of force is required to cause pulmonary contusion; a person injured with such force is likely to have other types of injuries as well. In fact, pulmonary contusion can be used to gauge the severity of trauma. Up to three quarters of cases are accompanied by other chest injuries, the most common of these being hemothorax and pneumothorax. Flail chest is usually associated with significant pulmonary contusion, and the contusion, rather than the chest wall injury, is often the main cause of respiratory failure in people with these injuries. Other indications of thoracic trauma may be associated, including fracture of the sternum and bruising of the chest wall. Over half of fractures of the scapula are associated with pulmonary contusion. The contusion is frequently found underlying fracture sites. When accompanied by a fracture, it is usually concentrated into a specific location—the contusion is more diffuse when there is no fracture. Pulmonary lacerations may Pulmonary contusion is found in 30–75% of severe cases of chest injury, making it the most common serious injury to occur in association with thoracic trauma. Of people who have multiple injuries with an injury severity score of over 15, pulmonary contusion occurs in about 17%. It is difficult to determine the death rate (mortality) because pulmonary contusion rarely occurs by itself. Usually, deaths of people with pulmonary contusion result from other injuries, commonly traumatic brain injury. It is controversial whether pulmonary contusion with flail chest is a major factor in mortality on its own or whether it merely contributes to mortality in people with multiple injuries. The estimated mortality rate of pulmonary contusion ranges from 14–40%, depending on the severity of the contusion itself and on associated injuries. When the contusions are small, they do not normally increase the chance of death or poor outcome for people with blunt chest trauma; however, these chances Signs and symptoms take time to develop, and as many as half of cases are asymptomatic at the initial presentation. The more severe the injury, the more quickly symptoms become apparent. In severe cases, symptoms may occur as quickly as three or four hours after the trauma. Hypoxemia (low oxygen concentration in the arterial blood) typically becomes progressively worse over 24–48 hours after injury. In general, pulmonary contusion tends to worsen slowly over a few days, but it may also cause rapid deterioration or death if untreated. Causes A protocol for treating thoracic trauma is proposed. Severe pulmonary lesion with increased venous admixture (e.g. contusio, atelectasis, aspiration) is treated by mechanical ventilation. Rib fractures with minor pulmonary lesion and therefore with only moderately abnormal gas exchange but with remarkably reduced vital capacity (even with flail chest) are controlled by thoracic epidural analgesia following vital capacity, tidal volume and respiratory rate. If both a severe pulmonary lesion and serial rib fractures are present, the patient is ventilated for 2-3 days and then extubated to breath spontaneously with epidural analgesia. The indication for a mechanical ventilation or for spontaneous breathing with thoracic epidural analgesia is therefore deducted more from functional variables than from morphological facts. The course of a consecutive series of 283 patients is presented. 155 patients were treated with primary ventilation and 112 patients with primary epidural analgesia, while 16 patients could be managed with general analgesia. The duration of treatment morbidity and mortality show this protocol to be very useful. Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a valuable treatment option for chest trauma individuals and some patients required surgery. A 35-year-old female patient with severe chest trauma was admitted to Affiliated Hospital of Zunyi Medical University on February 27, 2020. The patient was hospitalized with chest pain and dyspnea due to fall from a height. Emergency chest CT revealed a right fluid pneumothorax (60% of right lung compression), left hemothorax, little pericardial effusion, and multiple emphysemas in the lower neck, chest, back and mediastinum. Invasive ventilator was difficult to maintain oxygen saturation. After evaluation, the VV-ECMO was established, then, she received a thoracotomy. There was a 1.2 cm trachea rupture observed during operation, and the trachea was repaired. The operation lasted 4 hours with the continuous support of VV-ECMO. When the patient's haemodynamics and oxygenation was stable, ECMO was removed. Sixteen days later, the patient's chest CT showed that, the chest wall subcutaneous emphysema was reduced, and the exudative lesions of both lungs were absorbed, indicating that the patient was treated effectively and reached the discharge standard with no complication. During the treatment of this patient, VV-ECMO was applied rapidly and lasted for a short period, which provided the patient with the opportunity of emergency operation and finally the patient was fully recovered. VV-ECMO can provide support for patients with severe trauma and refractory hypoxemia. The severity ranges from mild to severe: small contusions may have little or no impact on health, yet pulmonary contusion is the most common type of potentially lethal chest trauma. It occurs in 30–75% of severe chest injuries. The risk of death following a pulmonary contusion is between 14–40%. Pulmonary contusion is usually accompanied by other injuries. Although associated injuries are often the cause of death, pulmonary contusion is thought to cause death directly in a quarter to half of cases. Children are at especially high risk for the injury because the relative flexibility of their bones prevents the chest wall from absorbing force from an impact, causing it to be transmitted instead to the lung. Pulmonary contusion is associated with complications including pneumonia and acute respiratory distress syndrome, and it can cause long-term respiratory disability. Classification Causes Pulmonary contusion is the most common injury found in blunt chest trauma, occurring in 25–35% of cases. It is usually caused by the rapid deceleration that results when the moving chest strikes a fixed object. About 70% of cases result from motor vehicle collisions, most often when the chest strikes the inside of the car. Falls, assaults, and sports injuries are other causes. Pulmonary contusion can also be caused by explosions; the organs most vulnerable to blast injuries are those that contain gas, such as the lungs. Blast lung is severe pulmonary contusion, bleeding, or edema with damage to alveoli and blood vessels, or a combination of these. This is the primary cause of death among people who initially survive an explosion. Unlike other mechanisms of injury in which pulmonary contusion is often found alongside other injuries, explosions can cause pulmonary contusion without damage to the chest wall. In the one-year prospective study 71 injured patients were observed (75% male and 25% female). Traffic traumatism was the dominant case (45%). The wounded are divided in the groups with one side fracture of ribs (left/right) and on both sides fracture of ribs considering the side of fracture, and there is consideration about the kind of fracture--there are single fracture of ribs and serial fracture of ribs. The samples of artery blood were followed in PaCO2, %SaO2 and level pH in three points of time: when the patients came, after 24 and after 48 hours. In the group with the both side fracture of the ribs, the fall of worth pH was observed after 48 hours, PaCO2 is increasing to the 6.98 kPa. PaO2 is falling after 48 hours. In %SaO2 there is no considerable difference at any time, but%SaO2 is the highest in the second group. With the serial fracture of ribs wounded are considerate the fall of worth pH which is progressively increasing and is the highest after 48 hours. PaCO2 is increasing in the both groups, but with the serial fracture the worth are considerably higher. PaO2 and %SaO2 are much lower after 48 hours. The authors conclude that the wounded on both sides and wounded with serial fracture along one or several lines of with fracture of all ribs suffer the highest respiratory insufficiency (ARI), so they need artificial ventilation as respiratory support. There are few reports in the literature regarding the use of venoarterial extracorporeal membrane oxygenation (ECMO) for double-dysfunction from both heart and lung contusions in polytrauma patients. This article reports a 48-year-old patient admitted after a traffic accident. He rapidly progressed to shock with low cardiac output due to myocardial contusion and refractory hypoxemia due to pulmonary contusion, an unstable chest wall and bilateral pneumothorax. ECMO was an effective rescue procedure in this dramatic situation and was successfully discontinued on the fourth day after the trauma. The patient also developed an extensive brain infarction and eventually died on the seventh day after admission.  A 53-year-old man was admitted to our trauma center after sustaining thoracoabdominal injuries, secondary to a rear-end motor vehicle collision. As he stepped out of his vehicle, he was struck by a tractor trailer at 55 mph. The following were the initial vital signs on his arrival: heart rate 140 beats/min, blood pressure 142/80 mm Hg, respiratory rate 28 breaths/min, temperature 36.8°C, and oxygen saturation 93%. The Glasgow Coma Scale score was 15 and the Injury Severity Score was 59. He was evaluated and resuscitated per the advanced trauma life support protocols. The focused assessment with sonography for trauma examination was negative. Initial findings included bilateral chest wall and thoracic spine tenderness, subcutaneous emphysema in the chest and neck, and an unstable pelvis. He required bilateral chest tubes and a pelvic binder. CT imaging revealed a left temporal epidural hematoma, multiple facial fractures, a sternal fracture, a left scapula fracture, acromioclavicular fractures, bilateral hemopneumothoraces, pulmonary contusions, extensive pneumomediastinum compressing the right atrium, multiple rib fractures (2-10 on the left with a flail segment and 2-8 on the right) (figure 1), an unstable open-book pelvic fracture which included bilateral superior and inferior pubic rami fractures, sacral and left iliac wing fractures, and symphysis pubis diastasis.Figure 1Three-dimensional CT scan reconstruction demonstrating left-sided flail chest.The patient developed hypotension and severe respiratory distress, and was intubated. ECG revealed no dysrhythmias. Echocardiogram revealed significant left ventricular wall dysfunction consistent with myocardial contusion and right atrial compression. His troponins were also significantly elevated. He required significant resuscitation with crystalloids, blood products and vasopressors. He underwent bronchoscopy, esophagram and upper endoscopy to exclude tracheoesophageal injury, and these were negative. On hospital day 2, the patient was hemodynamically stable, and pressors were discontinued. His pelvic fractures were repaired using external fixation and sacral screws. Given his extensive left flail chest, he underwent reconstruction of his left chest wall on hospital day 5. Open reduction and internal fixation of his left ribs, 3 to 6 anteriorly and 4 to 7 posteriorly, with titanium plates was performed (figure 2). He had an epidural catheter inserted for analgesia. On postoperative day 2 after chest wall reconstruction, the patient was extubated and resumed enteral feeds. Overnight, the output from the left-sided chest tube changed from serosanguinous to milky. A sample was sent for triglycerides and lymphocyte counts confirming the diagnosis of chylothorax. His chest tube output increased to approximately 2000 mL/day. A lymphangiogram was performed with Lipiodol to diagnose the location of the chylous leak. It revealed contrast extravasation at the level of T3 to T4. An MRI was also performed to better define the anatomic course of the thoracic duct.Figure 2Postoperative chest X-ray demonstrating left chest wall reconstruction. Conservative management: placing the patient nulla per os (NPO), and starting total parenteral nutrition (TPN), octreotide and midodrine.Thoracic duct embolization by interventional radiology.CT-guided thoracic duct disruption.Thoracotomy with thoracic duct ligation. Twenty-four patients with severe lung contusion and multiple rib fractures were studied at a mean 4.9 years (range 2-9 years) after injury. All patients had been in good health before the accident. After the accident 15 (63 per cent) patients had respiratory symptoms such as dyspnoea at rest or moderate exercise (4), pain (8), cough or increased expectoration (11) and frequent bronchopulmonary infections (5). Three patients had changed their job because of respiratory disturbance. The average vital capacity, forced expiratory volume in 1 s, maximal voluntary ventilation and CO transfer factor were reduced respectively to 87, 88, 82 and 83 per cent of predicted values (P less than 0.01), while total lung capacity, residual volume and helium mixing time showed no definite changes (P greater than 0.05). Arterial blood gases at rest and at maximum exercise showed slight changes only. Maximal working capacity and ECG, as well as the ventilatory cost of moderate exercise were normal, where as the CO2 recovery time after moderate exercise was slightly increased (P less than 0.05). Overall there was a tendency towards poorer function in patients treated with artificial ventilation. Chest radiographs were normal in 10 patients (42 per cent), and moderate changes were seen in 14 patients. Diaphragmatic movements were essentially normal in all patients. Severe injury to the chest causes frequent respiratory symptoms. However, objective tests were only moderately reduced when compared with normal values. There was no unequivocal association between the subjective symptoms and the pulmonary function. Multiple rib fractures with segmental chest wall instability are caused by high-energy chest trauma and are associated with significant morbidity and mortality. Flail chest injuries are mostly combined with lung injury (contusion, rupture, laceration) and subsequent pneumothorax or haemothorax. Early mechanical ventilation with internal pneumatic splinting is a conservative treatment for flail chest in patients with respiratory insufficiency. The surgical stabilisation of a flail chest is an effective method of treatment and is beneficial for selected patients. It shortens the duration of mechanical ventilation and thus reduces morbidity associated with prolonged ventilatory support. In addition, it decreases long-term pain and the inability of a flail chest to heal due to malunion, non-union or progressive collapse of the flail segment. Surgical stabilisation of a flail chest is indicated when the clinical examination shows progressive respiratory dysfunction confirmed by the results of multiple detector computer tomography (MDCT) of the thorax. Thirty-three consecutive patients who underwent surgical stabilisation of a flail chest at the Trauma Centre between 2010 and 2014 were retrospectively evaluated. This included patient demographics, chest injury extent, results of pre-operative chest imaging (MDCT), surgical stabilisation technique and post-operative outcome. In addition to providing a radiographic finding of respiratory failure, the result of MDCT chest examination was considered an important criterion for surgical intervention. Surgical stabilisation of the chest wall was performed at an interval ranging from 2 hours to 11 days after injury. Intra-thoracic procedures were indicated in patients with lung injury (pulmonary laceration). The surgical procedure was completed by chest tube placement. Surgical stabilisation was carried out using 3 to 8 plates for flail segment fixation involving 3 to 4 ribs. The duration of post- operative mechanical ventilation was 5 days on the average. It was longer in patients with associated injuries such as craniocerebral trauma or severe pulmonary contusion. Tracheostomy was performed in seven patients requiring prolonged mechanical ventilation. Two patients had superficial surgical site infection. No death was recorded in the follow-up period. Surgical stabilisation of the flail chest segment is considered an effective procedure in selected patients, leading to improvement of respiratory function. By allowing for a shorter period of time on mechanical ventilation, it reduces the occurrence of complications due to ventilatory support. The result of MDCT chest examination in patients with fail chest is an important indication criterion for surgical fixation. The body's response to the effects of mechanical injury, taking the form of shock during the first hours and the onset of fat embolism in the subsequent period, is substantially higher in patients with multiple or associated injuries, both as regards the severity of manifestations and prognostic risk. Also the death rate due to this sort of complication is seen rising. Two groups of injured persons with isolated (n = 33) and multiple fractures (n = 33) were used to show that dynamic follow-up of PaO2 in the blood could serve as a criterion of the risk of fat embolism development in the body and, in particular, as a prognostic criterion for the progress of fat embolism. Special point was made of findings demonstrating a time relationship between PaO2 deterioration in the early post-injury period (up to 24-36 hours) as compared with the period of 48-72 hours after the injury. PaO2 is seen dropping rapidly in injured persons showing signs of fat embolism syndrome development. The decrease can be recorded as early as the free interval phase, i.e. prior to the manifestation of the clinical signs of fat embolism. The findings of low PaO2 levels in the blood are in accordance with respiratory ventilation disturbances and impaired diffusion documented in our investigation. The stove-in chest is a rare form of flail chest in which there is collapse of a segment of the chest wall, associated with a high immediate mortality. A 65-year-old male pedestrian was admitted with severe chest pain and dyspnoea, after being struck by a car. The initial chest radiograph demonstrated multiple right-sided rib fractures and pulmonary contusion. His gas exchange was good, and after pain relief via an epidural catheter was achieved, an intercostal drain was inserted into the right hemi-thorax. Clinically apparent deformation of the chest then occurred. A further chest radiograph confirmed the stove-in chest. The patient remained well initially, but on day 5 he deteriorated precipitously with respiratory failure, and signs of systemic sepsis. He died despite maximal ventilatory and inotropic support on the Intensive Care Unit (ICU). Post-mortem examination demonstrated congested, oedematous lungs with a right-sided empyema. The management of complex flail chest injuries requires treatment to be tailored to the individual patient. Early ventilatory support, despite good gas exchange, may have closed down the pleural space prevented the empyema. Prophylactic ventilation and possibly surgical stabilisation of the chest wall should be considered early in the course of admission, even when the conventional parameters to indicate ventilation are not met. One hundred nine patients with the diagnosis of pulmonary contusion were studied retrospectively. Thirteen deaths were respiratory related (12 percent of patients). All of the patients were quickly resuscitated with crystalloid solutions as necessary to restore perfusion to normal. Twenty-eight of the most severely injured patients, all of whom were intubated and ventilated and in whom serial PaO2 and total protein determinations were available, were examined for the relationship between crystalloid induced hemodilution as measured by the plasma colloid oncotic pressure and oxygenation as measured by the PaO2/FiO2 ratio. When survivors and nonsurvivors were analyzed by group, both individually and collectively, no correlation was found between oxygenation and oncotic pressure. Survivors and nonsurvivors exhibited similar post-traumatic courses in the PaO2/FiO2 ratios with differences not becoming significant until the eleventh day after injury. We conclude that contusion is not a progressive lesion unless pneumonia supervenes and that pulmonary dysfunction after contusion is unrelated to hemodilution. Blunt chest trauma is an important cause of morbidity and mortality in traumatized emergency patients. We report the case of a 74-year-old man who suffered a glenohumeral joint dislocation, trans trochanteric femur fracture, multiple rib fractures, diaphragmatic rupture with chest herniation of the spleen and stomach associated with herniation of the lung through an anterior chest wall defect after blunt trauma. Although immediate surgical repair was performed, he developed a delayed complication of multiple rib fracture in the form of large extrapleural hematoma that had to be surgically removed. Due to massive pulmonary contusion and prolonged pulmonary collapse, we used surfactant to facilitate alveolar opening after evacuation of the hematoma.\nHere is the question:\nCRITICAL CARE: 35-year-old man admitted for severe chest trauma with multiple rib fractures. After responding favorably to treatment with analgesics and oxygen, he begins to present severe hypoxemia. Indicate the most probable cause of this deterioration:\nHere are the potential choices:\n1. Chest wall instability due to multiple fractures.\n2. Aspiration respiratory infection.\n3. Alteration of gas exchange due to pulmonary contusion.\n4. Post-traumatic hypovolemia.\nThe correct answer is: 3. Alteration of gas exchange due to pulmonary contusion."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n We investigated predictive value of albuminuria and estimated GFR (eGFR) for ESRD in Pima Indians with type 2 diabetes. Beginning in 1982, 2420 diabetic Pima Indians ≥18 years old were followed until they developed ESRD or died or until December 31, 2005. Individuals were classified at baseline by urinary albumin-to-creatinine ratio (ACR) and by eGFR, calculated by the Chronic Kidney Disease Epidemiology Collaboration equation. Predictors of ESRD and mortality were examined by proportional hazards regression. During a mean follow-up of 10.2 years, 287 individuals developed ESRD. Incidence of ESRD among individuals with macroalbuminuria (ACR ≥ 300 mg/g) was 9.3 times that of those with normoalbuminuria (ACR &lt; 30 mg/g), controlled for age, gender, and duration of diabetes. Incidence among individuals with eGFR 15 to 29 ml/min per 1.73 m(2) was 81.9 times that of those with eGFR 90 to 119 ml/min per 1.73 m(2). Models that combined albuminuria and eGFR added significant predictive information about risk of ESRD or death compared with models containing eGFR or albuminuria alone. The hazard ratio for ESRD associated with a 10-ml/min per 1.73 m(2) lower eGFR was 1.36, whereas that associated with an increase in albuminuria category was 2.69; corresponding hazard ratios for death were 1.15 and 1.37. These results suggest that incorporation of quantitative information about albuminuria into staging systems based on eGFR adds significant prognostic information about risk for diabetic ESRD and death. The 6 categories include: G1: GFR 90 ml/min per 1.73 m 2 and above G2: GFR 60 to 89 ml/min per 1.73 m 2 G3a: GFR 45 to 59 ml/min per 1.73 m 2 G3b: GFR 30 to 44 ml/min per 1.73 m 2 G4: GFR 15 to 29 ml/min per 1.73 m 2 G5: GFR less than 15 ml/min per 1.73 m 2 or treatment by dialysis The 3 levels of albuminuria include albumin-creatinine ratio (ACR): A1: ACR less than 30 mg/gm (less than 3.4 mg/mmol) A2: ACR 30 to 299 mg/gm (3.4 to 34 mg/mmol) A3: ACR greater than 300 mg/gm (greater than 34 mg/mmol) The 6 categories include: G1: GFR 90 ml/min per 1.73 m 2 and above G2: GFR 60 to 89 ml/min per 1.73 m 2 G3a: GFR 45 to 59 ml/min per 1.73 m 2 G3b: GFR 30 to 44 ml/min per 1.73 m 2 G4: GFR 15 to 29 ml/min per 1.73 m 2 G5: GFR less than 15 ml/min per 1.73 m 2 or treatment by dialysis The three levels of albuminuria include an albumin-creatinine ratio (ACR) A1: ACR less than 30 mg/gm (less than 3.4 mg/mmol) A2: ACR 30 to 299 mg/gm (3.4 to 34 mg/mmol) A3: ACR greater than 300 mg/gm (greater than 34 mg/mmol). The significance of estimated glomerular filtration rate (e-GFR) in diabetic nephropathy has yet to be clearly determined. We therefore compared albuminuria and e-GFR for usefulness in predicting progressive decline in renal function. A total of 1,303 subjects with type 2 diabetes mellitus whose e-GFR was more than 30 mL/min/1.73 m(2) were followed for three years. Associations of clinical staging based on AER and that based on e-GFR with progression of renal insufficiency (e-GFR &lt;30 mL/min/1.73 m(2)) were evaluated. On univariate analysis, both clinical stages based on e-GFR and AER were significant variables (p&lt;0.05). On multiple logistic regression analysis, the odds ratio for macroalbuminuria was 132.3, and that for microalbuminuria was 10.3 while that for e-GFR less than 60 mL/min/1.73 m(2) was 9.0 for further deterioration of renal function. On the other hand, subjects without albuminuria exhibited a rate of disease progression of less than 1% irrespective of e-GFR level. Both albuminuria and reduced e-GFR are significant and independent risk factors for further deterioration of diabetic nephropathy, though albuminuria had a greater odds ratio than reduced e-GFR for deterioration of renal function over a three-year period. e-GFR exhibited additive risk for deterioration of diabetic nephropathy within three years only when albuminuria was present. The sensitivity of albuminuria in predicting loss of kidney function has been questioned. We determined the sequence of kidney disease stages (microalbuminuria, macroalbuminuria, low estimated glomerular filtration rate [eGFR], and end-stage renal disease [ESRD]) and characterized those without albuminuria before a low eGFR. The Pittsburgh Epidemiology of Diabetes Complications Study is a prospective cohort investigation of childhood-onset type 1 diabetes. 480 study participants with eGFR greater than 60 mL/min/1.73 m(2) (mean age, 27 years; diabetes duration, 19 years at study entry) were prospectively followed up for 16 years. Low eGFR was defined as creatinine clearance less than 60 mL/min/1.73 m(2) from timed urine collections; microalbuminuria, as albumin excretion rate between 20 to 200 microg/min (30 to 300 mg/24 h); macroalbuminuria, as albumin excretion rate greater than 200 microg/min (&gt;300 mg/24 h); and ESRD, as dialysis or renal transplantation. The 33 of 480 individuals (7%) who developed ESRD had prior albuminuria. 71 of 480 (15%) individuals developed low eGFR. 66 of 71 (93%) had prior/concurrent albuminuria, and 5 of 71 (7%) did not. Incident low eGFR values in the 5 patients were: (1) 54, (2) 58, (3) 59, (4) 59.7, and (5) 59.8 mL/min/1.73 m(2). 3 of 5 (60%; patients 1, 4, and 5) subsequently developed albuminuria. Final eGFRs in the 5 patients were: (1) 94, (2) 86, (3) 60, (4) 65, and (5) 54 mL/min/1.73 m(2), respectively. GFR and insulin sensitivity were not measured, but estimated. Incident decreased eGFR in patients without preceding/concurrent albuminuria may be caused by misclassification or a temporary eGFR decrease. Moderately decreased eGFR may occur rarely in patients with type 1 diabetes without preceding albuminuria. Albuminuria is associated with an increased risk of death independent of level of renal function. Whether this association is similar for adults of all ages is not known. We examined the association between the albumin to creatinine ratio (ACR) and all-cause mortality after stratification by estimated glomerular filtration rate (eGFR) and age group in 94 934 veterans with diabetes mellitus. Cohort members had at least 1 ACR recorded in the Veterans Affairs Health Care System between October 1, 2002, and September 30, 2003, and were followed up for death through October 15, 2009. From the youngest to the oldest age group, the prevalence of an eGFR less than 60 mL/min/1.73 m(2) ranged from 11% to 41%; microalbuminuria (ACR 30-299 mg/g) ranged from 19% to 28%; and macroalbuminuria (ACR &gt; or =300 mg/g) ranged from 3.2% to 3.7%. Of patients with an eGFR less than 60 mL/min/1.73 m(2), 72% of those younger than 65 years, 74% of those 65 to 74 years old, and 59% of those 75 years and older had an eGFR of 45 to 59 mL/min/1.73 m(2). In all age groups, less than 35% of these patients had albuminuria (ie, ACR &gt; or =30 mg/g). In patients 75 years and older, the ACR was independently associated with an increased risk of death at all levels of eGFR after adjusting for potential confounders. In younger age groups, this association was present at higher levels of eGFR but seemed to be attenuated at lower levels [corrected]. The ACR is independently associated with mortality at all levels of eGFR in older adults with diabetes and may be particularly helpful for risk stratification in the large group with moderate reductions in eGFR. The first clinical manifestation of diabetic kidney disease is usually the development of microalbuminuria. However, recent studies have focused on diabetic patients with reduced glomerular filtration rate (GFR) without albuminuria. To evaluate the association of albuminuria and GFR with renal outcomes, we performed an observational study. A total of 3231 type 2 diabetic patients were included in this study between 2003 and 2005. There were 1249 women and the mean age was 59 ± 12 years. The renal endpoints were defined as the initiation of renal replacement therapy (RRT) or 50% reduction from the baseline of estimated GFR (eGFR). At baseline, 669 (20.7%) patients had eGFR &lt;60 mL/min per 1.73 m(2) and 1134 (35.1%) had albuminuria. During the mean follow-up period of 5.9 ± 1.6 years, 107 patients initiated RRT. A 50% reduction of eGFR from the baseline value was found in 279 patients. None of the normoalbuminuric subjects with or without reduced eGFR required RRT during the observational period (P &lt; 0.01). Compared to normoalbuminuria patients with eGFR ≥60 mL/min per 1.73 m(2) at baseline, the group of normoalbuminuria patients with reduced eGFR had a 2.5-fold risk of developing the renal endpoints, (95% confidence interval (CI): 1.0-6.3, P = 0.053). Patients with microalbuminuria with eGFR ≥60 mL/min per 1.73 m(2) at baseline had a 5.0-fold risk of developing the evaluated renal endpoints (95% CI: 2.8-8.8, P &lt; 0.001). Albuminuria was a significant predictor for the evaluated renal endpoints, but the impact of eGFR is likely to be less than that of albuminuria. The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g., proteinuria): 0) Normal kidney function – GFR above 90 mL/min/1.73 m2 and no proteinuria 1) CKD1 – GFR above 90 mL/min/1.73 m2 with evidence of kidney damage 2) CKD2 (mild) – GFR of 60 to 89 mL/min/1.73 m2 with evidence of kidney damage 3) CKD3 (moderate) – GFR of 30 to 59 mL/min/1.73 m2 4) CKD4 (severe) – GFR of 15 to 29 mL/min/1.73 m2 5) CKD5 kidney failure – GFR less than 15 mL/min/1.73 m2 Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis. Note: others add a \"T\" to patients who have had a transplant regardless of stage. Normal ranges The normal range of GFR, adjusted for body surface area, is 100–130 average 125 mL/min/1.73m2 in men and 90–120 ml/min/1.73m2 in women younger than the age of 40. In children, GFR measured by inulin clearance is 110 mL/min/1.73 m2 until 2 years of age in both sexes, and then it progressively decreases. After age 40, GFR decreases progressively with age, by 0.4–1.2 mL/min per year. Decreased GFR A decreased renal function can be caused by many types of kidney disease. Upon presentation of decreased renal function, it is recommended to perform a history and physical examination, as well as performing a renal ultrasound and a urinalysis. The most relevant items in the history are medications, edema, nocturia, gross hematuria, family history of kidney disease, diabetes and polyuria. The most important items in a physical examination are signs of vasculitis, lupus erythematosus, diabetes, endocarditis and hypertension. To elucidate the association of glomerular filtration rate (GFR) at baseline with subsequent progression of albuminuria in individuals with type 2 diabetes. This was a single-center retrospective cohort study of 6,618 Japanese adults with type 2 diabetes and urinary albumin-to-creatinine ratio of &lt;300 mg/g, comprising 2,459 women and 4,159 men with a mean (± SD) age of 60 ± 12 years. The exposure was baseline estimated GFR (eGFR) (mL/min/1.73 m2), treated as a categorical variable and classified into five categories: ≥90, 75-90, 60-75, 45-60, and &lt;45, as well as a continuous variable. The outcome was progression of albuminuria category (i.e., from normoalbuminuria to micro- or macroalbuminuria or from micro- to macroalbuminuria). Hazard ratios (HRs) for the outcome were estimated using the multivariable Cox proportional hazards model. In the analysis treating baseline eGFR as a continuous variable, the multivariable-adjusted restricted cubic spline model was used. During the median follow-up period of 6.3 years, 1,190 individuals reached the outcome. When those with a baseline eGFR of 75-90 mL/min/1.73 m2 were considered the reference group, HRs (95% CIs) for the outcome in those with a baseline eGFR of ≥90, 60-75, 45-60, or &lt;45 mL/min/1.73 m2 were 1.38 (1.14-1.66), 1.34 (1.14-1.58), 1.81 (1.50-2.20), or 2.37 (1.84-3.05), respectively. Furthermore, the inverse J-shaped curve was more clearly shown by the spline model. This study of Japanese adults with type 2 diabetes suggests that both high and low GFRs are implicated in the pathogenesis of albuminuria progression. Glomerular hyperfiltration may induce kidney damage. We asked whether glomerular filtration rate (GFR) is associated with subsequent development and progression of albuminuria in people with diabetes. This retrospective cohort study of 6,618 adults with type 2 diabetes has shown that both an estimated GFR (eGFR) ≥90 mL/min/1.73m2 and an eGFR &lt;75 mL/min/1.73m2 at baseline were risk factors for the subsequent category progression of albuminuria. This study suggests that both a high and low GFR are implicated in the pathogenesis of albuminuria development and progression in people with diabetes. Roxana Mehran score The Roxana Mehran score is a clinical prediction rule to estimate probability of nephropathy (increase ≥25% and/or ≥0.5 mg/dl in serum creatinine at 48 h): Risk Factors: Systolic blood pressure <80 mm Hg - 5 points (if systolic BP less than 80 mmHg for at least one hour requiring inotropic support) Intra-arterial balloon pump - 5 points Congestive heart failure, counting as NYHA class III (marked limitation in activity due to symptoms, even during less-than-ordinary activity) or worse, or history of pulmonary edema - 5 points Age >75 y - 4 points Hematocrit level <39% for men and <35% for women - 3 points Diabetes mellitus- 3 points Contrast media volume - 1 point for each 100 mL Decreased kidney function: Serum creatinine level >1.5 g/dL - 4 points or Estimated Glomerular filtration rate (online calculator) 2 for 40–60 mL/min/1.73 m2 4 for 20–40 mL/min/1.73 m2 6 for < 20 mL/min/1.73 m2 Although chronic kidney disease is a risk factor for cardiovascular disease it is unclear whether diabetic patients with a reduced glomerular filtration rate (GFR), independent of (micro)albuminuria, carry an increased risk of stroke. We therefore investigated the independent effect of estimated GFR (eGFR) on stroke events in patients with type 2 diabetes mellitus (T2DM). We studied T2DM patients with an eGFR &gt;or=15 ml min(-1) per 1.73 m(2), who had no history of stroke. Patients were divided into four categories by the eGFR at baseline for comparison: &gt;or=90, 60-89, 30-59 and 15-29 ml min(-1) per 1.73 m(2). The end point was an incident stroke event. The Cox proportional hazard model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI). The study included a total of 1300 T2DM patients (546 women and 754 men) with a mean (+/-s.d.) age of 63+/-13 years. During a mean follow-up period of 3.7+/-1.4 years, 91 patients experienced an incident stroke event. Although a lower eGFR was associated with an increased stroke risk using a univariate model, statistical significance disappeared after adjusting for other risk factors including albuminuria. The HR (95% CI) was 0.75 (0.40-1.41, P=0.373), 0.99 (0.50-1.95, P=0.964) and 0.91 (0.36-2.28, P=0.844) for patients with eGFRs of 60-89, 30-59 and 15-29 ml min(-1) per 1.73 m(2), respectively, compared with patients with an eGFR &gt;or=90. Clinical albuminuria remained a significant risk factor for stroke, and the adjusted HR compared with normoalbuminuria was 2.40 (1.46-3.95, P=0.001). In conclusion, the association between reduced GFR and stroke events in patients with T2DM is likely to be mediated by albuminuria. Serum creatinine is also utilized in GFR estimating equations such as the Modified Diet in Renal Disease (MDRD) and the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. These eGFR equations are superior to serum creatinine alone since they include race, age, and gender variables. GFR is classified into the following stages based on kidney disease. Kidney Disease Improving Global Outcomes (KDIGO) stages of chronic kidney disease (CKD): Stage 1 GFR greater than 90 ml/min/1.73 m² Stage 2 GFR-between 60 to 89 ml/min/1.73 m² Stage 3a  GFR 45 to 59 ml/min/1.73 m² Stage 3b GFR 30 to 44 ml/min/1.73 m² Stage 4 GFR of 15 to 29 ml/min/1.73 m² Stage 5-GFR less than 15 ml/min/1.73 m² (end-stage renal disease) Although much emphasis has been placed on screening for albuminuria in type II diabetic patients, less attention has been focused on the role of glomerular filtration rate (GFR) in the assessment of risk. Herein, we examined the association between GFR and vascular complications in a consecutive cohort of 5174 type II diabetic patients between 1995 and 2000. Renal function was assessed by GFR (estimated by Modification of Diet in Renal Disease equation). The frequency of chronic kidney disease (CKD) as defined by GFR &lt;60 ml/min/1.73 m(2), micro- and macrovascular complications, and their associations were analyzed. In this study cohort, 6% had serum creatinine &gt; or =150 micromol/l and 15.8% had CKD. After adjustment for potential confounders, including urinary albumin excretion, odds ratios [95% confidence interval (CI)] across different stages of estimated GFR (&gt; or =90, 60-89, 30-59, 15-29, &lt;15 ml/min/1.73 m(2)) for macrovascular disease were 1.00, 1.42 [1.12-1.80], 1.80 [1.32-2.45], 2.74 [1.64-4.56], and 4.05 [1.77-9.26], respectively (P for trend &lt;0.001); for retinopathy were 1.00, 1.23 [1.04-1.46], 1.80 [1.40-2.30], 2.05 [1.25-3.37], and 4.12 [1.56-10.90], respectively (P for trend &lt;0.001); for sensory neuropathy were 1.00, 1.53[1.27-1.85], 2.09 [1.58-2.76], 4.32 [2.41-7.77], and 3.16 [1.25-8.02], respectively (P for trend &lt;0.001); and for microalbumuria (with GFR &lt;15 ml/min/1.73 m(2) excluded from the analysis) were 1.00, 1.51 [1.30-1.75], 5.80 [4.52-7.44], and 52.5 [16.4-168.2] respectively (P for trend &lt;0.001). Measurement of serum creatinine alone without GFR may underestimate renal impairment in type II diabetic patients. Decreasing GFR was significantly associated with increasing frequency of micro- and macrovascular complications. There are several different techniques used to calculate or estimate the glomerular filtration rate (GFR or eGFR). The above formula only applies for GFR calculation when it is equal to the Clearance Rate. The normal range of GFR, adjusted for body surface area, is 100–130 average 125 (mL/min)/(1.73 m2) in men and 90–120 (mL/min)/(1.73 m2) in women younger than the age of 40. In children, GFR measured by inulin clearance is 110 (mL/min)/(1.73 m2) until 2 years of age in both sexes, and then it progressively decreases. After age 40, GFR decreases progressively with age, by 0.4–1.2 mL/min per year. Estimated GFR (eGFR) is now recommended by clinical practice guidelines and regulatory agencies for routine evaluation of GFR whereas measured GFR (mGFR) is recommended as a confirmatory test when more accurate assessment is required. Protein in the urine is regarded as an independent marker for worsening of kidney function and cardiovascular disease. Hence, British guidelines append the letter \"P\" to the stage of chronic kidney disease if protein loss is significant. Stage 1: Slightly diminished function; kidney damage with normal or relatively high GFR (≥90 ml/min/1.73 m2) and persistent albuminuria. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. Stage 2: Mild reduction in GFR (60–89 ml/min/1.73 m2) with kidney damage. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. Stage 3: Moderate reduction in GFR (30–59 ml/min/1.73 m2):. British guidelines distinguish between stage 3A (GFR 45–59) and stage 3B (GFR 30–44) for purposes of screening and referral. Evidence shows that apart from positive effects on glycemic levels, canagliflozin also reduces the risk of heart attacks and heart failures. SGLT2 inhibitors, including canagliflozin, reduce the likelihood of hospitalization for congestive heart failure or progression of renal disease in persons with diabetes mellitus type 2 and reduce the likelihood of stroke and heart attack in persons with diabetes mellitus type 2 who have known atherosclerotic vascular disease. Contraindications Canaglifozin is contraindicated in: Type 1 diabetes Diabetic ketoacidosis Severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2), end-stage renal disease Patients on dialysis The normal range of GFR, adjusted for body surface area, is 100–130 average 125 mL/min/1.73m2 in men and 90–120 mL/min/1.73m2 in women younger than the age of 40. In children, GFR measured by inulin clearance is 110 mL/min/1.73 m2 until 2 years of age in both sexes, and then it progressively decreases. After age 40, GFR decreases progressively with age, by 0.4–1.2 mL/min per year. Estimated GFR (eGFR) is now recommended by clinical practice guidelines and regulatory agencies for routine evaluation of GFR whereas measured GFR (mGFR) is recommended as a confirmatory test when more accurate assessment is required. To determine the renal and cardiovascular prognosis and all-cause mortality of Japanese patients with type 2 diabetes showing a reduced estimated glomerular filtration rate (eGFR) without albuminuria. A population of 675 patients with type 2 diabetes was prospectively observed for 4 years to determine the renal and cardiovascular outcomes and mortality. The subjects were divided into the four groups: those with a preserved eGFR and no albuminuria (n = 306), a preserved eGFR and albuminuria (n = 151), a reduced eGFR and no albuminuria (n = 96), and a reduced eGFR and albuminuria (n = 122). The Cox proportional hazard model and Fine and Gray method were used to assess between-group differences in the risk of mortality and cardiovascular events. In the group with a reduced eGFR, the eGFR value did not significantly change in the subjects without albuminuria (0 ± 8 mL/min/1.73 m<sup2</sup), whereas it decreased continuously in those with albuminuria (-6 ± 12 mL/min/1.73 m<sup2</sup). The incidence of cardiovascular events was significantly (P = 0.03) higher in the subjects with albuminuria (17%) than those without albuminuria (7%) in the group with a reduced eGFR. Cardiovascular events were significantly (P &lt; 0.01) more frequent in the group with a reduced eGFR than in those with a preserved eGFR in both subjects with and without albuminuria. The risk of end-stage kidney disease in non-albuminuric subjects with a reduced eGFR is considered to be low. We should focus on cardiovascular prognosis, because these patients are still at high risk of cardiovascular events, even though the prognosis is better in comparison to albuminuric patients.\nHere is the question:\nNEPHROLOGY: A 66-year-old woman with type 2 diabetes mellitus. When assessing her renal function, she presents a G3a/A1 stage. To which values does this stage correspond, the most frequent in patients with diabetic nephropathy?\nHere are the potential choices:\n1. Glomerular filtration rate 45-59 ml/min/1.73 m² and albuminuria <30 mg/ml.\n2. Glomerular filtration rate 30-44 ml/min/1.73 m² and albuminuria <30 mg/ml.\n3. Glomerular filtration rate 45-59 ml/min/1.73 m² and albuminuria 30-300 mg/ml.\n4. Glomerular filtration rate 15-29 ml/min/1.73 m² and albuminuria <30 mg/ml.\nThe correct answer is: ",
        "gold_answer": "1 Glomerular filtration rate 45-59 ml/min/1.73 m² and albuminuria <30 mg/ml.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n We investigated predictive value of albuminuria and estimated GFR (eGFR) for ESRD in Pima Indians with type 2 diabetes. Beginning in 1982, 2420 diabetic Pima Indians ≥18 years old were followed until they developed ESRD or died or until December 31, 2005. Individuals were classified at baseline by urinary albumin-to-creatinine ratio (ACR) and by eGFR, calculated by the Chronic Kidney Disease Epidemiology Collaboration equation. Predictors of ESRD and mortality were examined by proportional hazards regression. During a mean follow-up of 10.2 years, 287 individuals developed ESRD. Incidence of ESRD among individuals with macroalbuminuria (ACR ≥ 300 mg/g) was 9.3 times that of those with normoalbuminuria (ACR &lt; 30 mg/g), controlled for age, gender, and duration of diabetes. Incidence among individuals with eGFR 15 to 29 ml/min per 1.73 m(2) was 81.9 times that of those with eGFR 90 to 119 ml/min per 1.73 m(2). Models that combined albuminuria and eGFR added significant predictive information about risk of ESRD or death compared with models containing eGFR or albuminuria alone. The hazard ratio for ESRD associated with a 10-ml/min per 1.73 m(2) lower eGFR was 1.36, whereas that associated with an increase in albuminuria category was 2.69; corresponding hazard ratios for death were 1.15 and 1.37. These results suggest that incorporation of quantitative information about albuminuria into staging systems based on eGFR adds significant prognostic information about risk for diabetic ESRD and death. The 6 categories include: G1: GFR 90 ml/min per 1.73 m 2 and above G2: GFR 60 to 89 ml/min per 1.73 m 2 G3a: GFR 45 to 59 ml/min per 1.73 m 2 G3b: GFR 30 to 44 ml/min per 1.73 m 2 G4: GFR 15 to 29 ml/min per 1.73 m 2 G5: GFR less than 15 ml/min per 1.73 m 2 or treatment by dialysis The 3 levels of albuminuria include albumin-creatinine ratio (ACR): A1: ACR less than 30 mg/gm (less than 3.4 mg/mmol) A2: ACR 30 to 299 mg/gm (3.4 to 34 mg/mmol) A3: ACR greater than 300 mg/gm (greater than 34 mg/mmol) The 6 categories include: G1: GFR 90 ml/min per 1.73 m 2 and above G2: GFR 60 to 89 ml/min per 1.73 m 2 G3a: GFR 45 to 59 ml/min per 1.73 m 2 G3b: GFR 30 to 44 ml/min per 1.73 m 2 G4: GFR 15 to 29 ml/min per 1.73 m 2 G5: GFR less than 15 ml/min per 1.73 m 2 or treatment by dialysis The three levels of albuminuria include an albumin-creatinine ratio (ACR) A1: ACR less than 30 mg/gm (less than 3.4 mg/mmol) A2: ACR 30 to 299 mg/gm (3.4 to 34 mg/mmol) A3: ACR greater than 300 mg/gm (greater than 34 mg/mmol). The significance of estimated glomerular filtration rate (e-GFR) in diabetic nephropathy has yet to be clearly determined. We therefore compared albuminuria and e-GFR for usefulness in predicting progressive decline in renal function. A total of 1,303 subjects with type 2 diabetes mellitus whose e-GFR was more than 30 mL/min/1.73 m(2) were followed for three years. Associations of clinical staging based on AER and that based on e-GFR with progression of renal insufficiency (e-GFR &lt;30 mL/min/1.73 m(2)) were evaluated. On univariate analysis, both clinical stages based on e-GFR and AER were significant variables (p&lt;0.05). On multiple logistic regression analysis, the odds ratio for macroalbuminuria was 132.3, and that for microalbuminuria was 10.3 while that for e-GFR less than 60 mL/min/1.73 m(2) was 9.0 for further deterioration of renal function. On the other hand, subjects without albuminuria exhibited a rate of disease progression of less than 1% irrespective of e-GFR level. Both albuminuria and reduced e-GFR are significant and independent risk factors for further deterioration of diabetic nephropathy, though albuminuria had a greater odds ratio than reduced e-GFR for deterioration of renal function over a three-year period. e-GFR exhibited additive risk for deterioration of diabetic nephropathy within three years only when albuminuria was present. The sensitivity of albuminuria in predicting loss of kidney function has been questioned. We determined the sequence of kidney disease stages (microalbuminuria, macroalbuminuria, low estimated glomerular filtration rate [eGFR], and end-stage renal disease [ESRD]) and characterized those without albuminuria before a low eGFR. The Pittsburgh Epidemiology of Diabetes Complications Study is a prospective cohort investigation of childhood-onset type 1 diabetes. 480 study participants with eGFR greater than 60 mL/min/1.73 m(2) (mean age, 27 years; diabetes duration, 19 years at study entry) were prospectively followed up for 16 years. Low eGFR was defined as creatinine clearance less than 60 mL/min/1.73 m(2) from timed urine collections; microalbuminuria, as albumin excretion rate between 20 to 200 microg/min (30 to 300 mg/24 h); macroalbuminuria, as albumin excretion rate greater than 200 microg/min (&gt;300 mg/24 h); and ESRD, as dialysis or renal transplantation. The 33 of 480 individuals (7%) who developed ESRD had prior albuminuria. 71 of 480 (15%) individuals developed low eGFR. 66 of 71 (93%) had prior/concurrent albuminuria, and 5 of 71 (7%) did not. Incident low eGFR values in the 5 patients were: (1) 54, (2) 58, (3) 59, (4) 59.7, and (5) 59.8 mL/min/1.73 m(2). 3 of 5 (60%; patients 1, 4, and 5) subsequently developed albuminuria. Final eGFRs in the 5 patients were: (1) 94, (2) 86, (3) 60, (4) 65, and (5) 54 mL/min/1.73 m(2), respectively. GFR and insulin sensitivity were not measured, but estimated. Incident decreased eGFR in patients without preceding/concurrent albuminuria may be caused by misclassification or a temporary eGFR decrease. Moderately decreased eGFR may occur rarely in patients with type 1 diabetes without preceding albuminuria. Albuminuria is associated with an increased risk of death independent of level of renal function. Whether this association is similar for adults of all ages is not known. We examined the association between the albumin to creatinine ratio (ACR) and all-cause mortality after stratification by estimated glomerular filtration rate (eGFR) and age group in 94 934 veterans with diabetes mellitus. Cohort members had at least 1 ACR recorded in the Veterans Affairs Health Care System between October 1, 2002, and September 30, 2003, and were followed up for death through October 15, 2009. From the youngest to the oldest age group, the prevalence of an eGFR less than 60 mL/min/1.73 m(2) ranged from 11% to 41%; microalbuminuria (ACR 30-299 mg/g) ranged from 19% to 28%; and macroalbuminuria (ACR &gt; or =300 mg/g) ranged from 3.2% to 3.7%. Of patients with an eGFR less than 60 mL/min/1.73 m(2), 72% of those younger than 65 years, 74% of those 65 to 74 years old, and 59% of those 75 years and older had an eGFR of 45 to 59 mL/min/1.73 m(2). In all age groups, less than 35% of these patients had albuminuria (ie, ACR &gt; or =30 mg/g). In patients 75 years and older, the ACR was independently associated with an increased risk of death at all levels of eGFR after adjusting for potential confounders. In younger age groups, this association was present at higher levels of eGFR but seemed to be attenuated at lower levels [corrected]. The ACR is independently associated with mortality at all levels of eGFR in older adults with diabetes and may be particularly helpful for risk stratification in the large group with moderate reductions in eGFR. The first clinical manifestation of diabetic kidney disease is usually the development of microalbuminuria. However, recent studies have focused on diabetic patients with reduced glomerular filtration rate (GFR) without albuminuria. To evaluate the association of albuminuria and GFR with renal outcomes, we performed an observational study. A total of 3231 type 2 diabetic patients were included in this study between 2003 and 2005. There were 1249 women and the mean age was 59 ± 12 years. The renal endpoints were defined as the initiation of renal replacement therapy (RRT) or 50% reduction from the baseline of estimated GFR (eGFR). At baseline, 669 (20.7%) patients had eGFR &lt;60 mL/min per 1.73 m(2) and 1134 (35.1%) had albuminuria. During the mean follow-up period of 5.9 ± 1.6 years, 107 patients initiated RRT. A 50% reduction of eGFR from the baseline value was found in 279 patients. None of the normoalbuminuric subjects with or without reduced eGFR required RRT during the observational period (P &lt; 0.01). Compared to normoalbuminuria patients with eGFR ≥60 mL/min per 1.73 m(2) at baseline, the group of normoalbuminuria patients with reduced eGFR had a 2.5-fold risk of developing the renal endpoints, (95% confidence interval (CI): 1.0-6.3, P = 0.053). Patients with microalbuminuria with eGFR ≥60 mL/min per 1.73 m(2) at baseline had a 5.0-fold risk of developing the evaluated renal endpoints (95% CI: 2.8-8.8, P &lt; 0.001). Albuminuria was a significant predictor for the evaluated renal endpoints, but the impact of eGFR is likely to be less than that of albuminuria. The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g., proteinuria): 0) Normal kidney function – GFR above 90 mL/min/1.73 m2 and no proteinuria 1) CKD1 – GFR above 90 mL/min/1.73 m2 with evidence of kidney damage 2) CKD2 (mild) – GFR of 60 to 89 mL/min/1.73 m2 with evidence of kidney damage 3) CKD3 (moderate) – GFR of 30 to 59 mL/min/1.73 m2 4) CKD4 (severe) – GFR of 15 to 29 mL/min/1.73 m2 5) CKD5 kidney failure – GFR less than 15 mL/min/1.73 m2 Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis. Note: others add a \"T\" to patients who have had a transplant regardless of stage. Normal ranges The normal range of GFR, adjusted for body surface area, is 100–130 average 125 mL/min/1.73m2 in men and 90–120 ml/min/1.73m2 in women younger than the age of 40. In children, GFR measured by inulin clearance is 110 mL/min/1.73 m2 until 2 years of age in both sexes, and then it progressively decreases. After age 40, GFR decreases progressively with age, by 0.4–1.2 mL/min per year. Decreased GFR A decreased renal function can be caused by many types of kidney disease. Upon presentation of decreased renal function, it is recommended to perform a history and physical examination, as well as performing a renal ultrasound and a urinalysis. The most relevant items in the history are medications, edema, nocturia, gross hematuria, family history of kidney disease, diabetes and polyuria. The most important items in a physical examination are signs of vasculitis, lupus erythematosus, diabetes, endocarditis and hypertension. To elucidate the association of glomerular filtration rate (GFR) at baseline with subsequent progression of albuminuria in individuals with type 2 diabetes. This was a single-center retrospective cohort study of 6,618 Japanese adults with type 2 diabetes and urinary albumin-to-creatinine ratio of &lt;300 mg/g, comprising 2,459 women and 4,159 men with a mean (± SD) age of 60 ± 12 years. The exposure was baseline estimated GFR (eGFR) (mL/min/1.73 m2), treated as a categorical variable and classified into five categories: ≥90, 75-90, 60-75, 45-60, and &lt;45, as well as a continuous variable. The outcome was progression of albuminuria category (i.e., from normoalbuminuria to micro- or macroalbuminuria or from micro- to macroalbuminuria). Hazard ratios (HRs) for the outcome were estimated using the multivariable Cox proportional hazards model. In the analysis treating baseline eGFR as a continuous variable, the multivariable-adjusted restricted cubic spline model was used. During the median follow-up period of 6.3 years, 1,190 individuals reached the outcome. When those with a baseline eGFR of 75-90 mL/min/1.73 m2 were considered the reference group, HRs (95% CIs) for the outcome in those with a baseline eGFR of ≥90, 60-75, 45-60, or &lt;45 mL/min/1.73 m2 were 1.38 (1.14-1.66), 1.34 (1.14-1.58), 1.81 (1.50-2.20), or 2.37 (1.84-3.05), respectively. Furthermore, the inverse J-shaped curve was more clearly shown by the spline model. This study of Japanese adults with type 2 diabetes suggests that both high and low GFRs are implicated in the pathogenesis of albuminuria progression. Glomerular hyperfiltration may induce kidney damage. We asked whether glomerular filtration rate (GFR) is associated with subsequent development and progression of albuminuria in people with diabetes. This retrospective cohort study of 6,618 adults with type 2 diabetes has shown that both an estimated GFR (eGFR) ≥90 mL/min/1.73m2 and an eGFR &lt;75 mL/min/1.73m2 at baseline were risk factors for the subsequent category progression of albuminuria. This study suggests that both a high and low GFR are implicated in the pathogenesis of albuminuria development and progression in people with diabetes. Roxana Mehran score The Roxana Mehran score is a clinical prediction rule to estimate probability of nephropathy (increase ≥25% and/or ≥0.5 mg/dl in serum creatinine at 48 h): Risk Factors: Systolic blood pressure <80 mm Hg - 5 points (if systolic BP less than 80 mmHg for at least one hour requiring inotropic support) Intra-arterial balloon pump - 5 points Congestive heart failure, counting as NYHA class III (marked limitation in activity due to symptoms, even during less-than-ordinary activity) or worse, or history of pulmonary edema - 5 points Age >75 y - 4 points Hematocrit level <39% for men and <35% for women - 3 points Diabetes mellitus- 3 points Contrast media volume - 1 point for each 100 mL Decreased kidney function: Serum creatinine level >1.5 g/dL - 4 points or Estimated Glomerular filtration rate (online calculator) 2 for 40–60 mL/min/1.73 m2 4 for 20–40 mL/min/1.73 m2 6 for < 20 mL/min/1.73 m2 Although chronic kidney disease is a risk factor for cardiovascular disease it is unclear whether diabetic patients with a reduced glomerular filtration rate (GFR), independent of (micro)albuminuria, carry an increased risk of stroke. We therefore investigated the independent effect of estimated GFR (eGFR) on stroke events in patients with type 2 diabetes mellitus (T2DM). We studied T2DM patients with an eGFR &gt;or=15 ml min(-1) per 1.73 m(2), who had no history of stroke. Patients were divided into four categories by the eGFR at baseline for comparison: &gt;or=90, 60-89, 30-59 and 15-29 ml min(-1) per 1.73 m(2). The end point was an incident stroke event. The Cox proportional hazard model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI). The study included a total of 1300 T2DM patients (546 women and 754 men) with a mean (+/-s.d.) age of 63+/-13 years. During a mean follow-up period of 3.7+/-1.4 years, 91 patients experienced an incident stroke event. Although a lower eGFR was associated with an increased stroke risk using a univariate model, statistical significance disappeared after adjusting for other risk factors including albuminuria. The HR (95% CI) was 0.75 (0.40-1.41, P=0.373), 0.99 (0.50-1.95, P=0.964) and 0.91 (0.36-2.28, P=0.844) for patients with eGFRs of 60-89, 30-59 and 15-29 ml min(-1) per 1.73 m(2), respectively, compared with patients with an eGFR &gt;or=90. Clinical albuminuria remained a significant risk factor for stroke, and the adjusted HR compared with normoalbuminuria was 2.40 (1.46-3.95, P=0.001). In conclusion, the association between reduced GFR and stroke events in patients with T2DM is likely to be mediated by albuminuria. Serum creatinine is also utilized in GFR estimating equations such as the Modified Diet in Renal Disease (MDRD) and the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. These eGFR equations are superior to serum creatinine alone since they include race, age, and gender variables. GFR is classified into the following stages based on kidney disease. Kidney Disease Improving Global Outcomes (KDIGO) stages of chronic kidney disease (CKD): Stage 1 GFR greater than 90 ml/min/1.73 m² Stage 2 GFR-between 60 to 89 ml/min/1.73 m² Stage 3a  GFR 45 to 59 ml/min/1.73 m² Stage 3b GFR 30 to 44 ml/min/1.73 m² Stage 4 GFR of 15 to 29 ml/min/1.73 m² Stage 5-GFR less than 15 ml/min/1.73 m² (end-stage renal disease) Although much emphasis has been placed on screening for albuminuria in type II diabetic patients, less attention has been focused on the role of glomerular filtration rate (GFR) in the assessment of risk. Herein, we examined the association between GFR and vascular complications in a consecutive cohort of 5174 type II diabetic patients between 1995 and 2000. Renal function was assessed by GFR (estimated by Modification of Diet in Renal Disease equation). The frequency of chronic kidney disease (CKD) as defined by GFR &lt;60 ml/min/1.73 m(2), micro- and macrovascular complications, and their associations were analyzed. In this study cohort, 6% had serum creatinine &gt; or =150 micromol/l and 15.8% had CKD. After adjustment for potential confounders, including urinary albumin excretion, odds ratios [95% confidence interval (CI)] across different stages of estimated GFR (&gt; or =90, 60-89, 30-59, 15-29, &lt;15 ml/min/1.73 m(2)) for macrovascular disease were 1.00, 1.42 [1.12-1.80], 1.80 [1.32-2.45], 2.74 [1.64-4.56], and 4.05 [1.77-9.26], respectively (P for trend &lt;0.001); for retinopathy were 1.00, 1.23 [1.04-1.46], 1.80 [1.40-2.30], 2.05 [1.25-3.37], and 4.12 [1.56-10.90], respectively (P for trend &lt;0.001); for sensory neuropathy were 1.00, 1.53[1.27-1.85], 2.09 [1.58-2.76], 4.32 [2.41-7.77], and 3.16 [1.25-8.02], respectively (P for trend &lt;0.001); and for microalbumuria (with GFR &lt;15 ml/min/1.73 m(2) excluded from the analysis) were 1.00, 1.51 [1.30-1.75], 5.80 [4.52-7.44], and 52.5 [16.4-168.2] respectively (P for trend &lt;0.001). Measurement of serum creatinine alone without GFR may underestimate renal impairment in type II diabetic patients. Decreasing GFR was significantly associated with increasing frequency of micro- and macrovascular complications. There are several different techniques used to calculate or estimate the glomerular filtration rate (GFR or eGFR). The above formula only applies for GFR calculation when it is equal to the Clearance Rate. The normal range of GFR, adjusted for body surface area, is 100–130 average 125 (mL/min)/(1.73 m2) in men and 90–120 (mL/min)/(1.73 m2) in women younger than the age of 40. In children, GFR measured by inulin clearance is 110 (mL/min)/(1.73 m2) until 2 years of age in both sexes, and then it progressively decreases. After age 40, GFR decreases progressively with age, by 0.4–1.2 mL/min per year. Estimated GFR (eGFR) is now recommended by clinical practice guidelines and regulatory agencies for routine evaluation of GFR whereas measured GFR (mGFR) is recommended as a confirmatory test when more accurate assessment is required. Protein in the urine is regarded as an independent marker for worsening of kidney function and cardiovascular disease. Hence, British guidelines append the letter \"P\" to the stage of chronic kidney disease if protein loss is significant. Stage 1: Slightly diminished function; kidney damage with normal or relatively high GFR (≥90 ml/min/1.73 m2) and persistent albuminuria. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. Stage 2: Mild reduction in GFR (60–89 ml/min/1.73 m2) with kidney damage. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. Stage 3: Moderate reduction in GFR (30–59 ml/min/1.73 m2):. British guidelines distinguish between stage 3A (GFR 45–59) and stage 3B (GFR 30–44) for purposes of screening and referral. Evidence shows that apart from positive effects on glycemic levels, canagliflozin also reduces the risk of heart attacks and heart failures. SGLT2 inhibitors, including canagliflozin, reduce the likelihood of hospitalization for congestive heart failure or progression of renal disease in persons with diabetes mellitus type 2 and reduce the likelihood of stroke and heart attack in persons with diabetes mellitus type 2 who have known atherosclerotic vascular disease. Contraindications Canaglifozin is contraindicated in: Type 1 diabetes Diabetic ketoacidosis Severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2), end-stage renal disease Patients on dialysis The normal range of GFR, adjusted for body surface area, is 100–130 average 125 mL/min/1.73m2 in men and 90–120 mL/min/1.73m2 in women younger than the age of 40. In children, GFR measured by inulin clearance is 110 mL/min/1.73 m2 until 2 years of age in both sexes, and then it progressively decreases. After age 40, GFR decreases progressively with age, by 0.4–1.2 mL/min per year. Estimated GFR (eGFR) is now recommended by clinical practice guidelines and regulatory agencies for routine evaluation of GFR whereas measured GFR (mGFR) is recommended as a confirmatory test when more accurate assessment is required. To determine the renal and cardiovascular prognosis and all-cause mortality of Japanese patients with type 2 diabetes showing a reduced estimated glomerular filtration rate (eGFR) without albuminuria. A population of 675 patients with type 2 diabetes was prospectively observed for 4 years to determine the renal and cardiovascular outcomes and mortality. The subjects were divided into the four groups: those with a preserved eGFR and no albuminuria (n = 306), a preserved eGFR and albuminuria (n = 151), a reduced eGFR and no albuminuria (n = 96), and a reduced eGFR and albuminuria (n = 122). The Cox proportional hazard model and Fine and Gray method were used to assess between-group differences in the risk of mortality and cardiovascular events. In the group with a reduced eGFR, the eGFR value did not significantly change in the subjects without albuminuria (0 ± 8 mL/min/1.73 m<sup2</sup), whereas it decreased continuously in those with albuminuria (-6 ± 12 mL/min/1.73 m<sup2</sup). The incidence of cardiovascular events was significantly (P = 0.03) higher in the subjects with albuminuria (17%) than those without albuminuria (7%) in the group with a reduced eGFR. Cardiovascular events were significantly (P &lt; 0.01) more frequent in the group with a reduced eGFR than in those with a preserved eGFR in both subjects with and without albuminuria. The risk of end-stage kidney disease in non-albuminuric subjects with a reduced eGFR is considered to be low. We should focus on cardiovascular prognosis, because these patients are still at high risk of cardiovascular events, even though the prognosis is better in comparison to albuminuric patients.\nHere is the question:\nNEPHROLOGY: A 66-year-old woman with type 2 diabetes mellitus. When assessing her renal function, she presents a G3a/A1 stage. To which values does this stage correspond, the most frequent in patients with diabetic nephropathy?\nHere are the potential choices:\n1. Glomerular filtration rate 45-59 ml/min/1.73 m² and albuminuria <30 mg/ml.\n2. Glomerular filtration rate 30-44 ml/min/1.73 m² and albuminuria <30 mg/ml.\n3. Glomerular filtration rate 45-59 ml/min/1.73 m² and albuminuria 30-300 mg/ml.\n4. Glomerular filtration rate 15-29 ml/min/1.73 m² and albuminuria <30 mg/ml.\nThe correct answer is: 3. Glomerular filtration rate 45-59 ml/min/1.73 m² and albuminuria 30-300 mg/ml."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A total of 15 patients 1 to 16 years of age were treated for aplastic anemia (13 of a severe degree) and followed-up for a mean of 24 months (range 2 to 64 months). Six patients had an HLA-matched sibling and underwent allogeneic bone marrow transplantation. Nine patients who lacked a suitable donor were given immunosuppressive therapy. Antithymocyte globulin was the initial treatment for eight of these nine patients. Two patients who failed to respond to antithymocyte globulin were then treated with cyclosporine A. Pretreatment age, hematologic measurements, duration of follow-up, and interval prior to therapy were similar between the two groups. All of the patients receiving bone marrow transplants had a complete response and now have normal blood cell counts. Six of nine patients (67%) responded to antithymocyte globulin and are now transfusion free, although three have mild thrombocytopenia. Both patients given cyclosporine A had a good response and are also transfusion free. Patients who underwent marrow transplantation had a significantly shorter period of transfusion dependence for RBCs (9 v 4 weeks, P less than .005) and platelets (5 v 21 weeks, P less than .05). The patients given immunosuppressive therapy have significantly lesser platelet counts in follow-up but have similar values for both hemoglobin and absolute granulocyte counts. Although HLA-matched bone marrow transplantation leads to a faster and more complete recovery for children with aplastic anemia, immunosuppressive therapy can provide a good outcome for children with this disorder. Allogeneic bone marrow transplantation (BMT) is the treatment of choice in young patients (pts) with severe aplastic anemia (SAA) who have an HLA identical sibling donor. Late graft rejection to following allogeneic BMT for SAA is a significant clinical problem and is associated with a high risk of mortality. The optimal treatment strategy for patients with late graft rejection after first BMT is still an open question. We report 12-year-old patient with acquired SAA who underwent BMT from his HLA identical sister. BMT was first-line treatment within 3 months of diagnosis. Preparative therapy was Cyclophosphamide (Cy) 200 mg/kg body mass (BM) during 4 days. Graft versus host disease (GVHD) was prevented with Methotrexate (MTX), Methylprednisolone (MPDN) and Cyclosporin A (CsA). After 17 months, during which patient was with normal blood counts and full donor chimaerism, graft rejection occurred. The patient was re-engrafted from the same donor after conditioning with Cy 200 mg/kg BM plus horse antithymocyte globulin (ATG)--2 vials (á 25 mg)/10 kg BM over 4 days. Before the collection, donor's bone marrow was activated with low dose rhGM-CSF (3 micrograms/kg one day). Following a secondary BMT engraftment has sustained. The patient is alive with full donor chimaerism 26 months from secondary transplantation, without acute or chronic GVHD. Between 1998 and 2001, 31 (24 male, 7 female) patients with severe aplastic anemia (SAA) and a median age of 19 years (range, 4-39 years) received an allogeneic bone marrow transplantation. Marrow donors were genotypically HLA-identical siblings in 30 cases and a monozygous twin in one case. The median time from diagnosis to bone marrow transplantation was 1 month (range, 0.5-5 months). Conditioning regimen consisted of cyclophosphamide (CY) combined with antithymocyte globulin (ATG), in all patients. For graft-versus-host disease (GvHD) prophylaxis, all patients received methotrexate and cyclosporin. A total of 84% of patients had sustained grafts, whereas 16% rejected grafts between 3 and 20 months after transplantation. Of the five rejecting patients, three are alive with successful second engraftments and two died from infections. Acute grade II-IV GvHD was seen in only 11% of patients. A limited chronic GvHD was seen in one patient. With a median follow-up of 18 months (range, 5-42 months), survival rate was 86% and Karnofsky score was at least 90%. This study confirms the high success rate of the CY/ATG regimen in SAA allografted from an HLA-identical sibling. Early and late graft failure remains a problem and may require modification of this regimen. Severe aplastic anemia is a rare syndrome characterized by bone marrow failure with cytopenias and hypocellular bone marrow biopsy (usually 10-15%), without blasts or myelodysplasia. The first choice treatment for these patients is allogeneic bone marrow transplantation from a sibling matched for HLA-A, HLA-B and HLA-DR. Unfortunately only 30% of patients have an HLA-matched sibling (a 25% chance per sibling). The alternative treatment for severe aplastic anemia for the rest of the patients (70%) is immunosuppression with antithymocyte globuline and cyclosporine. The evolution of bone marrow transplantation since 1970's has been positive in terms of survival and transplant success (initial overall survival 43% vs. 90% lately, and graft rejection of 29% vs. 4%). The favorable outcome of bone marrow transplantation for severe or very severe aplastic anemia is due to: the use of conditioning with antithymocyte globuline and cyclophosphamide, the use of graft-vs.-host disease prophylaxis with short curse methotrexate and cyclosporine and the use of filtrated and irradiated blood products. For those patients without an HLA-matched related donor the first treatment to use is the immunosuppression with antithymocyte globuline and cyclosporine. Another option emerged in the late 80's is the unrelated bone marrow transplantation, with survival hardly half of the HLA-identical related bone marrow transplants. In our country, the first allogeneic bone marrow transplant was done in the Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, in a patient with aplastic anemia, making possible to perform this procedure safely in our country. Graft rejection has been a problem after marrow grafts for patients with aplastic anemia who were conditioned with cyclophosphamide (CY). Rejection lessened when patients were given the marrow donor's peripheral blood buffy-coat cells in addition to the marrow, but this result was achieved at the price of more chronic graft-versus-host disease (GVHD). Results with second transplants suggested that CY alternating with antithymocyte globulin (ATG) was more immunosuppressive than CY alone. Therefore, the current study explored CY and ATG without buffy-coat cell transfusions in 39 patients with aplastic anemia given marrow transplants from HLA-identical family members (siblings in 38 cases, father in 1 case). We hoped both to minimize the risks of graft rejection and of chronic GVHD and to improve survival. Patients were 2 to 52 years of age (median, 24.5); 87% had received previous transfusions, and 41% had therapy with immunosuppressive agents before transplant. They were administered four daily doses of CY (total, 200 mg/kg) alternating with three doses of ATG (total, 90 mg/kg) followed by an HLA-identical marrow graft. Methotrexate and cyclosporine were administered to prevent GVHD. Two patients rejected their grafts (5%), and both were successfully retransplanted. Acute (grade 2 or 3) GVHD occurred in 15% and chronic GVHD in 34% of patients. The actuarial survival rate at 3 years was 92%, which compares favorably to the 72% survival rate in 39 historical patients who were matched with current patients for age and risk factors for rejection and GVHD. CY/ATG is a well-tolerated and effective conditioning program for marrow grafting in aplastic anemia that, when combined with GVHD prevention by methotrexate/cyclosporine, results in excellent survival. Prior to the availability of specific treatment for aplastic anaemia (AA) with antithymocyte globulin (ATG) and cyclosporin or bone marrow transplantation (BMT), most patients died within 6 months of presentation, but the survival of patients with severe AA has improved dramatically over the last two decades and many patients now survive long term. Nevertheless, AA still remains a potentially life threatening disease. Because response to treatment with ATG and cyclosporin is delayed for two to three months and sometimes longer, patients usually need intensive transfusional support and careful attention to infection prophylaxis and treatment, particularly fungal infection. It is important to adopt a careful transfusional policy at diagnosis, in particular to help prevent HLA alloimmunisation which results in refractoriness to platelet transfusions, and sensitisation to minor histocompatibility antigens which is thought to mediate graft rejection between HLA identical siblings. The indications for immunosuppressive therapy or HLA identical sibling BMT are fairly clear, but transplantation from volunteer unrelated donors remains a highly controversial and high risk procedure in patients with AA. The effects of haemopoietic growth factors in AA patients have been perhaps not surprisingly disappointing, and not without significant toxicity, with the exception of granulocyte colony stimulating factor (G-CSF) which is well tolerated clinically. G-CSF may be useful in the treatment of severe resistant infections and it may be of benefit when used after treatment with ATG and cyclosporin.  Allogeneic hematopoietic stem cell transplantation is a curative modality for aplastic anemia; the preferred stem cell source is bone marrow. However, allogeneic peripheral blood stem cell transplantation (PBSCT) used in high-risk patients is associated with higher risk of chronic graft-versus-host disease (GVHD). Our center receives multitransfused, alloimmunized, infected, late referrals for transplant. Forty-one patients of median age 22 years (range 8-37) received allogeneic-PBSCT from human leukocyte antigen (HLA)-matched sibling donors. The median time since diagnosis was 12 months (range 4-65) and median pretransplant transfusions were 37 (range 6-160). Six patients were platelet refractory and one alloimmunized for pan-red blood cell (RBC) antigens. Several patients had pretransplant icterus or renal dysfunction and 26 (63.4%) had unresponsive bacterial/fungal infections. Our conditioning regimen included fludarabine 30 mg/m(2) for 6 days (days -10 to -5), cyclophosphamide 60 mg/kg/d for 2 days (days -6 to -5), and antithymocyte globulin (ATGAM) 30 mg/kg/d for 4 days (day -4 to -1), which was reduced to 2 days in 2 patients. We used standard GVHD prophylaxis with cyclosporine and methotrexate on days 1, 3, 6, 11. The median follow-up period was 29 months (range 6-78) and median engraftment time 10 days (range 8-17). Thirty-one patients (75.6%) were treated for infections, with 20 of these on antifungals for preexisting infections. There were two graft rejections and 10 (24.4%) deaths, with three intracranial hemorrhages, two rejections with infection, three cases of refractory GVHD (acute/overlap syndrome) with cytomegalovirus reactivation, and two invasive fungal infections. Overall incidence of acute GVHD was 39% with 2 grade IV cases. Ten (25%) cases developed chronic GVHD, with extensive GVHD in four. With more experience using shortened course of ATGAM, HLA-matched donor transfusions, and availability of newer antifungals, we have been able to decrease PBSCT-related mortality. Further improvement will be possible with early referrals. Bone marrow transplantations were performed on 15 patients (aged 5-39 years) with severe aplastic anaemia. Twelve patients are alive 76-1930 days (median 668 d) after transplantation, with complete haematopoetic recovery. Total-body radiation with 3.6 Gy in four patients, cyclosporin A administration to ten patients and buffy-coat transfusion to nine patients entirely prevented early rejection. Two patients died of pneumonia (aspergillus; varicella-zoster virus), one patient died of bleeding from a splenic-artery aneurysm. In patients under the age of 40 years with severe aplastic anaemia bone marrow transplantation as early as possible after diagnosis is the treatment of choice if HLA-identical siblings are available as donors. In patients over 40 years treatment should at first be tried with antithymocyte globulin. We are concerned about the inappropriate use of haemopoietic growth factors in patients with severe aplastic anaemia (SAA). The treatment of choice for this disorder is bone-marrow transplantation from an HLA-identical sibling donor if the patient is younger than 45 years, but it must be done soon after onset before the patient becomes sensitised by multiple red-cell and platelet transfusions. Other patients should receive immunosuppressive therapy with antithymocyte globulin alone or with cyclosporin or oxymetholone. Haemopoietic growth factors may have a role in stimulation of granulopoiesis after immunosuppressive therapy, but there is no evidence that they can correct the underlying stem-cell defect in SAA, and therefore no justification for their use alone in newly diagnosed SAA. Such treatment is harmful because it delays bone-marrow transplantation, or immunosuppressive therapy in older patients and those without suitable donors, thus reducing the chances of a successful outcome. Severe acquired aplastic anaemia is associated with high morbidity and mortality despite improvement in the results obtained both with bone marrow transplantation and with immunosuppressive treatment. Early bone marrow transplantation is the treatment of choice for patients under 45 years of age, if the neutrophil granulocyte count is less than 0.2-0.5 x 10(9)/l and an HLA-identical sibling donor is available. Other patients should receive primary immunosuppression with antithymocyte globulin, cyclosporin and glucocorticoid in combination with granulocyte colony-stimulating factor. If they fail to respond after three months, and a donor is available, such patients may be treated with bone marrow transplantation. However, transplantation with marrow from donors other than HLA-identical siblings is still at an experimental stage. For young adults and children who have a bone marrow donor who is a genotypic or phenotypic sibling match, bone marrow transplantation is now the preferred treatment for severe aplastic anemia. For those who lack such a matched donor, use of matched unrelated donors and family member donors who are mismatched for a single HLA antigen have been successful and appear to be the treatment of choice. Patients lacking either of these alternatives should receive antilymphocyte globulin, either alone or combined with cyclosporine as a first step. Although the success rate of marrow transplants in our series using mismatched family donors is similar to that following treatment with antilymphocyte globulin, several caveats must be kept in mind. First, the results reported with use of alternative donors must be confirmed with study of larger numbers of patients and longer follow-up. Second, the preparative regimen given prior to bone marrow transplantation destroys the patient's residual bone marrow, whereas antilymphocyte globulin cyclosporine A and androgens do not. The sequence of immunosuppression followed by transplantation with alternative donor marrow should produce greater long-term hematopoietic improvement. Unfortunately, when marrow transplant follows one or more courses of immunosuppressive therapy, nonengraftment is then a problem because of sensitization to blood cell antigens. It should also be kept in mind that studies done in children, especially in those younger than 6 years old, show that these patients respond better to transplantation than to treatment regimens not including marrow transplantation. Therefore, for the child with severe aplastic anemia, every effort should be made to identify a suitable bone marrow donor. Finally, we need to determine the specific components of the conditioning regimen and the constitution of the donor marrow necessary for engraftment and to minimize potential long-term complications, and there should be only a tolerable degree of graft-versus-host disease. Many of the transplant-related problems that plagued us in the 1970s have still not been fully resolved, but many have shown improvement. As we enter the 1990s, increasing the pool of marrow donors for patients with severe aplastic anemia who lack an HLA-matched sibling will continue to be a top priority for research. Treatment Treating immune-mediated aplastic anemia involves suppression of the immune system, an effect achieved by daily medicine or, in more severe cases, a bone marrow transplant, a potential cure. The transplanted bone marrow replaces the failing bone marrow cells with new ones from a matching donor. The multipotent stem cells in the bone marrow reconstitute all three blood cell lines, giving the patient a new immune system, red blood cells, and platelets. However, besides the risk of graft failure, there is also a risk that the newly created white blood cells may attack the rest of the body (\"graft-versus-host disease\"). In young patients with an HLA-matched sibling donor, bone marrow transplant can be considered as a first-line treatment. Patients lacking a matched sibling donor typically pursue immunosuppression as a first-line treatment, and matched, unrelated donor transplants are considered second-line therapy. To evaluate the results of 30 years of allogeneic HLA-identical bone marrow transplantation (BMT) as the treatment for children with acquired severe aplastic anaemia. Retrospective, descriptive. Of all patients who underwent an HLA-identical sibling-donor BMT for severe aplastic anaemia at the Department of Paediatrics, Leiden University Medical Center, in the period 1971-2000, and had a follow-up period of at least 1 year, the medical data were reviewed. The patients were split into 2 groups: patients transplanted before 1989 (n = 24), and patients who had their BMT from 1989 onwards (n = 20). This was due to a change in the treatment policy, namely a reduction in the period between diagnosis and BMT, resulting in fewer blood transfusions as well as changes in the prophylaxis against graft-versus-host disease (GvHD) from 1989 onwards (combination therapy using methotrexate and cyclosporin). There was an increase in the 1-year actuarial survival rate from 67% in the period before 1989 to 90% thereafter. The incidence of GvHD has significantly decreased since the introduction, in 1989, of the combination therapy using methotrexate and cyclosporin, with only 1/20 patients suffering from acute GvHD versus 13/24 prior to 1989 (p = 0.002). No patients acquired chronic GvHD after 1989, whereas before 1989, 10 patients had acquired this (p = 0.001). The prognosis of allogeneic HLA-identical sibling transplantation for paediatric patients with severe aplastic anaemia has considerably improved over the last 30 years due to improved supportive care, a significant decrease in GvHD and a shorter period between diagnosis and BMT, with the result that less blood transfusions have been required and less sensitisation has occurred. The long-term survival chance has increased to 90%. A 19-year-old male with therapy-related myelodysplastic syndrome underwent allogeneic bone marrow transplantation with reduced-intensity conditioning from his HLA-identical sibling whose ABO blood type exhibited major incompatibility with the patient. After post-transplantation 1 month, chimerism analysis of the bone marrow revealed mixed chimerism with 30% of recipient cells, and after post-transplantation 3 months, complete remission was maintained; however, recipient granulocytes were elevated up to 50% per the chimerism analysis. Next, pancytopenia developed following the rapid discontinuation of the immunosuppressive agent. Although neutrophils and platelets spontaneously recovered, anemia progressed. Based on severe erythroid hypoplasia in the bone marrow and the elevation of anti-ABO isohemagglutinin against donor-derived red blood cells, the patient was diagnosed with pure red cell aplasia (PRCA) following hematopoietic cell transplantation. Because complete chimerism was attained at the PRCA onset even for B cells, we decided to conservatively manage PRCA with only red blood cell transfusion. Notably, after 2 months of the PRCA onset, anemia improved. This case suggests that the therapeutic strategy for PRCA following hematopoietic cell transplantation should be determined by considering the status of each patient, including chimerism. Aplastic anemia is a bone marrow disease characterized by marrow aplasia and pancytopenia. Because hematopoietic stem cell transplantation (HSCT) cures severe aplastic anemia (SAA), it is the treatment of choice for younger patients. For many years, antithymocyte globulin (ATG) has been standard immunosuppressive therapy for those aplastic anemia patients that have no HLA matched related donor. ATG significantly improves aplastic anemia outcome, especially when combined with cyclosporine (CSP). The response rate varies from 40% to 70% and long-term survival is comparable with patients receiving marrow transplant. From 1983 until 2006, 46 SAA patients received HLA identical sibling marrow graft. In the same period, 50 patients received standard immunosuppressive therapy combined from horse or rabbit ATG, 6 methyl prednisolone and cyclosporine. Out of 46 transplant patients, 27 received a combination of cyclophosphamide and thoraco-abdominal irradiation. The overall probability of survival for SAA patients that underwent marrow grafting is 51%, and for patients receiving immunosuppressive treatment 20%. We analyzed a cohort of patients receiving treatment after 1990 and found the probability of survival to be 64% for bone marrow transplanted patients and 36% for patients receiving immunosuppression. Infection is the main cause of death in both groups. In conclusion, we documented improving results using ATG in patients with SAA. To evaluate a policy of immunosuppression with antithymocyte globulin (ATG) as primary therapy for adults with severe aplastic anemia (SAA) regardless of the availability of an HLA-identical bone marrow donor. Thirty-one consecutive adults with SAA who satisfied the age criteria for allogeneic bone marrow transplantation (BMT) (age less than 51 years) were treated with ATG 20 mg/kg/day for 10 days along with high-dose corticosteroids. Patients with an HLA-identical donor received a transplant if they did not respond to ATG or if they developed life-threatening complications during or soon after ATG administration. Eight patients with no response to ATG were also treated with oral cyclosporine 12.5 mg/kg/day. Eleven patients had a complete and five a partial response to ATG; two patients improved with cyclosporine treatment, resulting in an overall response rate of 58% to immunosuppression. Nine of 14 patients with donors received a BMT: seven because they did not respond to ATG and two because of serious infections. Seven grafts were obtained from related and two from unrelated donors. There was no significant difference in survival between those with and without a related HLA-identical donor (log-rank p value = 0.969). At a median follow-up of 58 months, 26 of 31 are alive with an actuarial survival of 80% at 5 years. Two patients died of infection, two died from complications of BMT, and one remains transfusion-dependent. One patient died of refractory leukemia at 30 months; one patient relapsed with hypoplasia 95 months after initial therapy with ATG. He showed a complete response to treatment with cyclosporine. No other late hematologic events have occurred. This treatment approach resulted in the restoration of hematopoiesis and independence from transfusion in 80% of patients with SAA entered into the study. The efficacy of allogeneic BMT in salvaging cases in which ATG failed does not appear to be compromised. Follow-up for the development of clonal hematologic disorders remains an important part of this treatment policy. From January 1978 to December 2001, 133 patients with severe aplastic anemia (SAA) underwent non-T cell-depleted allogeneic bone marrow transplantation from an HLA-identical sibling donor, at the Hospital Saint Louis using either the combination of cyclophosphamide (Cy) and thoracoabdominal irradiation (TAI; n=100) or Cy and antithymocyte globulin (ATG; n=33), as a conditioning regimen. With 13.6 years of follow-up, the 10-year survival estimate was 64%. Four factors were associated with lower survival: older age, use of Cy-TAI, any form of treatment prior to transplantation (either androgens or immunosuppressive therapy, [IST]), and grade II to IV acute graft-versus-host disease (GvHD). TAI was the sole factor associated with the occurrence of acute GvHD. The risk of cancers (15-year cumulative incidence, 10.9%) was associated with older age and with the use of cyclosporine as IST before transplantation. Cumulative incidences and risk factors of nonmalignant late effect including avascular osteonecrosis and late bacterial, viral, and fungal infection were also analyzed. Improved results using Cy-ATG as conditioning can lead to more than 90% chance of cure in patients with SAA. Even if, in our experience, the role of Cy-ATG versus that of Cy-TAI remained inextricably related to the year of transplantation, the major detrimental role of the GvHD disease in the long-term outcome and its relation to TAI supports avoidance of irradiation in the conditioning regimen. Furthermore, avoidance of any IST before transplantation in patients with a sibling donor is a prerequisite for attaining such excellent results. Graft rejection has been a problem after bone marrow transplantation for patients with severe aplastic anemia (SAA). Ten children with SAA were conditioned for bone marrow transplantation from HLA-identical siblings, using cyclophosphamide (CY, 50 mg/kg) plus antithymocyte globulin (ATG, 15 mg/kg) for 4 successive days. Marrow was infused 36 h after the last dose of CY. Cyclosporin A and methotrexate were administered as graft-versus-host disease (GVHD) prophylaxis. All patients achieved durable engraftment at follow-up of 7-41+ months (mean, 25) without significant GVHD. Since investigators have used different sources, doses, and time schedules of ATG, we compared our results with other published reports. We conclude that CY/ATG conditioning is well tolerated and effective in children with SAA. Treatments may include supportive care, drug therapy, and hematopoietic stem cell transplantation. Supportive care may include blood transfusions, medications to increase the making of red blood cells, and antibiotics. Drug therapy may include the medications lenalidomide, antithymocyte globulin, and azacitidine. Certain people can be cured with chemotherapy followed by a stem-cell transplant from a donor. About seven per 100,000 people are affected, with about four per 100,000 people newly acquiring the condition each year. The typical age of onset is 70 years. The outlook depends on the type of cells affected, the number of blasts in the bone marrow or blood, and the changes present in the chromosomes of the affected cells. The typical survival time following diagnosis is 2.5 years. The conditions were first recognized in the early 1900s. The current name came into use in 1976. Signs and symptoms One hundred patients with severe aplastic anemia were treated and evaluated in a prospective study at our hospital between January 1976 and October 1983. 28 patients had a HLA-identical sibling donor and were treated with bone marrow transplantation. 72 patients without a HLA-identical sibling donor were given antilymphocyte globulin followed by oral low dose androgen therapy. One and a half years to nine years after treatment 13 patients (46%) survive in the transplant group and 53 patients (74%) survive in the second group. All except one in the second group have self-sustaining hematopoiesis without need for transfusions. There is one major difference between the two therapies. Marrow transplantation restores bone marrow function completely and no late hematological complications have been seen in this group. The majority of patients treated with antilymphocyte globulin in contrast have residual abnormalities of hemopoiesis: macrocytosis, mild granulocytopenia and mild thrombocytopenia. Relapse (11 of 72 patients) and clonal hematological disorders, such as paroxysmal nocturnal hemoglobinuria (4 patients) and leukemia (one patient) can occur years after complete bone marrow reconstitution with antilymphocyte globulin. These late disorders are of concern. In spite of this we conclude that antilymphocyte globulin treatment is an effective therapy with low early mortality and morbidity and a high chance for a long sustained remission. Results are better or at least equivalent to bone marrow transplantation and patients with donors should be given the option of transplantation or antilymphocyte globulin.\nHere is the question:\nHEMATOLOGY: A 29-year-old patient comes to your office with a diagnosis of severe bone marrow aplasia. What is the treatment of choice?\nHere are the potential choices:\n1. Periodic transfusions and antibiotics.\n2. Androgens and platelet transfusions.\n3. Allogeneic bone marrow transplantation if HLA identical sibling.\n4. Autologous bone marrow transplantation to avoid rejection.\n5. Cyclosporin A and antithymocyte globulin.\nThe correct answer is: ",
        "gold_answer": "3 Allogeneic bone marrow transplantation if HLA identical sibling.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A total of 15 patients 1 to 16 years of age were treated for aplastic anemia (13 of a severe degree) and followed-up for a mean of 24 months (range 2 to 64 months). Six patients had an HLA-matched sibling and underwent allogeneic bone marrow transplantation. Nine patients who lacked a suitable donor were given immunosuppressive therapy. Antithymocyte globulin was the initial treatment for eight of these nine patients. Two patients who failed to respond to antithymocyte globulin were then treated with cyclosporine A. Pretreatment age, hematologic measurements, duration of follow-up, and interval prior to therapy were similar between the two groups. All of the patients receiving bone marrow transplants had a complete response and now have normal blood cell counts. Six of nine patients (67%) responded to antithymocyte globulin and are now transfusion free, although three have mild thrombocytopenia. Both patients given cyclosporine A had a good response and are also transfusion free. Patients who underwent marrow transplantation had a significantly shorter period of transfusion dependence for RBCs (9 v 4 weeks, P less than .005) and platelets (5 v 21 weeks, P less than .05). The patients given immunosuppressive therapy have significantly lesser platelet counts in follow-up but have similar values for both hemoglobin and absolute granulocyte counts. Although HLA-matched bone marrow transplantation leads to a faster and more complete recovery for children with aplastic anemia, immunosuppressive therapy can provide a good outcome for children with this disorder. Allogeneic bone marrow transplantation (BMT) is the treatment of choice in young patients (pts) with severe aplastic anemia (SAA) who have an HLA identical sibling donor. Late graft rejection to following allogeneic BMT for SAA is a significant clinical problem and is associated with a high risk of mortality. The optimal treatment strategy for patients with late graft rejection after first BMT is still an open question. We report 12-year-old patient with acquired SAA who underwent BMT from his HLA identical sister. BMT was first-line treatment within 3 months of diagnosis. Preparative therapy was Cyclophosphamide (Cy) 200 mg/kg body mass (BM) during 4 days. Graft versus host disease (GVHD) was prevented with Methotrexate (MTX), Methylprednisolone (MPDN) and Cyclosporin A (CsA). After 17 months, during which patient was with normal blood counts and full donor chimaerism, graft rejection occurred. The patient was re-engrafted from the same donor after conditioning with Cy 200 mg/kg BM plus horse antithymocyte globulin (ATG)--2 vials (á 25 mg)/10 kg BM over 4 days. Before the collection, donor's bone marrow was activated with low dose rhGM-CSF (3 micrograms/kg one day). Following a secondary BMT engraftment has sustained. The patient is alive with full donor chimaerism 26 months from secondary transplantation, without acute or chronic GVHD. Between 1998 and 2001, 31 (24 male, 7 female) patients with severe aplastic anemia (SAA) and a median age of 19 years (range, 4-39 years) received an allogeneic bone marrow transplantation. Marrow donors were genotypically HLA-identical siblings in 30 cases and a monozygous twin in one case. The median time from diagnosis to bone marrow transplantation was 1 month (range, 0.5-5 months). Conditioning regimen consisted of cyclophosphamide (CY) combined with antithymocyte globulin (ATG), in all patients. For graft-versus-host disease (GvHD) prophylaxis, all patients received methotrexate and cyclosporin. A total of 84% of patients had sustained grafts, whereas 16% rejected grafts between 3 and 20 months after transplantation. Of the five rejecting patients, three are alive with successful second engraftments and two died from infections. Acute grade II-IV GvHD was seen in only 11% of patients. A limited chronic GvHD was seen in one patient. With a median follow-up of 18 months (range, 5-42 months), survival rate was 86% and Karnofsky score was at least 90%. This study confirms the high success rate of the CY/ATG regimen in SAA allografted from an HLA-identical sibling. Early and late graft failure remains a problem and may require modification of this regimen. Severe aplastic anemia is a rare syndrome characterized by bone marrow failure with cytopenias and hypocellular bone marrow biopsy (usually 10-15%), without blasts or myelodysplasia. The first choice treatment for these patients is allogeneic bone marrow transplantation from a sibling matched for HLA-A, HLA-B and HLA-DR. Unfortunately only 30% of patients have an HLA-matched sibling (a 25% chance per sibling). The alternative treatment for severe aplastic anemia for the rest of the patients (70%) is immunosuppression with antithymocyte globuline and cyclosporine. The evolution of bone marrow transplantation since 1970's has been positive in terms of survival and transplant success (initial overall survival 43% vs. 90% lately, and graft rejection of 29% vs. 4%). The favorable outcome of bone marrow transplantation for severe or very severe aplastic anemia is due to: the use of conditioning with antithymocyte globuline and cyclophosphamide, the use of graft-vs.-host disease prophylaxis with short curse methotrexate and cyclosporine and the use of filtrated and irradiated blood products. For those patients without an HLA-matched related donor the first treatment to use is the immunosuppression with antithymocyte globuline and cyclosporine. Another option emerged in the late 80's is the unrelated bone marrow transplantation, with survival hardly half of the HLA-identical related bone marrow transplants. In our country, the first allogeneic bone marrow transplant was done in the Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, in a patient with aplastic anemia, making possible to perform this procedure safely in our country. Graft rejection has been a problem after marrow grafts for patients with aplastic anemia who were conditioned with cyclophosphamide (CY). Rejection lessened when patients were given the marrow donor's peripheral blood buffy-coat cells in addition to the marrow, but this result was achieved at the price of more chronic graft-versus-host disease (GVHD). Results with second transplants suggested that CY alternating with antithymocyte globulin (ATG) was more immunosuppressive than CY alone. Therefore, the current study explored CY and ATG without buffy-coat cell transfusions in 39 patients with aplastic anemia given marrow transplants from HLA-identical family members (siblings in 38 cases, father in 1 case). We hoped both to minimize the risks of graft rejection and of chronic GVHD and to improve survival. Patients were 2 to 52 years of age (median, 24.5); 87% had received previous transfusions, and 41% had therapy with immunosuppressive agents before transplant. They were administered four daily doses of CY (total, 200 mg/kg) alternating with three doses of ATG (total, 90 mg/kg) followed by an HLA-identical marrow graft. Methotrexate and cyclosporine were administered to prevent GVHD. Two patients rejected their grafts (5%), and both were successfully retransplanted. Acute (grade 2 or 3) GVHD occurred in 15% and chronic GVHD in 34% of patients. The actuarial survival rate at 3 years was 92%, which compares favorably to the 72% survival rate in 39 historical patients who were matched with current patients for age and risk factors for rejection and GVHD. CY/ATG is a well-tolerated and effective conditioning program for marrow grafting in aplastic anemia that, when combined with GVHD prevention by methotrexate/cyclosporine, results in excellent survival. Prior to the availability of specific treatment for aplastic anaemia (AA) with antithymocyte globulin (ATG) and cyclosporin or bone marrow transplantation (BMT), most patients died within 6 months of presentation, but the survival of patients with severe AA has improved dramatically over the last two decades and many patients now survive long term. Nevertheless, AA still remains a potentially life threatening disease. Because response to treatment with ATG and cyclosporin is delayed for two to three months and sometimes longer, patients usually need intensive transfusional support and careful attention to infection prophylaxis and treatment, particularly fungal infection. It is important to adopt a careful transfusional policy at diagnosis, in particular to help prevent HLA alloimmunisation which results in refractoriness to platelet transfusions, and sensitisation to minor histocompatibility antigens which is thought to mediate graft rejection between HLA identical siblings. The indications for immunosuppressive therapy or HLA identical sibling BMT are fairly clear, but transplantation from volunteer unrelated donors remains a highly controversial and high risk procedure in patients with AA. The effects of haemopoietic growth factors in AA patients have been perhaps not surprisingly disappointing, and not without significant toxicity, with the exception of granulocyte colony stimulating factor (G-CSF) which is well tolerated clinically. G-CSF may be useful in the treatment of severe resistant infections and it may be of benefit when used after treatment with ATG and cyclosporin.  Allogeneic hematopoietic stem cell transplantation is a curative modality for aplastic anemia; the preferred stem cell source is bone marrow. However, allogeneic peripheral blood stem cell transplantation (PBSCT) used in high-risk patients is associated with higher risk of chronic graft-versus-host disease (GVHD). Our center receives multitransfused, alloimmunized, infected, late referrals for transplant. Forty-one patients of median age 22 years (range 8-37) received allogeneic-PBSCT from human leukocyte antigen (HLA)-matched sibling donors. The median time since diagnosis was 12 months (range 4-65) and median pretransplant transfusions were 37 (range 6-160). Six patients were platelet refractory and one alloimmunized for pan-red blood cell (RBC) antigens. Several patients had pretransplant icterus or renal dysfunction and 26 (63.4%) had unresponsive bacterial/fungal infections. Our conditioning regimen included fludarabine 30 mg/m(2) for 6 days (days -10 to -5), cyclophosphamide 60 mg/kg/d for 2 days (days -6 to -5), and antithymocyte globulin (ATGAM) 30 mg/kg/d for 4 days (day -4 to -1), which was reduced to 2 days in 2 patients. We used standard GVHD prophylaxis with cyclosporine and methotrexate on days 1, 3, 6, 11. The median follow-up period was 29 months (range 6-78) and median engraftment time 10 days (range 8-17). Thirty-one patients (75.6%) were treated for infections, with 20 of these on antifungals for preexisting infections. There were two graft rejections and 10 (24.4%) deaths, with three intracranial hemorrhages, two rejections with infection, three cases of refractory GVHD (acute/overlap syndrome) with cytomegalovirus reactivation, and two invasive fungal infections. Overall incidence of acute GVHD was 39% with 2 grade IV cases. Ten (25%) cases developed chronic GVHD, with extensive GVHD in four. With more experience using shortened course of ATGAM, HLA-matched donor transfusions, and availability of newer antifungals, we have been able to decrease PBSCT-related mortality. Further improvement will be possible with early referrals. Bone marrow transplantations were performed on 15 patients (aged 5-39 years) with severe aplastic anaemia. Twelve patients are alive 76-1930 days (median 668 d) after transplantation, with complete haematopoetic recovery. Total-body radiation with 3.6 Gy in four patients, cyclosporin A administration to ten patients and buffy-coat transfusion to nine patients entirely prevented early rejection. Two patients died of pneumonia (aspergillus; varicella-zoster virus), one patient died of bleeding from a splenic-artery aneurysm. In patients under the age of 40 years with severe aplastic anaemia bone marrow transplantation as early as possible after diagnosis is the treatment of choice if HLA-identical siblings are available as donors. In patients over 40 years treatment should at first be tried with antithymocyte globulin. We are concerned about the inappropriate use of haemopoietic growth factors in patients with severe aplastic anaemia (SAA). The treatment of choice for this disorder is bone-marrow transplantation from an HLA-identical sibling donor if the patient is younger than 45 years, but it must be done soon after onset before the patient becomes sensitised by multiple red-cell and platelet transfusions. Other patients should receive immunosuppressive therapy with antithymocyte globulin alone or with cyclosporin or oxymetholone. Haemopoietic growth factors may have a role in stimulation of granulopoiesis after immunosuppressive therapy, but there is no evidence that they can correct the underlying stem-cell defect in SAA, and therefore no justification for their use alone in newly diagnosed SAA. Such treatment is harmful because it delays bone-marrow transplantation, or immunosuppressive therapy in older patients and those without suitable donors, thus reducing the chances of a successful outcome. Severe acquired aplastic anaemia is associated with high morbidity and mortality despite improvement in the results obtained both with bone marrow transplantation and with immunosuppressive treatment. Early bone marrow transplantation is the treatment of choice for patients under 45 years of age, if the neutrophil granulocyte count is less than 0.2-0.5 x 10(9)/l and an HLA-identical sibling donor is available. Other patients should receive primary immunosuppression with antithymocyte globulin, cyclosporin and glucocorticoid in combination with granulocyte colony-stimulating factor. If they fail to respond after three months, and a donor is available, such patients may be treated with bone marrow transplantation. However, transplantation with marrow from donors other than HLA-identical siblings is still at an experimental stage. For young adults and children who have a bone marrow donor who is a genotypic or phenotypic sibling match, bone marrow transplantation is now the preferred treatment for severe aplastic anemia. For those who lack such a matched donor, use of matched unrelated donors and family member donors who are mismatched for a single HLA antigen have been successful and appear to be the treatment of choice. Patients lacking either of these alternatives should receive antilymphocyte globulin, either alone or combined with cyclosporine as a first step. Although the success rate of marrow transplants in our series using mismatched family donors is similar to that following treatment with antilymphocyte globulin, several caveats must be kept in mind. First, the results reported with use of alternative donors must be confirmed with study of larger numbers of patients and longer follow-up. Second, the preparative regimen given prior to bone marrow transplantation destroys the patient's residual bone marrow, whereas antilymphocyte globulin cyclosporine A and androgens do not. The sequence of immunosuppression followed by transplantation with alternative donor marrow should produce greater long-term hematopoietic improvement. Unfortunately, when marrow transplant follows one or more courses of immunosuppressive therapy, nonengraftment is then a problem because of sensitization to blood cell antigens. It should also be kept in mind that studies done in children, especially in those younger than 6 years old, show that these patients respond better to transplantation than to treatment regimens not including marrow transplantation. Therefore, for the child with severe aplastic anemia, every effort should be made to identify a suitable bone marrow donor. Finally, we need to determine the specific components of the conditioning regimen and the constitution of the donor marrow necessary for engraftment and to minimize potential long-term complications, and there should be only a tolerable degree of graft-versus-host disease. Many of the transplant-related problems that plagued us in the 1970s have still not been fully resolved, but many have shown improvement. As we enter the 1990s, increasing the pool of marrow donors for patients with severe aplastic anemia who lack an HLA-matched sibling will continue to be a top priority for research. Treatment Treating immune-mediated aplastic anemia involves suppression of the immune system, an effect achieved by daily medicine or, in more severe cases, a bone marrow transplant, a potential cure. The transplanted bone marrow replaces the failing bone marrow cells with new ones from a matching donor. The multipotent stem cells in the bone marrow reconstitute all three blood cell lines, giving the patient a new immune system, red blood cells, and platelets. However, besides the risk of graft failure, there is also a risk that the newly created white blood cells may attack the rest of the body (\"graft-versus-host disease\"). In young patients with an HLA-matched sibling donor, bone marrow transplant can be considered as a first-line treatment. Patients lacking a matched sibling donor typically pursue immunosuppression as a first-line treatment, and matched, unrelated donor transplants are considered second-line therapy. To evaluate the results of 30 years of allogeneic HLA-identical bone marrow transplantation (BMT) as the treatment for children with acquired severe aplastic anaemia. Retrospective, descriptive. Of all patients who underwent an HLA-identical sibling-donor BMT for severe aplastic anaemia at the Department of Paediatrics, Leiden University Medical Center, in the period 1971-2000, and had a follow-up period of at least 1 year, the medical data were reviewed. The patients were split into 2 groups: patients transplanted before 1989 (n = 24), and patients who had their BMT from 1989 onwards (n = 20). This was due to a change in the treatment policy, namely a reduction in the period between diagnosis and BMT, resulting in fewer blood transfusions as well as changes in the prophylaxis against graft-versus-host disease (GvHD) from 1989 onwards (combination therapy using methotrexate and cyclosporin). There was an increase in the 1-year actuarial survival rate from 67% in the period before 1989 to 90% thereafter. The incidence of GvHD has significantly decreased since the introduction, in 1989, of the combination therapy using methotrexate and cyclosporin, with only 1/20 patients suffering from acute GvHD versus 13/24 prior to 1989 (p = 0.002). No patients acquired chronic GvHD after 1989, whereas before 1989, 10 patients had acquired this (p = 0.001). The prognosis of allogeneic HLA-identical sibling transplantation for paediatric patients with severe aplastic anaemia has considerably improved over the last 30 years due to improved supportive care, a significant decrease in GvHD and a shorter period between diagnosis and BMT, with the result that less blood transfusions have been required and less sensitisation has occurred. The long-term survival chance has increased to 90%. A 19-year-old male with therapy-related myelodysplastic syndrome underwent allogeneic bone marrow transplantation with reduced-intensity conditioning from his HLA-identical sibling whose ABO blood type exhibited major incompatibility with the patient. After post-transplantation 1 month, chimerism analysis of the bone marrow revealed mixed chimerism with 30% of recipient cells, and after post-transplantation 3 months, complete remission was maintained; however, recipient granulocytes were elevated up to 50% per the chimerism analysis. Next, pancytopenia developed following the rapid discontinuation of the immunosuppressive agent. Although neutrophils and platelets spontaneously recovered, anemia progressed. Based on severe erythroid hypoplasia in the bone marrow and the elevation of anti-ABO isohemagglutinin against donor-derived red blood cells, the patient was diagnosed with pure red cell aplasia (PRCA) following hematopoietic cell transplantation. Because complete chimerism was attained at the PRCA onset even for B cells, we decided to conservatively manage PRCA with only red blood cell transfusion. Notably, after 2 months of the PRCA onset, anemia improved. This case suggests that the therapeutic strategy for PRCA following hematopoietic cell transplantation should be determined by considering the status of each patient, including chimerism. Aplastic anemia is a bone marrow disease characterized by marrow aplasia and pancytopenia. Because hematopoietic stem cell transplantation (HSCT) cures severe aplastic anemia (SAA), it is the treatment of choice for younger patients. For many years, antithymocyte globulin (ATG) has been standard immunosuppressive therapy for those aplastic anemia patients that have no HLA matched related donor. ATG significantly improves aplastic anemia outcome, especially when combined with cyclosporine (CSP). The response rate varies from 40% to 70% and long-term survival is comparable with patients receiving marrow transplant. From 1983 until 2006, 46 SAA patients received HLA identical sibling marrow graft. In the same period, 50 patients received standard immunosuppressive therapy combined from horse or rabbit ATG, 6 methyl prednisolone and cyclosporine. Out of 46 transplant patients, 27 received a combination of cyclophosphamide and thoraco-abdominal irradiation. The overall probability of survival for SAA patients that underwent marrow grafting is 51%, and for patients receiving immunosuppressive treatment 20%. We analyzed a cohort of patients receiving treatment after 1990 and found the probability of survival to be 64% for bone marrow transplanted patients and 36% for patients receiving immunosuppression. Infection is the main cause of death in both groups. In conclusion, we documented improving results using ATG in patients with SAA. To evaluate a policy of immunosuppression with antithymocyte globulin (ATG) as primary therapy for adults with severe aplastic anemia (SAA) regardless of the availability of an HLA-identical bone marrow donor. Thirty-one consecutive adults with SAA who satisfied the age criteria for allogeneic bone marrow transplantation (BMT) (age less than 51 years) were treated with ATG 20 mg/kg/day for 10 days along with high-dose corticosteroids. Patients with an HLA-identical donor received a transplant if they did not respond to ATG or if they developed life-threatening complications during or soon after ATG administration. Eight patients with no response to ATG were also treated with oral cyclosporine 12.5 mg/kg/day. Eleven patients had a complete and five a partial response to ATG; two patients improved with cyclosporine treatment, resulting in an overall response rate of 58% to immunosuppression. Nine of 14 patients with donors received a BMT: seven because they did not respond to ATG and two because of serious infections. Seven grafts were obtained from related and two from unrelated donors. There was no significant difference in survival between those with and without a related HLA-identical donor (log-rank p value = 0.969). At a median follow-up of 58 months, 26 of 31 are alive with an actuarial survival of 80% at 5 years. Two patients died of infection, two died from complications of BMT, and one remains transfusion-dependent. One patient died of refractory leukemia at 30 months; one patient relapsed with hypoplasia 95 months after initial therapy with ATG. He showed a complete response to treatment with cyclosporine. No other late hematologic events have occurred. This treatment approach resulted in the restoration of hematopoiesis and independence from transfusion in 80% of patients with SAA entered into the study. The efficacy of allogeneic BMT in salvaging cases in which ATG failed does not appear to be compromised. Follow-up for the development of clonal hematologic disorders remains an important part of this treatment policy. From January 1978 to December 2001, 133 patients with severe aplastic anemia (SAA) underwent non-T cell-depleted allogeneic bone marrow transplantation from an HLA-identical sibling donor, at the Hospital Saint Louis using either the combination of cyclophosphamide (Cy) and thoracoabdominal irradiation (TAI; n=100) or Cy and antithymocyte globulin (ATG; n=33), as a conditioning regimen. With 13.6 years of follow-up, the 10-year survival estimate was 64%. Four factors were associated with lower survival: older age, use of Cy-TAI, any form of treatment prior to transplantation (either androgens or immunosuppressive therapy, [IST]), and grade II to IV acute graft-versus-host disease (GvHD). TAI was the sole factor associated with the occurrence of acute GvHD. The risk of cancers (15-year cumulative incidence, 10.9%) was associated with older age and with the use of cyclosporine as IST before transplantation. Cumulative incidences and risk factors of nonmalignant late effect including avascular osteonecrosis and late bacterial, viral, and fungal infection were also analyzed. Improved results using Cy-ATG as conditioning can lead to more than 90% chance of cure in patients with SAA. Even if, in our experience, the role of Cy-ATG versus that of Cy-TAI remained inextricably related to the year of transplantation, the major detrimental role of the GvHD disease in the long-term outcome and its relation to TAI supports avoidance of irradiation in the conditioning regimen. Furthermore, avoidance of any IST before transplantation in patients with a sibling donor is a prerequisite for attaining such excellent results. Graft rejection has been a problem after bone marrow transplantation for patients with severe aplastic anemia (SAA). Ten children with SAA were conditioned for bone marrow transplantation from HLA-identical siblings, using cyclophosphamide (CY, 50 mg/kg) plus antithymocyte globulin (ATG, 15 mg/kg) for 4 successive days. Marrow was infused 36 h after the last dose of CY. Cyclosporin A and methotrexate were administered as graft-versus-host disease (GVHD) prophylaxis. All patients achieved durable engraftment at follow-up of 7-41+ months (mean, 25) without significant GVHD. Since investigators have used different sources, doses, and time schedules of ATG, we compared our results with other published reports. We conclude that CY/ATG conditioning is well tolerated and effective in children with SAA. Treatments may include supportive care, drug therapy, and hematopoietic stem cell transplantation. Supportive care may include blood transfusions, medications to increase the making of red blood cells, and antibiotics. Drug therapy may include the medications lenalidomide, antithymocyte globulin, and azacitidine. Certain people can be cured with chemotherapy followed by a stem-cell transplant from a donor. About seven per 100,000 people are affected, with about four per 100,000 people newly acquiring the condition each year. The typical age of onset is 70 years. The outlook depends on the type of cells affected, the number of blasts in the bone marrow or blood, and the changes present in the chromosomes of the affected cells. The typical survival time following diagnosis is 2.5 years. The conditions were first recognized in the early 1900s. The current name came into use in 1976. Signs and symptoms One hundred patients with severe aplastic anemia were treated and evaluated in a prospective study at our hospital between January 1976 and October 1983. 28 patients had a HLA-identical sibling donor and were treated with bone marrow transplantation. 72 patients without a HLA-identical sibling donor were given antilymphocyte globulin followed by oral low dose androgen therapy. One and a half years to nine years after treatment 13 patients (46%) survive in the transplant group and 53 patients (74%) survive in the second group. All except one in the second group have self-sustaining hematopoiesis without need for transfusions. There is one major difference between the two therapies. Marrow transplantation restores bone marrow function completely and no late hematological complications have been seen in this group. The majority of patients treated with antilymphocyte globulin in contrast have residual abnormalities of hemopoiesis: macrocytosis, mild granulocytopenia and mild thrombocytopenia. Relapse (11 of 72 patients) and clonal hematological disorders, such as paroxysmal nocturnal hemoglobinuria (4 patients) and leukemia (one patient) can occur years after complete bone marrow reconstitution with antilymphocyte globulin. These late disorders are of concern. In spite of this we conclude that antilymphocyte globulin treatment is an effective therapy with low early mortality and morbidity and a high chance for a long sustained remission. Results are better or at least equivalent to bone marrow transplantation and patients with donors should be given the option of transplantation or antilymphocyte globulin.\nHere is the question:\nHEMATOLOGY: A 29-year-old patient comes to your office with a diagnosis of severe bone marrow aplasia. What is the treatment of choice?\nHere are the potential choices:\n1. Periodic transfusions and antibiotics.\n2. Androgens and platelet transfusions.\n3. Allogeneic bone marrow transplantation if HLA identical sibling.\n4. Autologous bone marrow transplantation to avoid rejection.\n5. Cyclosporin A and antithymocyte globulin.\nThe correct answer is: 3. Allogeneic bone marrow transplantation if HLA identical sibling."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Neurovascular integrity should similarly be monitored frequently and in a scheduled manner. Capillary refilling time, Doppler signals, pulse oximetry, and sensation distal to the burned area should be checked every hour. Limb deep compartment pressures should be checked initially to establish a baseline. Subsequently, any increase in capillary refill time, decrease in Doppler signal, or change in sensation should lead to rechecking the compartment pressures. Compartment pressures greater than 30 mm Hg should be treated by immediate decompression via escharotomy and fasciotomy, if needed. explored to evaluate for bleeding points. One must be very cautious if attempting to ligate these to ensure that adjacent structures such as nerves are not included in the ligature.The hand must be evaluated for adequacy of perfusion to the hand as a whole as well as the individual digits. Capillary refill, turgor, Doppler signal, and bleeding to pinprick all pro-vide useful information regarding vascular status. The finger or hand with vascular compromise requires urgent operative explo-ration. Unlike the complete amputation, in which the amputated part can be cold preserved (see later section, “Amputation and Replantation”), devascularization without amputation produces warm ischemia, which is tolerated only for a matter of hours.For the noncritical vascular injury, two treatment options exist. Simple ligation will control hemorrhage. At least one of the palmar arterial arches is intact in 97% of patients, so this will usually not compromise hand perfusion.5 Each digit also has two A Doppler ultrasound blood flow detector, commonly called Doppler wand or Doppler probe, and a sphygmomanometer (blood pressure cuff) are usually needed. The blood pressure cuff is inflated proximal to the artery in question. Measured by the Doppler wand, the inflation continues until the pulse in the artery ceases. The blood pressure cuff is then slowly deflated. When the artery's pulse is re-detected through the Doppler probe the pressure in the cuff at that moment indicates the systolic pressure of that artery. The higher systolic reading of the left and right arm brachial artery is generally used in the assessment. The pressures in each foot's posterior tibial artery and dorsalis pedis artery are measured with the higher of the two values used as the ABI for that leg. Where PLeg is the systolic blood pressure of dorsalis pedis or posterior tibial arteries and PArm is the highest of the left and right arm brachial systolic blood pressure Compartment syndrome is a serious complication of high voltage electrical burns, limb carbonization and deep circular burns with delayed escharotomy. Without treatment, ischemic tissue damage leads to irreversible necrosis. Treatment is emergency surgical decompression. The burned patient is usually not searchable and cannot always be readily examined because of bulky dressings; diagnosis of compartment syndrome is always hard to make. The pressure transducer used in central arterial catheters is easy available. We used it to measure pressure in muscular compartments. We measured compartment pressure three times at different depths in all cases of electrical burn, carbonization and deep circumferential burns with delayed escharotomy. We also took the pressure in the uninjured limb. The pressure assessment device was composed of a blood pressure transducer commonly used in arterial catheters for arterial pressure monitoring with three connecting branches. The first branch was connected to the 'arterial pressure exit' in the monitoring device. The second, an IV tube, was connected to one litre of physiological serum in a pressure bag inflated to 200 mmHg. The third, also an IV tube with a sterile extension cable, was directly connected to an 18G standard straight needle to be inserted in the tissues for which interstitial pressure had to be measured. In patients with thermal burns, we measured pressure before and after escharotomy. Threshold intracompartmental pressure was 35 mmHg. We carried out pressure assessment of all muscular compartments during and at the end of surgery. The pressure transducer provides a pressure value in all muscular compartments with a time of installation and measuring of less than 5 minutes. Sensitivity is measured at +/- 1 mmHg. Operation is simple, non-operator dependent, and accessible to medical and paramedic teams. The pressure transducer allows accurate diagnosis of early or established compartment syndrome. It requires no additional equipment and its application does not delay therapeutic management. Its use helps with fasciotomy decision, especially after escharotomy, guides the surgeon in the exploration of different compartments and verifies the effectiveness of surgery. A study was made of the course of ischemia and hemodynamic disorders in 53 patients with occlusion of the distal arterial system of the upper extremities. Circulation was examined by ultrasound Doppler, tetrapolar rheology, transcutaneous oxymetry and angiography. Critical ischemia was discovered in 58.5% of patients. In occlusion of one of the forearm arteries, extremity circulation was made for. Circulatory decompensation was recorded in occlusion of both forearm arteries with intact distal bed and non-functioning palmar arches of the hand as well as in lesions of hand and finger arteries. All 53 patients were operated on, 66 operations were accomplished using magnifying optic appliances. Provided the distal bed was well preserved, use was made of direct revascularization techniques (36) whereas non-standard methods were employed in the event of its obliteration: arterialization of the outlets of the subcutaneous veins of the hand and autotransplantation of the greater omentum (30). Beneficial results were obtained in 91.5% and unsatisfactory in 8.5% of patients. The lethality accounted for 1.2% while the incidence of amputations was quoted as 5.7%. Good results offer the period as long as 5 years were well preserved in 87.6% of patients. Our experience indicates the efficacy of the use of revascularization techniques for the treatment of different versions of occlusion of the distal segments of upper extremity arteries. Thorocostomy and pericardiocentesis to relieve pneumothorax and pericardial tamponade Intravenous (IV) and intraosseous (IO) cannulation Oxygen administration and positive pressure ventilation via bag-valve-mask, CPAP device, or ventilator Fluid resuscitation Administration of emergency drugs/medications (see section below) Bleeding control and management of shock Spinal injury management, including immobilization and safe transport Fracture management, including assessment, splinting, and dislocation reduction Obstetrics, including assessment, childbirth, and recognition of and procedures for obstetrical emergencies such as breech presentation, cord presentation, and placental abruption Management of burns, including classification, estimate of surface area, recognition of more serious burns, and treatment Triage of patients in a mass casualty incident Surgical procedures such as field amputation, escharotomy, or thorocotomy (if trained and credentialed) In order to decrease the number of amputations for \"diabetic foot\", these patients should undergo elective or delayed operations. It is obligatory before the operation to correct carbohydrate metabolism and hemodynamics. Sodium succinate in combination with conventional angioprotective treatment is used for this purpose. Microcirculation is evaluated using oxymonitor ISM-2 and tetrapolar rheography. Blood flow disturbances are evaluated according to ultrasound dopplerography data. Operations are performed with the use of a primary or delayed suture at the definite level of the extremity where oxygen tension of the skin is not lower than 33 mm Hg, and the index of minute blood flow--not lower than 1.8 ml/min per 100 cm3 of the tissue. When operating on the foot it is obligatory to leave loose excessive brims of tissues to facilitate the placement of broad-grip sutures without tension. It is advisable to use through flowing--aspiration drainage and to perform surgical treatment of the deep phlegmon of the foot through club-shaped approach. In order to evaluate the epidemiology and functional results of hand burns in young children, 92 consecutive patients (126 hand burns) under age 5 years admitted to a Burn Center were reviewed. Scald burns (49 per cent) were most common, followed by flame (34 per cent), contact (14 per cent) and electrical burns (3 per cent). The child was left unattended by an adult in 53 per cent of cases and documented abuse was present in 6 per cent. The mean total body surface area (TBSA) burned was 17 per cent, and 77 patients (85 per cent) had additional burns in other areas (arms 34 per cent, legs 31 per cent, chest 29 per cent and face 27 per cent). Palmar burns occurred in 24 hands (19 per cent), dorsal in 41 (33 per cent), while both surfaces were burned in 61 (48 per cent). Joints involved included the MP in 96 (76 per cent), PIP in 87 (69 per cent) and DIP in 80 (63 per cent). The depth was superficial partial thickness in 53 (47 per cent), deep partial in 55 (44 per cent), and full thickness in 18 hands (14 per cent); a total of 29 hands were grafted (15 deep partial and 14 full thickness). Escharotomies were required in 12 hands (9 per cent) (9 flame and 3 scald) and partial amputation of digits was required in 3 (2 per cent). Follow-up was available in 46 hands from 7 to 120 months (mean 39 months). Partial thickness burns (34) healed with normal (32) or near-normal (2) hand function and developmental delay occurred in one patient.(ABSTRACT TRUNCATED AT 250 WORDS) To examine the state of regional circulation in replanted segment of upper limb and hand, to determine diagnostic and prognostic value of radionuclide scintigraphy. The study included 26 patients who underwent replantation of upper extremity segments. The control group included 12 patients who underwent autologous transplantation of toes on hand. All patients underwent isotope scintigraphy, ultrasound Doppler and pulse oximetry. Groups were comparable by gender, age, severity of injury. Depending on postoperative course two groups were determined: with favorable (27 patients) and complicated postoperative period (11 patients). Two types of regional circulation were identified according to dynamic scintigraphy: prevalence of blood flow in operated limb (type 1); prevalence of blood flow in healthy limb, or equal volumetric blood flow in operated and healthy limbs (type 2). Favorable early postoperative period was associated with prevalence of blood flow in operated limb. Only in 2 (7.7%) patients patients in this group acute arterial thrombosis was diagnosed. At the same time thrombosis of microanastomosis occurred in 45.4% of cases in the second group what is 5.5 times higher than in the first group. Significant prevalence of blood flow in operated limb is favorable prognostic sign of the early postoperative period. On the other hand the identity of blood flow or prevalence of such in healthy limb predispose to acute vascular complications in replantate or autoplantate. Radionuclide scintigraphy provides detailed assessment of regional blood flow in operated limb. However clinical monitoring has leading role in diagnosis of acute circulatory disorders in replantate or autoplantate. To summarize the experience of early treatment of high-voltage electric burn wounds in the limbs. Fifty-four patients (50 males and 4 females, aged from 10 to 56 years) with high-voltage electric burn wounds in 97 limbs (67 upper limbs and 30 lower limbs) were hospitalized in our burn wards from January 2003 to December 2010. A total of 119 burn wounds in wrist-forearm, forearm-elbow-upper arm, shoulder-axillary region, ankle-foot, lower leg, around the knee, thigh-inguinal region were treated with incision for decompression within 10 days after burn. Under the premise of relatively stable systemic condition of the patients, certain surgical operations were performed as follows. (1) Sixteen limbs with 16 wounds were amputated, among them forearm amputation was performed for 5 upper limbs with necrosis, with preservation of elbow joints, and the residual wounds of the elbow and upper arm were repaired with pedicled latissimus dorsi musculo-cutaneous flaps; 1 upper limb with upper arm amputated, with preservation of shoulder joint, was repaired with pedicled latissimus dorsi musculo-cutaneous flap. (2) Ninety-five wounds were covered with various tissue flaps with abundant blood supply after early debridement, in which 3 brachial arteries, 1 vein, 1 brachial artery and vein were reconstructed in 5 wrist wounds, artery reconstruction was performed in elbow wound of 1 case with injured brachial artery. (3) Eight wounds were treated with free skin grafting. Wound healing conditions were observed and followed up. Wounds in 16 limbs healed after amputation and repair. Blood supply and (or) venous return of hands were restored in 5 wrist wounds after vessel reconstruction. After artery reconstruction, abundant blood supply was observed in 1 case with injured brachial artery and amputation was avoided. Necrosis occurred in distal parts of tissue flaps in 5 wounds after grafting, in which 2 wounds healed after removal of necrotic tissue followed by closure with suture, and 3 wounds healed after debridement and free skin grafting. Tissue flap infection occurred in wrist (5 wounds), elbow (1 wound), ankle-foot (2 wounds), and healed after debridement and suture. The other tissue flaps survived after grafting. Six wounds healed after skin grafting. Partial necrosis occurred in 2 wounds after skin grafting, and they were healed after second skin grafting. Thirty-seven patients were followed up for 6 to 12 months, the skin flaps survived with satisfactory appearance and texture. Early extensive compartment release through fasciectomies and escharectomies, early debridement, early vascular grafting, early wound coverage with contemporary reparative and reconstructive surgical techniques are rational options for the treatment of high-voltage electric burns in the limbs. To evaluate the accuracy of Hadeco ES-1000spm hand-held doppler during the anterolateral thigh (ALT) flap harvest. Twenty-five patients (26 sides) with ALT flaps for head and neck reconstruction between May 2005 and May 2010 received preoperative Doppler examination for the location of the cutaneous perforators of ALT flaps. The Doppler signals and body mass index (BMI) were recorded preoperatively according to ABC system. The locations of Doppler signals and of the actual cutaneous perforators at surgery were plotted and compared. The diameter of perforators was measured. One to three cutaneous perforators of the ALT flap were consistently found at specific locations. They were named perforators A, B, C from proximal to distal. Perforators A, B and C were present in 15 (58%), 24 (92%) and 20 (77%) cases and the diameter (&gt; 0.5 mm) of A, B and C were 11/15, 22 (92%) and 8 (40%) respectively. The Doppler signal was within 0.5 cm of the actual perforator location in 85% flaps. The accuracy of Doppler decreased with increase of BMI. Preoperative assessment by hand-held Doppler is useful in predicting the perforator vessels' locations and diameter although it's accuracy is limited. Treatment and result of burned total hand was reported here in 4 hands (4 cases). According to the treatment and anatomical characteristics, burned hand was divided into 4 areas: dorsum of hand, dorsum of finger, thenar-wrist area and volar-digit area. The treatment of total hand in third degree burns included emergency escharotomy of hand and digits, early escharotomy and immediate skin grafting on the dorsum of hand, thenar-wrist and volar-digit area. But on the dorsum of digit area this sort of hand was often deepen to the phalangeal bones and joints. After healing of early graft, the exposed bones and joints were decorticated with immediate grafting on the fresh bone marrow surface and with the finger tip repair so as to preserve the length of digits. When the bone marrow surface grafting healed metallic finger splints were bent sequentially to functional position for 8 weeks in order to ankylosis of interphalangeal joints. Followed up 4 hands with good results. And only 5 distal phalanges were loss in 20 digits. But in previous cases this kinds of digits were often amputated with poor results. The problem relating to leg amputation following ischemia are analysed in the first part of this study, bearing in mind that amputation must be as conservative as possible in order to ensure the best quality of life. Following a short review of the topic and the introduction of recent trends, the case for amputation, which must be early in order to be conservative, is studied. The first part of this article concludes with a discussion of Doppler and clinical evaluations as techniques used to determine the level of amputation. In this chapter the local therapy for burns is discussed. Between 400 and 500 children with burns are treated every year at the Red Cross War Memorial Children's Hospital in Cape Town, but in only 10% of them do the burns affect over 20% of the body surface. These latter patients are treated in special rooms equipped for intensive therapy. Open and closed methods of treatment for burns used in addition to early excision are compared. The first aim is early skin cover for areas with skin loss preserving as much function as possible and achieving the best possible cosmetic result. Local therapy must be atraumatic to prevent extension of the skin lesion. Bacterial contamination must be prevented as far as possible by keeping the wound clean. Emergency treatment and the course of wound healing up to the third week after the injury using the appropriate dressings are described. Early excision until the fifth day after the accident should be used mainly for burns of the hand, deep second degree burns of up to 10% of the body surface, deep second degree burns over the joints and deep second degree burns of the neck. It must be admitted that the depth of the burn can only be definitely estimated between the seventh and tenth day after the accident. If no autografts are available homografts or grafts from animals are used. The age of the patient, associated injuries, associated diseases and the extent of the burn all play a role in determining the prognosis. Furthermore endogenous bacterial infections, absorption of local therapeutic agents and the state of the surrounding skin do also influence the healing process. Finally the various local therapeutic agents like sulphamylon, silver sulphadiazine and betadine are discussed. A 0.05% solution of silver nitrate is also active against gram-negative infections. Skin transplants are disinfected with a solution containing one third 0.25% acetic acid, one third 3% cent hydrogen peroxide and one third saline. Hydrogen peroxide must not be applied to burns that are healing spontaneously. A classification of burns to help to choose the appropriate local therapy is proposed. The results of the Elevation Reactive Hyperemia Test (ERHT) and the transcutaneous Doppler ultrasound ankle blood pressure (DAP) have been compared in a series of 115 cases with ischemic lesions of the foot. The ERHT was carried out by simple elevation of the foot or elevation with the circulation temporarily obstructed by a blood pressure cuff following which the foot was gradually lowered until the reactive hyperemia was seen in the skin and the height above the right atrium was estimated. The appearance of the hyperemia at 35 cm above the right atrium will allow healing of local ischemic lesions and at the height of 45 cm or above indicates a zone at which amputation may be carried out successfully. In the same series the DAP using 60 mmHg as the cut off point showed 40% healing with a pressure less than this level and 40% failed with a pressure above this level. The DAP gave no consistent prediction of the healing of ischemic lesions or of amputations. We report a severe case of compartment syndrome due to a compressive burn dressing. An otherwise healthy 2-year-old girl presented at her local health center with a superficial partial-thickness thermal burn on the dorsum of the mid phalanx of the second finger of her right hand. A compressive dressing was applied solely to the affected finger. Forty-eight hours afterward, the patient presented in the emergency room with severe pain of the finger. After removal of the dressing, a circular constrictive eschar was observed at the base of the finger, secondary to ischemia due to the compressive dressing. Emergent lateral escharotomies were performed, with immediate recovery of distal perfusion. One week afterward, the patient underwent surgical debridement of the burn on the dorsum of her finger and escharectomy of the ischemic eschar at the base. The lesions were covered with partial-thickness skin grafts. This case shows that acute compartment syndrome can lead to severe sequelae, such as the loss of an extremity or body segment. We must take utmost care in all our actions to avoid any (negligent) act that could lead to severe or permanent damage to our patients. The history and physical examination are extremely important in the management of vascular surgical patients because a correct diagnosis can usually be made on the basis of information obtained from these two modalities. The severity of the chronic occlusive process leads to characteristic symptoms in the extremity: claudication, rest pain, skin ulcerations and gangrene. Chronic progressive lesions permit enlargement of collateral blood supply which, for a time, minimizes the severity of symptoms. Milde degrees of arterial insufficiency (claudication) can be treated conservatively. Unreconstructed chronic critical ischemia predicts a poor outcome in terms of survival and limb salvage. The outlook with arterial reconstructive surgery is by far better. Arteriography ist the most reliable diagnostic test for occlusive lesions. It ist essential for the operative planning. Vein-bypass procedures are, if feasible, very effective in most cases. Acute embolic occlusion: Sudden occlusion of a previously patent artery is usually a dramatic event producing severe ischemia of the distal tissue. The characteristic symptoms and signs are the 5 P's: pallor, pain, paresthesia, paralysis, pulselessness. Emergent restoration of blood flow by operation may be essential to prevent limb loss. Milder forms of ischemia (acute thrombosis--acute or chronic disease) can be treated initially with intravenous heparin if the extremity is not threatened (minimal sensory loss, no muscle weakness). Elective surgery at a later date is highly successful. Using a wick catheter technique, sequential measurements of intramuscular pressure were obtained in 31 burned arms in 18 patients. Abnormally high pressures were recorded in 90 percent of extremities and exceeded the potentially harmful level of 30 mm Hg in 42 percent. Correlation of intramuscular pressure with signs and symptoms of extremity compression, including Doppler pulses, was poor. Intramuscular pressure elevation appeared to parallel edema formation beneath the burn wound. A high incidence of pressure measurements in excess of 30 mm Hg was found in patients who had 30 percent or greater total body surface area injury (67 percent), 10 percent or greater full-thickness burns (75 percent), and extremities with circumferential involvement (57 percent). In every case echarotomy produced a dramatic decrease in intramuscular pressure, while a randomized group of extremities that were not decompressed developed sustained pressures as high as 64 mm Hg despite the presence of intact Doppler pulses. Extremities treated in this manner appeared slower in resolving edema and regaining motion and strength. Measurement of intramuscular pressure beneath the burn eschar is recommended in evaluating all patients at risk from extremity burns. Doppler may assess for gross blood flow, and ankle-brachial indices can evaluate an individual and lower versus upper extremities. Oxygen pressures in the toes and transcutaneous oxygen pressure are useful for determining oxygenation on a microvascular level. In cases of profound vascular insufficiency, bypass grafting or the placement of stents may be necessary before performing a BKA. Some researchers used indocyanine green near-infrared (ICG NIR) fluorescence imaging to predict postoperative skin flap necrosis. [18] [19] There is limited English literature describing the experience of a civilian hospital managing blast-related burn injuries. As the largest regional burn unit, we reviewed our cases with the aim of identifying means to improve current management. A 6-year retrospective analysis of all patients coded as sustaining blast-related burns was conducted through the unit's burns database. Medical case notes were reviewed for information on burn demographics, management and outcomes. 42 patients were identified. Male to female ratio was 37:5. Age range was 12-84 years, (mean=33 years). Total body surface area (%TBSA) burn ranged from 0.25% to 60%, (median=1%). The most common burn injury was flame (31/42, 73.8%). Gas explosions were the most common mechanism of injury (19 cases; 45.2%). 7/42 cases (16.7%) had full ATLS management pre-transfer to the burns unit. The Injury Severity Score (ISS) ranged from 0-43 (median=2). 17/42 (40.4%) patients required admission. 37/36 (88.1%) patients were managed conservatively of which 1 patient later required surgery due to deeper burns. 5/42 (11.9%) patients required surgical management at presentation and these were noted to be burns with &gt;15% TBSA requiring resuscitation. One case required emergency escharotomies and finger amputations. All patients survived their burn injuries. Blast-related burn injuries are generally uncommon in the civilian setting. Following proper assessment, most of these cases can be deemed as minor injuries and managed conservatively. Improvement in burns management education and training at local emergency departments would provide efficient patient care and avoid unnecessary referrals to a burns unit. Critical limb ischemia is a condition that has increased in prevalence and carries a high degree of morbidity. Although endovascular therapy for treatment of patients with critical limb ischemia has undergone significant advances with improved outcomes over the past decade, these patients often have multilevel disease, and it may take weeks or months for ulceration healing. For this reason, the acceptable therapeutic end points during and immediately following revascularization remain somewhat obscure. There are multiple tools available to guide the treating vascular specialist in this regard. Establishment of in-line flow to the foot and the angiosome containing the ulceration, appearance of a \"wound blush,\" restoration of pulses, and bleeding at the ulcer site are basic tenets intraprocedurally. Postprocedural noninvasive testing including the ankle-brachial and toe-brachial indices, segmental pressure measurements, pulse volume recordings, transcutaneous oxygen tension, skin perfusion pressures (SPPs), and toe pressures all play a role in determining the likelihood of clinical improvement. Newer technologies such as two-dimensional (2D) perfusion angiography, fluorescence angiography, and tissue oxygen saturation mapping may allow better real-time assessment of flow restoration. In combination with close clinical follow-up and wound care, these tools provide treating physicians with a better grasp of the necessary end points to optimize patients for clinical improvement.  usually are used in conjunction with pharmacologic thrombolysis. Surgical revascularization is preferred when restoration of blood flow must occur within 24 h to prevent limb loss or when symptoms of occlusion have been present for more than 2 weeks. Amputation is performed when the limb is not viable, as characterized by loss of sensation, paralysis, and the absence of Doppler-detected blood flow in both arteries and veins.\nHere is the question:\nDERMATOLOGY AND PLASTIC SURGERY: A young man comes to the emergency room with a second-degree flame burn of 10% of the body surface, affecting the right arm in an extensive and circular manner. There is no arterial pulse in the hand measured by Doppler. What is the treatment of choice?\nHere are the potential choices:\n1. Occlusive sulfadiazine-arginine cures and depth assessment at one week.\n2. Lymphatic drainage and assess a vascular by-pass.\n3. Escharotomy or emergency decompression incisions.\n4. Expectant management.\n5. Amputation of the extremity.\nThe correct answer is: ",
        "gold_answer": "3 Escharotomy or emergency decompression incisions.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Neurovascular integrity should similarly be monitored frequently and in a scheduled manner. Capillary refilling time, Doppler signals, pulse oximetry, and sensation distal to the burned area should be checked every hour. Limb deep compartment pressures should be checked initially to establish a baseline. Subsequently, any increase in capillary refill time, decrease in Doppler signal, or change in sensation should lead to rechecking the compartment pressures. Compartment pressures greater than 30 mm Hg should be treated by immediate decompression via escharotomy and fasciotomy, if needed. explored to evaluate for bleeding points. One must be very cautious if attempting to ligate these to ensure that adjacent structures such as nerves are not included in the ligature.The hand must be evaluated for adequacy of perfusion to the hand as a whole as well as the individual digits. Capillary refill, turgor, Doppler signal, and bleeding to pinprick all pro-vide useful information regarding vascular status. The finger or hand with vascular compromise requires urgent operative explo-ration. Unlike the complete amputation, in which the amputated part can be cold preserved (see later section, “Amputation and Replantation”), devascularization without amputation produces warm ischemia, which is tolerated only for a matter of hours.For the noncritical vascular injury, two treatment options exist. Simple ligation will control hemorrhage. At least one of the palmar arterial arches is intact in 97% of patients, so this will usually not compromise hand perfusion.5 Each digit also has two A Doppler ultrasound blood flow detector, commonly called Doppler wand or Doppler probe, and a sphygmomanometer (blood pressure cuff) are usually needed. The blood pressure cuff is inflated proximal to the artery in question. Measured by the Doppler wand, the inflation continues until the pulse in the artery ceases. The blood pressure cuff is then slowly deflated. When the artery's pulse is re-detected through the Doppler probe the pressure in the cuff at that moment indicates the systolic pressure of that artery. The higher systolic reading of the left and right arm brachial artery is generally used in the assessment. The pressures in each foot's posterior tibial artery and dorsalis pedis artery are measured with the higher of the two values used as the ABI for that leg. Where PLeg is the systolic blood pressure of dorsalis pedis or posterior tibial arteries and PArm is the highest of the left and right arm brachial systolic blood pressure Compartment syndrome is a serious complication of high voltage electrical burns, limb carbonization and deep circular burns with delayed escharotomy. Without treatment, ischemic tissue damage leads to irreversible necrosis. Treatment is emergency surgical decompression. The burned patient is usually not searchable and cannot always be readily examined because of bulky dressings; diagnosis of compartment syndrome is always hard to make. The pressure transducer used in central arterial catheters is easy available. We used it to measure pressure in muscular compartments. We measured compartment pressure three times at different depths in all cases of electrical burn, carbonization and deep circumferential burns with delayed escharotomy. We also took the pressure in the uninjured limb. The pressure assessment device was composed of a blood pressure transducer commonly used in arterial catheters for arterial pressure monitoring with three connecting branches. The first branch was connected to the 'arterial pressure exit' in the monitoring device. The second, an IV tube, was connected to one litre of physiological serum in a pressure bag inflated to 200 mmHg. The third, also an IV tube with a sterile extension cable, was directly connected to an 18G standard straight needle to be inserted in the tissues for which interstitial pressure had to be measured. In patients with thermal burns, we measured pressure before and after escharotomy. Threshold intracompartmental pressure was 35 mmHg. We carried out pressure assessment of all muscular compartments during and at the end of surgery. The pressure transducer provides a pressure value in all muscular compartments with a time of installation and measuring of less than 5 minutes. Sensitivity is measured at +/- 1 mmHg. Operation is simple, non-operator dependent, and accessible to medical and paramedic teams. The pressure transducer allows accurate diagnosis of early or established compartment syndrome. It requires no additional equipment and its application does not delay therapeutic management. Its use helps with fasciotomy decision, especially after escharotomy, guides the surgeon in the exploration of different compartments and verifies the effectiveness of surgery. A study was made of the course of ischemia and hemodynamic disorders in 53 patients with occlusion of the distal arterial system of the upper extremities. Circulation was examined by ultrasound Doppler, tetrapolar rheology, transcutaneous oxymetry and angiography. Critical ischemia was discovered in 58.5% of patients. In occlusion of one of the forearm arteries, extremity circulation was made for. Circulatory decompensation was recorded in occlusion of both forearm arteries with intact distal bed and non-functioning palmar arches of the hand as well as in lesions of hand and finger arteries. All 53 patients were operated on, 66 operations were accomplished using magnifying optic appliances. Provided the distal bed was well preserved, use was made of direct revascularization techniques (36) whereas non-standard methods were employed in the event of its obliteration: arterialization of the outlets of the subcutaneous veins of the hand and autotransplantation of the greater omentum (30). Beneficial results were obtained in 91.5% and unsatisfactory in 8.5% of patients. The lethality accounted for 1.2% while the incidence of amputations was quoted as 5.7%. Good results offer the period as long as 5 years were well preserved in 87.6% of patients. Our experience indicates the efficacy of the use of revascularization techniques for the treatment of different versions of occlusion of the distal segments of upper extremity arteries. Thorocostomy and pericardiocentesis to relieve pneumothorax and pericardial tamponade Intravenous (IV) and intraosseous (IO) cannulation Oxygen administration and positive pressure ventilation via bag-valve-mask, CPAP device, or ventilator Fluid resuscitation Administration of emergency drugs/medications (see section below) Bleeding control and management of shock Spinal injury management, including immobilization and safe transport Fracture management, including assessment, splinting, and dislocation reduction Obstetrics, including assessment, childbirth, and recognition of and procedures for obstetrical emergencies such as breech presentation, cord presentation, and placental abruption Management of burns, including classification, estimate of surface area, recognition of more serious burns, and treatment Triage of patients in a mass casualty incident Surgical procedures such as field amputation, escharotomy, or thorocotomy (if trained and credentialed) In order to decrease the number of amputations for \"diabetic foot\", these patients should undergo elective or delayed operations. It is obligatory before the operation to correct carbohydrate metabolism and hemodynamics. Sodium succinate in combination with conventional angioprotective treatment is used for this purpose. Microcirculation is evaluated using oxymonitor ISM-2 and tetrapolar rheography. Blood flow disturbances are evaluated according to ultrasound dopplerography data. Operations are performed with the use of a primary or delayed suture at the definite level of the extremity where oxygen tension of the skin is not lower than 33 mm Hg, and the index of minute blood flow--not lower than 1.8 ml/min per 100 cm3 of the tissue. When operating on the foot it is obligatory to leave loose excessive brims of tissues to facilitate the placement of broad-grip sutures without tension. It is advisable to use through flowing--aspiration drainage and to perform surgical treatment of the deep phlegmon of the foot through club-shaped approach. In order to evaluate the epidemiology and functional results of hand burns in young children, 92 consecutive patients (126 hand burns) under age 5 years admitted to a Burn Center were reviewed. Scald burns (49 per cent) were most common, followed by flame (34 per cent), contact (14 per cent) and electrical burns (3 per cent). The child was left unattended by an adult in 53 per cent of cases and documented abuse was present in 6 per cent. The mean total body surface area (TBSA) burned was 17 per cent, and 77 patients (85 per cent) had additional burns in other areas (arms 34 per cent, legs 31 per cent, chest 29 per cent and face 27 per cent). Palmar burns occurred in 24 hands (19 per cent), dorsal in 41 (33 per cent), while both surfaces were burned in 61 (48 per cent). Joints involved included the MP in 96 (76 per cent), PIP in 87 (69 per cent) and DIP in 80 (63 per cent). The depth was superficial partial thickness in 53 (47 per cent), deep partial in 55 (44 per cent), and full thickness in 18 hands (14 per cent); a total of 29 hands were grafted (15 deep partial and 14 full thickness). Escharotomies were required in 12 hands (9 per cent) (9 flame and 3 scald) and partial amputation of digits was required in 3 (2 per cent). Follow-up was available in 46 hands from 7 to 120 months (mean 39 months). Partial thickness burns (34) healed with normal (32) or near-normal (2) hand function and developmental delay occurred in one patient.(ABSTRACT TRUNCATED AT 250 WORDS) To examine the state of regional circulation in replanted segment of upper limb and hand, to determine diagnostic and prognostic value of radionuclide scintigraphy. The study included 26 patients who underwent replantation of upper extremity segments. The control group included 12 patients who underwent autologous transplantation of toes on hand. All patients underwent isotope scintigraphy, ultrasound Doppler and pulse oximetry. Groups were comparable by gender, age, severity of injury. Depending on postoperative course two groups were determined: with favorable (27 patients) and complicated postoperative period (11 patients). Two types of regional circulation were identified according to dynamic scintigraphy: prevalence of blood flow in operated limb (type 1); prevalence of blood flow in healthy limb, or equal volumetric blood flow in operated and healthy limbs (type 2). Favorable early postoperative period was associated with prevalence of blood flow in operated limb. Only in 2 (7.7%) patients patients in this group acute arterial thrombosis was diagnosed. At the same time thrombosis of microanastomosis occurred in 45.4% of cases in the second group what is 5.5 times higher than in the first group. Significant prevalence of blood flow in operated limb is favorable prognostic sign of the early postoperative period. On the other hand the identity of blood flow or prevalence of such in healthy limb predispose to acute vascular complications in replantate or autoplantate. Radionuclide scintigraphy provides detailed assessment of regional blood flow in operated limb. However clinical monitoring has leading role in diagnosis of acute circulatory disorders in replantate or autoplantate. To summarize the experience of early treatment of high-voltage electric burn wounds in the limbs. Fifty-four patients (50 males and 4 females, aged from 10 to 56 years) with high-voltage electric burn wounds in 97 limbs (67 upper limbs and 30 lower limbs) were hospitalized in our burn wards from January 2003 to December 2010. A total of 119 burn wounds in wrist-forearm, forearm-elbow-upper arm, shoulder-axillary region, ankle-foot, lower leg, around the knee, thigh-inguinal region were treated with incision for decompression within 10 days after burn. Under the premise of relatively stable systemic condition of the patients, certain surgical operations were performed as follows. (1) Sixteen limbs with 16 wounds were amputated, among them forearm amputation was performed for 5 upper limbs with necrosis, with preservation of elbow joints, and the residual wounds of the elbow and upper arm were repaired with pedicled latissimus dorsi musculo-cutaneous flaps; 1 upper limb with upper arm amputated, with preservation of shoulder joint, was repaired with pedicled latissimus dorsi musculo-cutaneous flap. (2) Ninety-five wounds were covered with various tissue flaps with abundant blood supply after early debridement, in which 3 brachial arteries, 1 vein, 1 brachial artery and vein were reconstructed in 5 wrist wounds, artery reconstruction was performed in elbow wound of 1 case with injured brachial artery. (3) Eight wounds were treated with free skin grafting. Wound healing conditions were observed and followed up. Wounds in 16 limbs healed after amputation and repair. Blood supply and (or) venous return of hands were restored in 5 wrist wounds after vessel reconstruction. After artery reconstruction, abundant blood supply was observed in 1 case with injured brachial artery and amputation was avoided. Necrosis occurred in distal parts of tissue flaps in 5 wounds after grafting, in which 2 wounds healed after removal of necrotic tissue followed by closure with suture, and 3 wounds healed after debridement and free skin grafting. Tissue flap infection occurred in wrist (5 wounds), elbow (1 wound), ankle-foot (2 wounds), and healed after debridement and suture. The other tissue flaps survived after grafting. Six wounds healed after skin grafting. Partial necrosis occurred in 2 wounds after skin grafting, and they were healed after second skin grafting. Thirty-seven patients were followed up for 6 to 12 months, the skin flaps survived with satisfactory appearance and texture. Early extensive compartment release through fasciectomies and escharectomies, early debridement, early vascular grafting, early wound coverage with contemporary reparative and reconstructive surgical techniques are rational options for the treatment of high-voltage electric burns in the limbs. To evaluate the accuracy of Hadeco ES-1000spm hand-held doppler during the anterolateral thigh (ALT) flap harvest. Twenty-five patients (26 sides) with ALT flaps for head and neck reconstruction between May 2005 and May 2010 received preoperative Doppler examination for the location of the cutaneous perforators of ALT flaps. The Doppler signals and body mass index (BMI) were recorded preoperatively according to ABC system. The locations of Doppler signals and of the actual cutaneous perforators at surgery were plotted and compared. The diameter of perforators was measured. One to three cutaneous perforators of the ALT flap were consistently found at specific locations. They were named perforators A, B, C from proximal to distal. Perforators A, B and C were present in 15 (58%), 24 (92%) and 20 (77%) cases and the diameter (&gt; 0.5 mm) of A, B and C were 11/15, 22 (92%) and 8 (40%) respectively. The Doppler signal was within 0.5 cm of the actual perforator location in 85% flaps. The accuracy of Doppler decreased with increase of BMI. Preoperative assessment by hand-held Doppler is useful in predicting the perforator vessels' locations and diameter although it's accuracy is limited. Treatment and result of burned total hand was reported here in 4 hands (4 cases). According to the treatment and anatomical characteristics, burned hand was divided into 4 areas: dorsum of hand, dorsum of finger, thenar-wrist area and volar-digit area. The treatment of total hand in third degree burns included emergency escharotomy of hand and digits, early escharotomy and immediate skin grafting on the dorsum of hand, thenar-wrist and volar-digit area. But on the dorsum of digit area this sort of hand was often deepen to the phalangeal bones and joints. After healing of early graft, the exposed bones and joints were decorticated with immediate grafting on the fresh bone marrow surface and with the finger tip repair so as to preserve the length of digits. When the bone marrow surface grafting healed metallic finger splints were bent sequentially to functional position for 8 weeks in order to ankylosis of interphalangeal joints. Followed up 4 hands with good results. And only 5 distal phalanges were loss in 20 digits. But in previous cases this kinds of digits were often amputated with poor results. The problem relating to leg amputation following ischemia are analysed in the first part of this study, bearing in mind that amputation must be as conservative as possible in order to ensure the best quality of life. Following a short review of the topic and the introduction of recent trends, the case for amputation, which must be early in order to be conservative, is studied. The first part of this article concludes with a discussion of Doppler and clinical evaluations as techniques used to determine the level of amputation. In this chapter the local therapy for burns is discussed. Between 400 and 500 children with burns are treated every year at the Red Cross War Memorial Children's Hospital in Cape Town, but in only 10% of them do the burns affect over 20% of the body surface. These latter patients are treated in special rooms equipped for intensive therapy. Open and closed methods of treatment for burns used in addition to early excision are compared. The first aim is early skin cover for areas with skin loss preserving as much function as possible and achieving the best possible cosmetic result. Local therapy must be atraumatic to prevent extension of the skin lesion. Bacterial contamination must be prevented as far as possible by keeping the wound clean. Emergency treatment and the course of wound healing up to the third week after the injury using the appropriate dressings are described. Early excision until the fifth day after the accident should be used mainly for burns of the hand, deep second degree burns of up to 10% of the body surface, deep second degree burns over the joints and deep second degree burns of the neck. It must be admitted that the depth of the burn can only be definitely estimated between the seventh and tenth day after the accident. If no autografts are available homografts or grafts from animals are used. The age of the patient, associated injuries, associated diseases and the extent of the burn all play a role in determining the prognosis. Furthermore endogenous bacterial infections, absorption of local therapeutic agents and the state of the surrounding skin do also influence the healing process. Finally the various local therapeutic agents like sulphamylon, silver sulphadiazine and betadine are discussed. A 0.05% solution of silver nitrate is also active against gram-negative infections. Skin transplants are disinfected with a solution containing one third 0.25% acetic acid, one third 3% cent hydrogen peroxide and one third saline. Hydrogen peroxide must not be applied to burns that are healing spontaneously. A classification of burns to help to choose the appropriate local therapy is proposed. The results of the Elevation Reactive Hyperemia Test (ERHT) and the transcutaneous Doppler ultrasound ankle blood pressure (DAP) have been compared in a series of 115 cases with ischemic lesions of the foot. The ERHT was carried out by simple elevation of the foot or elevation with the circulation temporarily obstructed by a blood pressure cuff following which the foot was gradually lowered until the reactive hyperemia was seen in the skin and the height above the right atrium was estimated. The appearance of the hyperemia at 35 cm above the right atrium will allow healing of local ischemic lesions and at the height of 45 cm or above indicates a zone at which amputation may be carried out successfully. In the same series the DAP using 60 mmHg as the cut off point showed 40% healing with a pressure less than this level and 40% failed with a pressure above this level. The DAP gave no consistent prediction of the healing of ischemic lesions or of amputations. We report a severe case of compartment syndrome due to a compressive burn dressing. An otherwise healthy 2-year-old girl presented at her local health center with a superficial partial-thickness thermal burn on the dorsum of the mid phalanx of the second finger of her right hand. A compressive dressing was applied solely to the affected finger. Forty-eight hours afterward, the patient presented in the emergency room with severe pain of the finger. After removal of the dressing, a circular constrictive eschar was observed at the base of the finger, secondary to ischemia due to the compressive dressing. Emergent lateral escharotomies were performed, with immediate recovery of distal perfusion. One week afterward, the patient underwent surgical debridement of the burn on the dorsum of her finger and escharectomy of the ischemic eschar at the base. The lesions were covered with partial-thickness skin grafts. This case shows that acute compartment syndrome can lead to severe sequelae, such as the loss of an extremity or body segment. We must take utmost care in all our actions to avoid any (negligent) act that could lead to severe or permanent damage to our patients. The history and physical examination are extremely important in the management of vascular surgical patients because a correct diagnosis can usually be made on the basis of information obtained from these two modalities. The severity of the chronic occlusive process leads to characteristic symptoms in the extremity: claudication, rest pain, skin ulcerations and gangrene. Chronic progressive lesions permit enlargement of collateral blood supply which, for a time, minimizes the severity of symptoms. Milde degrees of arterial insufficiency (claudication) can be treated conservatively. Unreconstructed chronic critical ischemia predicts a poor outcome in terms of survival and limb salvage. The outlook with arterial reconstructive surgery is by far better. Arteriography ist the most reliable diagnostic test for occlusive lesions. It ist essential for the operative planning. Vein-bypass procedures are, if feasible, very effective in most cases. Acute embolic occlusion: Sudden occlusion of a previously patent artery is usually a dramatic event producing severe ischemia of the distal tissue. The characteristic symptoms and signs are the 5 P's: pallor, pain, paresthesia, paralysis, pulselessness. Emergent restoration of blood flow by operation may be essential to prevent limb loss. Milder forms of ischemia (acute thrombosis--acute or chronic disease) can be treated initially with intravenous heparin if the extremity is not threatened (minimal sensory loss, no muscle weakness). Elective surgery at a later date is highly successful. Using a wick catheter technique, sequential measurements of intramuscular pressure were obtained in 31 burned arms in 18 patients. Abnormally high pressures were recorded in 90 percent of extremities and exceeded the potentially harmful level of 30 mm Hg in 42 percent. Correlation of intramuscular pressure with signs and symptoms of extremity compression, including Doppler pulses, was poor. Intramuscular pressure elevation appeared to parallel edema formation beneath the burn wound. A high incidence of pressure measurements in excess of 30 mm Hg was found in patients who had 30 percent or greater total body surface area injury (67 percent), 10 percent or greater full-thickness burns (75 percent), and extremities with circumferential involvement (57 percent). In every case echarotomy produced a dramatic decrease in intramuscular pressure, while a randomized group of extremities that were not decompressed developed sustained pressures as high as 64 mm Hg despite the presence of intact Doppler pulses. Extremities treated in this manner appeared slower in resolving edema and regaining motion and strength. Measurement of intramuscular pressure beneath the burn eschar is recommended in evaluating all patients at risk from extremity burns. Doppler may assess for gross blood flow, and ankle-brachial indices can evaluate an individual and lower versus upper extremities. Oxygen pressures in the toes and transcutaneous oxygen pressure are useful for determining oxygenation on a microvascular level. In cases of profound vascular insufficiency, bypass grafting or the placement of stents may be necessary before performing a BKA. Some researchers used indocyanine green near-infrared (ICG NIR) fluorescence imaging to predict postoperative skin flap necrosis. [18] [19] There is limited English literature describing the experience of a civilian hospital managing blast-related burn injuries. As the largest regional burn unit, we reviewed our cases with the aim of identifying means to improve current management. A 6-year retrospective analysis of all patients coded as sustaining blast-related burns was conducted through the unit's burns database. Medical case notes were reviewed for information on burn demographics, management and outcomes. 42 patients were identified. Male to female ratio was 37:5. Age range was 12-84 years, (mean=33 years). Total body surface area (%TBSA) burn ranged from 0.25% to 60%, (median=1%). The most common burn injury was flame (31/42, 73.8%). Gas explosions were the most common mechanism of injury (19 cases; 45.2%). 7/42 cases (16.7%) had full ATLS management pre-transfer to the burns unit. The Injury Severity Score (ISS) ranged from 0-43 (median=2). 17/42 (40.4%) patients required admission. 37/36 (88.1%) patients were managed conservatively of which 1 patient later required surgery due to deeper burns. 5/42 (11.9%) patients required surgical management at presentation and these were noted to be burns with &gt;15% TBSA requiring resuscitation. One case required emergency escharotomies and finger amputations. All patients survived their burn injuries. Blast-related burn injuries are generally uncommon in the civilian setting. Following proper assessment, most of these cases can be deemed as minor injuries and managed conservatively. Improvement in burns management education and training at local emergency departments would provide efficient patient care and avoid unnecessary referrals to a burns unit. Critical limb ischemia is a condition that has increased in prevalence and carries a high degree of morbidity. Although endovascular therapy for treatment of patients with critical limb ischemia has undergone significant advances with improved outcomes over the past decade, these patients often have multilevel disease, and it may take weeks or months for ulceration healing. For this reason, the acceptable therapeutic end points during and immediately following revascularization remain somewhat obscure. There are multiple tools available to guide the treating vascular specialist in this regard. Establishment of in-line flow to the foot and the angiosome containing the ulceration, appearance of a \"wound blush,\" restoration of pulses, and bleeding at the ulcer site are basic tenets intraprocedurally. Postprocedural noninvasive testing including the ankle-brachial and toe-brachial indices, segmental pressure measurements, pulse volume recordings, transcutaneous oxygen tension, skin perfusion pressures (SPPs), and toe pressures all play a role in determining the likelihood of clinical improvement. Newer technologies such as two-dimensional (2D) perfusion angiography, fluorescence angiography, and tissue oxygen saturation mapping may allow better real-time assessment of flow restoration. In combination with close clinical follow-up and wound care, these tools provide treating physicians with a better grasp of the necessary end points to optimize patients for clinical improvement.  usually are used in conjunction with pharmacologic thrombolysis. Surgical revascularization is preferred when restoration of blood flow must occur within 24 h to prevent limb loss or when symptoms of occlusion have been present for more than 2 weeks. Amputation is performed when the limb is not viable, as characterized by loss of sensation, paralysis, and the absence of Doppler-detected blood flow in both arteries and veins.\nHere is the question:\nDERMATOLOGY AND PLASTIC SURGERY: A young man comes to the emergency room with a second-degree flame burn of 10% of the body surface, affecting the right arm in an extensive and circular manner. There is no arterial pulse in the hand measured by Doppler. What is the treatment of choice?\nHere are the potential choices:\n1. Occlusive sulfadiazine-arginine cures and depth assessment at one week.\n2. Lymphatic drainage and assess a vascular by-pass.\n3. Escharotomy or emergency decompression incisions.\n4. Expectant management.\n5. Amputation of the extremity.\nThe correct answer is: 3. Escharotomy or emergency decompression incisions."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n This type of respiratory failure is caused by conditions that affect oxygenation, such as: Low ambient oxygen (e.g. at high altitude) Ventilation-perfusion mismatch (parts of the lung receive oxygen but not enough blood to absorb it, e.g. pulmonary embolism) Alveolar hypoventilation (decreased minute volume due to reduced respiratory muscle activity, e.g. in acute neuromuscular disease); this form can also cause type 2 respiratory failure if severe. Diffusion problem (oxygen cannot enter the capillaries due to parenchymal disease, e.g. in pneumonia or ARDS) Shunt (oxygenated blood mixes with non-oxygenated blood from the venous system, e.g. right to left shunt) Type 2 Hypoxemia (PaO2 <8kPa or normal) with hypercapnia (PaCO2 >6.0kPa). The basic defect in type 2 respiratory failure is characterized by: {| class=\"wikitable\" |PaO2 || decreased (< )or normal |- | PaCO2 || increased (> ) |- | PA-aO2 || normal |- |pH || <7.35 |} Intubation may be necessary for a patient with decreased oxygen content and oxygen saturation of the blood caused when their breathing is inadequate (hypoventilation), suspended (apnea), or when the lungs are unable to sufficiently transfer gasses to the blood. Such patients, who may be awake and alert, are typically critically ill with a multisystem disease or multiple severe injuries. Examples of such conditions include cervical spine injury, multiple rib fractures, severe pneumonia, acute respiratory distress syndrome (ARDS), or near-drowning. Specifically, intubation is considered if the arterial partial pressure of oxygen (PaO2) is less than 60 millimeters of mercury (mm Hg) while breathing an inspired O2 concentration (FIO2) of 50% or greater. In patients with elevated arterial carbon dioxide, an arterial partial pressure of CO2 (PaCO2) greater than 45 mm Hg in the setting of acidemia would prompt intubation, especially if a series of measurements demonstrate a worsening Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise in arterial carbon dioxide levels is called hypercapnia. Respiratory failure is classified as either Type 1 or Type 2, based on whether there is a high carbon dioxide level, and can be acute or chronic. In clinical trials, the definition of respiratory failure usually includes increased respiratory rate, abnormal blood gases (hypoxemia, hypercapnia, or both), and evidence of increased work of breathing. Respiratory failure causes an altered mental status due to ischemia in the brain. The typical partial pressure reference values are oxygen Pa O2 more than 80 mmHg (11 kPa) and carbon dioxide Pa CO2 less than 45 mmHg (6.0 kPa). Cause Causes Restricted oxygen flow to the body's tissue that leads to hypoxia can be caused by a variety of situations or other underlying conditions. High altitude (above 3048 metres/10,000 feet) Hypoventilation – failure of respiratory pump due to any cause (fatigue, barbiturate poisoning, pneumothorax, etc.) Ventilation perfusion mismatch Obstructed airway Drowning Abnormal pulmonary function Chronic obstructive pulmonary diseases (COPD) Neuromuscular diseases or interstitial lung disease Constrained blood flow to a tissue (such as atherosclerosis or vasoconstriction) Blockage in blood flow like a sickle cell crisis Low or no blood flow caused by bleeding or heart attack Malformed vascular system such as an anomalous coronary artery Limited oxygen transportation due to anemia While respiring in the open air at high altitudes, the human body experiences altitude sickness and hypoxemia due to a low partial pressure of oxygen, decreasing the carriage of oxygen by hemoglobin. Because A–a gradient is approximated as: (150 − 5/4(P)) – at sea level and on room air (0.21x(760-47) = 149.7 mmHg for the alveolar oxygen partial pressure, after accounting for the water vapor), the direct mathematical cause of a large value is that the blood has a low , a low Pa, or both. is very easily exchanged in the lungs and low Pa directly correlates with high minute ventilation; therefore a low arterial Pa indicates that extra respiratory effort is being used to oxygenate the blood. A low indicates that the patient's current minute ventilation (whether high or normal) is not enough to allow adequate oxygen diffusion into the blood. Therefore, the A–a gradient essentially demonstrates a high respiratory effort (low arterial Pa) relative to the achieved level of oxygenation (arterial ). A high A–a gradient could indicate a patient breathing hard to achieve normal oxygenation, a patient breathing normally and attaining low oxygenation, or a patient breathing hard and still Asthma and COPD Acute exacerbations of chronic respiratory diseases, mainly asthma and chronic obstructive pulmonary disease (COPD), are assessed as emergencies and treated with oxygen therapy, bronchodilators, steroids or theophylline, have an urgent chest X-ray and arterial blood gases and are referred for intensive care if necessary. Noninvasive ventilation in the ED has reduced the requirement for tracheal intubation in many cases of severe exacerbations of COPD. Special facilities, training, and equipment An ED requires different equipment and different approaches than most other hospital divisions. Patients frequently arrive with unstable conditions, and so must be treated quickly. They may be unconscious, and information such as their medical history, allergies, and blood type may be unavailable. ED staff are trained to work quickly and effectively even with minimal information. When 100% oxygen (1.00 Fi) is used initially for an adult, it is easy to calculate the next Fi to be used, and easy to estimate the shunt fraction. The estimated shunt fraction refers to the amount of oxygen not being absorbed into the circulation. In normal physiology, gas exchange of oxygen and carbon dioxide occurs at the level of the alveoli in the lungs. The existence of a shunt refers to any process that hinders this gas exchange, leading to wasted oxygen inspired and the flow of un-oxygenated blood back to the left heart, which ultimately supplies the rest of the body with de-oxygenated blood. When using 100% oxygen, the degree of shunting is estimated as 700 mmHg - measured Pa. For each difference of 100 mmHg, the shunt is 5%. A shunt of more than 25% should prompt a search for the cause of this hypoxemia, such as mainstem intubation or pneumothorax, and should be treated accordingly. If such complications are not present, other causes must be sought after, and positive Berlin Criteria: as stated on UpToDate (2020) Timing: onset of respiratory symptoms within one week of a injury/insult. Chest Imaging: either chest x-ray or CT scan, must show bilateral opacities that cannot be fully explained by other conditions such as effusion, lung/lobar collapse, or lung nodules. Origin of Edema: respiratory failure that cannot be fully explained by cardiac failure or fluid overload, this needs objective assessment such as an echocardiogram. Impaired Oxygenation: this can be determined by looking at the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2) that can be obtained based on an arterial blood gas test. Note: all PaO2/FiO2 ratios used in the determination of the severity of ARDS require that the patient be on a ventilator at a setting that includes 5 cm H2O or more of positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP). The typical partial pressure reference values are oxygen Pa O2 more than 80 mmHg (11 kPa) and carbon dioxide Pa CO2 less than 45 mmHg (6.0 kPa). Cause Several types of conditions can potentially result in respiratory failure: Conditions that reduce the flow of air into and out of the lungs, including physical obstruction by foreign bodies or masses and reduced breathing due to drugs or changes to the chest. Conditions that impair the lungs' blood supply. These include thromboembolic conditions and conditions that reduce the output of the right heart, such as right heart failure and some myocardial infarctions. Conditions that limit the ability of the lung tissue to exchange oxygen and carbon dioxide between the blood and the air within the lungs. Any disease which can damage the lung tissue can fit into this category. The most common causes are (in no particular order) infections, interstitial lung disease, and pulmonary oedema. Diagnosis Intermittent positive pressure breathing (IPPB) is a respiratory therapy treatment for people who are hypoventilating. While not a preferred method due to cost, IPPB is used to expand the lungs, deliver aerosol medications, and in some circumstances ventilate the patient. Indications IPPB may be indicated for patients who are at risk for developing atelectasis and who are unable or unwilling to breathe deeply without assistance. In patients with severe lung hyperinflation, IPPB may decrease dyspnea and discomfort during nebulized therapy. Contraindications Most contraindications are relative, such as nausea, hemodynamic instability, tracheal fistula, singulation and hemoptysis. Untreated tension pneumothorax is an absolute contraindication. IMPLEMENTATION When treating atelectasis - Therapy should be volume-oriented 2. Tidal volumes(VT) must be measured 3. VT goals must be set 4. VT goal of 10-15mL/kg ofbody weight A 68-year-old man with severe dyspnea was admitted as an emergency case. He had no past history of any respiratory or neuromuscular diseases. Immediately after insufflation of oxygen, respiratory arrest occurred. The blood gas analysis showed hypoxemia and severe hypercapnia (PaO2; 32 mmHg, PaCO2; 127 mmHg). We diagnosed as CO2 narcosis, and he was treated with a respirator in the ICU. He showed nonflaccid bilateral diaphragmatic paralysis and muscle atrophy of the upper extremities. As the EMG showed giant spikes of neurogenic pattern, he was diagnosed as ALS. Weaning from the respirator failed because of his respiratory muscle fatigue. He was given rehabilitation during the day time and ventilatory support with the respirator during the night. We conclude that if we meet with an emergency patient with CO2 narcosis without any pulmonary disorder, we have to suspect neuromuscular diseases, e.q. ALS. In some of such cases, mechanical ventilation supports social rehabilitation. We present a case of postural hypoxemia with a final diagnosis of myasthenia gravis (MG). A 62-year-old man experienced double vision in his left eye from December 2008 and received a diagnosis of diabetic neuropathy. From mid-December he began to experience breathing difficulties at night when in a supine position and was admitted to our hospital. Bilateral diaphragmatic elevation was observed on a chest X-ray film, and lower lung atelectasis and an anterior mediastinal tumor were observed on chest CT. However, his breathing difficulties only occurred when he was in a supine position. Therefore, we performed blood gas analysis in supine and sitting positions. Hypoxemia, hypercapnia and an increase in A-aDO2 were observed in the supine position, leading to a diagnosis of postural hypoxemia. Due to the exacerbation of his double vision, the patient was referred to the ophthalmology and neurology departments where he tested positive for anti-acetylcholine receptor antibodies and also on a tensilon test, resulting in a final diagnosis of MG. During the tensilon test, the patient's breathing difficulties in the supine position improved, and therefore his postural hypoxemia was thought to have resulted from diaphragmatic muscle weakness as a result of MG. MG respiratory failure is typically of the acute fulminating type and is considered to be a critical condition. However, it should be noted that there are cases, such as the present one, in which MG presents as postural hypoxemia. The authors report a rare, recently diagnosed and atypical mishap during one-lung ventilation (OLV) via a double lumen tube (DLT) and left-sided thoracotomy: an ipsilateral pneumothorax during ventilation of the right lung. This occurred in a 63-year-old patient with chronic obstructive airway disease who was scheduled for urgent repair of a descending thoracic aortic aneurysm. Anaesthesia and surgery were uneventful until aortic cross-clamping release. The common presentation of increased intrathoracic extrapleural pressure owing to a pneumothorax in patients with mechanically ventilated lungs is a rapid decrease in oxygen saturation, followed or paralleled by haemodynamic deterioration. Although the above presentation could be seen in this case, the diagnosis of a tension pneumothorax was delayed twice. First, symptoms were initially obscured by haemodynamic changes resulting from a head-down tilt and aortic declamping. Second, since the lack of consolidation after aortic declamping focused attention on the airway problems, complications resulting from the use of a DLT were primarily considered. In particular, since breathing sounds were detectable initially, malposition or torsion of the DLT had to be excluded by fibre-optic bronchoscopy, which involved a further delay. Finally, two observations led to the diagnosis of a right-sided tension pneumothorax: (1) bullae of the contralateral lung, detected during thoracotomy; (2) the finding that ventilation of both lungs and the left lung subsequently increased arterial (SaO2) and mixed venous oxygen saturation (SvO2) and the circulatory status, but ventilation of the right lung caused a deterioration. Chest radiography and insertion of a chest tube with drainage of air, thereafter, validated our hypothesis. The time course of oxygen desaturation during OLV and tension pneumothorax was as severe as expected; the time course of haemodynamic deterioration, however, appeared quicker and had more impact than expected. Assuming that mediastinal deviation was not hindered by contralateral intrathoracic pressure during thoracotomy, we believed that circulation should be depressed later or to a lesser extent in patients with an intraoperative pneumothorax. Yet, during thoracotomy, decrease in cardiac filling and output during tension pneumothorax in OLV obviously results primarily from the immovability of the mediastinum owing to mediastinal fixation and is at least as decisive as the contralateral intrathoracic pressure in closed-chest patients. In summary, a tension pneumothorax during one-lung ventilation and thoracotomy is a rare, but disastrous complication during the use of a DLT, which has not, to our knowledge, been reported previously. We recommend that tension pneumothorax be added to the list of complications and problems during OLV by the use of a DLT, especially in patients with structural lung diseases. Respiratory compromise describes a deterioration in respiratory function with a high likelihood of rapid progression to respiratory failure and death. Respiratory failure occurs when inadequate gas exchange by the respiratory system occurs, with a low oxygen level or a high carbon dioxide level. Causes Patients in acute care hospitals, particularly those with respiratory conditions, are at risk for developing respiratory compromise. Respiratory failure requiring emergency mechanical ventilation occurs in over 40,000 patients per year in the United States. In postoperative patients in the United States, the National Surgical Quality Improvement Program reports that 1.03% of all surgical patients require an unplanned intubation postoperatively. General principles of respiratory evaluation in patients with PNS involvement, regardless of cause, include assessment of pulmonary mechanics, such as maximal inspiratory force (MIF) and vital capacity (VC), and evaluation of strength of bulbar muscles. Regardless of the cause of weakness, endotracheal intubation should be considered when the MIF falls to <–25 cmH2O or the VC is <1 L. Also, patients with severe palatal weakness may require endotracheal intubation in order to prevent acute upper airway obstruction or recurrent aspiration. Arterial blood gases and oxygen saturation from pulse oximetry are used to follow patients with potential respiratory compromise from PNS dysfunction. However, intubation and mechanical ventilation should be undertaken based on clinical assessment rather than waiting until oxygen saturation drops or CO2 retention develops from hypoventilation. Noninvasive mechanical ventilation may be considered initially in lieu of endotracheal intubation but is If Pa:Fi < 300 mmHg (40 kPa), then the definitions recommended a classification as \"acute lung injury\" (ALI). Note that according to these criteria, arterial blood gas analysis and chest X-ray were required for formal diagnosis. Limitations of these definitions include lack of precise definition of acuity, nonspecific imaging criteria, lack of precise definition of hypoxemia with regards to PEEP (affects arterial oxygen partial pressure), arbitrary Pa thresholds without systematic data. are usually necessary (see further on). However, a fairly severe impairment of ventilation may occur before the first sign of dyspnea appears and before there is elevation of arterial carbon dioxide content. Incipient respiratory failure may be evident by tachypnea and a decrease in arterial oxygen tension (Po2 less than 85 mm Hg) reflecting pulmonary atelectasis. When respiratory failure arises gradually as the patient weakens over days, there is slight tachycardia, diaphoresis, restlessness, and tachypnea. Attempts to forestall intubation and positive-pressure ventilation by using negative-pressure cuirass-type devices have been unsatisfactory in our experience. Patients with oropharyngeal weakness require intubation even earlier so as to prevent aspiration, but full mechanical ventilation is not always necessary at the same time. Patients in these circumstances should obviously be admitted to an intensive care unit staffed by personnel skilled in maintaining ventilation and airway A 33-year-old woman visited the emergency department presenting with fever and dyspnea. She was pregnant with gestational age of 31 weeks and 6 days. She had dysuria for 7 days, and fever and dyspnea for 1 day. The vital signs were as follows: blood pressure 110/70 mmHg, heart rate 118 beats/minute, respiratory rate 28/minute, body temperature 38.7℃, and oxygen saturation by pulse oximetry 84% during inhalation of 5 liters of oxygen by nasal prongs. Crackles were heard over both lung fields. There were no signs of uterine contractions. Chest X-ray and chest computed tomography scan showed multiple consolidations and air bronchograms in both lungs. According to urinalysis, there was pyuria and microscopic hematuria. She was diagnosed with community-acquired pneumonia and urinary tract infection (UTI) that progressed to severe sepsis and acute respiratory failure. We found extended-spectrum beta-lactamase producing <iEscherichia coli</i in the blood culture and methicillin-resistant Staphylococcus aureus in the sputum culture. The patient was transferred to the intensive care unit with administration of antibiotics and supplementation of high-flow oxygen. On hospital day 2, hypoxemia was aggravated. She underwent endotracheal intubation and mechanical ventilation. After 3 hours, fetal distress was suspected. Under 100% fraction of inspired oxygen, her oxygen partial pressure was 87 mmHg in the arterial blood. She developed acute kidney injury and thrombocytopenia. We diagnosed her with multi-organ failure due to severe sepsis. After an emergent cesarean section, pneumonia, UTI, and other organ failures gradually recovered. The patient and baby were discharged soon thereafter. Three patients had chronic respiratory disorders: a 42-year-old man with glycogenosis type II was tired, had headaches, poor pulmonary function values and, according to the arterial blood gas values, hypercapnia; a man aged 24 with Duchenne's muscular dystrophy had variable moderate dyspnoea with hypoxia and hypercapnia, and a man aged 64 years with an mitochondrial myopathy complained of dyspnoea and headache but had good blood gas values. The symptoms and abnormalities of the first patient were suppressed by nocturnal ventilatory support through a nasal mask system, the second preferred to refrain from ventilatory support and died a few weeks later and the symptoms of the third patient decreased without ventilatory support. Assessing a ventilatory disorder in patients with a neuromuscular disease is not always simple. Symptoms suggestive of nocturnal hypoventilation may occur in patients without respiratory insufficiency. It is also possible for patients with chronic respiratory insufficiency to be free of symptoms. Determinations of the arterial blood gas values are the most reliable method. Since normal daytime values do not exclude a nocturnal respiratory insufficiency, it is advisable in case of suspicion of nocturnal hypoventilation to measure the arterial blood gas values at night, as well. Nocturnal pulse oximetry does not always adequately reflect the degree of hypoventilation. In view of the positive effects of assisted respiration, adequate diagnostic examinations and early referral to a centre for home mechanical ventilation are advisable. Whichever mode of MV is used in acute respiratory failure, the evidence from several important controlled trials indicates that a protective ventilation approach guided by the following principles (and summarized in Fig. 323-1) is safe and offers the best chance of a good outcome: (1) Set a target tidal volume close to 6 mL/kg of ideal body weight. (2) Prevent plateau pressure (static pressure in the airway at the end of inspiration) exceeding 30 cm H2O. (3) Use the lowest possible fraction of inspired oxygen (Fio2) to keep the Sao2 at ≥90%. (4) Adjust the PEEP to maintain alveolar patency while preventing overdistention and closure/reopening. With the application of these techniques, the mortality rate among patients with acute hypoxemic respiratory failure has decreased to ~30% from close to 50% a decade ago. To describe a clinical case and to analyze our own practice of using NIVL in a myasthenia (MG) gravis patient. Since 2018 in the Republican Research and Clinical Center of Neurology and Neurosurgery NIVL has been performed in 29 patients (21 amyotrophic lateral sclerosis patients and 8 MG patients). The research was carried out using the portable polysomnograph Polymate YH-1000C (BMC, China) and in the Sleep Laboratory of the Republican Clinical Medical Center of the Presidential Administration of the Republic of Belarus using SOMNOlab V 2.19 (Weinmann, Germany). Respiratory support was provided by the Ventimotion 2 device (Weinmann, Germany). The article presents our own experience of using NIVL in MG patient and profound description of the diagnostic and therapeutic complex. The development of chronic respiratory failure in NMD is based on a violation of the ventilation-perfusion ratio in the alveoli as a result of the development of hypoventilation due to restrictive disorders (namely, due to weakness of the respiratory muscles). Compensatory mechanisms eventually lead to an increase in the work on the affected respiratory muscles that leads to the formation of a vicious circle. The use of NIVL provides adequate ventilation of the lungs providing rest for the respiratory muscles. Like any other medical intervention NIVL has indications and contraindications, advantages and disadvantages that are described in this article. The use of NIVL helps to reduce the risk and frequency of respiratory complications, the number and duration of hospitalizations that significantly affects the prognosis and course of NMD as well as improves the quality of life and the level of adaptation of patients. It has been hypothesized that silent hypoxemia is the cause of rapid progressive respiratory failure with severe hypoxia that occurs in some COVID-19 patients without warning. A 60-year-old male presented cough without any breathing difficulty. Vital signs showed blood pressure 130/75 mmHg, pulse 84x/minute, respiratory rate (RR) 21x/minute, body temperature 36.5C, and oxygen saturation (SpO2) 75% on room air. RT-PCR for COVID-19 were positive. On third day, he complained of worsening of breath shortness, but his RR was still normal (22x/minute) with SpO2 of 98% on 3 L/minute oxygen via nasal cannula. On fifth day, he experienced severe shortness of breath with RR 38x/minute. He was then intubated using a synchronized intermittent mandatory ventilation. Blood gas analysis showed pH 7.54, PaO2 58.9 mmHg, PaCO2 31.1 mmHg, HCO3 26.9mEq/L, SaO2 94.7%, FiO2 30%, and P/F ratio 196 mmHg. On eighth day, his condition deteriorated with blood pressure 80/40 mmHg with norepinephrine support, pulse 109x/minute, and SpO2 72% with ventilator. He experienced cardiac arrest and underwent basic life support, then resumed strained breathing with return of spontaneous circulation. Blood gas analysis showed pH 7.07, PaO2 58.1 mmHg, PaCO2 108.9 mmHg, HCO3 32.1mEq/L, SaO2 78.7%, FiO2 90%, and P/F ratio 65 mmHg. Three hours later, he suffered cardiac arrest again and eventually died. Possible mechanisms of silent hypoxemia are V/Q mismatch, intrapulmonary shunting, and intravascular microthrombi. Silent hypoxemia might be considered as an early sign of deterioration of COVID-19 patients, thus, physician may be able to intervene early and decrease its morbidity and mortality. Non-invasive ventilation (NIV) given to the right patient, in the right setting, in the right way and at the right time improves outcomes. However, national audits reveal poor practice in patient selection, clinical judgement, treatment initiation and availability of trained staff. NIV is indicated for persistent acute hypercapnic respiratory failure (AHRF) with acidosis after usual medical management in chronic obstructive pulmonary disease (COPD) exacerbation and even without acidosis in neuromuscular disorders or other restrictive conditions eg obesity hypoventilation or kyphoscoliosis. Having trained staff in a suitable environment with adequate equipment are keys to its success, along with close monitoring. A plan should be put in place at the time of initiating NIV about the ceiling of care, eg escalation to intubation or palliation, if the patient is not improving with NIV. Early NIV failure is most likely due to technical issues, such as inadequate pressures or mask leak, while late failure is usually the consequence of advanced disease. Any presentation with AHRF is a poor prognostic indicator and outpatient respiratory follow-up is indicated following discharge. For selected patients with COPD who remain hypercapnic 2 weeks after an exacerbation, domiciliary NIV can reduce admissions and improve survival. For patients with neuromuscular disorders or kyphoscoliosis a presentation with AHRF almost always indicates the need for domiciliary NIV. Minute ventilation, then, will depend on T low and the patient's tidal volumes during T high. Indications for the use of APRV: ARDS that is difficult to oxygenate with AC Acute lung injury Postoperative atelectasis. Advantages of APRV: APRV is a good mode for lung protection ventilation. The ability to set the P high means that the operator has control over the plateau pressure which can significantly lower the incidence of barotrauma Because the patient initiates his respiratory efforts, there is better gas distribution secondary to improved V/Q matching. Constant high pressure means more recruitment (open lung strategy) APRV may improve oxygenation in ARDS patients who are difficult to oxygenate on AC APRV may reduce the need for sedation and neuromuscular blocking agents as the patient may be more comfortable than with other modes. Disadvantages and contraindications: The mortality of severe ARDS is almost 60%. Ventilation-associated lung-injury can be avoided by low-pressure, low-volume ventilation. Potential use of ECMO in case of refractory hypoxemia beside modern ventilatory therapy can be considered. Increasing numbers of respiratory ECMO runs are seen worldwide, though the efficacy remains controversial. The authors present the first successful venovenous-ECMO treatment in severe ARDS in our Institute. We report the case of a 67-year-old male who was admitted with community-acquired pneumonia caused by Legionella. Despite empirical and later targeted antibiotic therapy, severe ARDS with sepsis evolved. Neither ventilation nor prone position resulted in permanent improvement in oxygenation. The patient was referred to our Institute for extracorporeal life support (ECLS) therapy. On admission, blood gas showed severe hypoxemia with mild hypercapnia (PaO<sub2</sub/FiO<sub2</sub: 60, pCO<sub2</sub: 53 mmHg at PEEP: 14 mmHg, PIP: 45 mmHg). X-ray showed bilateral patchy infiltrates while cardiac impairment (EF: 45%) and dilated right ventricle were seen on echocardiography. Elevated pulmonary artery pressure (mPAP: 41 mmHg) was measured. After implantation of femoral-jugular VV ECMO, oxygen saturation was appropriate with lung protective ventilation (FiO<sub2</sub: 0.5, TV: 3-4 ml/kg). Improving lung function enabled us to stop ECMO after 8 days and further 5 days later the patient was weaned off ventilation. After 21 days of intensive care we discharged him to the referral hospital. By reporting this case we emphasise the potential role of respiratory ECMO. Consideration should be given to increase the contingent of this modality in the Hungarian intensive care in accordance with international practice. Orv Hetil. 2019; 160(6): 235-240.\nHere is the question:\nPNEUMOLOGY AND THORACIC SURGERY: While you are on call in the Emergency Department of your hospital, you have to attend a 64-year-old patient with acute respiratory failure. His clinical condition is critical, with low oxygen saturation and hemodynamic instability. An urgent chest X-ray was performed showing atelectasis of 2/3 of the right lung. Orotracheal intubation and assisted ventilation were performed, with Fi02 of 1.0. Subsequent arterial blood gas analysis showed pH 7.23, Pa02 60 mmHg and PaC02 30 mmHg. What was the cause of the hypoxemia?\nHere are the potential choices:\n1. Short circuit.\n2. Hypoventilation.\n3. Low inspired 02 pressure.\n4. Neuromuscular disease.\nThe correct answer is: ",
        "gold_answer": "1 Short circuit.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n This type of respiratory failure is caused by conditions that affect oxygenation, such as: Low ambient oxygen (e.g. at high altitude) Ventilation-perfusion mismatch (parts of the lung receive oxygen but not enough blood to absorb it, e.g. pulmonary embolism) Alveolar hypoventilation (decreased minute volume due to reduced respiratory muscle activity, e.g. in acute neuromuscular disease); this form can also cause type 2 respiratory failure if severe. Diffusion problem (oxygen cannot enter the capillaries due to parenchymal disease, e.g. in pneumonia or ARDS) Shunt (oxygenated blood mixes with non-oxygenated blood from the venous system, e.g. right to left shunt) Type 2 Hypoxemia (PaO2 <8kPa or normal) with hypercapnia (PaCO2 >6.0kPa). The basic defect in type 2 respiratory failure is characterized by: {| class=\"wikitable\" |PaO2 || decreased (< )or normal |- | PaCO2 || increased (> ) |- | PA-aO2 || normal |- |pH || <7.35 |} Intubation may be necessary for a patient with decreased oxygen content and oxygen saturation of the blood caused when their breathing is inadequate (hypoventilation), suspended (apnea), or when the lungs are unable to sufficiently transfer gasses to the blood. Such patients, who may be awake and alert, are typically critically ill with a multisystem disease or multiple severe injuries. Examples of such conditions include cervical spine injury, multiple rib fractures, severe pneumonia, acute respiratory distress syndrome (ARDS), or near-drowning. Specifically, intubation is considered if the arterial partial pressure of oxygen (PaO2) is less than 60 millimeters of mercury (mm Hg) while breathing an inspired O2 concentration (FIO2) of 50% or greater. In patients with elevated arterial carbon dioxide, an arterial partial pressure of CO2 (PaCO2) greater than 45 mm Hg in the setting of acidemia would prompt intubation, especially if a series of measurements demonstrate a worsening Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise in arterial carbon dioxide levels is called hypercapnia. Respiratory failure is classified as either Type 1 or Type 2, based on whether there is a high carbon dioxide level, and can be acute or chronic. In clinical trials, the definition of respiratory failure usually includes increased respiratory rate, abnormal blood gases (hypoxemia, hypercapnia, or both), and evidence of increased work of breathing. Respiratory failure causes an altered mental status due to ischemia in the brain. The typical partial pressure reference values are oxygen Pa O2 more than 80 mmHg (11 kPa) and carbon dioxide Pa CO2 less than 45 mmHg (6.0 kPa). Cause Causes Restricted oxygen flow to the body's tissue that leads to hypoxia can be caused by a variety of situations or other underlying conditions. High altitude (above 3048 metres/10,000 feet) Hypoventilation – failure of respiratory pump due to any cause (fatigue, barbiturate poisoning, pneumothorax, etc.) Ventilation perfusion mismatch Obstructed airway Drowning Abnormal pulmonary function Chronic obstructive pulmonary diseases (COPD) Neuromuscular diseases or interstitial lung disease Constrained blood flow to a tissue (such as atherosclerosis or vasoconstriction) Blockage in blood flow like a sickle cell crisis Low or no blood flow caused by bleeding or heart attack Malformed vascular system such as an anomalous coronary artery Limited oxygen transportation due to anemia While respiring in the open air at high altitudes, the human body experiences altitude sickness and hypoxemia due to a low partial pressure of oxygen, decreasing the carriage of oxygen by hemoglobin. Because A–a gradient is approximated as: (150 − 5/4(P)) – at sea level and on room air (0.21x(760-47) = 149.7 mmHg for the alveolar oxygen partial pressure, after accounting for the water vapor), the direct mathematical cause of a large value is that the blood has a low , a low Pa, or both. is very easily exchanged in the lungs and low Pa directly correlates with high minute ventilation; therefore a low arterial Pa indicates that extra respiratory effort is being used to oxygenate the blood. A low indicates that the patient's current minute ventilation (whether high or normal) is not enough to allow adequate oxygen diffusion into the blood. Therefore, the A–a gradient essentially demonstrates a high respiratory effort (low arterial Pa) relative to the achieved level of oxygenation (arterial ). A high A–a gradient could indicate a patient breathing hard to achieve normal oxygenation, a patient breathing normally and attaining low oxygenation, or a patient breathing hard and still Asthma and COPD Acute exacerbations of chronic respiratory diseases, mainly asthma and chronic obstructive pulmonary disease (COPD), are assessed as emergencies and treated with oxygen therapy, bronchodilators, steroids or theophylline, have an urgent chest X-ray and arterial blood gases and are referred for intensive care if necessary. Noninvasive ventilation in the ED has reduced the requirement for tracheal intubation in many cases of severe exacerbations of COPD. Special facilities, training, and equipment An ED requires different equipment and different approaches than most other hospital divisions. Patients frequently arrive with unstable conditions, and so must be treated quickly. They may be unconscious, and information such as their medical history, allergies, and blood type may be unavailable. ED staff are trained to work quickly and effectively even with minimal information. When 100% oxygen (1.00 Fi) is used initially for an adult, it is easy to calculate the next Fi to be used, and easy to estimate the shunt fraction. The estimated shunt fraction refers to the amount of oxygen not being absorbed into the circulation. In normal physiology, gas exchange of oxygen and carbon dioxide occurs at the level of the alveoli in the lungs. The existence of a shunt refers to any process that hinders this gas exchange, leading to wasted oxygen inspired and the flow of un-oxygenated blood back to the left heart, which ultimately supplies the rest of the body with de-oxygenated blood. When using 100% oxygen, the degree of shunting is estimated as 700 mmHg - measured Pa. For each difference of 100 mmHg, the shunt is 5%. A shunt of more than 25% should prompt a search for the cause of this hypoxemia, such as mainstem intubation or pneumothorax, and should be treated accordingly. If such complications are not present, other causes must be sought after, and positive Berlin Criteria: as stated on UpToDate (2020) Timing: onset of respiratory symptoms within one week of a injury/insult. Chest Imaging: either chest x-ray or CT scan, must show bilateral opacities that cannot be fully explained by other conditions such as effusion, lung/lobar collapse, or lung nodules. Origin of Edema: respiratory failure that cannot be fully explained by cardiac failure or fluid overload, this needs objective assessment such as an echocardiogram. Impaired Oxygenation: this can be determined by looking at the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2) that can be obtained based on an arterial blood gas test. Note: all PaO2/FiO2 ratios used in the determination of the severity of ARDS require that the patient be on a ventilator at a setting that includes 5 cm H2O or more of positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP). The typical partial pressure reference values are oxygen Pa O2 more than 80 mmHg (11 kPa) and carbon dioxide Pa CO2 less than 45 mmHg (6.0 kPa). Cause Several types of conditions can potentially result in respiratory failure: Conditions that reduce the flow of air into and out of the lungs, including physical obstruction by foreign bodies or masses and reduced breathing due to drugs or changes to the chest. Conditions that impair the lungs' blood supply. These include thromboembolic conditions and conditions that reduce the output of the right heart, such as right heart failure and some myocardial infarctions. Conditions that limit the ability of the lung tissue to exchange oxygen and carbon dioxide between the blood and the air within the lungs. Any disease which can damage the lung tissue can fit into this category. The most common causes are (in no particular order) infections, interstitial lung disease, and pulmonary oedema. Diagnosis Intermittent positive pressure breathing (IPPB) is a respiratory therapy treatment for people who are hypoventilating. While not a preferred method due to cost, IPPB is used to expand the lungs, deliver aerosol medications, and in some circumstances ventilate the patient. Indications IPPB may be indicated for patients who are at risk for developing atelectasis and who are unable or unwilling to breathe deeply without assistance. In patients with severe lung hyperinflation, IPPB may decrease dyspnea and discomfort during nebulized therapy. Contraindications Most contraindications are relative, such as nausea, hemodynamic instability, tracheal fistula, singulation and hemoptysis. Untreated tension pneumothorax is an absolute contraindication. IMPLEMENTATION When treating atelectasis - Therapy should be volume-oriented 2. Tidal volumes(VT) must be measured 3. VT goals must be set 4. VT goal of 10-15mL/kg ofbody weight A 68-year-old man with severe dyspnea was admitted as an emergency case. He had no past history of any respiratory or neuromuscular diseases. Immediately after insufflation of oxygen, respiratory arrest occurred. The blood gas analysis showed hypoxemia and severe hypercapnia (PaO2; 32 mmHg, PaCO2; 127 mmHg). We diagnosed as CO2 narcosis, and he was treated with a respirator in the ICU. He showed nonflaccid bilateral diaphragmatic paralysis and muscle atrophy of the upper extremities. As the EMG showed giant spikes of neurogenic pattern, he was diagnosed as ALS. Weaning from the respirator failed because of his respiratory muscle fatigue. He was given rehabilitation during the day time and ventilatory support with the respirator during the night. We conclude that if we meet with an emergency patient with CO2 narcosis without any pulmonary disorder, we have to suspect neuromuscular diseases, e.q. ALS. In some of such cases, mechanical ventilation supports social rehabilitation. We present a case of postural hypoxemia with a final diagnosis of myasthenia gravis (MG). A 62-year-old man experienced double vision in his left eye from December 2008 and received a diagnosis of diabetic neuropathy. From mid-December he began to experience breathing difficulties at night when in a supine position and was admitted to our hospital. Bilateral diaphragmatic elevation was observed on a chest X-ray film, and lower lung atelectasis and an anterior mediastinal tumor were observed on chest CT. However, his breathing difficulties only occurred when he was in a supine position. Therefore, we performed blood gas analysis in supine and sitting positions. Hypoxemia, hypercapnia and an increase in A-aDO2 were observed in the supine position, leading to a diagnosis of postural hypoxemia. Due to the exacerbation of his double vision, the patient was referred to the ophthalmology and neurology departments where he tested positive for anti-acetylcholine receptor antibodies and also on a tensilon test, resulting in a final diagnosis of MG. During the tensilon test, the patient's breathing difficulties in the supine position improved, and therefore his postural hypoxemia was thought to have resulted from diaphragmatic muscle weakness as a result of MG. MG respiratory failure is typically of the acute fulminating type and is considered to be a critical condition. However, it should be noted that there are cases, such as the present one, in which MG presents as postural hypoxemia. The authors report a rare, recently diagnosed and atypical mishap during one-lung ventilation (OLV) via a double lumen tube (DLT) and left-sided thoracotomy: an ipsilateral pneumothorax during ventilation of the right lung. This occurred in a 63-year-old patient with chronic obstructive airway disease who was scheduled for urgent repair of a descending thoracic aortic aneurysm. Anaesthesia and surgery were uneventful until aortic cross-clamping release. The common presentation of increased intrathoracic extrapleural pressure owing to a pneumothorax in patients with mechanically ventilated lungs is a rapid decrease in oxygen saturation, followed or paralleled by haemodynamic deterioration. Although the above presentation could be seen in this case, the diagnosis of a tension pneumothorax was delayed twice. First, symptoms were initially obscured by haemodynamic changes resulting from a head-down tilt and aortic declamping. Second, since the lack of consolidation after aortic declamping focused attention on the airway problems, complications resulting from the use of a DLT were primarily considered. In particular, since breathing sounds were detectable initially, malposition or torsion of the DLT had to be excluded by fibre-optic bronchoscopy, which involved a further delay. Finally, two observations led to the diagnosis of a right-sided tension pneumothorax: (1) bullae of the contralateral lung, detected during thoracotomy; (2) the finding that ventilation of both lungs and the left lung subsequently increased arterial (SaO2) and mixed venous oxygen saturation (SvO2) and the circulatory status, but ventilation of the right lung caused a deterioration. Chest radiography and insertion of a chest tube with drainage of air, thereafter, validated our hypothesis. The time course of oxygen desaturation during OLV and tension pneumothorax was as severe as expected; the time course of haemodynamic deterioration, however, appeared quicker and had more impact than expected. Assuming that mediastinal deviation was not hindered by contralateral intrathoracic pressure during thoracotomy, we believed that circulation should be depressed later or to a lesser extent in patients with an intraoperative pneumothorax. Yet, during thoracotomy, decrease in cardiac filling and output during tension pneumothorax in OLV obviously results primarily from the immovability of the mediastinum owing to mediastinal fixation and is at least as decisive as the contralateral intrathoracic pressure in closed-chest patients. In summary, a tension pneumothorax during one-lung ventilation and thoracotomy is a rare, but disastrous complication during the use of a DLT, which has not, to our knowledge, been reported previously. We recommend that tension pneumothorax be added to the list of complications and problems during OLV by the use of a DLT, especially in patients with structural lung diseases. Respiratory compromise describes a deterioration in respiratory function with a high likelihood of rapid progression to respiratory failure and death. Respiratory failure occurs when inadequate gas exchange by the respiratory system occurs, with a low oxygen level or a high carbon dioxide level. Causes Patients in acute care hospitals, particularly those with respiratory conditions, are at risk for developing respiratory compromise. Respiratory failure requiring emergency mechanical ventilation occurs in over 40,000 patients per year in the United States. In postoperative patients in the United States, the National Surgical Quality Improvement Program reports that 1.03% of all surgical patients require an unplanned intubation postoperatively. General principles of respiratory evaluation in patients with PNS involvement, regardless of cause, include assessment of pulmonary mechanics, such as maximal inspiratory force (MIF) and vital capacity (VC), and evaluation of strength of bulbar muscles. Regardless of the cause of weakness, endotracheal intubation should be considered when the MIF falls to <–25 cmH2O or the VC is <1 L. Also, patients with severe palatal weakness may require endotracheal intubation in order to prevent acute upper airway obstruction or recurrent aspiration. Arterial blood gases and oxygen saturation from pulse oximetry are used to follow patients with potential respiratory compromise from PNS dysfunction. However, intubation and mechanical ventilation should be undertaken based on clinical assessment rather than waiting until oxygen saturation drops or CO2 retention develops from hypoventilation. Noninvasive mechanical ventilation may be considered initially in lieu of endotracheal intubation but is If Pa:Fi < 300 mmHg (40 kPa), then the definitions recommended a classification as \"acute lung injury\" (ALI). Note that according to these criteria, arterial blood gas analysis and chest X-ray were required for formal diagnosis. Limitations of these definitions include lack of precise definition of acuity, nonspecific imaging criteria, lack of precise definition of hypoxemia with regards to PEEP (affects arterial oxygen partial pressure), arbitrary Pa thresholds without systematic data. are usually necessary (see further on). However, a fairly severe impairment of ventilation may occur before the first sign of dyspnea appears and before there is elevation of arterial carbon dioxide content. Incipient respiratory failure may be evident by tachypnea and a decrease in arterial oxygen tension (Po2 less than 85 mm Hg) reflecting pulmonary atelectasis. When respiratory failure arises gradually as the patient weakens over days, there is slight tachycardia, diaphoresis, restlessness, and tachypnea. Attempts to forestall intubation and positive-pressure ventilation by using negative-pressure cuirass-type devices have been unsatisfactory in our experience. Patients with oropharyngeal weakness require intubation even earlier so as to prevent aspiration, but full mechanical ventilation is not always necessary at the same time. Patients in these circumstances should obviously be admitted to an intensive care unit staffed by personnel skilled in maintaining ventilation and airway A 33-year-old woman visited the emergency department presenting with fever and dyspnea. She was pregnant with gestational age of 31 weeks and 6 days. She had dysuria for 7 days, and fever and dyspnea for 1 day. The vital signs were as follows: blood pressure 110/70 mmHg, heart rate 118 beats/minute, respiratory rate 28/minute, body temperature 38.7℃, and oxygen saturation by pulse oximetry 84% during inhalation of 5 liters of oxygen by nasal prongs. Crackles were heard over both lung fields. There were no signs of uterine contractions. Chest X-ray and chest computed tomography scan showed multiple consolidations and air bronchograms in both lungs. According to urinalysis, there was pyuria and microscopic hematuria. She was diagnosed with community-acquired pneumonia and urinary tract infection (UTI) that progressed to severe sepsis and acute respiratory failure. We found extended-spectrum beta-lactamase producing <iEscherichia coli</i in the blood culture and methicillin-resistant Staphylococcus aureus in the sputum culture. The patient was transferred to the intensive care unit with administration of antibiotics and supplementation of high-flow oxygen. On hospital day 2, hypoxemia was aggravated. She underwent endotracheal intubation and mechanical ventilation. After 3 hours, fetal distress was suspected. Under 100% fraction of inspired oxygen, her oxygen partial pressure was 87 mmHg in the arterial blood. She developed acute kidney injury and thrombocytopenia. We diagnosed her with multi-organ failure due to severe sepsis. After an emergent cesarean section, pneumonia, UTI, and other organ failures gradually recovered. The patient and baby were discharged soon thereafter. Three patients had chronic respiratory disorders: a 42-year-old man with glycogenosis type II was tired, had headaches, poor pulmonary function values and, according to the arterial blood gas values, hypercapnia; a man aged 24 with Duchenne's muscular dystrophy had variable moderate dyspnoea with hypoxia and hypercapnia, and a man aged 64 years with an mitochondrial myopathy complained of dyspnoea and headache but had good blood gas values. The symptoms and abnormalities of the first patient were suppressed by nocturnal ventilatory support through a nasal mask system, the second preferred to refrain from ventilatory support and died a few weeks later and the symptoms of the third patient decreased without ventilatory support. Assessing a ventilatory disorder in patients with a neuromuscular disease is not always simple. Symptoms suggestive of nocturnal hypoventilation may occur in patients without respiratory insufficiency. It is also possible for patients with chronic respiratory insufficiency to be free of symptoms. Determinations of the arterial blood gas values are the most reliable method. Since normal daytime values do not exclude a nocturnal respiratory insufficiency, it is advisable in case of suspicion of nocturnal hypoventilation to measure the arterial blood gas values at night, as well. Nocturnal pulse oximetry does not always adequately reflect the degree of hypoventilation. In view of the positive effects of assisted respiration, adequate diagnostic examinations and early referral to a centre for home mechanical ventilation are advisable. Whichever mode of MV is used in acute respiratory failure, the evidence from several important controlled trials indicates that a protective ventilation approach guided by the following principles (and summarized in Fig. 323-1) is safe and offers the best chance of a good outcome: (1) Set a target tidal volume close to 6 mL/kg of ideal body weight. (2) Prevent plateau pressure (static pressure in the airway at the end of inspiration) exceeding 30 cm H2O. (3) Use the lowest possible fraction of inspired oxygen (Fio2) to keep the Sao2 at ≥90%. (4) Adjust the PEEP to maintain alveolar patency while preventing overdistention and closure/reopening. With the application of these techniques, the mortality rate among patients with acute hypoxemic respiratory failure has decreased to ~30% from close to 50% a decade ago. To describe a clinical case and to analyze our own practice of using NIVL in a myasthenia (MG) gravis patient. Since 2018 in the Republican Research and Clinical Center of Neurology and Neurosurgery NIVL has been performed in 29 patients (21 amyotrophic lateral sclerosis patients and 8 MG patients). The research was carried out using the portable polysomnograph Polymate YH-1000C (BMC, China) and in the Sleep Laboratory of the Republican Clinical Medical Center of the Presidential Administration of the Republic of Belarus using SOMNOlab V 2.19 (Weinmann, Germany). Respiratory support was provided by the Ventimotion 2 device (Weinmann, Germany). The article presents our own experience of using NIVL in MG patient and profound description of the diagnostic and therapeutic complex. The development of chronic respiratory failure in NMD is based on a violation of the ventilation-perfusion ratio in the alveoli as a result of the development of hypoventilation due to restrictive disorders (namely, due to weakness of the respiratory muscles). Compensatory mechanisms eventually lead to an increase in the work on the affected respiratory muscles that leads to the formation of a vicious circle. The use of NIVL provides adequate ventilation of the lungs providing rest for the respiratory muscles. Like any other medical intervention NIVL has indications and contraindications, advantages and disadvantages that are described in this article. The use of NIVL helps to reduce the risk and frequency of respiratory complications, the number and duration of hospitalizations that significantly affects the prognosis and course of NMD as well as improves the quality of life and the level of adaptation of patients. It has been hypothesized that silent hypoxemia is the cause of rapid progressive respiratory failure with severe hypoxia that occurs in some COVID-19 patients without warning. A 60-year-old male presented cough without any breathing difficulty. Vital signs showed blood pressure 130/75 mmHg, pulse 84x/minute, respiratory rate (RR) 21x/minute, body temperature 36.5C, and oxygen saturation (SpO2) 75% on room air. RT-PCR for COVID-19 were positive. On third day, he complained of worsening of breath shortness, but his RR was still normal (22x/minute) with SpO2 of 98% on 3 L/minute oxygen via nasal cannula. On fifth day, he experienced severe shortness of breath with RR 38x/minute. He was then intubated using a synchronized intermittent mandatory ventilation. Blood gas analysis showed pH 7.54, PaO2 58.9 mmHg, PaCO2 31.1 mmHg, HCO3 26.9mEq/L, SaO2 94.7%, FiO2 30%, and P/F ratio 196 mmHg. On eighth day, his condition deteriorated with blood pressure 80/40 mmHg with norepinephrine support, pulse 109x/minute, and SpO2 72% with ventilator. He experienced cardiac arrest and underwent basic life support, then resumed strained breathing with return of spontaneous circulation. Blood gas analysis showed pH 7.07, PaO2 58.1 mmHg, PaCO2 108.9 mmHg, HCO3 32.1mEq/L, SaO2 78.7%, FiO2 90%, and P/F ratio 65 mmHg. Three hours later, he suffered cardiac arrest again and eventually died. Possible mechanisms of silent hypoxemia are V/Q mismatch, intrapulmonary shunting, and intravascular microthrombi. Silent hypoxemia might be considered as an early sign of deterioration of COVID-19 patients, thus, physician may be able to intervene early and decrease its morbidity and mortality. Non-invasive ventilation (NIV) given to the right patient, in the right setting, in the right way and at the right time improves outcomes. However, national audits reveal poor practice in patient selection, clinical judgement, treatment initiation and availability of trained staff. NIV is indicated for persistent acute hypercapnic respiratory failure (AHRF) with acidosis after usual medical management in chronic obstructive pulmonary disease (COPD) exacerbation and even without acidosis in neuromuscular disorders or other restrictive conditions eg obesity hypoventilation or kyphoscoliosis. Having trained staff in a suitable environment with adequate equipment are keys to its success, along with close monitoring. A plan should be put in place at the time of initiating NIV about the ceiling of care, eg escalation to intubation or palliation, if the patient is not improving with NIV. Early NIV failure is most likely due to technical issues, such as inadequate pressures or mask leak, while late failure is usually the consequence of advanced disease. Any presentation with AHRF is a poor prognostic indicator and outpatient respiratory follow-up is indicated following discharge. For selected patients with COPD who remain hypercapnic 2 weeks after an exacerbation, domiciliary NIV can reduce admissions and improve survival. For patients with neuromuscular disorders or kyphoscoliosis a presentation with AHRF almost always indicates the need for domiciliary NIV. Minute ventilation, then, will depend on T low and the patient's tidal volumes during T high. Indications for the use of APRV: ARDS that is difficult to oxygenate with AC Acute lung injury Postoperative atelectasis. Advantages of APRV: APRV is a good mode for lung protection ventilation. The ability to set the P high means that the operator has control over the plateau pressure which can significantly lower the incidence of barotrauma Because the patient initiates his respiratory efforts, there is better gas distribution secondary to improved V/Q matching. Constant high pressure means more recruitment (open lung strategy) APRV may improve oxygenation in ARDS patients who are difficult to oxygenate on AC APRV may reduce the need for sedation and neuromuscular blocking agents as the patient may be more comfortable than with other modes. Disadvantages and contraindications: The mortality of severe ARDS is almost 60%. Ventilation-associated lung-injury can be avoided by low-pressure, low-volume ventilation. Potential use of ECMO in case of refractory hypoxemia beside modern ventilatory therapy can be considered. Increasing numbers of respiratory ECMO runs are seen worldwide, though the efficacy remains controversial. The authors present the first successful venovenous-ECMO treatment in severe ARDS in our Institute. We report the case of a 67-year-old male who was admitted with community-acquired pneumonia caused by Legionella. Despite empirical and later targeted antibiotic therapy, severe ARDS with sepsis evolved. Neither ventilation nor prone position resulted in permanent improvement in oxygenation. The patient was referred to our Institute for extracorporeal life support (ECLS) therapy. On admission, blood gas showed severe hypoxemia with mild hypercapnia (PaO<sub2</sub/FiO<sub2</sub: 60, pCO<sub2</sub: 53 mmHg at PEEP: 14 mmHg, PIP: 45 mmHg). X-ray showed bilateral patchy infiltrates while cardiac impairment (EF: 45%) and dilated right ventricle were seen on echocardiography. Elevated pulmonary artery pressure (mPAP: 41 mmHg) was measured. After implantation of femoral-jugular VV ECMO, oxygen saturation was appropriate with lung protective ventilation (FiO<sub2</sub: 0.5, TV: 3-4 ml/kg). Improving lung function enabled us to stop ECMO after 8 days and further 5 days later the patient was weaned off ventilation. After 21 days of intensive care we discharged him to the referral hospital. By reporting this case we emphasise the potential role of respiratory ECMO. Consideration should be given to increase the contingent of this modality in the Hungarian intensive care in accordance with international practice. Orv Hetil. 2019; 160(6): 235-240.\nHere is the question:\nPNEUMOLOGY AND THORACIC SURGERY: While you are on call in the Emergency Department of your hospital, you have to attend a 64-year-old patient with acute respiratory failure. His clinical condition is critical, with low oxygen saturation and hemodynamic instability. An urgent chest X-ray was performed showing atelectasis of 2/3 of the right lung. Orotracheal intubation and assisted ventilation were performed, with Fi02 of 1.0. Subsequent arterial blood gas analysis showed pH 7.23, Pa02 60 mmHg and PaC02 30 mmHg. What was the cause of the hypoxemia?\nHere are the potential choices:\n1. Short circuit.\n2. Hypoventilation.\n3. Low inspired 02 pressure.\n4. Neuromuscular disease.\nThe correct answer is: 1. Short circuit."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n On auscultation of a patient with mitral stenosis, there may be a holosystolic murmur at the apex, radiating to the back or clavicular area, a third heart sound, and a loud, palpable P2, heard best when lying on the left side. Patients also commonly have atrial fibrillation. Patients may have a laterally displaced apex beat, often with heave In acute cases, the murmur and tachycardia may be only distinctive signs. Tricuspid regurgitation Patients with tricuspid regurgitation may experience symptoms of right-sided heart failure, such as ascites, hepatomegaly, edema and jugular venous distension. Tricuspid regurgitation Patients with tricuspid regurgitation may experience symptoms of right-sided heart failure, such as ascites, hepatomegaly, edema and jugular venous distension. Signs of tricuspid regurgitation include pulsatile liver, prominent V waves and rapid y descents in jugular venous pressure. Auscultatory findings include inspiratory third heart sound at left lower sternal border (LLSB) and a blowing holosystolic murmur at LLSB, intensifying with inspiration, and decreasing with expiration and Valsalva maneuver. Patients may have a parasternal heave along LLSB. Atrial fibrillation is usually present in patients with tricuspid regurgitation Causes If there is increased stroke volume of the left ventricle due to volume overload, an ejection systolic 'flow' murmur may also be present when auscultating the same aortic area. Unless there is concomitant aortic valve stenosis, the murmur should not start with an ejection click. There may also be an Austin Flint murmur, a soft mid-diastolic rumble heard at the apical area; it appears when a regurgitant jet of blood from severe aortic regurgitation partially closes the anterior mitral leaflet. Peripheral physical signs of aortic regurgitation are related to the high pulse pressure and the rapid decrease in blood pressure during diastole due to blood returning to the heart from the aorta through the incompetent aortic valve, although the usefulness of some of the eponymous signs has been questioned: Phonocardiograms detect AI by having electric voltage mimic the sounds the heart makes. Characteristics- indicative of aortic regurgitation are as follow: Systolic and diastolic motions of the interventricular septum (IVS), especially of its lower portion at the level of the chordae tendineae, were evaluated by M-mode echocardiography in normal subjects and in patients with various cardiac disorders. The following conclusions were derived from this study. In normal subjects, downward motion of the IVS exhibited three patterns; namely, P1, between the onset of electrical depolarization and the onset of the second heart sound; P2, between the onset of the second heart sound and the E point of the anterior mitral leaflet; and P3, between the E point of the anterior mitral leaflet and the end of the left ventricular rapid filling phase, during each cardiac cycle. The systolic IVS pattern (P1) of atrial septal defect was classified as follows: Normal type: nearly normal posterior motion during ventricular systole, Flat type: flat motion during ventricular systole, Paradoxical (early systolic) type: anterior motion during the first half of ventricular systole, followed by normal posterior motion, Paradoxical (pansystolic) type: anterior motion during ventricular systole. In atrial septal defect, the right ventricular dimension was markedly increased in the flat and paradoxical (pansystolic) types compared with those of the normal and paradoxical (early systolic) types. Marked downward IVS motion (P2) was observed in cor pulmonale with paradoxical pulse, pulmonary hypertension, Ebstein's anomaly, pulmonic insufficiency, atrial septal defect, funnel chest, tricuspid insufficiency and constrictive pericarditis. In cor pulmonale with paradoxical pulse, the deep downward motion (P2) was observed more distinctly during inspiration compared to expiration, and right ventricular inflow velocity pattern was characterized by an apparent increase in peak flow in velocity of the diastolic rapid filling wave during inspiration. Two interesting findings were a deep \"y\" trough of the jugular pulse tracing and prominent P2 in funnel chest. Therefore, it was likely that exaggerated P2 seemed to be direct evidence of a marked increase in right ventricular rapid filling in the presence of normal or decreased left ventricular rapid filling. The augmented septal dip of P3 was observed in cases with the third heart sound as in normal subjects, and those with mitral insufficiency, and ventricular septal defect, constrictive pericarditis and mitral stenosis. We theorized that exaggerated P3 results from the \"sucking action\" secondary to increased left ventricular rapid filling velocity in cases with the third heart sound or constrictive pericarditis.(ABSTRACT TRUNCATED AT 400 WORDS) Associated lesions With severe pulmonary hypertension, a pansystolic murmur produced by functional tricuspid regurgitation may be audible along the left sternal border. This murmur is usually louder during inspiration and diminishes during forced expiration (Carvallo’s sign). When the cardiac output is markedly reduced in MS, the typical auscultatory findings, including the diastolic rumbling murmur, may not be detectable (silent MS), but they may reappear as compensation is restored. The Graham Steell murmur of pulmonary regurgitation, a high-pitched, diastolic, decrescendo blowing murmur along the left sternal border, results from dilation of the pulmonary valve ring and occurs in patients with mitral valve disease and severe pulmonary hypertension. This murmur may be indistinguishable from the more common murmur produced by aortic regurgitation (AR), although it may increase in intensity with inspiration and is accompanied by a loud and often palpable P2. Echocardiography Physiological tricuspid and pulmonary regurgitations are very often found by Echo-Doppler. They are generally slight, inaudible and devoid of significance. Tricuspid insufficiency nevertheless has the great advantage of enabling the calculation of pulmonary pressures. Auscultation is a good method for the diagnosis of rheumatic mitral insufficiency or related to prolapse, but is not reliable in other situations. Doppler is an excellent method for the qualitative and etiological diagnosis of mitral insufficiency but enables only semi-quantification. It also has the disadvantage of discovering minimal mitral insufficiency, the significance of which is uncertain. In contrast to auscultation, Doppler enables precise quantification in mitral stenosis. Auscultation is a good method for the diagnosis of aortic valve disease with the exception of slight insufficiency and stenosis in the elderly. Doppler enables the quantification of stenosis and semi-quantification of insufficiency. The existence of physiological aortic regurgitation is by no means certain. In conclusion, auscultation remains an important tool in cardiological diagnosis but has notable limitations. Echo-Doppler is a major advance but it is important to be aware of its limitations. For the best cardiac examination, it is important to have the patient both sit up and lay down at a 30-45˚ angle. Tapping with the fingertips (also known as percussion) can be used to estimate the size of the heart, though palpation is more accurate. From the left side of the chest, the doctor can tap the spaces between the ribs with the tips of their middle finger to listen for the dullness that will be present over the heart. Listening with a stethoscope (also known as auscultation) to all four areas of the heart: aortic, pulmonic, tricuspid and mitral. Any murmurs, rubs or gallops should be noted. Gallops are also known as a third (S3) or fourth (S4) heart sound. The absence of abnormalities (normal) may be recorded as \"no m/r/g\". The ACC and the AHA have called cardiac auscultation \"the most widely used method of screening for valvular heart disease.\" Because of its importance to the cardiac examination, cardiac auscultation has been covered in-depth elsewhere. Finally the sacrum and ankles are checked for pitting edema which is caused by right ventricular failure in isolation or as part of congestive cardiac failure. Auscultation One should comment on S1 and S2 – if the splitting is abnormal or louder than usual. S3 – the emphasis and timing of the syllables in the word Kentucky is similar to the pattern of sounds in a precordial S3. S4 – the emphasis and timing of the syllables in the word Tennessee is similar to the pattern of sounds in a precordial S4. If S4 S1 S2 S3 Also known as a gallop rhythm. diastolic murmurs (e.g. aortic regurgitation, mitral stenosis) systolic murmurs (e.g. aortic stenosis, mitral regurgitation) pericardial rub (suggestive of pericarditis) The base of the lungs should be auscultated for signs of pulmonary oedema due to a cardiac cause such as bilateral basal crepitations. A heart murmur was detected in a 10 mo old, female New Zealand White rabbit. Auscultation revealed cardiac murmurs both at the left and right hemithorax. Phonocardiography confirmed the systolic-diastolic nature of the left-sided and the systolic character of the right-sided murmur. Electrocardiography showed normal sinus rhythm; tall R waves and large T waves in lead II; and deep S waves in leads II, III, and aVF. Thoracic radiography demonstrated generalized cardiomegaly with prominent pulmonary vasculature. Echocardiography revealed a perimembraneous ventricular septal defect with aortic insufficiency. Signs of biventricular volume overload, relative pulmonic stenosis, and pulmonary valve insufficiency were also seen as consequences of the defect. Necropsy demonstrated a ventricular septal defect just below the aortic valve, a dilated pulmonary trunk, dilated and hypertrophied ventricles, dilated atria, and rightward displacement of the aortic root. Cardiac histopathology showed ventricular cardiomyocyte degeneration (swelling and hypereosinophilia of the cytoplasm with a loss of cross striation, and nuclear hyperchromasia), cartilaginous metaplasia of the aorta, and subendocardial fibrosis of the right ventricular flow tract. On auscultation of a patient with mitral stenosis, typically the most prominent sign is a loud S1. Another finding is an opening snap followed by a low-pitched diastolic rumble with presystolic accentuation. The opening snap follows closer to the S2 heart tone with worsening stenosis. The murmur is heard best with the bell of the stethoscope lying on the left side and its duration increases with worsening disease. Advanced disease may present with signs of right-sided heart failure such as parasternal heave, jugular venous distension, hepatomegaly, ascites and/or pulmonary hypertension (presenting with a loud P2). Signs increase with exercise and pregnancy. Mitral regurgitation Patients with mitral regurgitation may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, or pulmonary edema. An asymptomatic 29-year-old woman presented for prenatal counselling. She had a history of a heart murmur since childhood and a previous echocardiogram suggesting 'enlargement of the heart'. Physical exam revealed normal jugular venous pressure and contour. Precordial palpation was unremarkable. Auscultation, however, was abnormal; findings on inspiration and expiration are presented in Figure 1, sound clip. Based on the phonocardiogram and online supplementary audio clip, which of the following is correct? An early diastolic filling sound (S3) is heard, indicating increased right ventricular filling pressures.An ejection click without respiratory variation and a systolic ejection murmur are heard, consistent with bicuspid aortic valve stenosis.An ejection click with respiratory variation and a systolic ejection murmur are heard, consistent with pulmonic valve stenosis.A holosystolic murmur with inspiratory augmentation is heard, indicating tricuspid regurgitation. Mitral regurgitation typically is a holosystolic (pansystolic) murmur heard best at the apex, and may radiate to the axilla or precordium. A systolic click may be heard if there is associated mitral valve prolapse. Valsalva maneuver in mitral regurgitation associated with mitral valve prolapse will decrease left ventricular preload and move the murmur onset closer to S1, and isometric handgrip, which increases left ventricular afterload, will increase murmur intensity. In acute severe mitral regurgitation, a holosystolic (pansystolic) murmur may not be heard. Pulmonary valve stenosis typically is a crescendo-decrescendo systolic murmur heard best at the left upper sternal border, associated with a systolic ejection click that increases with inspiration (due to increased venous return to the right side of the heart) and sometimes radiates to the left clavicle. Medical signs of aortic regurgitation include increased pulse pressure by increased systolic and decreased diastolic blood pressure, but these findings may not be significant if acute. The patient may have a diastolic decrescendo murmur best heard at left sternal border, water hammer pulse, Austin Flint murmur, and a displaced apex beat down and to the left. A third heart sound may be present Mitral stenosis Patients with mitral stenosis may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, chest pain, hemoptysis, thromboembolism, or ascites and edema (if right-sided heart failure develops). Symptoms of mitral stenosis increase with exercise and pregnancy Tricuspid regurgitation (TR) with normal pulmonary artery pressures, as may occur with infective endocarditis, may produce an early systolic murmur. The murmur is soft (grade 1 or 2), is best heard at the lower left sternal border, and may increase in intensity with inspiration (Carvallo’s sign). Regurgitant “c-v” waves may be visible in the jugular venous pulse. TR in this setting is not associated with signs of right heart failure. Mid-Systolic Murmurs Mid-systolic murmurs begin at a short interval after , end before S (Fig. 51e-1C), and are usually crescendo-decrescendo in configuration. Aortic stenosis is the most common cause of a mid-systolic murmur in an adult. The murmur of AS is usually loudest to the right of the sternum in the second intercostal space (aortic area, Fig. 51e-2) and radiates into the carotids. Transmission of the mid-systolic murmur to the apex, where it becomes higher-pitched, is common (Gallavardin effect; see above). A double orifice mitral valve (DOMV) is usually an asymptomatic entity unless accompanied by mitral valve stenosis, regurgitation, or a concomitant congenital cardiac anomaly. In patients with an associated congenital heart defect, it is usual for that particular disorder to manifest on clinical examination as there are no signs specific to DOMV. In isolated DOMV, the extent of symptoms depends on the grade of left atrial pressure resulting in pulmonary congestion. Symptoms are primarily due to diminished cardiac output and can range from tachypnea, dyspnea, and wheezing to poor feeding and failure to thrive in the pediatric population. In asymptomatic patients, the physical examination may be completely unremarkable as isolated DOMV is benign, even to cardiac auscultation. However, if complicated by mitral valve stenosis (MS), one may appreciate the murmur of MS, a low-pitched mid-diastolic murmur best heard at the apex. The same can be said for DOMV with mitral regurgitation (MR), a blowing pansystolic murmur is appreciated at the apical region. As patients develop symptoms, one may find clinical signs of heart failure such as increased work of breathing, peripheral cyanosis, increased jugular venous pressure, palpation of a parasternal heave, pulmonary crackles on auscultation as well as evidence of hypervolemia such as peripheral edema. People may rarely present with the symptoms of Ortner's syndrome, which include cough, haemoptysis and hoarseness. Signs On physical examination, the most prominent features are due to the development of right-sided heart failure. These can include a raised jugular venous pressure, ascites, left parasternal heave and a tender, enlarged liver on palpation. On inspection, patients may be chronically ill, cyanotic, cachectic and occasionally jaundiced. On auscultation, an accentuated second pulmonary sound (S2), a third heart sound termed a ‘right ventricular gallop’, as well as a systolic murmur over the tricuspid area accentuated by inspiration may be present. On occasion, the systolic murmur can be transmitted and auscultated over the liver. Less typically, diastolic murmur may also be heard as a result of pulmonary insufficiency. DIASTOLIC HeART MuRMuRS early Diastolic Murmurs (Fig. 51e-1E) Chronic AR results in a high-pitched, blowing, decrescendo, early to mid-diastolic murmur that begins after the aortic component of S2 (A2) and is best heard at the second right interspace (Fig. 51e-6). The murmur may be soft and difficult to hear unless auscultation is performed with the patient leaning forward at end expiration. This maneuver brings the aortic root closer to the anterior chest wall. Radiation of the murmur may provide a clue to the cause of the AR. With primary valve disease, such as that due to congenital bicuspid disease, prolapse, or endocarditis, the diastolic murmur tends to radiate along the left sternal border, where it is often louder than appreciated in the second right interspace. When AR is caused by aortic root disease, the diastolic murmur may radiate along the right sternal border. Diseases of the aortic root cause dilation or distortion of the aortic annulus and failure of leaflet imaging. The evidence base that links the findings from the history and physi-cal examination to the presence, severity, and prognosis of cardiovas-cular disease has been established most rigorously for coronary artery disease, heart failure, and valvular heart disease. For example, obser-vations regarding heart rate, blood pressure, signs of pulmonary congestion, and the presence of mitral regurgitation (MR) contribute importantly to bedside risk assessment in patients with acute coronary syndromes. Observations from the physical examination in this set-ting can inform clinical decision making before the results of cardiac biomarkers testing are known. The prognosis of patients with systolic heart failure can be predicted on the basis of the jugular venous pressure (JVP) and the presence or absence of a third heart sound (S3). Accurate characterization of cardiac murmurs provides important insight into the natural history of many valvular and congenital heart lesions. Finally, the Structures Examples of TTE views of various structures of the heart. Aortic valve Mitral valve Tricuspid valve Pulmonary valve Measurements Routine TTE exams can provide a significant wealth of information about the heart's structure and function: Left ventricular size, thickness, systolic function, and diastolic function Right ventricular size and systolic function Aortic valve Aortic valve sclerosis & stenosis Aortic valve insufficiency Mitral valve Mitral stenosis Mitral regurgitation Tricuspid valve Tricuspid regurgitation (stenosis is possible, but rare) Pulmonary valve Pulmonary regurgitation (stenosis is possible, but rare) Inferior vena cava size as estimate of central venous pressure Aortic root size for thoracic ascending aortic aneurysm Pericardial effusion size The incidence of patients with degenerative valvular but also of patients with congenital heart disease surviving until adulthood or even old age will increase in the next decades. Auscultation with the stethoscope remains an important diagnostic means in the detection and treatment of heart disease. Heart murmurs (especially systolic heart murmurs) are extremely common. There are helpful clues to differentiate heart murmurs. It can occasionally be relatively simple to differentiate a systolic murmur due to valvular heart disease from an innocent, ejection murmur; however, there are important limitations of auscultation. Overall, auscultation and clinical examination alone do not suffice to correctly diagnose and treat patients with heart failure or a murmur Clinically significant aortic stenosis, aortic regurgitation and mitral regurgitation as well as hypertrophic cardiomyopathy are not uncommonly missed or misinterpreted. An echocardiographic exam is mandatory in all patients with more than a soft systolic murmur, any diastolic murmur, cardiac symptoms and/or ECG changes. The neck veins in patients with severe TR are distended with prominent c-v waves and rapid y descents (in the absence of TS). TR is more often diagnosed by examination of the neck veins than by auscultation of the heart sounds. Other findings may include marked hepatomegaly with systolic pulsations, ascites, pleural effusions, edema, and a positive hepatojugular reflex. A prominent RV pulsation along the left parasternal region and a blowing holosystolic murmur along the lower left sternal margin, which may be intensified during inspiration (Carvallo’s sign) and reduced during expiration or the strain phase of the Valsalva maneuver, are characteristic findings. The murmur of TR may sometimes be confused with that of MR unless attention is paid to its variation during the respiratory cycle and the extent of RV enlargement is appreciated. Atrial fibrillation (AF) is usually present in the chronic phase of the disease. Medical signs of aortic stenosis include pulsus parvus et tardus, that is, diminished and delayed carotid pulse, fourth heart sound, decreased A2 sound, sustained apex beat, precordial thrill. Auscultation may reveal a systolic murmur of a harsh crescendo-decrescendo type, heard in 2nd right intercostal space and radiating to the carotid arteries. Aortic regurgitation Patients with aortic regurgitation may experience heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, and angina pectoris. In acute cases patients may experience cyanosis and circulatory shock. Diagnosis Physical examination Upon auscultation of an individual with mitral stenosis, the first heart sound is usually loud and may be palpable (tapping apex beat) because of increased force in closing the mitral valve. The first heart sound is made by the mitral and tricuspid heart valves closing. These are normally synchronous, and the sounds are termed M1 and T1, respectively. M1 becomes louder in mitral stenosis. It may be the most prominent sign. If pulmonary hypertension secondary to mitral stenosis is severe, the P2 (pulmonic) component of the second heart sound (S2) will become loud. Evaluation Evaluation of the aortic valve can be done with several modalities. Auscultation with a stethoscope is quick and easy. It contributes the A2 component to the second heart sound and changes with inspiration (\"splitting\") Transthoracic echocardiography (TTE) is used as the first test because it is non-invasive. Using TTE, the degree of stenosis and insufficiency can be quantified to grade the valve dysfunction. Transesophageal echocardiography is less often used for aortic stenosis & insufficiency because the angle between the probe and the aortic valve is not optimal (the best window is a transgastric view). MRI and CT can be used to evaluate the valve, but much less commonly than TTE. Quantification of the maximum velocity through the valve, the area of the opening of the valve, calcification, morphology (tricuspid, bicuspid, unicuspid), and size of the valve (annulus, sinuses, sinotubular junction) are common parameters when evaluating the aortic valve. An exaggerated \"y\" wave or diastolic collapse of the neck veins from constrictive pericarditis is referred to as Friedreich's sign. Raised JVP, normal waveform Bradycardia Fluid overload Heart failure Raised JVP, absent pulsation Superior vena cava syndrome Large 'a' wave (increased atrial contraction pressure) Tricuspid stenosis Right heart failure Pulmonary hypertension Cannon 'a' wave (atria contracting against closed tricuspid valve) Atrial flutter Premature atrial rhythm (or tachycardia) Third degree heart block Ventricular ectopics Ventricular tachycardia Absent 'a' wave (no unifocal atrial depolarisation) Atrial fibrillation Large 'v' wave (c–v wave) Tricuspid regurgitation Absent 'x' descent Tricuspid regurgitation (sometimes 'x' wave is replaced by a positive wave) Prominent 'x' descent Cardiac tamponade Slow 'y' descent Tricuspid stenosis Cardiac tamponade Prominent & deep 'y' descent Constrictive pericarditis Tricuspid valve regurgitation presents as a holosystolic (pansystolic) murmur at the left lower sternal border with radiation to the left upper sternal border. Prominent v and c waves may be seen in the JVP (jugular venous pressure). The murmur will increase with inspiration. Hypertrophic obstructive cardiomyopathy (or hypertrophic subaortic stenosis) will be a systolic crescendo-decrescendo murmur best heard at the left lower sternal border. Valsalva maneuver will increase the intensity of the murmur, as will changing positions from squatting to standing. Atrial septal defect will present with a systolic crescendo-decrescendo murmur best heard at the left upper sternal border due to increased volume going through the pulmonary valve, and is associated with a fixed, split S2 and a right ventricular heave. Mitral stenosis typically presents as a diastolic low-pitched decrescendo murmur best heard at the cardiac apex in the left lateral decubitus position. It may be associated with an opening snap. Increasing severity will shorten the time between S2(A2) and the opening snap. (i.e. In severe MS the opening snap will occur earlier after A2) Tricuspid valve stenosis presents as a diastolic decrescendo murmur at the left lower sternal border, and signs of right heart failure may be seen on exam. Pulmonary valve regurgitation presents as a diastolic decrescendo murmur at the left lower sternal border. A palpable S2 in the second left intercostal space correlates with pulmonary hypertension due to mitral stenosis. Continuous and Combined Systolic/Diastolic Patent ductus arteriosus may present as a continuous murmur radiating to the back. Minor tricuspid insufficiency is common in healthy individuals. In more severe cases it is a consequence of dilation of the right ventricle, leading to displacement of the papillary muscles which control the valve's ability to close. Dilation of the right ventricle occurs secondary to ventricular septal defects, right to left shunting of blood, eisenmenger syndrome, hyperthyroidism, and pulmonary stenosis. Tricuspid insufficiency may also be the result of congenital defects of the tricuspid valve, such as Ebstein's anomaly. Signs and symptoms Aortic stenosis Symptoms of aortic stenosis may include heart failure symptoms, such as dyspnea on exertion (most frequent symptom), orthopnea and paroxysmal nocturnal dyspnea, angina pectoris, and syncope, usually exertional. Signs Many of the signs encountered in cor pulmonale are also present in HF patients with a depressed EF, including tachypnea, elevated jugular venous pressures, hepatomegaly, and lower-extremity edema. Patients may have prominent v waves in the jugular venous pulse as a result of tricuspid regurgitation. Other cardiovascular signs include an RV heave palpable along the left sternal border or in the epigastrium. The increase in intensity of the holosystolic murmur of tricuspid regurgitation with inspiration (“Carvallo’s sign”) may be lost eventually as RV failure worsens. Cyanosis is a late finding in cor pulmonale and is secondary to a low cardiac output with systemic vasoconstriction and ventilation-perfusion mismatches in the lung. With newer, non-invasive imaging techniques, the origin of other, so-called adventitial sounds or heart clicks has been appreciated. These are short, high-pitched sounds. The mitral valve in cases of mitral stenosis may open with an opening snap on the beginning of diastole. Patients with mitral valve prolapse may have a mid-systolic click along with a murmur, referred to as apical late systolic murmur. Early systolic clicks may also be present in some patients. Aortic and pulmonary stenosis may cause an ejection click immediately after S1. References Symptoms and signs: Cardiac Audible medical signs Cardiac examination findings are typically within normal limits in individuals with physiological pulmonary regurgitation. Some individuals with a lean physique may detect a faint early diastolic murmur in cases of mild pulmonary regurgitation. As pulmonary regurgitation increases significance, a systolic ejection murmur may be audible at the left upper sternal border due to increased right ventricle stroke volume. A third heart sound may be present, while a fourth one is uncommon. Mildly accentuated right ventricle impulse is generally observed in patients with severe pulmonary regurgitation; however, the jugular venous pressure is usually normal. A prominent jugular venous \"a\" wave may indicate pulmonary artery hypertension, while a prominent \"v\" wave is in patients with severe tricuspid valve regurgitation. [27] Cardiovascular Findings Tachycardia and hypotension may be present along with jugular venous distention. Auscultation of the heart helps to differentiate between the various causes of valvular lesions causing pulmonary edema. Auscultation typically reveals an S3 gallop in volume overload states, which may be associated with accentuation of the pulmonic component of S2. Several different types of murmurs can be heard depending on the cause of the valvular lesion. Mitral stenosis produces a low-pitched, rumbling diastolic murmur associated with an opening snap at the apex, which becomes accentuated on expiration and produces loud S1. Mitral regurgitation produces a blowing, high-pitched pan-systolic murmur best heard at the apex, radiating to the left axilla and accentuating on expiration, producing soft S1. Aortic stenosis produces a harsh crescendo-decrescendo ejection systolic murmur at the aortic area, increasing on expiration, usually radiating towards the right side of the neck. Aortic regurgitation produces a high-pitched blowing early diastolic murmur best heard in the aortic area, greatest during expiration.\nHere is the question:\nCARDIOLOGY AND CARDIOVASCULAR SURGERY: If in a patient with chronic heart failure we detect prominent v waves in the jugular venous pulse and on cardiac auscultation a holosystolic murmur is auscultated in the area of the xiphoid appendage that is accentuated with deep inspiration. What is the valvulopathy responsible for this physical examination?\nHere are the potential choices:\n1. Mitral insufficiency.\n2. Pulmonary insufficiency.\n3. Tricuspid insufficiency.\n4. Aortic insufficiency.\n5. Aortic stenosis.\nThe correct answer is: ",
        "gold_answer": "3 Tricuspid insufficiency.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n On auscultation of a patient with mitral stenosis, there may be a holosystolic murmur at the apex, radiating to the back or clavicular area, a third heart sound, and a loud, palpable P2, heard best when lying on the left side. Patients also commonly have atrial fibrillation. Patients may have a laterally displaced apex beat, often with heave In acute cases, the murmur and tachycardia may be only distinctive signs. Tricuspid regurgitation Patients with tricuspid regurgitation may experience symptoms of right-sided heart failure, such as ascites, hepatomegaly, edema and jugular venous distension. Tricuspid regurgitation Patients with tricuspid regurgitation may experience symptoms of right-sided heart failure, such as ascites, hepatomegaly, edema and jugular venous distension. Signs of tricuspid regurgitation include pulsatile liver, prominent V waves and rapid y descents in jugular venous pressure. Auscultatory findings include inspiratory third heart sound at left lower sternal border (LLSB) and a blowing holosystolic murmur at LLSB, intensifying with inspiration, and decreasing with expiration and Valsalva maneuver. Patients may have a parasternal heave along LLSB. Atrial fibrillation is usually present in patients with tricuspid regurgitation Causes If there is increased stroke volume of the left ventricle due to volume overload, an ejection systolic 'flow' murmur may also be present when auscultating the same aortic area. Unless there is concomitant aortic valve stenosis, the murmur should not start with an ejection click. There may also be an Austin Flint murmur, a soft mid-diastolic rumble heard at the apical area; it appears when a regurgitant jet of blood from severe aortic regurgitation partially closes the anterior mitral leaflet. Peripheral physical signs of aortic regurgitation are related to the high pulse pressure and the rapid decrease in blood pressure during diastole due to blood returning to the heart from the aorta through the incompetent aortic valve, although the usefulness of some of the eponymous signs has been questioned: Phonocardiograms detect AI by having electric voltage mimic the sounds the heart makes. Characteristics- indicative of aortic regurgitation are as follow: Systolic and diastolic motions of the interventricular septum (IVS), especially of its lower portion at the level of the chordae tendineae, were evaluated by M-mode echocardiography in normal subjects and in patients with various cardiac disorders. The following conclusions were derived from this study. In normal subjects, downward motion of the IVS exhibited three patterns; namely, P1, between the onset of electrical depolarization and the onset of the second heart sound; P2, between the onset of the second heart sound and the E point of the anterior mitral leaflet; and P3, between the E point of the anterior mitral leaflet and the end of the left ventricular rapid filling phase, during each cardiac cycle. The systolic IVS pattern (P1) of atrial septal defect was classified as follows: Normal type: nearly normal posterior motion during ventricular systole, Flat type: flat motion during ventricular systole, Paradoxical (early systolic) type: anterior motion during the first half of ventricular systole, followed by normal posterior motion, Paradoxical (pansystolic) type: anterior motion during ventricular systole. In atrial septal defect, the right ventricular dimension was markedly increased in the flat and paradoxical (pansystolic) types compared with those of the normal and paradoxical (early systolic) types. Marked downward IVS motion (P2) was observed in cor pulmonale with paradoxical pulse, pulmonary hypertension, Ebstein's anomaly, pulmonic insufficiency, atrial septal defect, funnel chest, tricuspid insufficiency and constrictive pericarditis. In cor pulmonale with paradoxical pulse, the deep downward motion (P2) was observed more distinctly during inspiration compared to expiration, and right ventricular inflow velocity pattern was characterized by an apparent increase in peak flow in velocity of the diastolic rapid filling wave during inspiration. Two interesting findings were a deep \"y\" trough of the jugular pulse tracing and prominent P2 in funnel chest. Therefore, it was likely that exaggerated P2 seemed to be direct evidence of a marked increase in right ventricular rapid filling in the presence of normal or decreased left ventricular rapid filling. The augmented septal dip of P3 was observed in cases with the third heart sound as in normal subjects, and those with mitral insufficiency, and ventricular septal defect, constrictive pericarditis and mitral stenosis. We theorized that exaggerated P3 results from the \"sucking action\" secondary to increased left ventricular rapid filling velocity in cases with the third heart sound or constrictive pericarditis.(ABSTRACT TRUNCATED AT 400 WORDS) Associated lesions With severe pulmonary hypertension, a pansystolic murmur produced by functional tricuspid regurgitation may be audible along the left sternal border. This murmur is usually louder during inspiration and diminishes during forced expiration (Carvallo’s sign). When the cardiac output is markedly reduced in MS, the typical auscultatory findings, including the diastolic rumbling murmur, may not be detectable (silent MS), but they may reappear as compensation is restored. The Graham Steell murmur of pulmonary regurgitation, a high-pitched, diastolic, decrescendo blowing murmur along the left sternal border, results from dilation of the pulmonary valve ring and occurs in patients with mitral valve disease and severe pulmonary hypertension. This murmur may be indistinguishable from the more common murmur produced by aortic regurgitation (AR), although it may increase in intensity with inspiration and is accompanied by a loud and often palpable P2. Echocardiography Physiological tricuspid and pulmonary regurgitations are very often found by Echo-Doppler. They are generally slight, inaudible and devoid of significance. Tricuspid insufficiency nevertheless has the great advantage of enabling the calculation of pulmonary pressures. Auscultation is a good method for the diagnosis of rheumatic mitral insufficiency or related to prolapse, but is not reliable in other situations. Doppler is an excellent method for the qualitative and etiological diagnosis of mitral insufficiency but enables only semi-quantification. It also has the disadvantage of discovering minimal mitral insufficiency, the significance of which is uncertain. In contrast to auscultation, Doppler enables precise quantification in mitral stenosis. Auscultation is a good method for the diagnosis of aortic valve disease with the exception of slight insufficiency and stenosis in the elderly. Doppler enables the quantification of stenosis and semi-quantification of insufficiency. The existence of physiological aortic regurgitation is by no means certain. In conclusion, auscultation remains an important tool in cardiological diagnosis but has notable limitations. Echo-Doppler is a major advance but it is important to be aware of its limitations. For the best cardiac examination, it is important to have the patient both sit up and lay down at a 30-45˚ angle. Tapping with the fingertips (also known as percussion) can be used to estimate the size of the heart, though palpation is more accurate. From the left side of the chest, the doctor can tap the spaces between the ribs with the tips of their middle finger to listen for the dullness that will be present over the heart. Listening with a stethoscope (also known as auscultation) to all four areas of the heart: aortic, pulmonic, tricuspid and mitral. Any murmurs, rubs or gallops should be noted. Gallops are also known as a third (S3) or fourth (S4) heart sound. The absence of abnormalities (normal) may be recorded as \"no m/r/g\". The ACC and the AHA have called cardiac auscultation \"the most widely used method of screening for valvular heart disease.\" Because of its importance to the cardiac examination, cardiac auscultation has been covered in-depth elsewhere. Finally the sacrum and ankles are checked for pitting edema which is caused by right ventricular failure in isolation or as part of congestive cardiac failure. Auscultation One should comment on S1 and S2 – if the splitting is abnormal or louder than usual. S3 – the emphasis and timing of the syllables in the word Kentucky is similar to the pattern of sounds in a precordial S3. S4 – the emphasis and timing of the syllables in the word Tennessee is similar to the pattern of sounds in a precordial S4. If S4 S1 S2 S3 Also known as a gallop rhythm. diastolic murmurs (e.g. aortic regurgitation, mitral stenosis) systolic murmurs (e.g. aortic stenosis, mitral regurgitation) pericardial rub (suggestive of pericarditis) The base of the lungs should be auscultated for signs of pulmonary oedema due to a cardiac cause such as bilateral basal crepitations. A heart murmur was detected in a 10 mo old, female New Zealand White rabbit. Auscultation revealed cardiac murmurs both at the left and right hemithorax. Phonocardiography confirmed the systolic-diastolic nature of the left-sided and the systolic character of the right-sided murmur. Electrocardiography showed normal sinus rhythm; tall R waves and large T waves in lead II; and deep S waves in leads II, III, and aVF. Thoracic radiography demonstrated generalized cardiomegaly with prominent pulmonary vasculature. Echocardiography revealed a perimembraneous ventricular septal defect with aortic insufficiency. Signs of biventricular volume overload, relative pulmonic stenosis, and pulmonary valve insufficiency were also seen as consequences of the defect. Necropsy demonstrated a ventricular septal defect just below the aortic valve, a dilated pulmonary trunk, dilated and hypertrophied ventricles, dilated atria, and rightward displacement of the aortic root. Cardiac histopathology showed ventricular cardiomyocyte degeneration (swelling and hypereosinophilia of the cytoplasm with a loss of cross striation, and nuclear hyperchromasia), cartilaginous metaplasia of the aorta, and subendocardial fibrosis of the right ventricular flow tract. On auscultation of a patient with mitral stenosis, typically the most prominent sign is a loud S1. Another finding is an opening snap followed by a low-pitched diastolic rumble with presystolic accentuation. The opening snap follows closer to the S2 heart tone with worsening stenosis. The murmur is heard best with the bell of the stethoscope lying on the left side and its duration increases with worsening disease. Advanced disease may present with signs of right-sided heart failure such as parasternal heave, jugular venous distension, hepatomegaly, ascites and/or pulmonary hypertension (presenting with a loud P2). Signs increase with exercise and pregnancy. Mitral regurgitation Patients with mitral regurgitation may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, or pulmonary edema. An asymptomatic 29-year-old woman presented for prenatal counselling. She had a history of a heart murmur since childhood and a previous echocardiogram suggesting 'enlargement of the heart'. Physical exam revealed normal jugular venous pressure and contour. Precordial palpation was unremarkable. Auscultation, however, was abnormal; findings on inspiration and expiration are presented in Figure 1, sound clip. Based on the phonocardiogram and online supplementary audio clip, which of the following is correct? An early diastolic filling sound (S3) is heard, indicating increased right ventricular filling pressures.An ejection click without respiratory variation and a systolic ejection murmur are heard, consistent with bicuspid aortic valve stenosis.An ejection click with respiratory variation and a systolic ejection murmur are heard, consistent with pulmonic valve stenosis.A holosystolic murmur with inspiratory augmentation is heard, indicating tricuspid regurgitation. Mitral regurgitation typically is a holosystolic (pansystolic) murmur heard best at the apex, and may radiate to the axilla or precordium. A systolic click may be heard if there is associated mitral valve prolapse. Valsalva maneuver in mitral regurgitation associated with mitral valve prolapse will decrease left ventricular preload and move the murmur onset closer to S1, and isometric handgrip, which increases left ventricular afterload, will increase murmur intensity. In acute severe mitral regurgitation, a holosystolic (pansystolic) murmur may not be heard. Pulmonary valve stenosis typically is a crescendo-decrescendo systolic murmur heard best at the left upper sternal border, associated with a systolic ejection click that increases with inspiration (due to increased venous return to the right side of the heart) and sometimes radiates to the left clavicle. Medical signs of aortic regurgitation include increased pulse pressure by increased systolic and decreased diastolic blood pressure, but these findings may not be significant if acute. The patient may have a diastolic decrescendo murmur best heard at left sternal border, water hammer pulse, Austin Flint murmur, and a displaced apex beat down and to the left. A third heart sound may be present Mitral stenosis Patients with mitral stenosis may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, chest pain, hemoptysis, thromboembolism, or ascites and edema (if right-sided heart failure develops). Symptoms of mitral stenosis increase with exercise and pregnancy Tricuspid regurgitation (TR) with normal pulmonary artery pressures, as may occur with infective endocarditis, may produce an early systolic murmur. The murmur is soft (grade 1 or 2), is best heard at the lower left sternal border, and may increase in intensity with inspiration (Carvallo’s sign). Regurgitant “c-v” waves may be visible in the jugular venous pulse. TR in this setting is not associated with signs of right heart failure. Mid-Systolic Murmurs Mid-systolic murmurs begin at a short interval after , end before S (Fig. 51e-1C), and are usually crescendo-decrescendo in configuration. Aortic stenosis is the most common cause of a mid-systolic murmur in an adult. The murmur of AS is usually loudest to the right of the sternum in the second intercostal space (aortic area, Fig. 51e-2) and radiates into the carotids. Transmission of the mid-systolic murmur to the apex, where it becomes higher-pitched, is common (Gallavardin effect; see above). A double orifice mitral valve (DOMV) is usually an asymptomatic entity unless accompanied by mitral valve stenosis, regurgitation, or a concomitant congenital cardiac anomaly. In patients with an associated congenital heart defect, it is usual for that particular disorder to manifest on clinical examination as there are no signs specific to DOMV. In isolated DOMV, the extent of symptoms depends on the grade of left atrial pressure resulting in pulmonary congestion. Symptoms are primarily due to diminished cardiac output and can range from tachypnea, dyspnea, and wheezing to poor feeding and failure to thrive in the pediatric population. In asymptomatic patients, the physical examination may be completely unremarkable as isolated DOMV is benign, even to cardiac auscultation. However, if complicated by mitral valve stenosis (MS), one may appreciate the murmur of MS, a low-pitched mid-diastolic murmur best heard at the apex. The same can be said for DOMV with mitral regurgitation (MR), a blowing pansystolic murmur is appreciated at the apical region. As patients develop symptoms, one may find clinical signs of heart failure such as increased work of breathing, peripheral cyanosis, increased jugular venous pressure, palpation of a parasternal heave, pulmonary crackles on auscultation as well as evidence of hypervolemia such as peripheral edema. People may rarely present with the symptoms of Ortner's syndrome, which include cough, haemoptysis and hoarseness. Signs On physical examination, the most prominent features are due to the development of right-sided heart failure. These can include a raised jugular venous pressure, ascites, left parasternal heave and a tender, enlarged liver on palpation. On inspection, patients may be chronically ill, cyanotic, cachectic and occasionally jaundiced. On auscultation, an accentuated second pulmonary sound (S2), a third heart sound termed a ‘right ventricular gallop’, as well as a systolic murmur over the tricuspid area accentuated by inspiration may be present. On occasion, the systolic murmur can be transmitted and auscultated over the liver. Less typically, diastolic murmur may also be heard as a result of pulmonary insufficiency. DIASTOLIC HeART MuRMuRS early Diastolic Murmurs (Fig. 51e-1E) Chronic AR results in a high-pitched, blowing, decrescendo, early to mid-diastolic murmur that begins after the aortic component of S2 (A2) and is best heard at the second right interspace (Fig. 51e-6). The murmur may be soft and difficult to hear unless auscultation is performed with the patient leaning forward at end expiration. This maneuver brings the aortic root closer to the anterior chest wall. Radiation of the murmur may provide a clue to the cause of the AR. With primary valve disease, such as that due to congenital bicuspid disease, prolapse, or endocarditis, the diastolic murmur tends to radiate along the left sternal border, where it is often louder than appreciated in the second right interspace. When AR is caused by aortic root disease, the diastolic murmur may radiate along the right sternal border. Diseases of the aortic root cause dilation or distortion of the aortic annulus and failure of leaflet imaging. The evidence base that links the findings from the history and physi-cal examination to the presence, severity, and prognosis of cardiovas-cular disease has been established most rigorously for coronary artery disease, heart failure, and valvular heart disease. For example, obser-vations regarding heart rate, blood pressure, signs of pulmonary congestion, and the presence of mitral regurgitation (MR) contribute importantly to bedside risk assessment in patients with acute coronary syndromes. Observations from the physical examination in this set-ting can inform clinical decision making before the results of cardiac biomarkers testing are known. The prognosis of patients with systolic heart failure can be predicted on the basis of the jugular venous pressure (JVP) and the presence or absence of a third heart sound (S3). Accurate characterization of cardiac murmurs provides important insight into the natural history of many valvular and congenital heart lesions. Finally, the Structures Examples of TTE views of various structures of the heart. Aortic valve Mitral valve Tricuspid valve Pulmonary valve Measurements Routine TTE exams can provide a significant wealth of information about the heart's structure and function: Left ventricular size, thickness, systolic function, and diastolic function Right ventricular size and systolic function Aortic valve Aortic valve sclerosis & stenosis Aortic valve insufficiency Mitral valve Mitral stenosis Mitral regurgitation Tricuspid valve Tricuspid regurgitation (stenosis is possible, but rare) Pulmonary valve Pulmonary regurgitation (stenosis is possible, but rare) Inferior vena cava size as estimate of central venous pressure Aortic root size for thoracic ascending aortic aneurysm Pericardial effusion size The incidence of patients with degenerative valvular but also of patients with congenital heart disease surviving until adulthood or even old age will increase in the next decades. Auscultation with the stethoscope remains an important diagnostic means in the detection and treatment of heart disease. Heart murmurs (especially systolic heart murmurs) are extremely common. There are helpful clues to differentiate heart murmurs. It can occasionally be relatively simple to differentiate a systolic murmur due to valvular heart disease from an innocent, ejection murmur; however, there are important limitations of auscultation. Overall, auscultation and clinical examination alone do not suffice to correctly diagnose and treat patients with heart failure or a murmur Clinically significant aortic stenosis, aortic regurgitation and mitral regurgitation as well as hypertrophic cardiomyopathy are not uncommonly missed or misinterpreted. An echocardiographic exam is mandatory in all patients with more than a soft systolic murmur, any diastolic murmur, cardiac symptoms and/or ECG changes. The neck veins in patients with severe TR are distended with prominent c-v waves and rapid y descents (in the absence of TS). TR is more often diagnosed by examination of the neck veins than by auscultation of the heart sounds. Other findings may include marked hepatomegaly with systolic pulsations, ascites, pleural effusions, edema, and a positive hepatojugular reflex. A prominent RV pulsation along the left parasternal region and a blowing holosystolic murmur along the lower left sternal margin, which may be intensified during inspiration (Carvallo’s sign) and reduced during expiration or the strain phase of the Valsalva maneuver, are characteristic findings. The murmur of TR may sometimes be confused with that of MR unless attention is paid to its variation during the respiratory cycle and the extent of RV enlargement is appreciated. Atrial fibrillation (AF) is usually present in the chronic phase of the disease. Medical signs of aortic stenosis include pulsus parvus et tardus, that is, diminished and delayed carotid pulse, fourth heart sound, decreased A2 sound, sustained apex beat, precordial thrill. Auscultation may reveal a systolic murmur of a harsh crescendo-decrescendo type, heard in 2nd right intercostal space and radiating to the carotid arteries. Aortic regurgitation Patients with aortic regurgitation may experience heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, and angina pectoris. In acute cases patients may experience cyanosis and circulatory shock. Diagnosis Physical examination Upon auscultation of an individual with mitral stenosis, the first heart sound is usually loud and may be palpable (tapping apex beat) because of increased force in closing the mitral valve. The first heart sound is made by the mitral and tricuspid heart valves closing. These are normally synchronous, and the sounds are termed M1 and T1, respectively. M1 becomes louder in mitral stenosis. It may be the most prominent sign. If pulmonary hypertension secondary to mitral stenosis is severe, the P2 (pulmonic) component of the second heart sound (S2) will become loud. Evaluation Evaluation of the aortic valve can be done with several modalities. Auscultation with a stethoscope is quick and easy. It contributes the A2 component to the second heart sound and changes with inspiration (\"splitting\") Transthoracic echocardiography (TTE) is used as the first test because it is non-invasive. Using TTE, the degree of stenosis and insufficiency can be quantified to grade the valve dysfunction. Transesophageal echocardiography is less often used for aortic stenosis & insufficiency because the angle between the probe and the aortic valve is not optimal (the best window is a transgastric view). MRI and CT can be used to evaluate the valve, but much less commonly than TTE. Quantification of the maximum velocity through the valve, the area of the opening of the valve, calcification, morphology (tricuspid, bicuspid, unicuspid), and size of the valve (annulus, sinuses, sinotubular junction) are common parameters when evaluating the aortic valve. An exaggerated \"y\" wave or diastolic collapse of the neck veins from constrictive pericarditis is referred to as Friedreich's sign. Raised JVP, normal waveform Bradycardia Fluid overload Heart failure Raised JVP, absent pulsation Superior vena cava syndrome Large 'a' wave (increased atrial contraction pressure) Tricuspid stenosis Right heart failure Pulmonary hypertension Cannon 'a' wave (atria contracting against closed tricuspid valve) Atrial flutter Premature atrial rhythm (or tachycardia) Third degree heart block Ventricular ectopics Ventricular tachycardia Absent 'a' wave (no unifocal atrial depolarisation) Atrial fibrillation Large 'v' wave (c–v wave) Tricuspid regurgitation Absent 'x' descent Tricuspid regurgitation (sometimes 'x' wave is replaced by a positive wave) Prominent 'x' descent Cardiac tamponade Slow 'y' descent Tricuspid stenosis Cardiac tamponade Prominent & deep 'y' descent Constrictive pericarditis Tricuspid valve regurgitation presents as a holosystolic (pansystolic) murmur at the left lower sternal border with radiation to the left upper sternal border. Prominent v and c waves may be seen in the JVP (jugular venous pressure). The murmur will increase with inspiration. Hypertrophic obstructive cardiomyopathy (or hypertrophic subaortic stenosis) will be a systolic crescendo-decrescendo murmur best heard at the left lower sternal border. Valsalva maneuver will increase the intensity of the murmur, as will changing positions from squatting to standing. Atrial septal defect will present with a systolic crescendo-decrescendo murmur best heard at the left upper sternal border due to increased volume going through the pulmonary valve, and is associated with a fixed, split S2 and a right ventricular heave. Mitral stenosis typically presents as a diastolic low-pitched decrescendo murmur best heard at the cardiac apex in the left lateral decubitus position. It may be associated with an opening snap. Increasing severity will shorten the time between S2(A2) and the opening snap. (i.e. In severe MS the opening snap will occur earlier after A2) Tricuspid valve stenosis presents as a diastolic decrescendo murmur at the left lower sternal border, and signs of right heart failure may be seen on exam. Pulmonary valve regurgitation presents as a diastolic decrescendo murmur at the left lower sternal border. A palpable S2 in the second left intercostal space correlates with pulmonary hypertension due to mitral stenosis. Continuous and Combined Systolic/Diastolic Patent ductus arteriosus may present as a continuous murmur radiating to the back. Minor tricuspid insufficiency is common in healthy individuals. In more severe cases it is a consequence of dilation of the right ventricle, leading to displacement of the papillary muscles which control the valve's ability to close. Dilation of the right ventricle occurs secondary to ventricular septal defects, right to left shunting of blood, eisenmenger syndrome, hyperthyroidism, and pulmonary stenosis. Tricuspid insufficiency may also be the result of congenital defects of the tricuspid valve, such as Ebstein's anomaly. Signs and symptoms Aortic stenosis Symptoms of aortic stenosis may include heart failure symptoms, such as dyspnea on exertion (most frequent symptom), orthopnea and paroxysmal nocturnal dyspnea, angina pectoris, and syncope, usually exertional. Signs Many of the signs encountered in cor pulmonale are also present in HF patients with a depressed EF, including tachypnea, elevated jugular venous pressures, hepatomegaly, and lower-extremity edema. Patients may have prominent v waves in the jugular venous pulse as a result of tricuspid regurgitation. Other cardiovascular signs include an RV heave palpable along the left sternal border or in the epigastrium. The increase in intensity of the holosystolic murmur of tricuspid regurgitation with inspiration (“Carvallo’s sign”) may be lost eventually as RV failure worsens. Cyanosis is a late finding in cor pulmonale and is secondary to a low cardiac output with systemic vasoconstriction and ventilation-perfusion mismatches in the lung. With newer, non-invasive imaging techniques, the origin of other, so-called adventitial sounds or heart clicks has been appreciated. These are short, high-pitched sounds. The mitral valve in cases of mitral stenosis may open with an opening snap on the beginning of diastole. Patients with mitral valve prolapse may have a mid-systolic click along with a murmur, referred to as apical late systolic murmur. Early systolic clicks may also be present in some patients. Aortic and pulmonary stenosis may cause an ejection click immediately after S1. References Symptoms and signs: Cardiac Audible medical signs Cardiac examination findings are typically within normal limits in individuals with physiological pulmonary regurgitation. Some individuals with a lean physique may detect a faint early diastolic murmur in cases of mild pulmonary regurgitation. As pulmonary regurgitation increases significance, a systolic ejection murmur may be audible at the left upper sternal border due to increased right ventricle stroke volume. A third heart sound may be present, while a fourth one is uncommon. Mildly accentuated right ventricle impulse is generally observed in patients with severe pulmonary regurgitation; however, the jugular venous pressure is usually normal. A prominent jugular venous \"a\" wave may indicate pulmonary artery hypertension, while a prominent \"v\" wave is in patients with severe tricuspid valve regurgitation. [27] Cardiovascular Findings Tachycardia and hypotension may be present along with jugular venous distention. Auscultation of the heart helps to differentiate between the various causes of valvular lesions causing pulmonary edema. Auscultation typically reveals an S3 gallop in volume overload states, which may be associated with accentuation of the pulmonic component of S2. Several different types of murmurs can be heard depending on the cause of the valvular lesion. Mitral stenosis produces a low-pitched, rumbling diastolic murmur associated with an opening snap at the apex, which becomes accentuated on expiration and produces loud S1. Mitral regurgitation produces a blowing, high-pitched pan-systolic murmur best heard at the apex, radiating to the left axilla and accentuating on expiration, producing soft S1. Aortic stenosis produces a harsh crescendo-decrescendo ejection systolic murmur at the aortic area, increasing on expiration, usually radiating towards the right side of the neck. Aortic regurgitation produces a high-pitched blowing early diastolic murmur best heard in the aortic area, greatest during expiration.\nHere is the question:\nCARDIOLOGY AND CARDIOVASCULAR SURGERY: If in a patient with chronic heart failure we detect prominent v waves in the jugular venous pulse and on cardiac auscultation a holosystolic murmur is auscultated in the area of the xiphoid appendage that is accentuated with deep inspiration. What is the valvulopathy responsible for this physical examination?\nHere are the potential choices:\n1. Mitral insufficiency.\n2. Pulmonary insufficiency.\n3. Tricuspid insufficiency.\n4. Aortic insufficiency.\n5. Aortic stenosis.\nThe correct answer is: 3. Tricuspid insufficiency."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n To describe the frequency and duration of remission in the Utrecht rheumatoid arthritis cohort of patients followed since diagnosis, and the clinical and treatment characteristics of patients with remission v those without. In 1990 the Utrecht rheumatoid arthritis cohort study group started a clinical trial in which patients with recent onset of rheumatoid arthritis (&lt;1 year) were randomised into four treatment groups: hydroxychloroquine (n = 169); intramuscular gold (n = 163); methotrexate (n = 166); and pyramid (n = 64). After two years, rheumatologists were allowed to prescribe any disease modifying antirheumatic drug. Remission was defined as: duration of morning stiffness &lt; or =15 min, mean VAS pain &lt; or =10 mm, Thompson joint score &lt; or =10, and ESR &lt; or =30 mm/h during at least six months. Cox regression analysis was used to determine baseline clinical, demographic, and treatment predictors of remission. Mean follow up duration was 62 months. Thirty six per cent achieved at least one period of remission. Median duration between diagnosis and the first remission period was 15 months for the intramuscular gold group, 18 months for the methotrexate and hydroxychloroquine groups, and 24 months for the pyramid group (NS). Predictors of remission were early response to initial treatment, less pain, rheumatoid factor negativity, and lower joint score at baseline. After a mean follow up duration of 62 months, only 36% of the patients had fulfilled the remission criteria at least once. A good response to treatment during the first year seems to be independently associated with remission rather than initial treatment alone. Leflunomide is a relatively new disease modifying antirheumatic drug (DMARD) and a number of studies evaluating its effectiveness and safety in daily medical practice is limited. Evaluation of effectiveness and safety of leflunomide treatment in patients with active rheumatoid arthritis in whom methotrexate was ineffective or contraindicated. Eighty one patients (66 women and 15 men) with RA diagnosed according to ARA (The American Rheumatism Association) criteria were included in the study. The mean age was 57.6+/-11.7 years and the mean disease duration was 7.7+/-7.1 years. The inclusion criteria were: disease activity according to DAS28 (Disease Activity Score)&gt;3.2 and contraindications to methotrexate or ineffective methotrexate treatment for at least 3 months. At the beginning of the study 49 of patients were treated with methotrexate in weekly dose of 17+4.2mg and 32 were not treated with DMARDs. Oral glicocorticosteroids in stable doses of 5-15mg of prednisone were given to 66 (77.7%) of them. There was no statistically significant difference in radiological progression of the disease according to Steinbrocker's scale between groups (treated and not treated with methotrexate). Monotherapy with leflunomide was started with loading dose of 100mg for 3 days, and then 20mg daily. Combination therapy was introduced without loading dose. Evaluation was performed monthly and included: duration of morning stiffness, pain and disease activity according to VAS (visual-analogue) scale, the number of tender and swollen joints, blood count, ESR, CRP, aminotransferases activity, and the presence and intensity of adverse reactions. The results of treatment were evaluated after 5 months in 37 of patients and adverse reactions which happened until the end of 5th month were evaluated in all included patients. The mean DAS28 values improved exponentially during consecutive months and the difference between them was statistically significant. Adverse reactions during 5 months of treatment were observed in 36(44,4%) of patients and in 6(7,4%) of cases the treatment had to be stopped because of side effects. The frequency of adverse reactions was similar in monotherapy and combination therapy group. Leflunomide therapy can be effective in patients with active rheumatoid arthritis in whom methotrexate is contraindicated or insufficient. Combination of leflunomide with methotrexate is safe and does not increase the frequency of adverse reactions. DAS28 index calculated with regard for ESR, the number of swollen/painful joints and evaluation of the patient's condition by VAS is universally used to estimate activity of rheumatoid arthritis (RA). There is a variant of calculation using C-reactive protein (CRP) instead of ESR. Our experience indicates that ESR decreases more slowly than CRP during treatment and better reflects dynamics of patients' condition. From the practical standpoint it is important to estimate activity of RA because therapeutic modalities are chosen based on the DAS28 value. To study the influence of pharmaceutical form of methotrexate on the acute-phase response in rheumatoid arthritis. The study included 32 patients (24 women, 8 men) aged 19-76 (mean 47.5 +/- 28.5) yr with active RA (DAS28 &gt; 3.2) 4-30 months (11.5 +/- 7.4, median 8) in duration. Diagnosis was made using AXR criteria (1987), none of the patients previously received methotrexate injections. Inclusion criteria: initially high ESR (Westegren, mm/hr) and/or CRP (mg/l measured by a highly sensitive method). All patients were given methotrexate subcutaneously for 12 weeks as monotherapy (initial dose 10 mg, maximum one 25 mg/week). The cumulative dose was 211.36 +/- 17.2 mg. Side effects did not require withdrawal of methotrexate. CRP level decreased faster than ERS: a 70% decrease of CRP by week 12 was recorded more frequently than that of ESR. Slow dynamics of the number of swollen joints compared with CRP may be due to the low cumulative dose of methotrexate. Duration of the disease had no effect on dynamics of acute phase characteristics. Methotrexate injections resulted in markedly delayed development of clinical signs of improvement compared with laboratory values. CFP levels fell down much faster than ESR, Remission or low activity of RA (estimated from DAS28) occurred only in 38% of the cases after 3 month monotherapy by methotrexate injections. It is concluded that efficacy of this drug should be estimated no sooner than 4 months after the onset of the treatment. To assess whether weekly pulse methotrexate therapy alters radiographic progression of joint disease in patients with rheumatoid arthritis. Prospective, controlled study. Hand, wrist and foot roentgenograms obtained before, at the onset of, and during methotrexate treatment were scored for degree of joint-space narrowing and erosions by three rheumatologists using a standard method. Sequential sample of 24 patients with active definite or classical rheumatoid arthritis and previous unsuccessful treatment; of these, 3 were excluded due to drug ineffectiveness; 2, due to side effects; and 1, due to refusal to take methotrexate. Treatment with nonsteroidal anti-inflammatory drugs and prednisone was continued. Methotrexate was given weekly to control clinical evidence of disease in patients. After having had an average of 30 months of therapy, the 18 patients who continued to receive methotrexate therapy showed significant (p less than 0.05) clinical improvement, as evidenced by their decreased joint counts and joint scores, duration of morning stiffness, pain scales, and sedimentation rates. Despite patients' prolonged clinical improvement, the mean rate of development of erosions and joint-space narrowing during methotrexate therapy was not significantly different from the rate of radiographic progression before methotrexate therapy (0.043 compared with 0.041; p greater than 0.05). Weekly pulse methotrexate is effective for the long-term management of clinical disease activity in patients with refractory rheumatoid arthritis but may not be a disease-modifying agent by roentgenographic criteria. 42-year-old old female patient, followed up with diagnosis of rheumatoid arthritis for 15 years, was admitted with necrotising ulcer of left hand 1st and 2nd fingertips and pain, swelling, limitation of movement, and morning stiffness at bilateral wrist, and metacarpophalangeal and proximal interphalangeal joints. Laboratory tests revealed elevated acute phase reactants. Radial and ulnar arteries were clear in upper extremity Doppler ultrasound. The patient was diagnosed as RA activation and digital ulcer and administered iloprost infusion for five days and 1 mg/kg corticosteroid and 20 mg/week methotrexate (MTX). After one month, a partial regression of clinical and laboratory findings was observed. However, 6 months later, due to relapsed and increased complaints and findings, adalimumab 40 mg was administered. Two months later, clinical and laboratory findings apparently decreased.  Another test that checks the level of C-reactive protein (CRP) in the blood may also be conducted. CRP is produced by the liver in response to an injury or infection, and people with polymyalgia rheumatica usually have high levels. However, like the ESR, this test is also not very specific. Polymyalgia rheumatica is sometimes associated with temporal arteritis, a condition requiring more aggressive therapy. To test for this additional disorder, a biopsy sample may be taken from the temporal artery. Treatment Prednisone is the drug of choice for PMR, and treatment duration is frequently greater than one year. If the patient does not experience dramatic improvement after three days of 10–20 mg oral prednisone per day, the diagnosis should be reconsidered. Sometimes relief of symptoms occurs in only several hours. This study aimed to evaluate remission in patients with early RA treated by conventional DMARDs and to identify its possible predictor factors. Patients with early RA (&lt;12 months) were enrolled in a 2-year follow-up study. Standard evaluation completed at baseline and at 24 months included clinical, laboratory, functional and structural assessment. Clinical remission after 2 years of follow-up was defined when DAS28 was less than 2.6. Possible predictor factors for remission were analyzed. Fifty-one patients (88.2% women, mean age of 46.9 [24-72] years, mean disease duration of 24 [6-48] weeks) were enrolled in this study. The delay in referral for specialist care was 140 [7-420] days. Rheumatoid factor, anti-CCP, HLA-DRB1*01 and DRB1*04 alleles were present respectively in 62.5, 56.6, 11.8, and 45.1% of patients. At 24 months, 77.2% received a median dose of 5 (0-8) mg/day of prednisone and 65.2% was taking methotrexate (MTX). 13.6% of patients had stopped their DMARD because of socioeconomic difficulties. At 24 months, we noted a significant improvement of morning stiffness, pain score, swollen joint count, ESR, CRP, DAS28 and HAQ scores. Remission at 2 years was noted in 34.8% of patients and was significantly associated in univariate but not in multivariate analysis to male sex (P=0.02) and to short delay in referral for specialist (P=0.03). In this cohort of early RA patients treated with conventional DMARDs, especially with methotrexate in monotherapy, remission at 2-year of follow-up was obtained in one third of patients. No predictor factors of remission were found out. These results should be verified by further studies. Not everyone with rheumatoid arthritis responds favorably to treatment with methotrexate, but multiple studies and reviews showed that the majority of people receiving methotrexate for up to one year had less pain, functioned better, had fewer swollen and tender joints, and had less disease activity overall as reported by themselves and their doctors. X-rays also showed that the progress of the disease slowed or stopped in many people receiving methotrexate, with the progression being completely halted in about 30% of those receiving the drug. Those individuals with rheumatoid arthritis treated with methotrexate have been found to have a lower risk of cardiovascular events such as myocardial infarctions (heart attacks) and strokes. Results of a systematic review exploring the comparative effectiveness of treatments of early rheumatoid arthritis can be improved with combination therapy of tumor necrosis factor (TNF) or non-TNF biologics with methotrexate alone. In 2012 a joint task force of the ACR and EULAR updated the treatment guidelines for RA. They do make a distinction between patients with early RA (<6 months of disease duration) and patients with established RA. These guidelines highlight the need to switch or add DMARD therapy after 3 months of worsening or persistent moderate/high disease activity. If disease still persists after 3 months of intense DMARD therapy, addition of a biologic agent is warranted. Treatment with a biologic agent or aggressive combination DMARD therapy was also recommended as initial therapy in certain patients with high disease activity and poor prognosis. However, it has not been clearly established that this more intensive initial approach is superior to starting with methotrexate alone and, in the absence of an inadequate therapeutic response, moving rapidly to combination therapy. Treatment Most rheumatic diseases are treated with analgesics, NSAIDs (nonsteroidal anti-inflammatory drug), steroids (in serious cases), DMARDs (disease-modifying antirheumatic drugs), monoclonal antibodies, such as infliximab and adalimumab, the TNF inhibitor etanercept, and methotrexate for moderate to severe rheumatoid arthritis. The biologic agent rituximab (anti-B cell therapy) is now licensed for use in refractory rheumatoid arthritis. Physiotherapy is vital in the treatment of many rheumatological disorders. Occupational therapy can help patients find alternative ways for common movements that would otherwise be restricted by their disease. Patients with rheumatoid arthritis often need a long term, coordinated and a multidisciplinary team approach towards management of individual patients. Treatment is often tailored according to the individual needs of each patient which is also dependent on the response and the tolerability of medications. The aim of this study was to evaluate the real-life immunogenicity of anti-drug antibodies, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab (TCZ). We evaluated 126 TCZ-treated patients with rheumatoid arthritis (16 males and 110 females; mean age 59±12 years, range 26-83; mean disease duration 11±5 years) with inadequate 12-week response to any synthetic and biological disease-modifying anti-rheumatic drugs, in a retrospective analysis. One-hundred and seven patients were treated with methotrexate mean dose 12.6±1.3 mg/week in combination with TCZ, 13 received TCZ monotherapy, and six received leflunomide 20 mg/day plus TCZ; all patients were treated with prednisone mean dose 6.4±1.2 mg/day. They had a 28-joint Disease Activity Score (DAS28) of &gt;3.2, an erythrocyte sedimentation rate (ESR) of &gt;30 mm/hour, and CRP levels of &gt;1.0 mg/dL. We evaluated at baseline and after 6 months of treatment: DAS28; rheumatoid factor (RF) IgM, IgA, and IgG; anti-citrullinated peptide antibody; ESR; CRP; TNF-α; and IL-6. TCZ and anti-TCZ antibodies were detected using LISA-TRACKER Duo TCZ. TCZ levels of &lt;10 µg/mL were considered low and &gt;10 µg/mL high. After 6 months of treatment only one patient was positive for anti-TCZ antibodies. There were correlations between DAS28, ESR, and CRP and IL-6 levels in all patients. Comparison of the 84 patients with TCZ levels of &lt;10 µg/mL and the 42 with TCZ levels of &gt;10 µg/mL showed the following differences: DAS28: 3.09±1.32 vs 2.78±1.32, P=0.0005; ESR: 27±14.8 vs 14±12 mm/hour, P=0.0001; CRP: 1.47±1.05 vs 0.65±0.80 mg/dL, P=0.0086; TNF-α: 10.2±1.2 vs 9.9±1.1 pg/mL, P=0.999; IL-6: 3.65±4.75 vs 3.62±4.41 pg/mL, P=0.97; anti-citrullinated peptide antibody: 85.2±93.7 vs 86.7±90.3 IU/mL, P=0.94; RF IgM: 72.4±62.7 vs 68.3±61.6 IU/mL, P=0.754; RF IgA: 41.7±36.4 vs 47.8±42.1 U/mL, P=0.449; and RF IgG: 46.4±46.1 vs 59.3±58.2 U/mL, P=0.212. These findings show that the occurrence of anti-drug antibodies against TCZ is very rare and that there are statistically significant correlations between TCZ levels of &gt;10 µg/mL and ESR, CRP levels, and DAS28.  The therapeutic efficacy and tolerability of the combination of cyclosporin A, methotrexate and fluocortolone was evaluated after 96 months of treatment in 140 patients with rheumatoid arthritis. The initial dose of CyA was 5 mg/kg per day and was subsequently modified on the basis of the individual clinical response. Fluocortolone was initially administered at a dose that was sufficient to control disease activity (80-130 mg/week) and then was gradually tapered down to a maintenance dose of 15-20 mg/week. MTX was given intravenously at a dose of 15 mg once weekly for 4 consecutive weeks and then, after a 2-week interval, every 2 weeks or every month depending on the evolution of the disease. At the end of the study a statistically significant improvement was observed in both clinical (VAS, grip-strength, duration of morning stiffness, number of swollen joints, number of painful joints, Ritchie's index and Lee's functional index) and laboratory parameters: ESR (p = 0.000); alpha 2 globulins (p = 0.000); hemoglobin (p = 0.000); CRP (p &lt; 0.001); and rheumatoid factor (p = 0.000). Radiological evaluation revealed little progression in anatomic lesions (Larsen score p = 0.699; number of erosions p = 0.344), thus suggesting that our protocol may be capable of showing down both bone resorption and cartilage loss. Renal toxicity, defined as an increase in plasma creatinine concentrations of more than 50% of the baseline value, was observed in 12 patients (8.5%), but the drug was discontinued in only one, who simultaneously presented high blood pressure. The positive results so far achieved in our study must be interpreted as being due to the combined action of the individual drugs, which made it possible for them to be used at relatively low dosages that minimised the onset of their side effects while maintaining the efficacy of their suppressive action. To evaluate whether the clinical advantages observed after 1 year in a randomized controlled clinical trial, in which 2 treatment strategies were compared (the early disease-modifying antirheumatic drug [DMARD] approach versus the pyramid approach), persist after 5 years. In this study, 238 patients with recently diagnosed rheumatoid arthritis (RA) were randomized to either the pyramid group (n = 56) or the early DMARD group (n = 182). Patients assigned to the pyramid group received nonsteroidal antiinflammatory drugs for at least 1 year after inclusion (the mean +/- SD lag time until first prescription of a DMARD was 14 +/- 9 months). Patients in the early DMARD group were treated with a DMARD immediately after inclusion. After 5 years, data were available for 44 patients in the pyramid group (79%) and 145 patients in the early DMARD group (80%). No prolongation of the clinical advantages in favor of the early DMARD group, as observed after the first year, was demonstrated. Nevertheless, a significantly shorter delay time until complete response and a higher number of patients with overall clinically relevant improvement at several assessment points were observed in the early DMARD group compared with the pyramid group. The clinical results in favor of the early DMARD group, as observed after the first year, were not as evident after 5 years. This indicates that a more aggressive treatment approach in early RA is required, and that treatment should be continued for a prolonged period of time, in order to maintain the advantages obtained in the first year. To determine whether early inflammatory activity in the first year of disease compared to persistent or later occurrence of swelling or tenderness in the wrist joints is associated with 5-year erosions in the same joint in patients with early rheumatoid arthritis (RA). A cohort of 195 patients with early active RA was enrolled in the Finnish RA Combination Trial. Swelling and tenderness of wrists were assessed at baseline and at 3, 6, 12, 24, 36, and 48 months. Radiographs of the wrists were taken at the baseline and at 5 years. The 237 wrist joints of 125 patients without erosions at baseline were classified according to wrist swelling, i.e., I: never swollen; II: swollen during first year only; III: swollen during the second to fourth year only; and IV: swollen during the first year and followup, and similarly according to tenderness. Thirty percent of the wrists were never swollen in all clinical examinations; 43% were swollen only during the first year; 11% were not swollen in the first year, but were swollen at some time during 24-48 months; and 16% of wrists were swollen during the first year and at some time during 24-48 months. At 5 years, 64% of 237 wrists remained free of erosions. Erosions developed in 82% of wrists that were swollen during both the first year and 24-48 months, versus 56% of wrists that were not swollen at first year but were swollen during 24-48 months, 31% of wrists that were swollen during the first year only, and 11% of wrists that were never swollen. Similar results were seen for joint tenderness. Wrist swelling during the first year only is associated with less future wrist radiographic damage than persistent swelling or swelling only during the followup. Our results emphasize the value of early and continuous suppression of inflammatory activity in early RA. To compare the effectiveness and toxicity of cyclosporin A (CsA) vs low-dose methotrexate (MTX) over a period of one year in the treatment of psoriatic arthritis (PsA) with peripheral involvement. Thirty-five patients with PsA were enrolled in a prospective, controlled, randomized trial. CsA was initially given in doses of 3 mg/kg/day to a maximum permitted dose of 5 mg/kg/day; MTX was given in oral doses of 2.5 mg every 12 hours for 3 consecutive doses each week up to a maximum dose of 15 mg/weekly. Clinical and laboratory evaluations were performed at entry and monthly thereafter. After 6 and 12 months the number of painful joints, the number of swollen joints, the Ritchie index, the duration of morning stiffness, grip strength, CRP, the patient's and the physician's assessment of PsA activity, as well as the PASI, were significantly improved in both treatment groups. ESR values were significantly reduced only in the MTX group (p &lt; 0.01), which also showed a significantly increase of liver enzymes. The changes in the main clinical and laboratory parameters during the course of CsA or MTX treatment were not significantly different except for the AST and ALT levels (p &lt; 0.05). After one year of therapy CsA and MTX were withdrawn in 41.2% and 27.8% of the patients respectively, but these differences were not statistically significant. Our one-year prospective trial shows that low-dose CsA and MTX are both effective in the treatment of PsA, but the differences in the tolerability of these drugs must be considered at the start of therapy. To compare two therapeutic strategies for patients with recent-onset rheumatoid arthritis. Open, randomized clinical trial. Outpatient clinics of six clinical centers. 238 consecutive patients with recently diagnosed rheumatoid arthritis. Delayed or immediate introduction of treatment with slow-acting antirheumatic drugs (SAARDs). Primary end points were functional disability, pain, joint score, and erythrocyte sedimentation rate at 6 and 12 months and progression of radiologic abnormalities at 12 months. Statistically significant advantages at 12 months for patients receiving the SAARD strategy (immediate treatment with SAARDs) with regard to all primary end points that may be clinically important are indicated by the differences in improvements from baseline and their 95% CIs. These differences were 0.3 (95% CI, 0.2 to 0.6) for disability (range, 0 to 3), 10 mm (CI, 1 to 19 mm) for pain (range, 0 to 100 mm), 39 (CI, 4 to 74) for joint score (range, 0 to 534), and 11 mm/h (CI, 3 to 19 mm/h) for erythrocyte sedimentation rate (range, 1 to 140 mm/h), all in favor of SAARD treatment. The SAARD strategy also appears to be advantageous at 6 months. Radiologic abnormalities progressed at an equal rate in the SAARD and the non-SAARD groups; the difference in progression (range, 0 to 448) was 1 (CI, -3 to 5). Analyses were based on the intention-to-treat principle and thus included 29% of patients in the non-SAARD group who discontinued the non-SAARD treatment strategy; treatment was usually discontinued because of insufficient effectiveness. The SAARD strategy including two alternative SAARDs could not be continued by 8% of patients, usually because of adverse reactions. Early introduction of SAARDs may be more beneficial than delayed introduction for patients with recently diagnosed rheumatoid arthritis. Rheumatoid Arthritis (RA) is the most prevalent inflammatory joint disease in adults and shows a destructive course in most cases. The outcome of the disease - functional decline and invalidity - necessitates an early therapy. Recent studies demonstrate that the initiation of the treatment with a disease modifying antirheumatic drug (DMARD) treatment within the first three months after the onset of symptoms is crucial for sustained improvement of prognosis as well as therapeutic success and outcome. In the early stage of the disease, the criteria for the classification of Rheumatoid Arthritis (RA) are frequently not met. Up to over 50% of the patients show an arthritis, which cannot be classified and therefore is seen as undifferentiated arthritis (UA). Early therapeutic intervention appears to prevent the chronification of the disease; thus an early and appropriate disease modifying therapy is mandatory. Age, gender, involvement of the hands, positive rheumatoid factor, as well as the detection of anti cyclic-citrullinated peptide antibodies (anti-CCP Ab) are predictors of the development of RA. Beside conventional X-rays, there are other imaging methods such as magnetic resonance tomography imaging, Power-Doppler or contrast medium enhanced sonography, which may enable the detection not only of synovitis but also of erosive lesions at very early stages. Those patients suffering from UA carry a high risk for the development of a destructive arthritis as seen in RA, and therefore should be treated with an adequate DMARD. In these cases methotrexate is still the drug of first choice.\nHere is the question:\nRHEUMATOLOGY: A 42-year-old female patient reports pain with inflammatory features and swelling in both wrists, 2nd and 3rd metacarpophalangeal and proximal interphalangeal joints bilaterally and left ankle of 4 months of evolution accompanied by morning stiffness of more than one hour duration. Hand X-ray shows an erosion in the styloid process of the ulna in the right carpus. Laboratory tests showed Hb: 10 g/dL with ESR of 45 mm in the first hour, CRP 16 mg/L, rheumatoid factor 160 IU/ML. After 6 months of treatment with indomethacin and methotrexate, the patient persists with pain and swelling of both carpals, morning stiffness lasting 30 minutes and a CBC showing an ESR 30 mm in the first hour and a CRP 9 mg/dL. Regarding the attitude to take, which of the following is true:\nHere are the potential choices:\n1. Suspend the prescribed treatment due to lack of response and initiate prednisone at high doses for symptom control only.\n2. Maintain the therapeutic attitude taken since we have only been on it for 6 months and it would be necessary to wait a minimum of 9 months to evaluate therapeutic response.\n3. If there is no medical contraindication, consider adding an anti-TNF alpha to the treatment.\n4. Start a second disease-modifying drug as soon as possible, since it would not be possible to start treatment with biologic therapy alone after methotrexate.\n5. Consider starting treatment with anti-CD20 therapy associated with methotrexate.\nThe correct answer is: ",
        "gold_answer": "2 Maintain the therapeutic attitude taken since we have only been on it for 6 months and it would be necessary to wait a minimum of 9 months to evaluate therapeutic response.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n To describe the frequency and duration of remission in the Utrecht rheumatoid arthritis cohort of patients followed since diagnosis, and the clinical and treatment characteristics of patients with remission v those without. In 1990 the Utrecht rheumatoid arthritis cohort study group started a clinical trial in which patients with recent onset of rheumatoid arthritis (&lt;1 year) were randomised into four treatment groups: hydroxychloroquine (n = 169); intramuscular gold (n = 163); methotrexate (n = 166); and pyramid (n = 64). After two years, rheumatologists were allowed to prescribe any disease modifying antirheumatic drug. Remission was defined as: duration of morning stiffness &lt; or =15 min, mean VAS pain &lt; or =10 mm, Thompson joint score &lt; or =10, and ESR &lt; or =30 mm/h during at least six months. Cox regression analysis was used to determine baseline clinical, demographic, and treatment predictors of remission. Mean follow up duration was 62 months. Thirty six per cent achieved at least one period of remission. Median duration between diagnosis and the first remission period was 15 months for the intramuscular gold group, 18 months for the methotrexate and hydroxychloroquine groups, and 24 months for the pyramid group (NS). Predictors of remission were early response to initial treatment, less pain, rheumatoid factor negativity, and lower joint score at baseline. After a mean follow up duration of 62 months, only 36% of the patients had fulfilled the remission criteria at least once. A good response to treatment during the first year seems to be independently associated with remission rather than initial treatment alone. Leflunomide is a relatively new disease modifying antirheumatic drug (DMARD) and a number of studies evaluating its effectiveness and safety in daily medical practice is limited. Evaluation of effectiveness and safety of leflunomide treatment in patients with active rheumatoid arthritis in whom methotrexate was ineffective or contraindicated. Eighty one patients (66 women and 15 men) with RA diagnosed according to ARA (The American Rheumatism Association) criteria were included in the study. The mean age was 57.6+/-11.7 years and the mean disease duration was 7.7+/-7.1 years. The inclusion criteria were: disease activity according to DAS28 (Disease Activity Score)&gt;3.2 and contraindications to methotrexate or ineffective methotrexate treatment for at least 3 months. At the beginning of the study 49 of patients were treated with methotrexate in weekly dose of 17+4.2mg and 32 were not treated with DMARDs. Oral glicocorticosteroids in stable doses of 5-15mg of prednisone were given to 66 (77.7%) of them. There was no statistically significant difference in radiological progression of the disease according to Steinbrocker's scale between groups (treated and not treated with methotrexate). Monotherapy with leflunomide was started with loading dose of 100mg for 3 days, and then 20mg daily. Combination therapy was introduced without loading dose. Evaluation was performed monthly and included: duration of morning stiffness, pain and disease activity according to VAS (visual-analogue) scale, the number of tender and swollen joints, blood count, ESR, CRP, aminotransferases activity, and the presence and intensity of adverse reactions. The results of treatment were evaluated after 5 months in 37 of patients and adverse reactions which happened until the end of 5th month were evaluated in all included patients. The mean DAS28 values improved exponentially during consecutive months and the difference between them was statistically significant. Adverse reactions during 5 months of treatment were observed in 36(44,4%) of patients and in 6(7,4%) of cases the treatment had to be stopped because of side effects. The frequency of adverse reactions was similar in monotherapy and combination therapy group. Leflunomide therapy can be effective in patients with active rheumatoid arthritis in whom methotrexate is contraindicated or insufficient. Combination of leflunomide with methotrexate is safe and does not increase the frequency of adverse reactions. DAS28 index calculated with regard for ESR, the number of swollen/painful joints and evaluation of the patient's condition by VAS is universally used to estimate activity of rheumatoid arthritis (RA). There is a variant of calculation using C-reactive protein (CRP) instead of ESR. Our experience indicates that ESR decreases more slowly than CRP during treatment and better reflects dynamics of patients' condition. From the practical standpoint it is important to estimate activity of RA because therapeutic modalities are chosen based on the DAS28 value. To study the influence of pharmaceutical form of methotrexate on the acute-phase response in rheumatoid arthritis. The study included 32 patients (24 women, 8 men) aged 19-76 (mean 47.5 +/- 28.5) yr with active RA (DAS28 &gt; 3.2) 4-30 months (11.5 +/- 7.4, median 8) in duration. Diagnosis was made using AXR criteria (1987), none of the patients previously received methotrexate injections. Inclusion criteria: initially high ESR (Westegren, mm/hr) and/or CRP (mg/l measured by a highly sensitive method). All patients were given methotrexate subcutaneously for 12 weeks as monotherapy (initial dose 10 mg, maximum one 25 mg/week). The cumulative dose was 211.36 +/- 17.2 mg. Side effects did not require withdrawal of methotrexate. CRP level decreased faster than ERS: a 70% decrease of CRP by week 12 was recorded more frequently than that of ESR. Slow dynamics of the number of swollen joints compared with CRP may be due to the low cumulative dose of methotrexate. Duration of the disease had no effect on dynamics of acute phase characteristics. Methotrexate injections resulted in markedly delayed development of clinical signs of improvement compared with laboratory values. CFP levels fell down much faster than ESR, Remission or low activity of RA (estimated from DAS28) occurred only in 38% of the cases after 3 month monotherapy by methotrexate injections. It is concluded that efficacy of this drug should be estimated no sooner than 4 months after the onset of the treatment. To assess whether weekly pulse methotrexate therapy alters radiographic progression of joint disease in patients with rheumatoid arthritis. Prospective, controlled study. Hand, wrist and foot roentgenograms obtained before, at the onset of, and during methotrexate treatment were scored for degree of joint-space narrowing and erosions by three rheumatologists using a standard method. Sequential sample of 24 patients with active definite or classical rheumatoid arthritis and previous unsuccessful treatment; of these, 3 were excluded due to drug ineffectiveness; 2, due to side effects; and 1, due to refusal to take methotrexate. Treatment with nonsteroidal anti-inflammatory drugs and prednisone was continued. Methotrexate was given weekly to control clinical evidence of disease in patients. After having had an average of 30 months of therapy, the 18 patients who continued to receive methotrexate therapy showed significant (p less than 0.05) clinical improvement, as evidenced by their decreased joint counts and joint scores, duration of morning stiffness, pain scales, and sedimentation rates. Despite patients' prolonged clinical improvement, the mean rate of development of erosions and joint-space narrowing during methotrexate therapy was not significantly different from the rate of radiographic progression before methotrexate therapy (0.043 compared with 0.041; p greater than 0.05). Weekly pulse methotrexate is effective for the long-term management of clinical disease activity in patients with refractory rheumatoid arthritis but may not be a disease-modifying agent by roentgenographic criteria. 42-year-old old female patient, followed up with diagnosis of rheumatoid arthritis for 15 years, was admitted with necrotising ulcer of left hand 1st and 2nd fingertips and pain, swelling, limitation of movement, and morning stiffness at bilateral wrist, and metacarpophalangeal and proximal interphalangeal joints. Laboratory tests revealed elevated acute phase reactants. Radial and ulnar arteries were clear in upper extremity Doppler ultrasound. The patient was diagnosed as RA activation and digital ulcer and administered iloprost infusion for five days and 1 mg/kg corticosteroid and 20 mg/week methotrexate (MTX). After one month, a partial regression of clinical and laboratory findings was observed. However, 6 months later, due to relapsed and increased complaints and findings, adalimumab 40 mg was administered. Two months later, clinical and laboratory findings apparently decreased.  Another test that checks the level of C-reactive protein (CRP) in the blood may also be conducted. CRP is produced by the liver in response to an injury or infection, and people with polymyalgia rheumatica usually have high levels. However, like the ESR, this test is also not very specific. Polymyalgia rheumatica is sometimes associated with temporal arteritis, a condition requiring more aggressive therapy. To test for this additional disorder, a biopsy sample may be taken from the temporal artery. Treatment Prednisone is the drug of choice for PMR, and treatment duration is frequently greater than one year. If the patient does not experience dramatic improvement after three days of 10–20 mg oral prednisone per day, the diagnosis should be reconsidered. Sometimes relief of symptoms occurs in only several hours. This study aimed to evaluate remission in patients with early RA treated by conventional DMARDs and to identify its possible predictor factors. Patients with early RA (&lt;12 months) were enrolled in a 2-year follow-up study. Standard evaluation completed at baseline and at 24 months included clinical, laboratory, functional and structural assessment. Clinical remission after 2 years of follow-up was defined when DAS28 was less than 2.6. Possible predictor factors for remission were analyzed. Fifty-one patients (88.2% women, mean age of 46.9 [24-72] years, mean disease duration of 24 [6-48] weeks) were enrolled in this study. The delay in referral for specialist care was 140 [7-420] days. Rheumatoid factor, anti-CCP, HLA-DRB1*01 and DRB1*04 alleles were present respectively in 62.5, 56.6, 11.8, and 45.1% of patients. At 24 months, 77.2% received a median dose of 5 (0-8) mg/day of prednisone and 65.2% was taking methotrexate (MTX). 13.6% of patients had stopped their DMARD because of socioeconomic difficulties. At 24 months, we noted a significant improvement of morning stiffness, pain score, swollen joint count, ESR, CRP, DAS28 and HAQ scores. Remission at 2 years was noted in 34.8% of patients and was significantly associated in univariate but not in multivariate analysis to male sex (P=0.02) and to short delay in referral for specialist (P=0.03). In this cohort of early RA patients treated with conventional DMARDs, especially with methotrexate in monotherapy, remission at 2-year of follow-up was obtained in one third of patients. No predictor factors of remission were found out. These results should be verified by further studies. Not everyone with rheumatoid arthritis responds favorably to treatment with methotrexate, but multiple studies and reviews showed that the majority of people receiving methotrexate for up to one year had less pain, functioned better, had fewer swollen and tender joints, and had less disease activity overall as reported by themselves and their doctors. X-rays also showed that the progress of the disease slowed or stopped in many people receiving methotrexate, with the progression being completely halted in about 30% of those receiving the drug. Those individuals with rheumatoid arthritis treated with methotrexate have been found to have a lower risk of cardiovascular events such as myocardial infarctions (heart attacks) and strokes. Results of a systematic review exploring the comparative effectiveness of treatments of early rheumatoid arthritis can be improved with combination therapy of tumor necrosis factor (TNF) or non-TNF biologics with methotrexate alone. In 2012 a joint task force of the ACR and EULAR updated the treatment guidelines for RA. They do make a distinction between patients with early RA (<6 months of disease duration) and patients with established RA. These guidelines highlight the need to switch or add DMARD therapy after 3 months of worsening or persistent moderate/high disease activity. If disease still persists after 3 months of intense DMARD therapy, addition of a biologic agent is warranted. Treatment with a biologic agent or aggressive combination DMARD therapy was also recommended as initial therapy in certain patients with high disease activity and poor prognosis. However, it has not been clearly established that this more intensive initial approach is superior to starting with methotrexate alone and, in the absence of an inadequate therapeutic response, moving rapidly to combination therapy. Treatment Most rheumatic diseases are treated with analgesics, NSAIDs (nonsteroidal anti-inflammatory drug), steroids (in serious cases), DMARDs (disease-modifying antirheumatic drugs), monoclonal antibodies, such as infliximab and adalimumab, the TNF inhibitor etanercept, and methotrexate for moderate to severe rheumatoid arthritis. The biologic agent rituximab (anti-B cell therapy) is now licensed for use in refractory rheumatoid arthritis. Physiotherapy is vital in the treatment of many rheumatological disorders. Occupational therapy can help patients find alternative ways for common movements that would otherwise be restricted by their disease. Patients with rheumatoid arthritis often need a long term, coordinated and a multidisciplinary team approach towards management of individual patients. Treatment is often tailored according to the individual needs of each patient which is also dependent on the response and the tolerability of medications. The aim of this study was to evaluate the real-life immunogenicity of anti-drug antibodies, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab (TCZ). We evaluated 126 TCZ-treated patients with rheumatoid arthritis (16 males and 110 females; mean age 59±12 years, range 26-83; mean disease duration 11±5 years) with inadequate 12-week response to any synthetic and biological disease-modifying anti-rheumatic drugs, in a retrospective analysis. One-hundred and seven patients were treated with methotrexate mean dose 12.6±1.3 mg/week in combination with TCZ, 13 received TCZ monotherapy, and six received leflunomide 20 mg/day plus TCZ; all patients were treated with prednisone mean dose 6.4±1.2 mg/day. They had a 28-joint Disease Activity Score (DAS28) of &gt;3.2, an erythrocyte sedimentation rate (ESR) of &gt;30 mm/hour, and CRP levels of &gt;1.0 mg/dL. We evaluated at baseline and after 6 months of treatment: DAS28; rheumatoid factor (RF) IgM, IgA, and IgG; anti-citrullinated peptide antibody; ESR; CRP; TNF-α; and IL-6. TCZ and anti-TCZ antibodies were detected using LISA-TRACKER Duo TCZ. TCZ levels of &lt;10 µg/mL were considered low and &gt;10 µg/mL high. After 6 months of treatment only one patient was positive for anti-TCZ antibodies. There were correlations between DAS28, ESR, and CRP and IL-6 levels in all patients. Comparison of the 84 patients with TCZ levels of &lt;10 µg/mL and the 42 with TCZ levels of &gt;10 µg/mL showed the following differences: DAS28: 3.09±1.32 vs 2.78±1.32, P=0.0005; ESR: 27±14.8 vs 14±12 mm/hour, P=0.0001; CRP: 1.47±1.05 vs 0.65±0.80 mg/dL, P=0.0086; TNF-α: 10.2±1.2 vs 9.9±1.1 pg/mL, P=0.999; IL-6: 3.65±4.75 vs 3.62±4.41 pg/mL, P=0.97; anti-citrullinated peptide antibody: 85.2±93.7 vs 86.7±90.3 IU/mL, P=0.94; RF IgM: 72.4±62.7 vs 68.3±61.6 IU/mL, P=0.754; RF IgA: 41.7±36.4 vs 47.8±42.1 U/mL, P=0.449; and RF IgG: 46.4±46.1 vs 59.3±58.2 U/mL, P=0.212. These findings show that the occurrence of anti-drug antibodies against TCZ is very rare and that there are statistically significant correlations between TCZ levels of &gt;10 µg/mL and ESR, CRP levels, and DAS28.  The therapeutic efficacy and tolerability of the combination of cyclosporin A, methotrexate and fluocortolone was evaluated after 96 months of treatment in 140 patients with rheumatoid arthritis. The initial dose of CyA was 5 mg/kg per day and was subsequently modified on the basis of the individual clinical response. Fluocortolone was initially administered at a dose that was sufficient to control disease activity (80-130 mg/week) and then was gradually tapered down to a maintenance dose of 15-20 mg/week. MTX was given intravenously at a dose of 15 mg once weekly for 4 consecutive weeks and then, after a 2-week interval, every 2 weeks or every month depending on the evolution of the disease. At the end of the study a statistically significant improvement was observed in both clinical (VAS, grip-strength, duration of morning stiffness, number of swollen joints, number of painful joints, Ritchie's index and Lee's functional index) and laboratory parameters: ESR (p = 0.000); alpha 2 globulins (p = 0.000); hemoglobin (p = 0.000); CRP (p &lt; 0.001); and rheumatoid factor (p = 0.000). Radiological evaluation revealed little progression in anatomic lesions (Larsen score p = 0.699; number of erosions p = 0.344), thus suggesting that our protocol may be capable of showing down both bone resorption and cartilage loss. Renal toxicity, defined as an increase in plasma creatinine concentrations of more than 50% of the baseline value, was observed in 12 patients (8.5%), but the drug was discontinued in only one, who simultaneously presented high blood pressure. The positive results so far achieved in our study must be interpreted as being due to the combined action of the individual drugs, which made it possible for them to be used at relatively low dosages that minimised the onset of their side effects while maintaining the efficacy of their suppressive action. To evaluate whether the clinical advantages observed after 1 year in a randomized controlled clinical trial, in which 2 treatment strategies were compared (the early disease-modifying antirheumatic drug [DMARD] approach versus the pyramid approach), persist after 5 years. In this study, 238 patients with recently diagnosed rheumatoid arthritis (RA) were randomized to either the pyramid group (n = 56) or the early DMARD group (n = 182). Patients assigned to the pyramid group received nonsteroidal antiinflammatory drugs for at least 1 year after inclusion (the mean +/- SD lag time until first prescription of a DMARD was 14 +/- 9 months). Patients in the early DMARD group were treated with a DMARD immediately after inclusion. After 5 years, data were available for 44 patients in the pyramid group (79%) and 145 patients in the early DMARD group (80%). No prolongation of the clinical advantages in favor of the early DMARD group, as observed after the first year, was demonstrated. Nevertheless, a significantly shorter delay time until complete response and a higher number of patients with overall clinically relevant improvement at several assessment points were observed in the early DMARD group compared with the pyramid group. The clinical results in favor of the early DMARD group, as observed after the first year, were not as evident after 5 years. This indicates that a more aggressive treatment approach in early RA is required, and that treatment should be continued for a prolonged period of time, in order to maintain the advantages obtained in the first year. To determine whether early inflammatory activity in the first year of disease compared to persistent or later occurrence of swelling or tenderness in the wrist joints is associated with 5-year erosions in the same joint in patients with early rheumatoid arthritis (RA). A cohort of 195 patients with early active RA was enrolled in the Finnish RA Combination Trial. Swelling and tenderness of wrists were assessed at baseline and at 3, 6, 12, 24, 36, and 48 months. Radiographs of the wrists were taken at the baseline and at 5 years. The 237 wrist joints of 125 patients without erosions at baseline were classified according to wrist swelling, i.e., I: never swollen; II: swollen during first year only; III: swollen during the second to fourth year only; and IV: swollen during the first year and followup, and similarly according to tenderness. Thirty percent of the wrists were never swollen in all clinical examinations; 43% were swollen only during the first year; 11% were not swollen in the first year, but were swollen at some time during 24-48 months; and 16% of wrists were swollen during the first year and at some time during 24-48 months. At 5 years, 64% of 237 wrists remained free of erosions. Erosions developed in 82% of wrists that were swollen during both the first year and 24-48 months, versus 56% of wrists that were not swollen at first year but were swollen during 24-48 months, 31% of wrists that were swollen during the first year only, and 11% of wrists that were never swollen. Similar results were seen for joint tenderness. Wrist swelling during the first year only is associated with less future wrist radiographic damage than persistent swelling or swelling only during the followup. Our results emphasize the value of early and continuous suppression of inflammatory activity in early RA. To compare the effectiveness and toxicity of cyclosporin A (CsA) vs low-dose methotrexate (MTX) over a period of one year in the treatment of psoriatic arthritis (PsA) with peripheral involvement. Thirty-five patients with PsA were enrolled in a prospective, controlled, randomized trial. CsA was initially given in doses of 3 mg/kg/day to a maximum permitted dose of 5 mg/kg/day; MTX was given in oral doses of 2.5 mg every 12 hours for 3 consecutive doses each week up to a maximum dose of 15 mg/weekly. Clinical and laboratory evaluations were performed at entry and monthly thereafter. After 6 and 12 months the number of painful joints, the number of swollen joints, the Ritchie index, the duration of morning stiffness, grip strength, CRP, the patient's and the physician's assessment of PsA activity, as well as the PASI, were significantly improved in both treatment groups. ESR values were significantly reduced only in the MTX group (p &lt; 0.01), which also showed a significantly increase of liver enzymes. The changes in the main clinical and laboratory parameters during the course of CsA or MTX treatment were not significantly different except for the AST and ALT levels (p &lt; 0.05). After one year of therapy CsA and MTX were withdrawn in 41.2% and 27.8% of the patients respectively, but these differences were not statistically significant. Our one-year prospective trial shows that low-dose CsA and MTX are both effective in the treatment of PsA, but the differences in the tolerability of these drugs must be considered at the start of therapy. To compare two therapeutic strategies for patients with recent-onset rheumatoid arthritis. Open, randomized clinical trial. Outpatient clinics of six clinical centers. 238 consecutive patients with recently diagnosed rheumatoid arthritis. Delayed or immediate introduction of treatment with slow-acting antirheumatic drugs (SAARDs). Primary end points were functional disability, pain, joint score, and erythrocyte sedimentation rate at 6 and 12 months and progression of radiologic abnormalities at 12 months. Statistically significant advantages at 12 months for patients receiving the SAARD strategy (immediate treatment with SAARDs) with regard to all primary end points that may be clinically important are indicated by the differences in improvements from baseline and their 95% CIs. These differences were 0.3 (95% CI, 0.2 to 0.6) for disability (range, 0 to 3), 10 mm (CI, 1 to 19 mm) for pain (range, 0 to 100 mm), 39 (CI, 4 to 74) for joint score (range, 0 to 534), and 11 mm/h (CI, 3 to 19 mm/h) for erythrocyte sedimentation rate (range, 1 to 140 mm/h), all in favor of SAARD treatment. The SAARD strategy also appears to be advantageous at 6 months. Radiologic abnormalities progressed at an equal rate in the SAARD and the non-SAARD groups; the difference in progression (range, 0 to 448) was 1 (CI, -3 to 5). Analyses were based on the intention-to-treat principle and thus included 29% of patients in the non-SAARD group who discontinued the non-SAARD treatment strategy; treatment was usually discontinued because of insufficient effectiveness. The SAARD strategy including two alternative SAARDs could not be continued by 8% of patients, usually because of adverse reactions. Early introduction of SAARDs may be more beneficial than delayed introduction for patients with recently diagnosed rheumatoid arthritis. Rheumatoid Arthritis (RA) is the most prevalent inflammatory joint disease in adults and shows a destructive course in most cases. The outcome of the disease - functional decline and invalidity - necessitates an early therapy. Recent studies demonstrate that the initiation of the treatment with a disease modifying antirheumatic drug (DMARD) treatment within the first three months after the onset of symptoms is crucial for sustained improvement of prognosis as well as therapeutic success and outcome. In the early stage of the disease, the criteria for the classification of Rheumatoid Arthritis (RA) are frequently not met. Up to over 50% of the patients show an arthritis, which cannot be classified and therefore is seen as undifferentiated arthritis (UA). Early therapeutic intervention appears to prevent the chronification of the disease; thus an early and appropriate disease modifying therapy is mandatory. Age, gender, involvement of the hands, positive rheumatoid factor, as well as the detection of anti cyclic-citrullinated peptide antibodies (anti-CCP Ab) are predictors of the development of RA. Beside conventional X-rays, there are other imaging methods such as magnetic resonance tomography imaging, Power-Doppler or contrast medium enhanced sonography, which may enable the detection not only of synovitis but also of erosive lesions at very early stages. Those patients suffering from UA carry a high risk for the development of a destructive arthritis as seen in RA, and therefore should be treated with an adequate DMARD. In these cases methotrexate is still the drug of first choice.\nHere is the question:\nRHEUMATOLOGY: A 42-year-old female patient reports pain with inflammatory features and swelling in both wrists, 2nd and 3rd metacarpophalangeal and proximal interphalangeal joints bilaterally and left ankle of 4 months of evolution accompanied by morning stiffness of more than one hour duration. Hand X-ray shows an erosion in the styloid process of the ulna in the right carpus. Laboratory tests showed Hb: 10 g/dL with ESR of 45 mm in the first hour, CRP 16 mg/L, rheumatoid factor 160 IU/ML. After 6 months of treatment with indomethacin and methotrexate, the patient persists with pain and swelling of both carpals, morning stiffness lasting 30 minutes and a CBC showing an ESR 30 mm in the first hour and a CRP 9 mg/dL. Regarding the attitude to take, which of the following is true:\nHere are the potential choices:\n1. Suspend the prescribed treatment due to lack of response and initiate prednisone at high doses for symptom control only.\n2. Maintain the therapeutic attitude taken since we have only been on it for 6 months and it would be necessary to wait a minimum of 9 months to evaluate therapeutic response.\n3. If there is no medical contraindication, consider adding an anti-TNF alpha to the treatment.\n4. Start a second disease-modifying drug as soon as possible, since it would not be possible to start treatment with biologic therapy alone after methotrexate.\n5. Consider starting treatment with anti-CD20 therapy associated with methotrexate.\nThe correct answer is: 2. Maintain the therapeutic attitude taken since we have only been on it for 6 months and it would be necessary to wait a minimum of 9 months to evaluate therapeutic response."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Community acquired pneumonia (CAP) due to Streptococcus pneumoniae is a frequent cause of morbidity and mortality. We communicate two cases of CAP with complications. In both cases levofloxacin-resistant S. pneumoniae was isolated in pleural effusion. Patient 1: A 51-year-old man who had not received previous treatment with quinolones was admitted to the hospital for CAP and initially treated with levofloxacin (500 mg/24h iv). Four days later pleural effusion developed and fluid culture isolated levofloxacin-resistant S. pneumoniae (MIC &gt; 32 .g/ml). The outcome was favorable following chest tube placement and treatment with beta-lactam antibiotics. Patient 2: A 73-year-old man with a history of chronic obstructive pulmonary disease was admitted due to CAP and was initially treated with levofloxacin (500 mg/24 h iv). He was transferred to our hospital after 10 days of treatment with this antibiotic, following the development of pleural effusion with isolation of levofloxacin-resistant S. pneumoniae (MIC = 12 .g/ml). The patient was treated with chest tube placement and beta-lactam antibiotics with a favorable outcome. Patients with CAP treated empirically must be closely followed, both clinically and radiologically, to facilitate early detection of complications due to bacterial resistance to the prescribed antibiotic. Patients with CAP who have received quinolones in the weeks before the development of pneumonia should not been treated empirically with these antibiotics because of the risk of resistance development. Community-Acquired Pneumonia (CAP) is a common reason for hospitalization of a pediatric patient. We report a 20-month-old female admitted for suspected CAP. History included a week-long cough, fever, dyspnea, single occurrence of seizure-like activity, and a sick contact. Initial chest X-ray (CXR) showed left lower lobe pneumonia and parapneumonic effusion with a complex left pleural effusion. Ultrasound findings prompted the need for contrast-enhanced computed tomography (CT) of the chest. Contrast-enhanced CT of the chest confirmed a large pleural effusion with major atelectasis and mediastinal shift. The patient was treated with empiric antibiotics, video-assisted thoracoscopic surgical (VATS) decortication of empyema, and chest tube placement. Due to intraoperative complications, the VATS decortication was aborted and patient was transferred to the pediatric intensive care unit (PICU). A thoracentesis with culture failed to isolate a bacterial organism. Dexamethasone was started after repeat CXR showed persistent infiltrate. Subsequent contrast-enhanced CT of the chest showed a large collection of air and persistent consolidation. The patient received repeat VATS decortication and reinsertion of a chest tube. Repeat pleural fluid cultures failed to isolate a bacterial organism. Infectious disease (ID) consult recommended linezolid 140 mg Q8H for 4 weeks. Seven days after second VATS, a respiratory pathogen panel was positive for rhinovirus/enterovirus. With resolution of leukocytosis and clinical improvement, the patient was discharged with the chest tube in place and pediatric surgery outpatient follow-up. After three months, sequalae from both the infection and interventions presented . Although gram-negative bacilli are a common cause they are rarely found in the respiratory tract of people without pneumonia, which has led to speculation of the mouth and throat as origin of the infection. Diagnosis In hospitalised patients who develop respiratory symptoms and fever, one should consider the diagnosis. The likelihood increases when upon investigation symptoms are found of respiratory insufficiency, purulent secretions, newly developed infiltrate on the chest X-Ray, and increasing leucocyte count. If pneumonia is suspected material from sputum or tracheal aspirates are sent to the microbiology department for cultures. In case of pleural effusion, thoracentesis is performed for examination of pleural fluid. In suspected ventilator-associated pneumonia it has been suggested that bronchoscopy or bronchoalveolar lavage is necessary because of the risks of incorrect clinical diagnoses. Treatment is typically with antibiotics such as clindamycin, meropenem, ampicillin/sulbactam, or moxifloxacin. For those with only chemical pneumonitis, antibiotics are not typically required. Among people hospitalized with pneumonia, about 10% are due to aspiration. It occurs more often in older people, especially those in nursing homes. Both sexes are equally affected. Signs and symptoms The person may have an insidious course with increased respiratory rate, foul-smelling sputum, hemoptysis, and fever. Complications may occur, such as exudative pleural effusion, empyema, and lung abscesses. If left untreated, aspiration pneumonia can progress to form a lung abscess. Another possible complication is an empyema, in which pus collects inside the lungs. If continual aspiration occurs, the chronic inflammation can cause compensatory thickening of the insides of the lungs, resulting in bronchiectasis. and oral therapy. Switching to oral antibiotics can be considered upon clinical and objective improvement (adequate drainage and removal of chest tube, declining CRP, temperature normalization). Oral antibiotic treatment should then be continued for another 1–4 weeks, again based on clinical, biochemical and radiological response. Treatment for relapsing fever can include various antibiotics. TBRF spirochaetes are susceptible to penicillin and other β-Lactam antibiotics, as well as tetracyclines, macrolides, and possibly fluoroquinolones. Although the CDC has not yet developed specific treatment guidelines for TBRF, experts generally recommend tetracycline 500 mg every 6 hours for 10 days as the preferred oral regimen for adults. If tetracyclines are contraindicated, erythromycin, 500 mg (or 12.5 mg/kg) every 6 hours for 10 days is an effective alternative. For patients with central nervous system involvement, parenteral therapy with ceftriaxone 2 g/day for 10–14 days is preferred. All patients treated with antibiotics should be observed during the first 4 hours of treatment for a Jarisch-Herxheimer reaction, which is a worsening of symptoms characterized by rigors, hypotension, and high fever. The reaction occurs in over 50% of cases and may be difficult to distinguish from a febrile crisis. Given appropriate We present the results of a retrospective study of 127 cases of empyema admitted to the pneumophtisiology department of the Centre hospitalier universitaire de Treichville (Abidjan), between January 1985 and December 1989. We present the pathogens identified in the pleural fluid and the course of the disease during treatment by repeat thoraco-centesis and systemic antibiotics. During the study period, pleural empyema represented 2.7% of all admissions to the pneumophtisiology department, and 20.5% of those presenting with pleural effusions. Bacteriological examination was recovered in 88 of the 127 patients, and was positive in 57 cases (64.7% of those examined). Of those with positive bacteriology, 50 (56.8%) had non-tuberculous bacterial infections, and 7 (7.9%) had tuberculous infection. Among the non-tuberculous bacterial infections, Gram-negative bacilli were most common (72%), and Pseudomonas was the species most frequently identified (48%). The mean stay in hospital was 47 days (range 10-143) and in 82 patients (64.6%), the outcome was favourable. The presentation was complicated by encystment in 36 cases (28.4%) and 9 patients (7%) died in hospital. Activity of natural streptogramin (NSG) appears well adapted to pathogens responsible for CAP. The goal of this multicenter pilot study was to bring first data about efficacy of NSG in treatment of CAP. PATIENTS METHOD: Ten days of a NSG (1 gr b.i.d. or t.i.d.) regimen was administered to 46 hospitalized adult patients for CAP defined with fever &gt; 38 degrees C, respiratory symptoms and X-ray opacity. Severely ill patients were excluded. A broncho-pulmonar sample (expectoration or trantracheal aspiration or protected distal sample) was performed in all patients. two patients were excluded because of pulmonary embolism (n = 1) or tuberculosis (n = 1) and 44 patients were analyzed. 50% of them had associated disease, 20% had failure of prior antibiotherapy. At inclusion, mean fever was 39.2 +/- 0.7 degrees C, respiratory rate was 22 +/- 5/mn, PaO2 was 74 +/- 10 mmHg, chest X-ray showed bilateral opacity in 16%, unilateral in 84% and pleural fluid level in 6 cases. Etiological diagnosis was determined in 70% of cases. Streptococcus pneumoniae (n = 14), Haemophilus influenzae (n = 5), Legionella pneumophila (n = 2), Mycoplasma pneumoniae (n = 2) and Chlamydia psittaci (n = 1) were the most frequent isolated pathogens. 40 patients (91%) were cured with NSG and delay to obtain apyrexia was 4.4 +/- 3.9 days. NSG was stopped in 4 patients: 1 clinical and bacteriological failure (Klebsiella pneumoniae), 2 clinical failures (1 pneumococcus with purulent pleurisy, 1 pneumococcus with worsening of respiratory status), 1 patient with resistant H. influenzae strain in spite of favourable clinical evolution. NSG was well tolerated in 86% of patients. these data invite to carry on evaluation of first line therapy of CAP with NSG. Fusobacterium necrophorum is a non-spore-forming gram-negative anaerobic bacillus that may be the causative agent of localized or severe systemic infections. Systemic infections due to F.necrophorum are known as Lemierre's syndrome, postanginal sepsis or necrobacillosis. The most common clinical course of severe infections in humans is a progressive illness from tonsillitis to septicemia in previously healthy young adults. A septic thrombophlebitis arising from the tonsillar veins and extending into the internal jugular vein leads to septicemia and septic emboli contributing to the development of necrotic abscesses especially in lungs and other tissues such as liver, bone and joints. In this case report, a previously healthy man with pneumonia and empyema due to F.necrophorum has been presented. A 22 year-old man suffering from sore throat for seven days was admitted to emergency department with ongoing fever and dysphagia for three days. On admission he was already taking amoxicillin-clavulanic acid and his complaints were relieved with continuation of therapy to a total of 10 days. However, five days after the cessation of treatment he developed productive cough, fever and generalized myalgia. On physical examination, there were crackles on right lower lung, and chest X-ray revealed pulmonary consolidation on the right middle lobe. Levofloxacin therapy was started based on the diagnosis of pneumonia. While polymorphonuclear leucocytes and intracellular gram-negative bacilli were seen in Gram stained sputum smear, sputum culture was reported as normal flora. Although the patient's status had started to improve with treatment, his condition deteriorated with development of fever and dyspnea. Chest X-ray revealed consolidation, pulmonary infiltrates, pleural effusion and air-fluid level on the right. Meropenem, clarithromycin and linezolid were initiated and a chest tube was inserted with the preliminary diagnosis of necrotizing pneumonia, empyema and type-1 respiratory failure. While there was no growth on bronchoalveolar lavage fluid culture, thoracentesis material inoculated into thioglycolate broth revealed turbidity. Further inoculation onto Schaedler agar which was incubated under anaerobic conditions, yielded growth of catalase negative, indol positive, gram-negative anaerobic bacilli identified as F.necrophorum by BBL Crystal system (Becton Dickinson, USA). The detailed history of the patient revealed that fish bone had stuck in his throat a week ago. Clarithromycin and linezolid were discontinued and he was recovered within six weeks of meropenem treatment. F.necrophorum infection should be considered in the differential diagnosis of persistent head and neck infections with rapidly progressive metastatic necrotic lesions especially in healthy young adults and clindamycin or metranidazol should be added to the treatment protocols. 77 cases of non-tuberculous empyema were studied retrospectively. The data of past history, laboratory, radiological, bacteriological and outcome were gathered. The mean delay between initial symptoms and clinical diagnosis was 2.6 weeks in this study. It was longer for those anaerobic features (p less than 0.02) whose details were unravelled. \"Blind\" antibiotic therapy before the first pleural aspirate is still common (46.7% of cases) and did not alter the frequency with which the causal bacteria was found, nor the distribution of the bacterial population. Pleural aspirate enabled the germ or germs responsible to be identified in 63% of cases. Streptococcus pneumoniae (n = 15) and anaerobic bacterias (n = 26) infections were predominant. Early pleural drainage in a trained unit care is the essential element in the treatment in association with appropriate antibiotics and prolonged physiotherapy. This triple therapy approach leads to a medical cure in practically all the patients and avoids a recourse to surgery. In the use of atomoxetine in children (6 years or older up to 70 kg) with attention-deficit hyperactivity disorder, acute treatment should be started with approximately 0.5 mg/kg orally daily. The dose should be increased after a minimum of 3 days up to approximately 1.2 mg/kg daily (target dose) as a single or two divided doses (in the morning and late afternoon). For children older than 6 years old, over 70 kg, acute treatment should be started with 40 mg/day orally and increased up to 80 mg/day after a minimum of 3 days. The dose can be taken as a single dose in the morning or in two divided doses (in the morning and late afternoon). After 2–4 weeks the dose can be increased to 100 mg/ daily. Purulent pleurisy has become rare. It is often masked by previous antibiotic treatment so that functional prognosis may be poor. Twenty children with purulent pleurisy of the large cavity admitted from 1987 to 1993 were included in the study: there were nine infants (age 5 to 18 months) with pleuro-pulmonary staphylococcal infection (group I) and 11 children (4-13 years) (group II). Clinical, biological, bacteriological and radiologic findings were analysed retrospectively as was the outcome. Patients of group I were admitted in poor general condition. X-ray showed moderate effusion and characteristic signs of staphylococcal infection. The bacteria identified in seven patients (77%) was S aureus. Recovery was rapid with antibiotics and simple local treatment. X-rays were normal two months after hospital discharge in seven patients (77%). One infant presented cicatricial bullous emphysema which required segmental resection. Patients of group II were admitted for moderate respiratory signs after a relatively long delay (14 days) since the onset of symptoms. X-rays showed considerable effusion in all and mediastinal shift in five patients (45%). Streptococcus pneumoniae was identified in one patient only. Local treatment of empyema was difficult; the effusion, already fibrinous, required repeated use of chest tubes in eight cases and surgical decortication in three. X-rays, performed 2 months after hospital discharge, were normal in only three patients. Long-term course was nevertheless favorable since chest X-rays at 5 months were normal in all children of both groups. Early recognition of purulent pleurisy is important in children aged over 3 years to ensure effective drainage before the effusion becomes fibrinous. All patients in whom the first tube was inserted after more than 10 days had a difficult follow-up requiring repeated chest drainages or surgery. Ultrasonography was a useful aid for diagnosis and local treatment. Computed tomography was useful for adapting treatment after several days of course. Medical treatment Medical treatment entails low dose antibiotic prophylaxis until resolution of VUR occurs. Antibiotics are administered nightly at half the normal therapeutic dose. The specific antibiotics used differ with the age of the patient and include: Amoxicillin or ampicillin – infants younger than 6 weeks Trimethoprim-sulfamethoxazole (co-trimoxazole) – 6 weeks to 2 months After 2 months the following antibiotics are suitable: Nitrofurantoin {5–7 mg/kg/24hrs} Nalidixic acid Bactrim Trimethoprim Cephalosporins Urine cultures are performed 3 monthly to exclude breakthrough infection. Annual radiological investigations are likewise indicated. Good perineal hygiene, and timed and double voiding are also important aspects of medical treatment. Bladder dysfunction is treated with the administration of anticholinergics. Antibiotic treatment of pleuro-pulmonary infectious diseases with ordinary germs brought a notable decrease in the frequency of pleural empyema without preventing them completely. The authors report 31 cases observed over the last 10 years. The initial signs corresponded to the classical picture but were rapidly masked by antibiotic treatment; it resulted in delay in hospital admission of over one month for more than half of the cases, for diagnosis was overlooked for a long time. In 19 patients, the pleural liquid was aseptic probably because of the antibiotics and of the lack of identification of anaerobic germs. The authors insist on the practical modalities of a medical treatment by puncture-lavage which, when associated with general antibiotic treatment, cured patients in 22 cases. On the other hand, the existence of bronchopleural fistula entailed surgery. Two main approaches to multiple sclerosis treatment maintenance therapy are used – immunomodulation and immunosuppression and alternatively, immune reconstitution therapy. Classified as the latter, cladribine tablets are administered intermittently as a short treatment course without continuous immunosuppression. In contrast to maintenance therapies, clinical efficacy extends beyond the dosing period. Cladribine tablets are administered as 2 courses separated by 1 year (a maximum of 20 days of treatment). The recommended cumulative dose is 3.5 mg/kg weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (1 or 2 tablets) as a single daily dose based on body weight. In a study of 44 infants and young children with staphylococcal pneumonia and pleurisy, cases were found to be divisible into three clinical groups: those with predominantly digestive tract symptomatology (seven); those in acute respiratory distress (28); and those with signs of central nervous system disorder (nine). Characteristic radiographic findings often permitted an early etiologic diagnosis, confirmed later by bacteriologic culture or by the course of the disease. The length of hospitalization was found to be directly proportional to the length of time between the onset of symptoms and the start of adequate therapy. Nineteen patients required thoracotomy, two were drained by a Küss trocar, 13 required repeated pleural aspiration, five underwent spontaneous resorption of the empyema and five had no pleural effusion. In several instances antibiotics were used in very high dosage (three to four times the suggested maximal dose). The main agents used were erythromycin, chloramphenicol and ristocetin; the dosage of the last named never exceeded the maximal recommended dose. Twenty-eight patients were less than one year old; of these seven died. Sixteen were over one year of age, the oldest being six years; all of these were cured. Any immunological mechanisms induced by influenza virus could cause severe secondary bacterial superinfection such as those by Streptococcus pyogenes [group A streptococcus (GAS)], Streptococcus pneumoniae or Staphylococcus aureus. Over recent years, the frequency of pleural empyema has increased in children with influenza infection. We present a severe case of acute empyema caused by S.pyogenes after influenza A infection. A previously healthy 39-year old woman was diagnosed as influenza A and received oral Oseltamivir 75 mg twice daily for 5 days. She had no vaccination of influenza A. Although her influenza A infection improved, she complained of fever and cough to our institute. Chest radiography showed encapsulated pleural effusion of the left lung and pleural effusion which was consistent with acute empyema. Then, she was diagnosed as having acute empyema and was admitted to our institute. Streptococcus pyogenes was identified by pleural fluid culture on day 4. thus, MNZ was changed to clindamycin (CLDM) 600 mg three times a day. While thoracic drainage with intrapleural urokinase and combination antibiotic therapy of ceftriaxone and CLDM were performed, her general condition and chest radiographic findings were not improved. She received video-assisted thoracic debridement on day 10. After the operation, the antibiotic therapy was changed to ABPC 6 g daily iv. Due to good clinical course, the antibiotic therapy was switched to oral amoxicillin 500 mg three times daily on day 28. Then, she was discharged. Influenza A virus infection could lead to severe GAS infection, while the latter can occur in otherwise healthy individual as well. Physician must consider the possibility of severe GAS infection after influenza A infection. Complicated parapneumonic effusion is one in which an invasive procedure is necessary for its resolution and empyema means pus in the pleural space. An early diagnosis and therapy of these conditions results in less morbidity and mortality. CT of the chest is important to study complex pleural effusions. Loculated effusions, those occupying more than 50% of the thorax, or which show positive Gram stain or bacterial culture, or a purulent effusion with a pH below 7.20, with a glucose level below 60 mg/dl or a LDH level more than three times the upper limit of normal for serum, are indications for an invasive procedure. These characteristics result from the evolution of a not well treated parapneumonic effusion, through the three stages: (1) exsudative; (2) fibrinopurulent; (3) fibrotic. Depending on the stage therapeutic methods vary from therapeutic thoracentesis, insertion of a chest tube with or without instillation of fibrinolytics, video-assisted thoracoscopic surgery, and lung decortication. A review of all these aspects are done based on a series of three cases reports with very different clinical presentation: one patient with empyema by Streptococcus pyogenes and that died rapidly due to massive hemoptysis; a patient with empyema due to acute pneumonia developing during an airflight; a patient with empyema and bacteraemia by Streptococcus pneumonia leading to the diagnosis of an unknown HIV infection. Antibiotics Macrolides are often used to treat chancroid. The CDC recommendation is either a single oral dose (1 gram) of azithromycin, a single IM dose (250 mg) of ceftriaxone, oral (500 mg) of erythromycin three times a day for seven days, or oral (500 mg) of ciprofloxacin twice a day for three days. Due to a paucity of reliable empirical evidence it is not clear whether macrolides are actually more effective and/or better tolerated than other antibiotics when treating chancroid. Data is limited, but there have been reports of ciprofloxacin and erythromycin resistance. Aminoglycosides such as gentamicin, streptomycin, and kanamycin has been used to successfully treat chancroid; however aminoglycoside-resistant strain of H. ducreyi have been observed in both laboratory and clinical settings.[7] Treatment with aminoglycosides should be considered as only a supplement to a primary treatment. Haemophilus influenzae tends to form part of the usual respiratory flora in adults, especially if they have a chronic underlying disease or are smokers. Pneumonia due to H. influenzae is frequently involved in respiratory infections and its level of resistance to ampicillin has remained stable over the last five years. Most of the literature on the subject was published more than 10 years ago. In this study, we describe the clinical features and evolution of 58 adult patients admitted to hospital for pneumonia due to H. influenzae over a 2-year period, with this group accounting for 6.5% of all the patients admitted with pneumonia during this time period. The etiological diagnosis was made using a good quality sputum sample. Forty patients (69%) were male. The mean age (+/- SD) of the group was 67 (+/-16.8) years and all the patients had at least one underlying disease. The mean duration of the symptoms was 6.7 days. All patients presented an increase in the quantity or purulence of the sputum. On admittance, respiratory failure was present in 52 patients (90%). Gram-negative coccus-bacilli were observed in the direct sputum test and H. influenzae grew in the culture. In two cases, H. influenzae was recovered from the blood culture and in one from bronchial aspiration obtained through bronchoscopy. Another pathogen was identified in 28 patients (48%). In 21 it was another pyogenic bacteria (15 S. pneumoniae, 4 M. catharralis, 1 K. pneumoniae, 1 E. coli), an atypical microorganism in 5 (3 C. pneumoniae, 2 C. burnetii) and a respiratory virus in 2 (syncytial and influenza A). Atypical bacteria and respiratory virus were detected using serological techniques. The radiographic infiltrate was unilobar in 54 of the 58 patients and all showed an alveolar pattern. The empirical treatment included the administration of a third generation cephalosporin (or a fluoroquinolone in patients allergic to penicillin). The evolution was favorable in all the cases in which H. influenzae was the only pathogen or was accompanied by an atypical microorganism or a respiratory virus. Four patients with mixed bacterial pneumonia died (2 S. pneumoniae, 1 E. coli and 1 M. catharralis). The study indicates that pneumoniae due to H. influenzae affects a population with an underlying disease, preferably pulmonary, that it has a longer clinical period than that for pneumococcal pneumonia, that it is slightly bacteremic and, that, usually, it evolves benignly with a low mortality. Treatment The main treatment of aspiration pneumonia revolves around the use of antibiotics to remove the bacteria causing the infection. Broad antibiotic coverage is required to account for the diverse types of bacteria possibly causing the infection. Currently recommended antibiotics include clindamycin, meropenem, ertapenem, ampicillin/sulbactam, and moxifloxacin. Treatment with piperacillin/tazobactam, cefepime, levofloxacin, imipenem, or meropenem is recommended in cases of potential antibiotic resistance. The typical duration of antibiotic therapy is about 5 to 7 days. If there is a large accumulation of fluid within the lungs, drainage of the fluid may also aid in the healing process. Pulmonary cryptococcosis is an opportunistic infection that mainly occurs among immunocompromised patients although it can sometimes occur in immunocompetent individuals. However, the imaging findings of pulmonary cryptococcosis in immunocompetent hosts differ from those in immunosuppressed patients. In addition, the most common imaging findings of isolated pulmonary cryptococcosis are single or multiple nodules. Cavities and the halo sign are, however, prevalent in immunosuppressed patients. In immunocompetent patients, lung consolidation, pleural effusion or cavities are scarce. A 29-year-old Asian male was admitted to our hospital with complaints of cough and fever that had persisted for a month. As a chest computed tomography scan showed consolidation in his left lower lobe, he was initially diagnosed with pneumonia and received antibiotic treatment. A second review of the chest computed tomography image revealed multiple cavities and pleural effusion. Flexible fiberoptic bronchoscopy was subsequently performed, bronchoalveolar lavage fluid and serum cryptococcal antigen tests were positive. Cryptococcus capsules were observed in bronchoalveolar lavage fluid ink stain. Histopathological examination of a percutaneous lung biopsy from the left lower lobe further revealed granulomatous inflammation, and periodic acid-Schiff staining showed red-colored yeast walls, signifying pulmonary cryptococcosis. The patient was then treated with a daily dose of fluconazole (0.4 g), but the cough and fever still persisted. We therefore changed treatment to voriconazole (0.2 g, twice a day), and the patient's clinical outcome was satisfactory. Although rare, clinicians should not disregard the possibility of cavities and pleural effusion occurring in immunocompetent hosts without underlying diseases.\nHere is the question:\nPNEUMOLOGY: A 56-year-old woman with a history of well-controlled schizophrenia and no toxic habits. Admitted for middle lobe pneumonia with a small associated metaneumonic pleural effusion and on treatment with levofloxacin 500 mg/24h . She presented good clinical evolution except for persistent febrile fever and leukocytosis on the sixth day of treatment. Microbiological studies are not available. The most appropriate course of action is:\nHere are the potential choices:\n1. The evolution is normal, treatment should be maintained until completing 10 days.\n2. It is considered a therapeutic failure and antibiotic treatment should be modified.\n3. Perform thoracentesis to rule out empyema.\n4. Add corticosteroids at a dose of 0.5 mg/Kg/day to antibiotic treatment.\n5. Bronchoscopy with biopsy, aspiration and bronchoalveolar lavage.\nThe correct answer is: ",
        "gold_answer": "3 Perform thoracentesis to rule out empyema.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Community acquired pneumonia (CAP) due to Streptococcus pneumoniae is a frequent cause of morbidity and mortality. We communicate two cases of CAP with complications. In both cases levofloxacin-resistant S. pneumoniae was isolated in pleural effusion. Patient 1: A 51-year-old man who had not received previous treatment with quinolones was admitted to the hospital for CAP and initially treated with levofloxacin (500 mg/24h iv). Four days later pleural effusion developed and fluid culture isolated levofloxacin-resistant S. pneumoniae (MIC &gt; 32 .g/ml). The outcome was favorable following chest tube placement and treatment with beta-lactam antibiotics. Patient 2: A 73-year-old man with a history of chronic obstructive pulmonary disease was admitted due to CAP and was initially treated with levofloxacin (500 mg/24 h iv). He was transferred to our hospital after 10 days of treatment with this antibiotic, following the development of pleural effusion with isolation of levofloxacin-resistant S. pneumoniae (MIC = 12 .g/ml). The patient was treated with chest tube placement and beta-lactam antibiotics with a favorable outcome. Patients with CAP treated empirically must be closely followed, both clinically and radiologically, to facilitate early detection of complications due to bacterial resistance to the prescribed antibiotic. Patients with CAP who have received quinolones in the weeks before the development of pneumonia should not been treated empirically with these antibiotics because of the risk of resistance development. Community-Acquired Pneumonia (CAP) is a common reason for hospitalization of a pediatric patient. We report a 20-month-old female admitted for suspected CAP. History included a week-long cough, fever, dyspnea, single occurrence of seizure-like activity, and a sick contact. Initial chest X-ray (CXR) showed left lower lobe pneumonia and parapneumonic effusion with a complex left pleural effusion. Ultrasound findings prompted the need for contrast-enhanced computed tomography (CT) of the chest. Contrast-enhanced CT of the chest confirmed a large pleural effusion with major atelectasis and mediastinal shift. The patient was treated with empiric antibiotics, video-assisted thoracoscopic surgical (VATS) decortication of empyema, and chest tube placement. Due to intraoperative complications, the VATS decortication was aborted and patient was transferred to the pediatric intensive care unit (PICU). A thoracentesis with culture failed to isolate a bacterial organism. Dexamethasone was started after repeat CXR showed persistent infiltrate. Subsequent contrast-enhanced CT of the chest showed a large collection of air and persistent consolidation. The patient received repeat VATS decortication and reinsertion of a chest tube. Repeat pleural fluid cultures failed to isolate a bacterial organism. Infectious disease (ID) consult recommended linezolid 140 mg Q8H for 4 weeks. Seven days after second VATS, a respiratory pathogen panel was positive for rhinovirus/enterovirus. With resolution of leukocytosis and clinical improvement, the patient was discharged with the chest tube in place and pediatric surgery outpatient follow-up. After three months, sequalae from both the infection and interventions presented . Although gram-negative bacilli are a common cause they are rarely found in the respiratory tract of people without pneumonia, which has led to speculation of the mouth and throat as origin of the infection. Diagnosis In hospitalised patients who develop respiratory symptoms and fever, one should consider the diagnosis. The likelihood increases when upon investigation symptoms are found of respiratory insufficiency, purulent secretions, newly developed infiltrate on the chest X-Ray, and increasing leucocyte count. If pneumonia is suspected material from sputum or tracheal aspirates are sent to the microbiology department for cultures. In case of pleural effusion, thoracentesis is performed for examination of pleural fluid. In suspected ventilator-associated pneumonia it has been suggested that bronchoscopy or bronchoalveolar lavage is necessary because of the risks of incorrect clinical diagnoses. Treatment is typically with antibiotics such as clindamycin, meropenem, ampicillin/sulbactam, or moxifloxacin. For those with only chemical pneumonitis, antibiotics are not typically required. Among people hospitalized with pneumonia, about 10% are due to aspiration. It occurs more often in older people, especially those in nursing homes. Both sexes are equally affected. Signs and symptoms The person may have an insidious course with increased respiratory rate, foul-smelling sputum, hemoptysis, and fever. Complications may occur, such as exudative pleural effusion, empyema, and lung abscesses. If left untreated, aspiration pneumonia can progress to form a lung abscess. Another possible complication is an empyema, in which pus collects inside the lungs. If continual aspiration occurs, the chronic inflammation can cause compensatory thickening of the insides of the lungs, resulting in bronchiectasis. and oral therapy. Switching to oral antibiotics can be considered upon clinical and objective improvement (adequate drainage and removal of chest tube, declining CRP, temperature normalization). Oral antibiotic treatment should then be continued for another 1–4 weeks, again based on clinical, biochemical and radiological response. Treatment for relapsing fever can include various antibiotics. TBRF spirochaetes are susceptible to penicillin and other β-Lactam antibiotics, as well as tetracyclines, macrolides, and possibly fluoroquinolones. Although the CDC has not yet developed specific treatment guidelines for TBRF, experts generally recommend tetracycline 500 mg every 6 hours for 10 days as the preferred oral regimen for adults. If tetracyclines are contraindicated, erythromycin, 500 mg (or 12.5 mg/kg) every 6 hours for 10 days is an effective alternative. For patients with central nervous system involvement, parenteral therapy with ceftriaxone 2 g/day for 10–14 days is preferred. All patients treated with antibiotics should be observed during the first 4 hours of treatment for a Jarisch-Herxheimer reaction, which is a worsening of symptoms characterized by rigors, hypotension, and high fever. The reaction occurs in over 50% of cases and may be difficult to distinguish from a febrile crisis. Given appropriate We present the results of a retrospective study of 127 cases of empyema admitted to the pneumophtisiology department of the Centre hospitalier universitaire de Treichville (Abidjan), between January 1985 and December 1989. We present the pathogens identified in the pleural fluid and the course of the disease during treatment by repeat thoraco-centesis and systemic antibiotics. During the study period, pleural empyema represented 2.7% of all admissions to the pneumophtisiology department, and 20.5% of those presenting with pleural effusions. Bacteriological examination was recovered in 88 of the 127 patients, and was positive in 57 cases (64.7% of those examined). Of those with positive bacteriology, 50 (56.8%) had non-tuberculous bacterial infections, and 7 (7.9%) had tuberculous infection. Among the non-tuberculous bacterial infections, Gram-negative bacilli were most common (72%), and Pseudomonas was the species most frequently identified (48%). The mean stay in hospital was 47 days (range 10-143) and in 82 patients (64.6%), the outcome was favourable. The presentation was complicated by encystment in 36 cases (28.4%) and 9 patients (7%) died in hospital. Activity of natural streptogramin (NSG) appears well adapted to pathogens responsible for CAP. The goal of this multicenter pilot study was to bring first data about efficacy of NSG in treatment of CAP. PATIENTS METHOD: Ten days of a NSG (1 gr b.i.d. or t.i.d.) regimen was administered to 46 hospitalized adult patients for CAP defined with fever &gt; 38 degrees C, respiratory symptoms and X-ray opacity. Severely ill patients were excluded. A broncho-pulmonar sample (expectoration or trantracheal aspiration or protected distal sample) was performed in all patients. two patients were excluded because of pulmonary embolism (n = 1) or tuberculosis (n = 1) and 44 patients were analyzed. 50% of them had associated disease, 20% had failure of prior antibiotherapy. At inclusion, mean fever was 39.2 +/- 0.7 degrees C, respiratory rate was 22 +/- 5/mn, PaO2 was 74 +/- 10 mmHg, chest X-ray showed bilateral opacity in 16%, unilateral in 84% and pleural fluid level in 6 cases. Etiological diagnosis was determined in 70% of cases. Streptococcus pneumoniae (n = 14), Haemophilus influenzae (n = 5), Legionella pneumophila (n = 2), Mycoplasma pneumoniae (n = 2) and Chlamydia psittaci (n = 1) were the most frequent isolated pathogens. 40 patients (91%) were cured with NSG and delay to obtain apyrexia was 4.4 +/- 3.9 days. NSG was stopped in 4 patients: 1 clinical and bacteriological failure (Klebsiella pneumoniae), 2 clinical failures (1 pneumococcus with purulent pleurisy, 1 pneumococcus with worsening of respiratory status), 1 patient with resistant H. influenzae strain in spite of favourable clinical evolution. NSG was well tolerated in 86% of patients. these data invite to carry on evaluation of first line therapy of CAP with NSG. Fusobacterium necrophorum is a non-spore-forming gram-negative anaerobic bacillus that may be the causative agent of localized or severe systemic infections. Systemic infections due to F.necrophorum are known as Lemierre's syndrome, postanginal sepsis or necrobacillosis. The most common clinical course of severe infections in humans is a progressive illness from tonsillitis to septicemia in previously healthy young adults. A septic thrombophlebitis arising from the tonsillar veins and extending into the internal jugular vein leads to septicemia and septic emboli contributing to the development of necrotic abscesses especially in lungs and other tissues such as liver, bone and joints. In this case report, a previously healthy man with pneumonia and empyema due to F.necrophorum has been presented. A 22 year-old man suffering from sore throat for seven days was admitted to emergency department with ongoing fever and dysphagia for three days. On admission he was already taking amoxicillin-clavulanic acid and his complaints were relieved with continuation of therapy to a total of 10 days. However, five days after the cessation of treatment he developed productive cough, fever and generalized myalgia. On physical examination, there were crackles on right lower lung, and chest X-ray revealed pulmonary consolidation on the right middle lobe. Levofloxacin therapy was started based on the diagnosis of pneumonia. While polymorphonuclear leucocytes and intracellular gram-negative bacilli were seen in Gram stained sputum smear, sputum culture was reported as normal flora. Although the patient's status had started to improve with treatment, his condition deteriorated with development of fever and dyspnea. Chest X-ray revealed consolidation, pulmonary infiltrates, pleural effusion and air-fluid level on the right. Meropenem, clarithromycin and linezolid were initiated and a chest tube was inserted with the preliminary diagnosis of necrotizing pneumonia, empyema and type-1 respiratory failure. While there was no growth on bronchoalveolar lavage fluid culture, thoracentesis material inoculated into thioglycolate broth revealed turbidity. Further inoculation onto Schaedler agar which was incubated under anaerobic conditions, yielded growth of catalase negative, indol positive, gram-negative anaerobic bacilli identified as F.necrophorum by BBL Crystal system (Becton Dickinson, USA). The detailed history of the patient revealed that fish bone had stuck in his throat a week ago. Clarithromycin and linezolid were discontinued and he was recovered within six weeks of meropenem treatment. F.necrophorum infection should be considered in the differential diagnosis of persistent head and neck infections with rapidly progressive metastatic necrotic lesions especially in healthy young adults and clindamycin or metranidazol should be added to the treatment protocols. 77 cases of non-tuberculous empyema were studied retrospectively. The data of past history, laboratory, radiological, bacteriological and outcome were gathered. The mean delay between initial symptoms and clinical diagnosis was 2.6 weeks in this study. It was longer for those anaerobic features (p less than 0.02) whose details were unravelled. \"Blind\" antibiotic therapy before the first pleural aspirate is still common (46.7% of cases) and did not alter the frequency with which the causal bacteria was found, nor the distribution of the bacterial population. Pleural aspirate enabled the germ or germs responsible to be identified in 63% of cases. Streptococcus pneumoniae (n = 15) and anaerobic bacterias (n = 26) infections were predominant. Early pleural drainage in a trained unit care is the essential element in the treatment in association with appropriate antibiotics and prolonged physiotherapy. This triple therapy approach leads to a medical cure in practically all the patients and avoids a recourse to surgery. In the use of atomoxetine in children (6 years or older up to 70 kg) with attention-deficit hyperactivity disorder, acute treatment should be started with approximately 0.5 mg/kg orally daily. The dose should be increased after a minimum of 3 days up to approximately 1.2 mg/kg daily (target dose) as a single or two divided doses (in the morning and late afternoon). For children older than 6 years old, over 70 kg, acute treatment should be started with 40 mg/day orally and increased up to 80 mg/day after a minimum of 3 days. The dose can be taken as a single dose in the morning or in two divided doses (in the morning and late afternoon). After 2–4 weeks the dose can be increased to 100 mg/ daily. Purulent pleurisy has become rare. It is often masked by previous antibiotic treatment so that functional prognosis may be poor. Twenty children with purulent pleurisy of the large cavity admitted from 1987 to 1993 were included in the study: there were nine infants (age 5 to 18 months) with pleuro-pulmonary staphylococcal infection (group I) and 11 children (4-13 years) (group II). Clinical, biological, bacteriological and radiologic findings were analysed retrospectively as was the outcome. Patients of group I were admitted in poor general condition. X-ray showed moderate effusion and characteristic signs of staphylococcal infection. The bacteria identified in seven patients (77%) was S aureus. Recovery was rapid with antibiotics and simple local treatment. X-rays were normal two months after hospital discharge in seven patients (77%). One infant presented cicatricial bullous emphysema which required segmental resection. Patients of group II were admitted for moderate respiratory signs after a relatively long delay (14 days) since the onset of symptoms. X-rays showed considerable effusion in all and mediastinal shift in five patients (45%). Streptococcus pneumoniae was identified in one patient only. Local treatment of empyema was difficult; the effusion, already fibrinous, required repeated use of chest tubes in eight cases and surgical decortication in three. X-rays, performed 2 months after hospital discharge, were normal in only three patients. Long-term course was nevertheless favorable since chest X-rays at 5 months were normal in all children of both groups. Early recognition of purulent pleurisy is important in children aged over 3 years to ensure effective drainage before the effusion becomes fibrinous. All patients in whom the first tube was inserted after more than 10 days had a difficult follow-up requiring repeated chest drainages or surgery. Ultrasonography was a useful aid for diagnosis and local treatment. Computed tomography was useful for adapting treatment after several days of course. Medical treatment Medical treatment entails low dose antibiotic prophylaxis until resolution of VUR occurs. Antibiotics are administered nightly at half the normal therapeutic dose. The specific antibiotics used differ with the age of the patient and include: Amoxicillin or ampicillin – infants younger than 6 weeks Trimethoprim-sulfamethoxazole (co-trimoxazole) – 6 weeks to 2 months After 2 months the following antibiotics are suitable: Nitrofurantoin {5–7 mg/kg/24hrs} Nalidixic acid Bactrim Trimethoprim Cephalosporins Urine cultures are performed 3 monthly to exclude breakthrough infection. Annual radiological investigations are likewise indicated. Good perineal hygiene, and timed and double voiding are also important aspects of medical treatment. Bladder dysfunction is treated with the administration of anticholinergics. Antibiotic treatment of pleuro-pulmonary infectious diseases with ordinary germs brought a notable decrease in the frequency of pleural empyema without preventing them completely. The authors report 31 cases observed over the last 10 years. The initial signs corresponded to the classical picture but were rapidly masked by antibiotic treatment; it resulted in delay in hospital admission of over one month for more than half of the cases, for diagnosis was overlooked for a long time. In 19 patients, the pleural liquid was aseptic probably because of the antibiotics and of the lack of identification of anaerobic germs. The authors insist on the practical modalities of a medical treatment by puncture-lavage which, when associated with general antibiotic treatment, cured patients in 22 cases. On the other hand, the existence of bronchopleural fistula entailed surgery. Two main approaches to multiple sclerosis treatment maintenance therapy are used – immunomodulation and immunosuppression and alternatively, immune reconstitution therapy. Classified as the latter, cladribine tablets are administered intermittently as a short treatment course without continuous immunosuppression. In contrast to maintenance therapies, clinical efficacy extends beyond the dosing period. Cladribine tablets are administered as 2 courses separated by 1 year (a maximum of 20 days of treatment). The recommended cumulative dose is 3.5 mg/kg weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (1 or 2 tablets) as a single daily dose based on body weight. In a study of 44 infants and young children with staphylococcal pneumonia and pleurisy, cases were found to be divisible into three clinical groups: those with predominantly digestive tract symptomatology (seven); those in acute respiratory distress (28); and those with signs of central nervous system disorder (nine). Characteristic radiographic findings often permitted an early etiologic diagnosis, confirmed later by bacteriologic culture or by the course of the disease. The length of hospitalization was found to be directly proportional to the length of time between the onset of symptoms and the start of adequate therapy. Nineteen patients required thoracotomy, two were drained by a Küss trocar, 13 required repeated pleural aspiration, five underwent spontaneous resorption of the empyema and five had no pleural effusion. In several instances antibiotics were used in very high dosage (three to four times the suggested maximal dose). The main agents used were erythromycin, chloramphenicol and ristocetin; the dosage of the last named never exceeded the maximal recommended dose. Twenty-eight patients were less than one year old; of these seven died. Sixteen were over one year of age, the oldest being six years; all of these were cured. Any immunological mechanisms induced by influenza virus could cause severe secondary bacterial superinfection such as those by Streptococcus pyogenes [group A streptococcus (GAS)], Streptococcus pneumoniae or Staphylococcus aureus. Over recent years, the frequency of pleural empyema has increased in children with influenza infection. We present a severe case of acute empyema caused by S.pyogenes after influenza A infection. A previously healthy 39-year old woman was diagnosed as influenza A and received oral Oseltamivir 75 mg twice daily for 5 days. She had no vaccination of influenza A. Although her influenza A infection improved, she complained of fever and cough to our institute. Chest radiography showed encapsulated pleural effusion of the left lung and pleural effusion which was consistent with acute empyema. Then, she was diagnosed as having acute empyema and was admitted to our institute. Streptococcus pyogenes was identified by pleural fluid culture on day 4. thus, MNZ was changed to clindamycin (CLDM) 600 mg three times a day. While thoracic drainage with intrapleural urokinase and combination antibiotic therapy of ceftriaxone and CLDM were performed, her general condition and chest radiographic findings were not improved. She received video-assisted thoracic debridement on day 10. After the operation, the antibiotic therapy was changed to ABPC 6 g daily iv. Due to good clinical course, the antibiotic therapy was switched to oral amoxicillin 500 mg three times daily on day 28. Then, she was discharged. Influenza A virus infection could lead to severe GAS infection, while the latter can occur in otherwise healthy individual as well. Physician must consider the possibility of severe GAS infection after influenza A infection. Complicated parapneumonic effusion is one in which an invasive procedure is necessary for its resolution and empyema means pus in the pleural space. An early diagnosis and therapy of these conditions results in less morbidity and mortality. CT of the chest is important to study complex pleural effusions. Loculated effusions, those occupying more than 50% of the thorax, or which show positive Gram stain or bacterial culture, or a purulent effusion with a pH below 7.20, with a glucose level below 60 mg/dl or a LDH level more than three times the upper limit of normal for serum, are indications for an invasive procedure. These characteristics result from the evolution of a not well treated parapneumonic effusion, through the three stages: (1) exsudative; (2) fibrinopurulent; (3) fibrotic. Depending on the stage therapeutic methods vary from therapeutic thoracentesis, insertion of a chest tube with or without instillation of fibrinolytics, video-assisted thoracoscopic surgery, and lung decortication. A review of all these aspects are done based on a series of three cases reports with very different clinical presentation: one patient with empyema by Streptococcus pyogenes and that died rapidly due to massive hemoptysis; a patient with empyema due to acute pneumonia developing during an airflight; a patient with empyema and bacteraemia by Streptococcus pneumonia leading to the diagnosis of an unknown HIV infection. Antibiotics Macrolides are often used to treat chancroid. The CDC recommendation is either a single oral dose (1 gram) of azithromycin, a single IM dose (250 mg) of ceftriaxone, oral (500 mg) of erythromycin three times a day for seven days, or oral (500 mg) of ciprofloxacin twice a day for three days. Due to a paucity of reliable empirical evidence it is not clear whether macrolides are actually more effective and/or better tolerated than other antibiotics when treating chancroid. Data is limited, but there have been reports of ciprofloxacin and erythromycin resistance. Aminoglycosides such as gentamicin, streptomycin, and kanamycin has been used to successfully treat chancroid; however aminoglycoside-resistant strain of H. ducreyi have been observed in both laboratory and clinical settings.[7] Treatment with aminoglycosides should be considered as only a supplement to a primary treatment. Haemophilus influenzae tends to form part of the usual respiratory flora in adults, especially if they have a chronic underlying disease or are smokers. Pneumonia due to H. influenzae is frequently involved in respiratory infections and its level of resistance to ampicillin has remained stable over the last five years. Most of the literature on the subject was published more than 10 years ago. In this study, we describe the clinical features and evolution of 58 adult patients admitted to hospital for pneumonia due to H. influenzae over a 2-year period, with this group accounting for 6.5% of all the patients admitted with pneumonia during this time period. The etiological diagnosis was made using a good quality sputum sample. Forty patients (69%) were male. The mean age (+/- SD) of the group was 67 (+/-16.8) years and all the patients had at least one underlying disease. The mean duration of the symptoms was 6.7 days. All patients presented an increase in the quantity or purulence of the sputum. On admittance, respiratory failure was present in 52 patients (90%). Gram-negative coccus-bacilli were observed in the direct sputum test and H. influenzae grew in the culture. In two cases, H. influenzae was recovered from the blood culture and in one from bronchial aspiration obtained through bronchoscopy. Another pathogen was identified in 28 patients (48%). In 21 it was another pyogenic bacteria (15 S. pneumoniae, 4 M. catharralis, 1 K. pneumoniae, 1 E. coli), an atypical microorganism in 5 (3 C. pneumoniae, 2 C. burnetii) and a respiratory virus in 2 (syncytial and influenza A). Atypical bacteria and respiratory virus were detected using serological techniques. The radiographic infiltrate was unilobar in 54 of the 58 patients and all showed an alveolar pattern. The empirical treatment included the administration of a third generation cephalosporin (or a fluoroquinolone in patients allergic to penicillin). The evolution was favorable in all the cases in which H. influenzae was the only pathogen or was accompanied by an atypical microorganism or a respiratory virus. Four patients with mixed bacterial pneumonia died (2 S. pneumoniae, 1 E. coli and 1 M. catharralis). The study indicates that pneumoniae due to H. influenzae affects a population with an underlying disease, preferably pulmonary, that it has a longer clinical period than that for pneumococcal pneumonia, that it is slightly bacteremic and, that, usually, it evolves benignly with a low mortality. Treatment The main treatment of aspiration pneumonia revolves around the use of antibiotics to remove the bacteria causing the infection. Broad antibiotic coverage is required to account for the diverse types of bacteria possibly causing the infection. Currently recommended antibiotics include clindamycin, meropenem, ertapenem, ampicillin/sulbactam, and moxifloxacin. Treatment with piperacillin/tazobactam, cefepime, levofloxacin, imipenem, or meropenem is recommended in cases of potential antibiotic resistance. The typical duration of antibiotic therapy is about 5 to 7 days. If there is a large accumulation of fluid within the lungs, drainage of the fluid may also aid in the healing process. Pulmonary cryptococcosis is an opportunistic infection that mainly occurs among immunocompromised patients although it can sometimes occur in immunocompetent individuals. However, the imaging findings of pulmonary cryptococcosis in immunocompetent hosts differ from those in immunosuppressed patients. In addition, the most common imaging findings of isolated pulmonary cryptococcosis are single or multiple nodules. Cavities and the halo sign are, however, prevalent in immunosuppressed patients. In immunocompetent patients, lung consolidation, pleural effusion or cavities are scarce. A 29-year-old Asian male was admitted to our hospital with complaints of cough and fever that had persisted for a month. As a chest computed tomography scan showed consolidation in his left lower lobe, he was initially diagnosed with pneumonia and received antibiotic treatment. A second review of the chest computed tomography image revealed multiple cavities and pleural effusion. Flexible fiberoptic bronchoscopy was subsequently performed, bronchoalveolar lavage fluid and serum cryptococcal antigen tests were positive. Cryptococcus capsules were observed in bronchoalveolar lavage fluid ink stain. Histopathological examination of a percutaneous lung biopsy from the left lower lobe further revealed granulomatous inflammation, and periodic acid-Schiff staining showed red-colored yeast walls, signifying pulmonary cryptococcosis. The patient was then treated with a daily dose of fluconazole (0.4 g), but the cough and fever still persisted. We therefore changed treatment to voriconazole (0.2 g, twice a day), and the patient's clinical outcome was satisfactory. Although rare, clinicians should not disregard the possibility of cavities and pleural effusion occurring in immunocompetent hosts without underlying diseases.\nHere is the question:\nPNEUMOLOGY: A 56-year-old woman with a history of well-controlled schizophrenia and no toxic habits. Admitted for middle lobe pneumonia with a small associated metaneumonic pleural effusion and on treatment with levofloxacin 500 mg/24h . She presented good clinical evolution except for persistent febrile fever and leukocytosis on the sixth day of treatment. Microbiological studies are not available. The most appropriate course of action is:\nHere are the potential choices:\n1. The evolution is normal, treatment should be maintained until completing 10 days.\n2. It is considered a therapeutic failure and antibiotic treatment should be modified.\n3. Perform thoracentesis to rule out empyema.\n4. Add corticosteroids at a dose of 0.5 mg/Kg/day to antibiotic treatment.\n5. Bronchoscopy with biopsy, aspiration and bronchoalveolar lavage.\nThe correct answer is: 3. Perform thoracentesis to rule out empyema."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Epilepsy with myoclonic absences (EMA) is a type of childhood epilepsy characterized by a specific seizure type, i.e. myoclonic absences (MA). This study aimed to investigate the clinical and electrophysiological characteristics of EMA. Video-EEG monitoring was carried out in 6 patients with EMA, and 2 of them were examined with simultaneous deltoid muscle surface electromyogram (EMG). The clinical and EEG characteristics, treatment and prognoses of EMA were analyzed. Of the 6 patients, 3 were female, and 3 were male. The age of onset was from 2 years and 3 months to 11 years (average 5 years and 2 months). MA was the sole seizure type in 5 patients. One patient presented generalized tonic clonic seizures (GTCS) at the onset and then switched to MA. The manifestations of MA included an impairment of consciousness of variable intensity, rhythmic myoclonic jerks with evident tonic contraction mainly involving the upper extremities, a deviation of head and body to one side or asymmetrical jerks observed in some cases, a duration ranging from 2 to 30 s, an abrupt onset and termination, a high frequency of attacks, at least several times to over 30 times per day, and easily provoked by hyperventilation. The ictal EEG consisted of rhythmic 3 Hz spike and wave discharges that were bilateral, synchronous and symmetrical in all patients. The deltoid muscle EMG recording in 2 patients showed rhythmic myoclonus at the same frequency as the spike and waves. The interictal EEG showed generalized spike and wave discharges in all patients, and focal discharges in some patients. Valproate was the drug of choice, which was often combined with other antiepileptic drugs. The ages at follow up ranged from 6 years and 4 months to 19 years. Seizures were controlled from 8 months to 3 years in 4 cases. The treatment at the onset was late in one case and was irregular in another who had GTCS during the course of the disease. These two cases were followed up for 2 years and 6 months and 5 years, respectively. Seizures could not be controlled in the 2 patients with intellectual impairment. EMA was a rare type of childhood epilepsy characterized by MA. Clinical observation and ictal video-EEG and EMG were essential to diagnose EMA. Valproate alone or combined with other antiepileptic drugs given early could have a favorable effect to EMA. Delayed therapy and the presence of GTCS might suggest poor prognosis. We conclude that despite inevitable variability the clinical picture of JME is characteristic. It is easy to diagnose JME if one thinks of it while the history should be thoroughly analyzed. An EEG recording during sleep confirms the diagnosis. An early diagnosis of JME permits adequate prognosis of the subsequent course of epilepsy, and adequate therapy brings remission in most of the patients. If treatment starts following the large number of severe GTC seizures, the response to therapy is incomplete. The persistency of the illness throughout the life, the need for continuous medication and therapeutic unresponsiveness in cases with late diagnosis, do not justify the increasing misconception that JME is of benign nature. Diagnosis of JME is rare because of insufficient familiarily of physicians with the illness. Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epileptic syndrome characterized with the combination of myoclonic, generalized tonic-clonic (GTC) and absence seizures that are readily provoked by sleep deprivation. Forty-three patients, aged from 14 to 51 years, participated in a 5-year follow-up study. Diagnosis was made according to the criteria (Table 1) for diagnosis of JME set by Panayiotopoulos et al. (1994). Nineteen patients made their first contact with a neurologist at the Institute of Neurology and were diagnosed as JME, while the remaining 24 were referred to from other medical institutions with a diagnosis of therapy resistant to focal epilepsy. All patients underwent a somatic and neurological examination, \"mini mental test,\" EEG in waking and CT scan of the brain. Some patients had EEG performed during sleep and some had MRI of the head. JME began between 9 and 26 (average 17) years. All patients had myoclonic seizures, 98% had GTC and 23% absence seizures. The first myoclonic seizure occurred between 9 and 24 years while the frst GTC seizure occurred between 10 and 32 years. Myoclonic seizures (83% of patients) and GTC seizures (70% of patients) occurred most often immediately after awaking. The most frequent provocative factors were insufficient sleep, alcohol abuse and tiredness. Epilepsy in the family was present in 39%, focal neurological deficiency in 9% and pathological findings on of CT and MRI in 7% of patients. Waking EEG was pathological in 77% of patients; it included generalized spike-wave discharges in 73%, multiple spike-wave complexes in 33% and focal discharges in 12% of patients, respectively. In all 26 patients tested, sleep EEG was pathological most often with multiple spike-wave complexes in 85% and 3-4 Hz spike-wave complexes in 57% of patients. The correct diagnosis of JME following a comprehensive examination was made in 24 (56%) patients after a delay of 1 to 35 years. In 24 patients with delayed diagnosis of JME the replacement of earlier medication with valproic acid (VPA) induced remission in 18 patients (75%) while 1 patient (4%) experienced a reduction in the number of seizures. Five patients (21%) did not respond to VPA medication: 2 due to a weak compliance, another 2 due to inefficient medication and 1 because of the preexistent malabsorption syndrome. In 19 patients (44%) with initial diagnosis of JME, VPA was introduced immediately upon diagnosis. Of them, 15 (79%) had excellent response to VPA, 1 refused therapy and for 3 patients there is no information. In 2 patients VPA was substituted due to side effects (hepatotoxicity and alopetia) with lamotrigine (low doses), which brought about decrease in frequency and mitigation in myoclonic seizures. The value of long-term cassette EEG (24-EEG) and Video/EEG for differential diagnosis and classification of idiopathic epilepsies with generalised tonic-clonic seizures (GTCS) was evaluated in twenty-eight patients. The analysis of clinical and EEG features allowed proper classification of epileptic syndrome in twenty-two (79%) patients. In twelve cases absences or myoclonic seizures appeared beside GTCS after 1-9 years from epilepsy onset (mean 3.3 yrs). EEG and clinical data allowed to classify epilepsy in nine (75%) of those patients: in six patients as juvenile absence epilepsy and in three as juvenile myoclonic epilepsy. Sixteen patients suffered from GTCS only (mean duration of epilepsy 10.6 years); in thirteen of them (81%) the diagnosis of epilepsy with GTCS on awakening (AGM) could be established. 24-EEG and Video/EEG helped to demonstrate (a) interictal generalized spike/polyspike-wave discharges (SW/PSW) 3-6 Hz not present in routine EEG in 25% of patients, (b) typical circadian distribution of discharges in AGM patients and (c) absences and myoclonic seizures in 32% of patients. Slow spike-wave variants and focal changes in EEG which could suggest secondarily generalized GTCS were the main diagnostic problem. We studied clinical features of 131 patients with juvenile myoclonic epilepsy (JME). The prevalence was 7.7% among the epileptic patients registered. The mean age at onset was 13.37+/-4.93 years and the diagnosis was established at a mean age of 19.53+/-7.85 years. Absence seizures were reported by 27 (20.6%) patients, myoclonic jerks by 131 (100%) and generalized tonic-clonic seizures (GTCS) by 111 (84.7%). The triad of absence seizures, myoclonic jerks and GTCS was noted in 23 (17.5%) patients, 88 (67.2%) had myoclonic jerks and GTCS, 4 (3%) had absence seizures and myoclonic jerks and 16 (12.2%) had only myoclonic jerks. Early onset absences were seen in 21 (16%) patients and the onset was late in 6 (4.6%). Absences antedated other types of seizures in all the patients. Myoclonic jerks were predominantly unilateral or had unilateral onset in 22 (16.8%). In 17 (13%) patients GTCS antedated myoclonic jerks. Myoclonic jerks had characteristic circadian distribution in 112 (85.5%) patients. On awakening GTCS occurred in 87 (78.4%) patients and in 4 (3.6%) patients they were purely nocturnal. Sleep deprivation was the most important precipitating factor (54.2%). Initial electroencephalogram (EEG) showed classical generalized spike or multiple-spike slow-wave paroxysms in 81% of records. Focal EEG abnormalities were noted in 20.6% of records. The most common focal abnormality was voltage asymmetry. A family history of epilepsy was noted in 31 (23.6%) probands. Diagnosis of JME was made in all the cases in the clinic. The factors responsible for delay in diagnosis of the 36 patients seen by neurologists included failure to ask or interpret the history which was otherwise suggestive of myoclonic jerks in all 36 (100%) cases, the type of seizure for which the patients sought medical attention, and misinterpretation of EEGs in 28 patients. Diagnosis of partial epilepsy was made in seven patients. The factors responsible for such diagnoses were, unilateral jerks in one patient, unilateral jerks and absence seizures in three patients and focal EEG abnormalities in three patients. Benign myoclonic epilepsy in infancy (BME) is characterized by the occurrence of brief myoclonic attacks in normal infants aged 4 months to 3 years. There is no prior personal history, although in some patients 1 or 2 isolated febrile convulsions may occur prior to the onset of myoclonias. A family history of epilepsy or febrile convulsions is present in 30% of cases. Myoclonic attacks are short and mild, they involve mainly the head and upper limbs. The psychomotor development continues normally after the onset of seizures. The EEG shows a normal background activity and generalized spike-wave or polyspike-wave discharges associated with the myoclonias. These abnormalities are activated by drowsiness and during the first stages of sleep. A clinical and EEG photosensitivity is present in one-third of the patients. Myoclonias can be easily controlled by valproate monotherapy. Rare grand mal seizures can occur during adolescence, after withdrawal of drug treatment. The psychomotor evolution is good if treatment is started early. When myoclonias begin during the first year of life, the diagnoses of cryptogenic infantile spasms and of non-epileptic benign infantile myoclonus must be eliminated. In cases with a later onset, the following diagnoses can usually be easily discarded: cryptogenic Lennox-Gastaut syndrome, myoclonic-astatic epilepsy and unclassified epilepsies with the association of myoclonias and other types of seizures. Lennox-Gastaut syndrome (LGS) is one of the most severe and refractory form of childhood epilepsy. The purpose of this study was to investigate the clinical and EEG characteristics of patients with LGS. Sixty-two patients with LGS, including 37 males and 25 females, were followed-up regularly per three months or per six months, therapy was adjusted according to the changes in seizures and EEG, and the clinical data were analyzed in detail. The onset occurred between the age of 8 months and 12 years, with the peak at 1-4 years of age, accounting for 61%; a late onset which occurred after 8 years of age, was unusual. Furthermore, one patient who developed LGS at the age of 13 years and remained to have all the features of seizures and EEG at 35 years of age was identified as adult's LGS. Forty-three patients were classified as symptomatic, perinatal events were the predominant factors in this group. The others were cryptogenic. It was noted that 11 cases had a history of West syndrome. A transformation process from West syndrome to LGS was observed in another 7 cases. Every patient had two or more seizure types during the course of the disease; tonic seizure, atypical absence seizure, head drop or sudden falls were the characteristic types. The degree of mental deficit was variable from slight to profound deterioration, but mental and behavioral disturbances existed in every case as a rule. In all cases electroencephalogram (EEG) background was abnormal and consisted of diffuse slow spike-and-waves (1-1.5CPS), predominant in frontal and temporal regions. Twenty-four cases had the polyspike-wave. Bursts of fast rhythms (10-14CPS) were observed in 29 patients during sleep. The choice of antiepileptic drugs (AEDs) was based on the seizure types; routinely, 2 or more kinds of AEDs were used in combination, the classic drugs, valproate and clonazepam were firstly recommended; the other drugs, such as lamotrigine and topiramate that are used as add-on therapy were further consideration. Although the total effect was not satisfactory, the severity and frequency of seizures in almost all cases had lessened to some extent. LGS shows diverse manifestations; comprehensive diagnosis is crucial, active and efficacious treatment can improve the mental and behavioral development and prognosis as a whole. On 62 cases with Lennox-Gastaut's syndrome aged four to 31, the clinical-electroencephalographic findings were summarized as follows; (1) Age of onset was over 10 years in 10 cases (16.1%). (2) Mental deficiencies were more severe in those with onset earlier than age three. (3) Behavioral problems were observed in 34 cases (54.8%); 21 with hyperactive and 13 with hypoactive ones -- 18 hyperactive cases (85.7%) with the onset taking place before age six, and 12 hypoactive cases (92.3%), all whose age is now over 10. (4) The number of clinical seizures showed a tendency in which monoictal manifestation decreased from 25 to three whereas polyictal one increased from 13 to 59 cases during the course of a decade. (5) Interictal EEG findings were pseudorhythm of slow spike-wave with or without focal spikes, and so-called runs of rapid spikes during sleep recording. Focal spikes were observed in 25 cases (40.3%); mainly in the frontal area among those under 10 years old, and in the anterior temporal area among those over 20. The rapid spikes were demonstrated in 19 cases (30.6%) in the over-15 age group and appeared to be correlated with epileptic drop seizures and atypical complex absences. West syndrome is an age-dependent epilepsy with onset peak in the first year of life whose aetiology may be symptomatic or cryptogenic. Long-term cognitive and neurological prognosis is usually poor and seizure outcome is also variable. Over the past two decades a few patients with favourable cognitive outcome and with total recovery from seizures were identified among the cryptogenic group suggesting an idiopathic aetiology. Recent research has described two children with idiopathic WS who later developed a childhood absence epilepsy. We reviewed the medical records of patients with West syndrome admitted to the our Child Neuropsychiatry Unit in the last 15 years in order to know the clinical evolution of infantile spasms.We report a child with West syndrome with onset at 8 months of age followed by some clusters of bilateral, arrhythmic myoclonic jerks of the upper limbs, mainly on awakening, synchronous with the generalized discharges of 4 Hz spike-wave occurring at 12 years of age and by co-occurrence of a later generalized tonic-clonic seizure at 14 years and four months, both sensitive to Levetiracetam suggesting a juvenile myoclonic epilepsy. This unusual evolution, never previously reported, suggests that both electroclinical features mentioned above may share some pathophysiological processes genetically determined which produce a susceptibility to seizure and emphasizes that the transition between different age-related epileptic phenotypes may involve also the West syndrome. Juvenile myoclonic epilepsy Juvenile myoclonic epilepsy (JME) is a genetic generalised epilepsy that occurs in patients aged 8 to 20 years. Patients have normal cognition and are otherwise neurologically intact. The most common seizure is myoclonic jerks, although generalized tonic-clonic seizures and absence seizures may occur as well. Myoclonic jerks usually cluster in the early morning after awakening. The EEG reveals generalized 4–6 Hz spike wave discharges or multiple spike discharges. These patients are often first diagnosed when they have their first generalized tonic-clonic seizure later in life, when they experience sleep deprivation (e.g., freshman year in college after staying up late to study for exams). Alcohol withdrawal can also be a major contributing factor in breakthrough seizures, as well. The risk of the tendency to have seizures is lifelong; however, the majority have well-controlled seizures with anticonvulsant medication and avoidance of seizure precipitants. Lennox-Gastaut syndrome Lennox-Gastaut syndrome (LGS) is a generalized epilepsy that consists of a triad of developmental delay or childhood dementia, mixed generalized seizures, and EEG demonstrating a pattern of approximately 2 Hz \"slow\" spike-waves. Onset occurs between two and 18 years. Epilepsy is consider a chronic (meaning it lasts for a long time) condition that is defined by seizures. Lennox-Gastaut syndrome (LGS) is a rare and severe form of epilepsy. As in West syndrome, LGS result from idiopathic, symptomatic, or cryptogenic causes, and many patients first have West syndrome. Authorities emphasize different seizure types as important in LGS, but most have astatic seizures (drop attacks), tonic seizures, tonic-clonic seizures, atypical absence seizures, and sometimes, focal seizures. Anticonvulsants are usually only partially successful in treatment. Among 62 children with myoclonic epilepsy who had first seizures between 1 and 10 years, without clinical or radiological evidence of brain lesion, we selected the 16 patients who had exhibited several types of fits and had stopped having seizures for over two years. First seizures occurred between 18 months and 4 years, and they were generalized clonic, tonic-clonic or tonic. After a mean 3 months' period, patients started also to have absence and myoclonic fits. During the period with various types of seizures, that lasted a mean 10 months, patients were ataxic and hyperkinetic, and 11 of them suffered myoclonic absence status for several hours or days. The EEG showed a high voltage rhythmic slow-wave activity with spikes, differing from the slow spike wave tracing of the Lennox-Gastaut syndrome, and there was no photosensitivity. The mean duration of the epilepsy was 1 year and 4 months and the last seizures were convulsive, occurring mainly during sleep. The clinical and EEG pattern, the high familial incidence are shared by the Doose syndrome, of which the present series seems to be a subgroup, as are other well-defined syndromes: benign and severe myoclonic epilepsies of infancy. Precipitation of spike and wave (SW) discharges in some epileptic patients by eye closure (EC) has rarely been reported. To disclose the clinical characteristics and classification of syndromes of epileptic patients with SW discharges induced by EC, we investigated 10 patients (1 M, 9 F) showing this peculiar EEG feature. The patients aged between 9-39 years (mean 20.6 +/- 9.058), underwent short-term (1-3.5 hr) video-EEG investigations in order to document the appearance of the SW discharges within 3 seconds of the act of EC, in at least two occasions. Clinical analysis showed that 5 female patients who had the syndrome of juvenile myoclonic epilepsy (JME) had a later onset of epilepsy (13-15 years) than the 3 patients (3 girls) with eyelid myoclonia with absences (EMA) (3-8 years of age at onset). The remaining 2 patients who were diagnosed as childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE) according to the international classification, did not show photosensitivity on the video-EEG. All but one of the 5 JME patients had experienced myoclonic seizures in intermittent photic stimulation (IPS) at the time of EC, associated with multiple spike and wave discharges. Two of the 3 EMA patients exhibited typical absences with eyelid myoclonia during the act of EC. The high rate of family history of epilepsy in first degree relatives of our patients was an outstanding feature, which could have future implications in research of the genetic basis of epilepsy patients with ECS. We made a long term prospective study of 66 patients with juvenile myoclonic epilepsy (JME). Prevalence was 10.2% among 672 patients with epilepsies. Sex distribution was equal. Sixty-three were not diagnosed on referral; JME was not initially recognized in the epilepsy clinic in 22. Clinical typical absence seizures were reported in 33.3%, myoclonic jerks in 97% and generalized tonic-clonic seizures (GTC) in 78.8% of the patients. Mean age (+/- SD) at onset was 10.5 +/- 3.4 years (range 5-16 years) for absence seizures, 15 +/- 3.5 years (range 8-26 years) for myoclonic jerks, and 16 +/- 3.5 years (9-28) years (range 1-9 years) and GTC by 4.4 +/- 2.7 years (range 1-8 years) in 14 (21.2%) patients who manifested all three types of seizure. Absence were never antedated by myoclonic jerks or GTC. Myoclonic jerks occurred on awakening in 87.5% of the patients. GTC occurred mainly on awakening, but other patients had nocturnal or diurnal GTC with no circadian distribution. Neurologic examination was normal for all patients except for tremor of the hands similar to essential tremor, noted in 35% of patients. Computed tomography (CT) brain scans were normal: 93% of patients had precipitating factors: sleep deprivation (89.5%), fatigue (73.7%), photosensitivity (36.8%; television and video games 8.8%), menstruation (24.1% of women), mental concentration (22.8%), and stress (12.3%). Incidence of JME among siblings (13 of 41 examined families) implies an autosomal recessive mode of inheritance for this Arab population. EEGs were frequently normal in treated patients. At least one abnormal EEG was recorded in 56 (84.9%) patients. Abnormalities consisted mainly of generalized discharges of spike/double spike and/or polyspike and slow wave. Frequent multiple spikes and discharge fragmentations varied from 0.5- to 20-s duration (mean 6.8 s). Twenty (30.3%) had focal abnormalities, and 18 (27.3%) had photoconvulsive discharges. Eighty-eight percent of patients remained seizure-free for &gt; or = 3 years of follow-up. Effective treatment was achieved with valproate (VPA); control of myoclonic jerks was improved with clonazepam (CZP). CZP monotherapy did not consistently prevent GTC. Adding small doses of CZP with simultaneous reduction of VPA was the most effective and better tolerated form of medication, particularly in patients demonstrating an adverse reaction or requiring a large VPA dosage. VPA dosage was successfully reduced in 15 patients who were seizure-free for &gt; 2 years and had infrequent seizures before treatment, but 9 of 11 patients relapsed after VPA discontinuation.(ABSTRACT TRUNCATED AT 400 WORDS) To summarize the electroclinical characteristics of myoclonic atonic epilepsy (MAE) in children. The clinical data, video electroencephalogram (EEG) and simultaneous electromyography (EMG) of MAE patients were analyzed. The treatment and its effects were followed up. In 47 MAE patients, 25 had a history of febrile seizures (FS), 20 had a family history of FS or epilepsy. All patients had a normal development before the illness. The age of afebrile seizure onset was between 1.4 years to 5.8 years. The first seizure was generalized tonic-clonic seizure (GTCS) in 41 patients (87.2%). All patients had multiple seizure types, including 47 GTCS (97.9%), 34 myoclonic atonic seizures (72.3%), 47 myoclonic seizures (100%), 32 atonic seizures (68.1%), 36 atypical absences (76.6%) and 3 tonic seizures (6.4%). EEG backgrounds were slow or parietal θ rhythm, interictal EEG showed 1-4 Hz (predominant 2-3 Hz) generalized spike and wave or poly spike and wave discharges in all cases. Seizures were controlled by antiepileptic drugs (AEDs) in 41 patients (87.2%). Valproate was used in 37. Lamotrigine was used in 26. Mild mental retardation was observed in 10 children after the onset of the illness. The clinical features of MAE included the following: the development was normal before the onset of the illness; the onset of seizure type was often GTCS. All patients had multiple generalized seizure types. Myoclonic atonic seizure was its characteristic seizure type. EEG showed generalized discharges. Early diagnosis and rational choice of AEDs are important for getting a better prognosis. The aim of this study is to elucidate the clinical and neurophysiological characteristics of the myoclonic, myoclonic-astatic, or astatic seizures in patients with myoclonic-astatic epilepsy (MAE) of early childhood, and to discuss on the nosology of this unique epileptic syndrome. The subjects included 30 patients, who fulfilled the following modified International League Against Epilepsy (ILAE) criteria for MAE, and whose main seizures were captured by video-electroencephalographs (EEG) or polygraphs. The modified ILAE criteria includes: (1) normal development before onset of epilepsy and absence of organic cerebral abnormalities; (2) onset of myoclonic, myoclonic-astatic or astatic seizures between 7 months and 6 years of age; (3) presence of generalized spike- or polyspike-wave EEG discharges at 2-3 Hz, without focal spike discharges; and (4) exclusion of severe and benign myoclonic epilepsy (SME, BME) in infants and cryptogenic Lennox-Gastaut syndrome based on the ILAE definitions. The seizures were investigated precisely by video-EEG (n=5), polygraph (n=2), and video-polygraph (n=23), which identified myoclonic seizures in 16 cases (myoclonic group), atonic seizures, with or without preceding minor myoclonus, in 11 cases (atonic group), and myoclonic-atonic seizures in three cases. All patients had a history of drop attacks, apart from ten patients with myoclonic seizures. Myoclonic seizures, involving mainly the axial muscles were classified into those with mild intensity not sufficient to cause the patients to fall (n=10) and those that are stronger and sufficient to cause astatic falling due to flexion of the waist or extension of the trunk (n=6). Patients in the atonic group fell straight downward, landed on their buttocks, and recovered immediately. Analysis of the ictal EEGs showed that all attacks corresponded to the generalized spike or polyspikes-and-wave complexes. In the atonic form, the spike-and-wave morphology was characterized by a positive-negative-deep-positive wave followed by a large negative slow wave. In two patients, the intensity of the atonia appeared to correspond to the depth of the positive component of the spike-and-wave complexes. We did not detect any significant differences in the clinical and EEG features and prognosis, between the atonic and myoclonic groups. Although the determination of exact seizure type is a prerequisite for diagnosing an epileptic syndrome, the strict differentiation of seizure type into either a myoclonic or atonic form, does not appear to have a significant impact on the outcome or in delineating this unique epileptic syndrome. At present, we consider it better to follow the current International Classification of Epileptic Syndromes and Epilepsies until a more appropriate system than the clinico-electrical approach for classifying patients with MAE is available.\nHere is the question:\nNEUROLOGY AND NEUROSURGERY: An 18-year-old female patient with a history of absences between 6 and 9 years of age, generalized tonic-clonic seizures of recent onset and violent jumping of the upper limbs at breakfast. The clinical manifestations worsen with nighttime weekend outings. An EEG shows acute polyp spike discharges at 6 cycles/second. The most likely diagnosis is:\nHere are the potential choices:\n1. Great epileptic disease.\n2. Lennox-Gastaut syndrome.\n3. Symptomatic epilepsy due to mesial temporal sclerosis.\n4. Small atypical disease.\n5. Juvenile myoclonic epilepsy.\nThe correct answer is: ",
        "gold_answer": "5 Juvenile myoclonic epilepsy.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Epilepsy with myoclonic absences (EMA) is a type of childhood epilepsy characterized by a specific seizure type, i.e. myoclonic absences (MA). This study aimed to investigate the clinical and electrophysiological characteristics of EMA. Video-EEG monitoring was carried out in 6 patients with EMA, and 2 of them were examined with simultaneous deltoid muscle surface electromyogram (EMG). The clinical and EEG characteristics, treatment and prognoses of EMA were analyzed. Of the 6 patients, 3 were female, and 3 were male. The age of onset was from 2 years and 3 months to 11 years (average 5 years and 2 months). MA was the sole seizure type in 5 patients. One patient presented generalized tonic clonic seizures (GTCS) at the onset and then switched to MA. The manifestations of MA included an impairment of consciousness of variable intensity, rhythmic myoclonic jerks with evident tonic contraction mainly involving the upper extremities, a deviation of head and body to one side or asymmetrical jerks observed in some cases, a duration ranging from 2 to 30 s, an abrupt onset and termination, a high frequency of attacks, at least several times to over 30 times per day, and easily provoked by hyperventilation. The ictal EEG consisted of rhythmic 3 Hz spike and wave discharges that were bilateral, synchronous and symmetrical in all patients. The deltoid muscle EMG recording in 2 patients showed rhythmic myoclonus at the same frequency as the spike and waves. The interictal EEG showed generalized spike and wave discharges in all patients, and focal discharges in some patients. Valproate was the drug of choice, which was often combined with other antiepileptic drugs. The ages at follow up ranged from 6 years and 4 months to 19 years. Seizures were controlled from 8 months to 3 years in 4 cases. The treatment at the onset was late in one case and was irregular in another who had GTCS during the course of the disease. These two cases were followed up for 2 years and 6 months and 5 years, respectively. Seizures could not be controlled in the 2 patients with intellectual impairment. EMA was a rare type of childhood epilepsy characterized by MA. Clinical observation and ictal video-EEG and EMG were essential to diagnose EMA. Valproate alone or combined with other antiepileptic drugs given early could have a favorable effect to EMA. Delayed therapy and the presence of GTCS might suggest poor prognosis. We conclude that despite inevitable variability the clinical picture of JME is characteristic. It is easy to diagnose JME if one thinks of it while the history should be thoroughly analyzed. An EEG recording during sleep confirms the diagnosis. An early diagnosis of JME permits adequate prognosis of the subsequent course of epilepsy, and adequate therapy brings remission in most of the patients. If treatment starts following the large number of severe GTC seizures, the response to therapy is incomplete. The persistency of the illness throughout the life, the need for continuous medication and therapeutic unresponsiveness in cases with late diagnosis, do not justify the increasing misconception that JME is of benign nature. Diagnosis of JME is rare because of insufficient familiarily of physicians with the illness. Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epileptic syndrome characterized with the combination of myoclonic, generalized tonic-clonic (GTC) and absence seizures that are readily provoked by sleep deprivation. Forty-three patients, aged from 14 to 51 years, participated in a 5-year follow-up study. Diagnosis was made according to the criteria (Table 1) for diagnosis of JME set by Panayiotopoulos et al. (1994). Nineteen patients made their first contact with a neurologist at the Institute of Neurology and were diagnosed as JME, while the remaining 24 were referred to from other medical institutions with a diagnosis of therapy resistant to focal epilepsy. All patients underwent a somatic and neurological examination, \"mini mental test,\" EEG in waking and CT scan of the brain. Some patients had EEG performed during sleep and some had MRI of the head. JME began between 9 and 26 (average 17) years. All patients had myoclonic seizures, 98% had GTC and 23% absence seizures. The first myoclonic seizure occurred between 9 and 24 years while the frst GTC seizure occurred between 10 and 32 years. Myoclonic seizures (83% of patients) and GTC seizures (70% of patients) occurred most often immediately after awaking. The most frequent provocative factors were insufficient sleep, alcohol abuse and tiredness. Epilepsy in the family was present in 39%, focal neurological deficiency in 9% and pathological findings on of CT and MRI in 7% of patients. Waking EEG was pathological in 77% of patients; it included generalized spike-wave discharges in 73%, multiple spike-wave complexes in 33% and focal discharges in 12% of patients, respectively. In all 26 patients tested, sleep EEG was pathological most often with multiple spike-wave complexes in 85% and 3-4 Hz spike-wave complexes in 57% of patients. The correct diagnosis of JME following a comprehensive examination was made in 24 (56%) patients after a delay of 1 to 35 years. In 24 patients with delayed diagnosis of JME the replacement of earlier medication with valproic acid (VPA) induced remission in 18 patients (75%) while 1 patient (4%) experienced a reduction in the number of seizures. Five patients (21%) did not respond to VPA medication: 2 due to a weak compliance, another 2 due to inefficient medication and 1 because of the preexistent malabsorption syndrome. In 19 patients (44%) with initial diagnosis of JME, VPA was introduced immediately upon diagnosis. Of them, 15 (79%) had excellent response to VPA, 1 refused therapy and for 3 patients there is no information. In 2 patients VPA was substituted due to side effects (hepatotoxicity and alopetia) with lamotrigine (low doses), which brought about decrease in frequency and mitigation in myoclonic seizures. The value of long-term cassette EEG (24-EEG) and Video/EEG for differential diagnosis and classification of idiopathic epilepsies with generalised tonic-clonic seizures (GTCS) was evaluated in twenty-eight patients. The analysis of clinical and EEG features allowed proper classification of epileptic syndrome in twenty-two (79%) patients. In twelve cases absences or myoclonic seizures appeared beside GTCS after 1-9 years from epilepsy onset (mean 3.3 yrs). EEG and clinical data allowed to classify epilepsy in nine (75%) of those patients: in six patients as juvenile absence epilepsy and in three as juvenile myoclonic epilepsy. Sixteen patients suffered from GTCS only (mean duration of epilepsy 10.6 years); in thirteen of them (81%) the diagnosis of epilepsy with GTCS on awakening (AGM) could be established. 24-EEG and Video/EEG helped to demonstrate (a) interictal generalized spike/polyspike-wave discharges (SW/PSW) 3-6 Hz not present in routine EEG in 25% of patients, (b) typical circadian distribution of discharges in AGM patients and (c) absences and myoclonic seizures in 32% of patients. Slow spike-wave variants and focal changes in EEG which could suggest secondarily generalized GTCS were the main diagnostic problem. We studied clinical features of 131 patients with juvenile myoclonic epilepsy (JME). The prevalence was 7.7% among the epileptic patients registered. The mean age at onset was 13.37+/-4.93 years and the diagnosis was established at a mean age of 19.53+/-7.85 years. Absence seizures were reported by 27 (20.6%) patients, myoclonic jerks by 131 (100%) and generalized tonic-clonic seizures (GTCS) by 111 (84.7%). The triad of absence seizures, myoclonic jerks and GTCS was noted in 23 (17.5%) patients, 88 (67.2%) had myoclonic jerks and GTCS, 4 (3%) had absence seizures and myoclonic jerks and 16 (12.2%) had only myoclonic jerks. Early onset absences were seen in 21 (16%) patients and the onset was late in 6 (4.6%). Absences antedated other types of seizures in all the patients. Myoclonic jerks were predominantly unilateral or had unilateral onset in 22 (16.8%). In 17 (13%) patients GTCS antedated myoclonic jerks. Myoclonic jerks had characteristic circadian distribution in 112 (85.5%) patients. On awakening GTCS occurred in 87 (78.4%) patients and in 4 (3.6%) patients they were purely nocturnal. Sleep deprivation was the most important precipitating factor (54.2%). Initial electroencephalogram (EEG) showed classical generalized spike or multiple-spike slow-wave paroxysms in 81% of records. Focal EEG abnormalities were noted in 20.6% of records. The most common focal abnormality was voltage asymmetry. A family history of epilepsy was noted in 31 (23.6%) probands. Diagnosis of JME was made in all the cases in the clinic. The factors responsible for delay in diagnosis of the 36 patients seen by neurologists included failure to ask or interpret the history which was otherwise suggestive of myoclonic jerks in all 36 (100%) cases, the type of seizure for which the patients sought medical attention, and misinterpretation of EEGs in 28 patients. Diagnosis of partial epilepsy was made in seven patients. The factors responsible for such diagnoses were, unilateral jerks in one patient, unilateral jerks and absence seizures in three patients and focal EEG abnormalities in three patients. Benign myoclonic epilepsy in infancy (BME) is characterized by the occurrence of brief myoclonic attacks in normal infants aged 4 months to 3 years. There is no prior personal history, although in some patients 1 or 2 isolated febrile convulsions may occur prior to the onset of myoclonias. A family history of epilepsy or febrile convulsions is present in 30% of cases. Myoclonic attacks are short and mild, they involve mainly the head and upper limbs. The psychomotor development continues normally after the onset of seizures. The EEG shows a normal background activity and generalized spike-wave or polyspike-wave discharges associated with the myoclonias. These abnormalities are activated by drowsiness and during the first stages of sleep. A clinical and EEG photosensitivity is present in one-third of the patients. Myoclonias can be easily controlled by valproate monotherapy. Rare grand mal seizures can occur during adolescence, after withdrawal of drug treatment. The psychomotor evolution is good if treatment is started early. When myoclonias begin during the first year of life, the diagnoses of cryptogenic infantile spasms and of non-epileptic benign infantile myoclonus must be eliminated. In cases with a later onset, the following diagnoses can usually be easily discarded: cryptogenic Lennox-Gastaut syndrome, myoclonic-astatic epilepsy and unclassified epilepsies with the association of myoclonias and other types of seizures. Lennox-Gastaut syndrome (LGS) is one of the most severe and refractory form of childhood epilepsy. The purpose of this study was to investigate the clinical and EEG characteristics of patients with LGS. Sixty-two patients with LGS, including 37 males and 25 females, were followed-up regularly per three months or per six months, therapy was adjusted according to the changes in seizures and EEG, and the clinical data were analyzed in detail. The onset occurred between the age of 8 months and 12 years, with the peak at 1-4 years of age, accounting for 61%; a late onset which occurred after 8 years of age, was unusual. Furthermore, one patient who developed LGS at the age of 13 years and remained to have all the features of seizures and EEG at 35 years of age was identified as adult's LGS. Forty-three patients were classified as symptomatic, perinatal events were the predominant factors in this group. The others were cryptogenic. It was noted that 11 cases had a history of West syndrome. A transformation process from West syndrome to LGS was observed in another 7 cases. Every patient had two or more seizure types during the course of the disease; tonic seizure, atypical absence seizure, head drop or sudden falls were the characteristic types. The degree of mental deficit was variable from slight to profound deterioration, but mental and behavioral disturbances existed in every case as a rule. In all cases electroencephalogram (EEG) background was abnormal and consisted of diffuse slow spike-and-waves (1-1.5CPS), predominant in frontal and temporal regions. Twenty-four cases had the polyspike-wave. Bursts of fast rhythms (10-14CPS) were observed in 29 patients during sleep. The choice of antiepileptic drugs (AEDs) was based on the seizure types; routinely, 2 or more kinds of AEDs were used in combination, the classic drugs, valproate and clonazepam were firstly recommended; the other drugs, such as lamotrigine and topiramate that are used as add-on therapy were further consideration. Although the total effect was not satisfactory, the severity and frequency of seizures in almost all cases had lessened to some extent. LGS shows diverse manifestations; comprehensive diagnosis is crucial, active and efficacious treatment can improve the mental and behavioral development and prognosis as a whole. On 62 cases with Lennox-Gastaut's syndrome aged four to 31, the clinical-electroencephalographic findings were summarized as follows; (1) Age of onset was over 10 years in 10 cases (16.1%). (2) Mental deficiencies were more severe in those with onset earlier than age three. (3) Behavioral problems were observed in 34 cases (54.8%); 21 with hyperactive and 13 with hypoactive ones -- 18 hyperactive cases (85.7%) with the onset taking place before age six, and 12 hypoactive cases (92.3%), all whose age is now over 10. (4) The number of clinical seizures showed a tendency in which monoictal manifestation decreased from 25 to three whereas polyictal one increased from 13 to 59 cases during the course of a decade. (5) Interictal EEG findings were pseudorhythm of slow spike-wave with or without focal spikes, and so-called runs of rapid spikes during sleep recording. Focal spikes were observed in 25 cases (40.3%); mainly in the frontal area among those under 10 years old, and in the anterior temporal area among those over 20. The rapid spikes were demonstrated in 19 cases (30.6%) in the over-15 age group and appeared to be correlated with epileptic drop seizures and atypical complex absences. West syndrome is an age-dependent epilepsy with onset peak in the first year of life whose aetiology may be symptomatic or cryptogenic. Long-term cognitive and neurological prognosis is usually poor and seizure outcome is also variable. Over the past two decades a few patients with favourable cognitive outcome and with total recovery from seizures were identified among the cryptogenic group suggesting an idiopathic aetiology. Recent research has described two children with idiopathic WS who later developed a childhood absence epilepsy. We reviewed the medical records of patients with West syndrome admitted to the our Child Neuropsychiatry Unit in the last 15 years in order to know the clinical evolution of infantile spasms.We report a child with West syndrome with onset at 8 months of age followed by some clusters of bilateral, arrhythmic myoclonic jerks of the upper limbs, mainly on awakening, synchronous with the generalized discharges of 4 Hz spike-wave occurring at 12 years of age and by co-occurrence of a later generalized tonic-clonic seizure at 14 years and four months, both sensitive to Levetiracetam suggesting a juvenile myoclonic epilepsy. This unusual evolution, never previously reported, suggests that both electroclinical features mentioned above may share some pathophysiological processes genetically determined which produce a susceptibility to seizure and emphasizes that the transition between different age-related epileptic phenotypes may involve also the West syndrome. Juvenile myoclonic epilepsy Juvenile myoclonic epilepsy (JME) is a genetic generalised epilepsy that occurs in patients aged 8 to 20 years. Patients have normal cognition and are otherwise neurologically intact. The most common seizure is myoclonic jerks, although generalized tonic-clonic seizures and absence seizures may occur as well. Myoclonic jerks usually cluster in the early morning after awakening. The EEG reveals generalized 4–6 Hz spike wave discharges or multiple spike discharges. These patients are often first diagnosed when they have their first generalized tonic-clonic seizure later in life, when they experience sleep deprivation (e.g., freshman year in college after staying up late to study for exams). Alcohol withdrawal can also be a major contributing factor in breakthrough seizures, as well. The risk of the tendency to have seizures is lifelong; however, the majority have well-controlled seizures with anticonvulsant medication and avoidance of seizure precipitants. Lennox-Gastaut syndrome Lennox-Gastaut syndrome (LGS) is a generalized epilepsy that consists of a triad of developmental delay or childhood dementia, mixed generalized seizures, and EEG demonstrating a pattern of approximately 2 Hz \"slow\" spike-waves. Onset occurs between two and 18 years. Epilepsy is consider a chronic (meaning it lasts for a long time) condition that is defined by seizures. Lennox-Gastaut syndrome (LGS) is a rare and severe form of epilepsy. As in West syndrome, LGS result from idiopathic, symptomatic, or cryptogenic causes, and many patients first have West syndrome. Authorities emphasize different seizure types as important in LGS, but most have astatic seizures (drop attacks), tonic seizures, tonic-clonic seizures, atypical absence seizures, and sometimes, focal seizures. Anticonvulsants are usually only partially successful in treatment. Among 62 children with myoclonic epilepsy who had first seizures between 1 and 10 years, without clinical or radiological evidence of brain lesion, we selected the 16 patients who had exhibited several types of fits and had stopped having seizures for over two years. First seizures occurred between 18 months and 4 years, and they were generalized clonic, tonic-clonic or tonic. After a mean 3 months' period, patients started also to have absence and myoclonic fits. During the period with various types of seizures, that lasted a mean 10 months, patients were ataxic and hyperkinetic, and 11 of them suffered myoclonic absence status for several hours or days. The EEG showed a high voltage rhythmic slow-wave activity with spikes, differing from the slow spike wave tracing of the Lennox-Gastaut syndrome, and there was no photosensitivity. The mean duration of the epilepsy was 1 year and 4 months and the last seizures were convulsive, occurring mainly during sleep. The clinical and EEG pattern, the high familial incidence are shared by the Doose syndrome, of which the present series seems to be a subgroup, as are other well-defined syndromes: benign and severe myoclonic epilepsies of infancy. Precipitation of spike and wave (SW) discharges in some epileptic patients by eye closure (EC) has rarely been reported. To disclose the clinical characteristics and classification of syndromes of epileptic patients with SW discharges induced by EC, we investigated 10 patients (1 M, 9 F) showing this peculiar EEG feature. The patients aged between 9-39 years (mean 20.6 +/- 9.058), underwent short-term (1-3.5 hr) video-EEG investigations in order to document the appearance of the SW discharges within 3 seconds of the act of EC, in at least two occasions. Clinical analysis showed that 5 female patients who had the syndrome of juvenile myoclonic epilepsy (JME) had a later onset of epilepsy (13-15 years) than the 3 patients (3 girls) with eyelid myoclonia with absences (EMA) (3-8 years of age at onset). The remaining 2 patients who were diagnosed as childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE) according to the international classification, did not show photosensitivity on the video-EEG. All but one of the 5 JME patients had experienced myoclonic seizures in intermittent photic stimulation (IPS) at the time of EC, associated with multiple spike and wave discharges. Two of the 3 EMA patients exhibited typical absences with eyelid myoclonia during the act of EC. The high rate of family history of epilepsy in first degree relatives of our patients was an outstanding feature, which could have future implications in research of the genetic basis of epilepsy patients with ECS. We made a long term prospective study of 66 patients with juvenile myoclonic epilepsy (JME). Prevalence was 10.2% among 672 patients with epilepsies. Sex distribution was equal. Sixty-three were not diagnosed on referral; JME was not initially recognized in the epilepsy clinic in 22. Clinical typical absence seizures were reported in 33.3%, myoclonic jerks in 97% and generalized tonic-clonic seizures (GTC) in 78.8% of the patients. Mean age (+/- SD) at onset was 10.5 +/- 3.4 years (range 5-16 years) for absence seizures, 15 +/- 3.5 years (range 8-26 years) for myoclonic jerks, and 16 +/- 3.5 years (9-28) years (range 1-9 years) and GTC by 4.4 +/- 2.7 years (range 1-8 years) in 14 (21.2%) patients who manifested all three types of seizure. Absence were never antedated by myoclonic jerks or GTC. Myoclonic jerks occurred on awakening in 87.5% of the patients. GTC occurred mainly on awakening, but other patients had nocturnal or diurnal GTC with no circadian distribution. Neurologic examination was normal for all patients except for tremor of the hands similar to essential tremor, noted in 35% of patients. Computed tomography (CT) brain scans were normal: 93% of patients had precipitating factors: sleep deprivation (89.5%), fatigue (73.7%), photosensitivity (36.8%; television and video games 8.8%), menstruation (24.1% of women), mental concentration (22.8%), and stress (12.3%). Incidence of JME among siblings (13 of 41 examined families) implies an autosomal recessive mode of inheritance for this Arab population. EEGs were frequently normal in treated patients. At least one abnormal EEG was recorded in 56 (84.9%) patients. Abnormalities consisted mainly of generalized discharges of spike/double spike and/or polyspike and slow wave. Frequent multiple spikes and discharge fragmentations varied from 0.5- to 20-s duration (mean 6.8 s). Twenty (30.3%) had focal abnormalities, and 18 (27.3%) had photoconvulsive discharges. Eighty-eight percent of patients remained seizure-free for &gt; or = 3 years of follow-up. Effective treatment was achieved with valproate (VPA); control of myoclonic jerks was improved with clonazepam (CZP). CZP monotherapy did not consistently prevent GTC. Adding small doses of CZP with simultaneous reduction of VPA was the most effective and better tolerated form of medication, particularly in patients demonstrating an adverse reaction or requiring a large VPA dosage. VPA dosage was successfully reduced in 15 patients who were seizure-free for &gt; 2 years and had infrequent seizures before treatment, but 9 of 11 patients relapsed after VPA discontinuation.(ABSTRACT TRUNCATED AT 400 WORDS) To summarize the electroclinical characteristics of myoclonic atonic epilepsy (MAE) in children. The clinical data, video electroencephalogram (EEG) and simultaneous electromyography (EMG) of MAE patients were analyzed. The treatment and its effects were followed up. In 47 MAE patients, 25 had a history of febrile seizures (FS), 20 had a family history of FS or epilepsy. All patients had a normal development before the illness. The age of afebrile seizure onset was between 1.4 years to 5.8 years. The first seizure was generalized tonic-clonic seizure (GTCS) in 41 patients (87.2%). All patients had multiple seizure types, including 47 GTCS (97.9%), 34 myoclonic atonic seizures (72.3%), 47 myoclonic seizures (100%), 32 atonic seizures (68.1%), 36 atypical absences (76.6%) and 3 tonic seizures (6.4%). EEG backgrounds were slow or parietal θ rhythm, interictal EEG showed 1-4 Hz (predominant 2-3 Hz) generalized spike and wave or poly spike and wave discharges in all cases. Seizures were controlled by antiepileptic drugs (AEDs) in 41 patients (87.2%). Valproate was used in 37. Lamotrigine was used in 26. Mild mental retardation was observed in 10 children after the onset of the illness. The clinical features of MAE included the following: the development was normal before the onset of the illness; the onset of seizure type was often GTCS. All patients had multiple generalized seizure types. Myoclonic atonic seizure was its characteristic seizure type. EEG showed generalized discharges. Early diagnosis and rational choice of AEDs are important for getting a better prognosis. The aim of this study is to elucidate the clinical and neurophysiological characteristics of the myoclonic, myoclonic-astatic, or astatic seizures in patients with myoclonic-astatic epilepsy (MAE) of early childhood, and to discuss on the nosology of this unique epileptic syndrome. The subjects included 30 patients, who fulfilled the following modified International League Against Epilepsy (ILAE) criteria for MAE, and whose main seizures were captured by video-electroencephalographs (EEG) or polygraphs. The modified ILAE criteria includes: (1) normal development before onset of epilepsy and absence of organic cerebral abnormalities; (2) onset of myoclonic, myoclonic-astatic or astatic seizures between 7 months and 6 years of age; (3) presence of generalized spike- or polyspike-wave EEG discharges at 2-3 Hz, without focal spike discharges; and (4) exclusion of severe and benign myoclonic epilepsy (SME, BME) in infants and cryptogenic Lennox-Gastaut syndrome based on the ILAE definitions. The seizures were investigated precisely by video-EEG (n=5), polygraph (n=2), and video-polygraph (n=23), which identified myoclonic seizures in 16 cases (myoclonic group), atonic seizures, with or without preceding minor myoclonus, in 11 cases (atonic group), and myoclonic-atonic seizures in three cases. All patients had a history of drop attacks, apart from ten patients with myoclonic seizures. Myoclonic seizures, involving mainly the axial muscles were classified into those with mild intensity not sufficient to cause the patients to fall (n=10) and those that are stronger and sufficient to cause astatic falling due to flexion of the waist or extension of the trunk (n=6). Patients in the atonic group fell straight downward, landed on their buttocks, and recovered immediately. Analysis of the ictal EEGs showed that all attacks corresponded to the generalized spike or polyspikes-and-wave complexes. In the atonic form, the spike-and-wave morphology was characterized by a positive-negative-deep-positive wave followed by a large negative slow wave. In two patients, the intensity of the atonia appeared to correspond to the depth of the positive component of the spike-and-wave complexes. We did not detect any significant differences in the clinical and EEG features and prognosis, between the atonic and myoclonic groups. Although the determination of exact seizure type is a prerequisite for diagnosing an epileptic syndrome, the strict differentiation of seizure type into either a myoclonic or atonic form, does not appear to have a significant impact on the outcome or in delineating this unique epileptic syndrome. At present, we consider it better to follow the current International Classification of Epileptic Syndromes and Epilepsies until a more appropriate system than the clinico-electrical approach for classifying patients with MAE is available.\nHere is the question:\nNEUROLOGY AND NEUROSURGERY: An 18-year-old female patient with a history of absences between 6 and 9 years of age, generalized tonic-clonic seizures of recent onset and violent jumping of the upper limbs at breakfast. The clinical manifestations worsen with nighttime weekend outings. An EEG shows acute polyp spike discharges at 6 cycles/second. The most likely diagnosis is:\nHere are the potential choices:\n1. Great epileptic disease.\n2. Lennox-Gastaut syndrome.\n3. Symptomatic epilepsy due to mesial temporal sclerosis.\n4. Small atypical disease.\n5. Juvenile myoclonic epilepsy.\nThe correct answer is: 5. Juvenile myoclonic epilepsy."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n 30 asymptomatic chronic carriers of hepatitis B surface antigen (HBsAg), 6 asymptomatic blood donors transiently infected with hepatitis B virus, and 38 patients with acute hepatitis B were tested for HBsAg, anti-HBs, HBeAg, anti-HBe and anti-HBc. Comparison of these results revealed significant variation in the frequency of HBeAg which was present in 1 (3.3%) carrier, 2 (33.3%) of the transiently positive donors, and in 24 (63.2%) of the patients with acute hepatitis. Anti-HBe was found in 28 (93.3%) of the carriers, 4 (66.6%) of the transiently positive donors, and in 8 (21%) of the patients. Variation was also seen in the strength of anti-HBc, with only the chronic carriers having titres which were consistently high (above 1,000). Retesting the two groups of donors after a period of approximately 2 years showed no change in the serologic status of the chronic carriers, while amongst the transient HBsAg positives the 2 HBeAg reactives had seroconverted, 1 of the anti-HBe positives had become non-reactive, and 2 of the 6 had developed anti-HBs. 6 of the patients with acute hepatitis B were serologically reexamined during convalescence and showed results similar to those seen in the transiently HBsAg-positive donors, with clearance of HBsAg in all, seroconversion from HBeAg to anti-HBe in 4, and the production of anti-HBs in 4. Hepatitis B virus (HBV) causes different clinical manifestations, ranging from asymptomatic carriage to fulminant or chronic hepatitis. Serological tests are widely used for the diagnosis of HBV infections to detect viral markers. However, facing with atypical serological profiles in some patients leads to problems in interpreting of the results and management of the patients. The aims of this study were to investigate the atypical serologic profiles seen in patients screened for HBV infection and the S gene mutations in patients with concurrent positivity of HBsAg and anti-HBs. A total of 592 sera from patients (332 male, 260 female; age range: 13-84 years, mean age: 43.9 years) prediagnosed as HBV infection between January to September 2013, and screened for HBV markers (HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc-IgM, anti-HBc-total and HBV-DNA) were included in the study. Of those samples 364 were screened only for HBsAg and anti-HBs markers. S gene mutations were investigated by direct sequencing method in sera which were concurrent positive for HBsAg and anti-HBs. In our study, 5.2% (31/592) of the sera yielded atypical serologic profiles. Of these 13 cases were concurrently positive for HBsAg and anti-HBs; nine were HBeAg positive, anti-HBe and HBV-DNA negative; eight were HBeAg, anti-HBe and HBV-DNA positive; and one was HBsAg and anti-HBs negative, anti-HBe and HBV-DNA positive. The rate of concurrent positivity of HBsAg and anti-HBs was 3.6% (13/364), while 76.9% (10/13) of those cases were also positive for HBV-DNA. DNA sequencing was performed for seven out of 10 samples which were positive for HBsAg, anti-HBs and HBV-DNA, however three samples were not used because of the low amounts. Sequence analysis of seven samples showed S gene mutations in two samples, one was sS143L with sS193L, a HBV vaccine escape mutation, and the other was sP120R, a HBV immune escape mutation. Of the patients 2.7% (10/364) was negative for both HBsAg and anti-HBs; in which nine were HBV-DNA negative and anti-HBe positive, while one was positive for both HBV-DNA and anti-HBe. The rate of concurrent positivity of HBeAg and anti-HBe was found as 1.4% (8/592), and all of these samples were HBV-DNA positive. No single positivity for HBsAg, anti-HBc, anti-HBs or HBV-DNA was not detected in any of the patients. In conclusion, HBsAg and anti-HBs concurrent positivity was the most frequently detected atypical profile in our study (3.6%), and in some (2/7) of these patients S gene mutations were determined. On a serological assay, the presence of hepatitis B surface antigen (HBsAg) indicates an individual with a currently active hepatitis B infection, whether acute or chronic. The presence of core antibody (anti-HBc) indicates an individual with an infection in general, whether current or previously resolved. The presence of surface antibody (anti-HBs) indicates an individual with immunity to hepatitis B, whether due to previously resolved infection or due to hepatitis B vaccination. For example, an individual who has never had any exposure to HBV, either by vaccine or by infection, would test negative for the entire serology panel. An individual who has been vaccinated and never had an infection will test seropositive for anti-HBs due to vaccination and negative for markers of infection. An individual with an acute HBV infection would test positive for HBsAg and anti-HBc (total and IgM) while negative for anti-HBs. An individual with a chronic infection would test positive for HBsAg and To study the etiology of acute hepatitis superimposed upon previously unrecognized asymptomatic HBsAg carriers, paired sera were collected in acute and convalescence phases for measurement of HBeAg, anti-HBe, hepatitis B virus DNA and anti-delta from 76 adult patients with acute hepatitis who were HBsAg positive but IgM anti-HBc negative or positive only at low titer. None of them were IgM anti-hepatitis A virus positive on admission. Of the 34 patients who were HBeAg positive initially, two (5.9%) were diagnosed as having delta superinfection, and another two (5.9%) were suspected to have non-A, non-B virus superinfection because of a transient decrease of serum hepatitis B virus DNA. The remaining 30 (88.2%) cases were hepatitis B virus DNA negative with or without anti-HBe seroconversion on follow-up. The episodes of acute hepatitis in these cases may represent \"immune clearance of HBeAg\" or \"immune clearance of hepatitis B virus with delayed anti-HBe seroconversion,\" respectively, in the natural course of chronic hepatitis B virus infection. Of the patients who were anti-HBe positive initially, 23 (54.8%) were diagnosed as having delta superinfection, including eight with de novo seroconversion of anti-delta and 15 with a rising titer of anti-delta; 10 (23.8%) were positive for hepatitis B virus DNA and were considered as reactivation of hepatitis B virus, and the other nine (21.4%) were suspected as having non-A, non-B virus superinfection.(ABSTRACT TRUNCATED AT 250 WORDS) Following serologic markers are often tested: Hepatitis B surface antigen (HBsAg), antibody to Hepatitis B surface antigen (anti-HBs), Hepatitis B core Ab (Anti-HBc) IgM, Hepatitis B core Ab (Anti-HBc) IgG, Hepatitis B e antigen (HBeAg), and Hepatitis B e antibody (anti-HBe). [10] HBsAg: Acute infection (less than 6 months) or chronic infection (more than 6 months). Anti-HBs: Recovery from acute infection or immunity from vaccination. HBeAg: Mostly associated with high viral load. Anti-HBe: Low replicative phase. Anti-HBc IgM: Acute infection, an only marker present in the window period, can be present during exacerbation of chronic infection. Anti-HBc IgG: Exposure to infection, chronic infection (if present along with HBsAg), recovery from acute infection (if present with anti-HBs), if isolated presence, may represent occult infection. Shortly after the appearance of the HBsAg, another antigen called e antigen (HBeAg) will appear. Traditionally, the presence of HBeAg in a host's serum is associated with much higher rates of viral replication and enhanced infectivity; however, variants of the virus do not produce the 'e' antigen, so this rule does not always hold true. During the natural course of an infection, the HBeAg may be cleared, and antibodies to the 'e' antigen (anti-HBe) will arise immediately afterwards. This conversion is usually associated with a dramatic decline in viral replication. If the host is able to clear the infection, eventually the HBsAg will become undetectable and will be followed by IgG antibodies to the surface antigen and core antigen (anti-HBs and anti HBc IgG). The time between the removal of the HBsAg and the appearance of anti-HBs is called the window period. A person negative for HBsAg but positive for anti-HBs either has cleared an infection or has been vaccinated previously. Hepatitis B Two periods may be referred to as window period in hepatitis B infection: (1) the period that elapses during HBsAg to HBsAb seroconversion, i.e. between the disappearance of surface antigen (HBsAg) from serum and the appearance of HBsAb (anti-HBs), and (2) the period between infection and appearance of HBsAg. During the window of HBsAg to HBsAb seroconversion, IgM anti-core (HBc-IgM) is the only detectable antibody. HBV DNA may be positive as well. This window period does not occur in persons who develop chronic hepatitis B, i.e. who continue to have detectable HBV DNA for greater than 6 months (HbsAg remains positive), or in people who develop isolated HBcAb positivity, i.e. who lose HBsAg, but do not develop HBsAb (HBV DNA may or may not remain positive). See also Incubation period, the time between infection and the appearance of symptoms References HIV/AIDS Serology individual with an acute HBV infection would test positive for HBsAg and anti-HBc (total and IgM) while negative for anti-HBs. An individual with a chronic infection would test positive for HBsAg and total anti-HBc (IgM and IgG), but negative for IgM anti-HBc and anti-HBs. An individual who has successfully resolved their HBV infection will test negative for HBsAg, positive for anti-HBc, and may test negative or positive for anti-HBs, although most will test positive. In the typical disease course for hepatitis B, the individual will first seroconvert for hepatitis B surface antigen (HBsAg). While some can convert within one week, most individuals take about four weeks after initial infection to convert. Anti-core antibodies (anti-HBc) are the first antibodies produced by the body, first in short-term IgM (anti-HBc IgM), and subsequently in long-term IgG; while levels of IgM anti-HBc will peak around sixteen weeks after exposure and fall within about seven to eight months, IgG anti-HBc will remain detectable in the serum as a sign of chronic infection for years. IgM anti-HBc concentration will fall regardless of whether or not the individual clears the infection. The window period for HBsAg/anti-HBs testing occurs as concentration of HBsAg falls and before the body develops anti-HBs antibodies, lasting approximately six to eight weeks in most individuals. During this time, serology assays can test for total anti-HBc. Levels of anti-surface antibody Hepatitis B When a person gets a hepatitis B vaccine then the most common test for hepatitis B will show them to be positive. The usual course of action, in this case, is to give the person a panel of tests for HBsAg, anti-HBc, and anti-HBs (hepatitis B surface antigen, anti-hepatitis B core, and anti-hepatitis B surface). A person who has never been exposed to hepatitis B but has gotten the vaccine will be positive for anti-HBs but negative for the other two tests in the panel. Other combinations of positive and negative in this test can mean other things, such as acute, chronic, or past infection. Viral hepatitis Viral hepatitis is primarily diagnosed through blood tests for levels of viral antigens (such as the hepatitis B surface or core antigen), anti-viral antibodies (such as the anti-hepatitis B surface antibody or anti-hepatitis A antibody), or viral DNA/RNA. In early infection (i.e. within 1 week), IgM antibodies are found in the blood. In late infection and after recovery, IgG antibodies are present and remain in the body for up to years. Therefore, when a patient is positive for IgG antibody but negative for IgM antibody, he is considered immune from the virus via either prior infection and recovery or prior vaccination. In the case of hepatitis B, blood tests exist for multiple virus antigens (which are different components of the virion particle) and antibodies. The combination of antigen and antibody positivity can provide information about the stage of infection (acute or chronic), the degree of viral replication, and the infectivity of the virus. Hepatitis B e antigen (HBeAg) is a marker to indicate active replication of hepatitis B virus (HBV). Occult HBV infection (OBI), referred to persistence of HBV DNA in serum and/or liver without detectable serum hepatitis B surface (HBsAg), usually has low HBV DNA levels. The presence of HBeAg in OBI is unusual. We report 2 patients who presented negative for HBsAg but positive for HBeAg and HBV DNA. HBV markers were quantified in the longitudinal sera in a period of 1-2years. The HBV DNA sequences were analyzed in 2 patients' sera and 1 patient's liver. Both patients were also positive for total anti-HBs and anti-HBc but negative for anti-HBe and anti-HBc IgM. HBV DNA levels were 234-567IU/ml in case 1 and 42-1130IU/ml in case 2. The alignment analysis of the S gene showed that HBV in both patients was genotype C, serotype adr. Cloning analysis of the a determinant of HBsAg showed that the immune escape mutants were predominant in both patients over the follow-up period. The HBV had double mutations (A1762T and G1764A) in the basal core promoter but had no mutation in the pre C/C gene in both patients. The patients with negative HBsAg but positive HBeAg may represent a unique type of OBI. Test for HBeAg would be critical to identifying such type of OBI. Figure 55-2 details the sequence of the various HBV antigens and antibodies in acute infection. The first serological marker to be detected is the hepatitis B surface antigen (HBsAg) , often preceding the increase in transaminase levels. As HBsAg disappears, antibodies to the surface antigen develop (anti-HBs), marking complete resolution of disease. Hepatitis B core antigen is an intracellular antigen and not detectable in serum. However, anti -HBc is detectable wi thin weeks of HBsAg appearance. The hepatitis Be antigen (HBeAg) is present during times of high viral replication and often correlates with detectable HBV DNA. After acute hepatitis, approximately 90 percent of adults recover completely. The 10 percent who remain chronically infected are considered to have chronic hepatitis B. Chronic HBV infection is oten asymptomatic but may be clinically suggested by persistent anorexia, weight loss, fatigue, and The surface antigen (HBsAg) is most frequently used to screen for the presence of this infection. It is the first detectable viral antigen to appear during infection. However, early in an infection, this antigen may not be present and it may be undetectable later in the infection as it is being cleared by the host. The infectious virion contains an inner \"core particle\" enclosing viral genome. The icosahedral core particle is made of 180 or 240 copies of the core protein, alternatively known as core antigen, or HBcAg. During this 'window' in which the host remains infected but is successfully clearing the virus, IgM antibodies specific to the core antigen (anti-HBc IgM) may be the only serological evidence of disease. Therefore, most diagnostic panels contain HBsAg and total anti-HBc (both IgM and IgG). Thirty-four persistent healthy carriers of HBsAg (serum HBsAg detectable for longer than 3 months with normal liver function tests and normal liver histology or slight aspecific abnormalities) were discovered by routine testing of household relatives of B virus hepatitis patients. The carriers were followed-up for 11 to 37 months by clinical control, liver function tests and liver needle biopsy. None carrier had previous jaundice. During the follow-up period, in 17 of the 34 subjects, was there no evidence of deterioration in either clinical state, liver function of pathological findings. In 5 of the 34 carriers, HBsAg disappeared from serum after a period ranging from 6 to 12 months. The remaining 12 cases developed clinical and histological picture of acute viral hepatitis after 6 to 29 months (mean 12 months). Of these 12 patients, 6 recovered and become HBsAg; 2 remained HBsAg healthy carriers despite normalization of biochemical and histological abnormalities; 3 progressed from the acute stage to antigen positive CAH. The remaining one case could not be followed-up after the acute hepatitis. Our data indicate that the outcome of the HBsAg carrier state is unpredictable and stress the need of long-term follow-up surveillance. We evaluated the clinical and epidemiological data of 142 HBsAg carriers. This prospective trial is part of a program of study and follow-up in HVB patients. The median age was 34.58 years old, males 56.3%. The average follow-up was 32.4 months. Complete clinical history, routine analysis, liver function tests, alfa-fetoprotein, serology for HVB, HCV and HDV and abdominal ecography were done in all patients. DNA-HVB was done only in special cases. Patients with less than 6 months of follow-up were excluded. The 118 remaining carriers were classified into two groups, depending on ALT values. Group 1 (normal ALT): included 98 carriers, 3 of them developed an active chronic hepatitis that was treated with interferon. A small CHC was diagnosed in another patient and it was resected. Group 2 (elevated ALT): included 20 carriers, only 9 of them agreed to biopsy and we found severe hepatic lesions in 4 of them. No group presented coinfection with HCV or HDV. No patient died. We conclude that the study and follow-up of asymptomatic HBsAg carriers permits an early diagnosis and treatment of the complications of this pathology (chronic hepatitis, CHC, etc); in our study, three patients developed chronic hepatitis, successfully treated with interferon, and one small size CHC was diagnosed in another patient. The study of relatives permits also detect subclinic liver disease and facilitates vaccination to prevention transmission of this infection. The study tries to clarify the affliction of liver as a consequence of the permanent HB antigenemy in apparently healthy persons. The study proves beyond doubt that in the majority of the HB antigen carriers such histological changes of the liver can be found that can be attributed only to an infection by the hepatitis virus. The majority of the HB antigen carriers are suffering either from the chronic focal (58%) or from the diffuse (21%) persistent hepatitis. A smaller percentage is suffering from more dangerous hepatopathies (acute viral hepatitis 4,2%, hepatitis chron. aggressiva 4.2%, cirrhosis 1,4%). The kind of the illness can be determined with the histological examination only because of the absence of the clinical symptomatology and because of the liver function tests are in such cases frequently normal. Our investigations indicate that the diffuse and focal forms of persistent hepatitis can remain unchanged overlong periods and the same histological findings over a number of years. The chronic persistent hepatitis, however, may develop through clinically imperceptible changes into a chronic aggressive hepatitis, and the inapparent acute hepatitis can even pass over directly into cirrhosis. The identification of various forms of hepatitis, from light instances to the most severe cases, among the HB antigen carriers proves that the acute viral hepatitis of the type B may have in all the phases of its development a clinically asymptomatic course; it may even asymptomatically pass over into hepatopathies of the most severe kinds. The state of health of persons with HB antigenemy must be systematically followed up. For these reasons the histological examinations of the bioptic liver material that are made from time to time during the follow up of the illness have a decisive role. Evaluation of hepatitis B virus infection can be complicated, and some uncommon but possible scenarios should be kept in mind while investigating. Patients can test negative for HBsAg and anti-HBs but can have the presence of anti-HBc. This situation is possible when the result is false positive but can also happen in patients who are in the time window where they have cleared HBsAg from the blood, but anti-HBs has not yet appeared. Some patients who have cleared hepatitis B virus infection but have lost the anti-HBs over the years can test negative both for HBsAg and anti-HBs but positive for anti-HBc.  Also, patients infected with the hepatitis B virus many years ago can sometimes develop a core mutant variant of the hepatitis B virus where they can test negative for HBeAg and positive for anti-HBe even though the virus may still be active and is replicating. When lab findings like these are detected, the hepatitis B virus DNA PCR assay to check for viral replication is recommended. Among the six species of hepatitis viruses, HBV (hepatitis B virus) and HCV (hepatitis C virus) can induce persistent infection. HBV and HCV are transmitted parenterally, of which maternal transmission and transfusion-associated infection is a major route respectively. We opened the special clinic for carriers detected through blood donation, and followed them at regular intervals for their health care. The prevalence rate of HBV carriers decreased from 3.0% to 1.2% in these 10 years, and that of HCV decreased from 0.9 to 0.4% in these 4 years. Prevalence rate of HBV peaks at 50s and that of HCV peaks at 60s. Due to nearly complete screening of donated blood, post-transfusion hepatitis almost disappeared. HBV vaccine for neonates born from infected mothers reduced the new incidence of HBV carriers. In HBV carriers seroconversion of HBeAg to HBeAb occurs at teens with transient hepatitis and appearance of mutant virus. Ninety percent of the carriers remains healthy for the lifetime but some of them aggravate into chronic hepatitis leading to HCC (hepatocellular carcinoma). In HCV acute infection at adult age succeeds to chronic infection and eventually to liver cirrhosis with sporadic appearance of HCC. On the other hand, less than 50% of HCV carriers seem to be asymptomatic and do not lead to grave disease. In HBV carriers tendency to reject the virus occurs and eventually HBV is cleared in some percentage of the population. In contrast HCV does not tend to be cleared. HBsAb is a defensive antibody. In contrast HCVAb is not a defensive antibody but an infective antibody like HBcAb. DNA polymerase is a good marker of disease state in HBV, and HCV RNA is a good marker of HCV proliferation. Treatment with IFN is sometimes effective for seroconversion in HBV, and for eradication of virus in HCV. Primary infection with Epstein-Barr virus (EBV) often occurs subclinically during childhood, resulting in a latent infection of B lymphocytes. In this report, a chronic hepatitis B case who presented with a serologic profile mimicking acute hepatitis B virus (HBV) infection and exhibiting transient autoantibody positivities because of the polyclonal activation of B cells due to EBV reactivation has been presented. The test results of 56 years old male patient who suffered from fatigue and pain on the right upper quadrant, revealed high levels of liver enzymes (AST: 187 U/L, ALT: 569 U/L), positivity of HBsAg, anti-HBc IgG and anti-HBe, and negativity of anti-HBc IgM, HBeAg and anti-HBs. Since HBV-DNA level was found 405,974 copies/mL by quantitative real time polymerase chain reaction (PCR), the patient was taken into follow-up. At the 6th month AST and ALT levels further elevated (352 U/L and 609 U/L, respectively), and anti-HBc IgM and anti-HBs became positive in addition to the previous positive markers of HBV. With the suspicion of superinfection, further laboratory investigations yielded negative results in CMV-IgM and Paul Bunnel test, while positive results in EBV anti-VCA IgM and IgG, anti-EBNA IgM and IgG, anti-p22 IgM and IgG and anti-EA IgM. In the follow-up period high levels of autoantibody positivities [rheumatoid factor (42.200 U/ml), anti-nuclear antibody (1/100) and anti-Ro-52] together with increased levels of total IgG, IgM and IgA were detected. In the following months, the levels of transaminases, total immunoglobulins and HBV-DNA have distinctively decreased, and in the 20th month the previous HBV profile regained (HBsAg, anti-HBc IgG and anti-HBe positive, anti-HBc IgM and anti-HBs negative, HBV-DNA: 6984 copies/ml) and the other pathological test results returned to normal. As a result, ALT increases seen during the course of chronic hepatitis B should not always be considered as HBV manifestations and the unusual serologic patterns should be evaluated as a consequence of superinfection with various viral agents. A 81 day old male infant developed an acute hepatitic failure and died shortly thereafter. Determinations of HBs antigen and antibody (AB) and HBeAg and AB were performed in the parents and sibling of the infected child. The mother and a sister were an asymptomatic carrier of HBsAg, the first HBeAg positive and the second HBeAB positive. An elder sibling was HBsAg and HBeAg positive in this serum. The father was anti-HBs positive. In the family of the sister, the man and two childs were HBsAg and anti-HBsAB negative. A new baby in the family of the propositus born and a combination of HB vaccine and HBIg (hepatite B immuno-globulin) was started at birth. Unfortunately the child died of S.D.I.S. (Sudden Death Infant Syndrome). The HB vaccine was immuno-genetic in this infant and the anti-HBs in the immuno-globulin M (IgM) was positive as in several adults controls. This case allow us to discuss vertical transmission of hepatitis B, the clinical aspect of neonatal hepatitis and the preventing HB infection by combinaison of HB vaccine and HBIg. Two groups of immigrants from Ethiopia, one of 86 and the other of 165 individuals, aged 0-40, were examined for hepatitis B virus (HBV) infection in 1987-88, 3-7 years after their arrival in Israel. The results were compared with those obtained in the same age-group among Ethiopians who immigrated to Israel in 1980-82. The immigrants were found to be in good physical condition, their liver function tests were normal and no clinical evidence of chronic liver disease was found. Of the 22 children aged 0-4, 16 had anti-HBs as a result of vaccination at birth against HBV and they were excluded from the comparative study. In the age-groups 5-40 there was no significant change in the percentage of individuals positive for HBsAg, anti-HBs or anti-HBc only, compared with the group examined in 1980-82. There were two significant findings in this study: a) In 1987-88 [corrected], 8-9% of HBsAg-positive individuals had HBeAg and 64-81% had anti-HBe, while in 1980-82, 36% of those positive for HBsAg had HBeAg and only 25% had anti-HBe. b) At the time of arrival recent infection by HBV was indicated by the presence of IgM anti-HBc in 57% of those positive for HBsAg and 21% in whom anti-HBc was the sole serological HBV marker. In 1987-88 no IgM anti-HBc was found in HBsAg-positive persons or in those with anti-HBc only. These results indicate that most HBV infections in this population had occurred before their arrival in Israel. There is a profound change in the epidemiology of HBV infection in this Ethiopian population following immigration, which is probably due to environmental changes as well as to vaccination against HBV of all young children aged less than or equal to 3 years.\nHere is the question:\nDIGESTIVE SYSTEM: Indicate the clinical situation in relation to hepatitis B virus infection in a 5-year-old patient from Nigeria, with normal physical examination and the following serology for hepatitis B: HBsAg + / ANTI-HBs - / HbeAg - / ANTI-HBe + / ANTI-HBc IgM - / ANTI-HBc IgG + / DNA HBV +:\nHere are the potential choices:\n1. Acute infection.\n2. Chronic infection.\n3. Vaccinated patient.\n4. Asymptomatic carrier.\nThe correct answer is: ",
        "gold_answer": "4 Asymptomatic carrier.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n 30 asymptomatic chronic carriers of hepatitis B surface antigen (HBsAg), 6 asymptomatic blood donors transiently infected with hepatitis B virus, and 38 patients with acute hepatitis B were tested for HBsAg, anti-HBs, HBeAg, anti-HBe and anti-HBc. Comparison of these results revealed significant variation in the frequency of HBeAg which was present in 1 (3.3%) carrier, 2 (33.3%) of the transiently positive donors, and in 24 (63.2%) of the patients with acute hepatitis. Anti-HBe was found in 28 (93.3%) of the carriers, 4 (66.6%) of the transiently positive donors, and in 8 (21%) of the patients. Variation was also seen in the strength of anti-HBc, with only the chronic carriers having titres which were consistently high (above 1,000). Retesting the two groups of donors after a period of approximately 2 years showed no change in the serologic status of the chronic carriers, while amongst the transient HBsAg positives the 2 HBeAg reactives had seroconverted, 1 of the anti-HBe positives had become non-reactive, and 2 of the 6 had developed anti-HBs. 6 of the patients with acute hepatitis B were serologically reexamined during convalescence and showed results similar to those seen in the transiently HBsAg-positive donors, with clearance of HBsAg in all, seroconversion from HBeAg to anti-HBe in 4, and the production of anti-HBs in 4. Hepatitis B virus (HBV) causes different clinical manifestations, ranging from asymptomatic carriage to fulminant or chronic hepatitis. Serological tests are widely used for the diagnosis of HBV infections to detect viral markers. However, facing with atypical serological profiles in some patients leads to problems in interpreting of the results and management of the patients. The aims of this study were to investigate the atypical serologic profiles seen in patients screened for HBV infection and the S gene mutations in patients with concurrent positivity of HBsAg and anti-HBs. A total of 592 sera from patients (332 male, 260 female; age range: 13-84 years, mean age: 43.9 years) prediagnosed as HBV infection between January to September 2013, and screened for HBV markers (HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc-IgM, anti-HBc-total and HBV-DNA) were included in the study. Of those samples 364 were screened only for HBsAg and anti-HBs markers. S gene mutations were investigated by direct sequencing method in sera which were concurrent positive for HBsAg and anti-HBs. In our study, 5.2% (31/592) of the sera yielded atypical serologic profiles. Of these 13 cases were concurrently positive for HBsAg and anti-HBs; nine were HBeAg positive, anti-HBe and HBV-DNA negative; eight were HBeAg, anti-HBe and HBV-DNA positive; and one was HBsAg and anti-HBs negative, anti-HBe and HBV-DNA positive. The rate of concurrent positivity of HBsAg and anti-HBs was 3.6% (13/364), while 76.9% (10/13) of those cases were also positive for HBV-DNA. DNA sequencing was performed for seven out of 10 samples which were positive for HBsAg, anti-HBs and HBV-DNA, however three samples were not used because of the low amounts. Sequence analysis of seven samples showed S gene mutations in two samples, one was sS143L with sS193L, a HBV vaccine escape mutation, and the other was sP120R, a HBV immune escape mutation. Of the patients 2.7% (10/364) was negative for both HBsAg and anti-HBs; in which nine were HBV-DNA negative and anti-HBe positive, while one was positive for both HBV-DNA and anti-HBe. The rate of concurrent positivity of HBeAg and anti-HBe was found as 1.4% (8/592), and all of these samples were HBV-DNA positive. No single positivity for HBsAg, anti-HBc, anti-HBs or HBV-DNA was not detected in any of the patients. In conclusion, HBsAg and anti-HBs concurrent positivity was the most frequently detected atypical profile in our study (3.6%), and in some (2/7) of these patients S gene mutations were determined. On a serological assay, the presence of hepatitis B surface antigen (HBsAg) indicates an individual with a currently active hepatitis B infection, whether acute or chronic. The presence of core antibody (anti-HBc) indicates an individual with an infection in general, whether current or previously resolved. The presence of surface antibody (anti-HBs) indicates an individual with immunity to hepatitis B, whether due to previously resolved infection or due to hepatitis B vaccination. For example, an individual who has never had any exposure to HBV, either by vaccine or by infection, would test negative for the entire serology panel. An individual who has been vaccinated and never had an infection will test seropositive for anti-HBs due to vaccination and negative for markers of infection. An individual with an acute HBV infection would test positive for HBsAg and anti-HBc (total and IgM) while negative for anti-HBs. An individual with a chronic infection would test positive for HBsAg and To study the etiology of acute hepatitis superimposed upon previously unrecognized asymptomatic HBsAg carriers, paired sera were collected in acute and convalescence phases for measurement of HBeAg, anti-HBe, hepatitis B virus DNA and anti-delta from 76 adult patients with acute hepatitis who were HBsAg positive but IgM anti-HBc negative or positive only at low titer. None of them were IgM anti-hepatitis A virus positive on admission. Of the 34 patients who were HBeAg positive initially, two (5.9%) were diagnosed as having delta superinfection, and another two (5.9%) were suspected to have non-A, non-B virus superinfection because of a transient decrease of serum hepatitis B virus DNA. The remaining 30 (88.2%) cases were hepatitis B virus DNA negative with or without anti-HBe seroconversion on follow-up. The episodes of acute hepatitis in these cases may represent \"immune clearance of HBeAg\" or \"immune clearance of hepatitis B virus with delayed anti-HBe seroconversion,\" respectively, in the natural course of chronic hepatitis B virus infection. Of the patients who were anti-HBe positive initially, 23 (54.8%) were diagnosed as having delta superinfection, including eight with de novo seroconversion of anti-delta and 15 with a rising titer of anti-delta; 10 (23.8%) were positive for hepatitis B virus DNA and were considered as reactivation of hepatitis B virus, and the other nine (21.4%) were suspected as having non-A, non-B virus superinfection.(ABSTRACT TRUNCATED AT 250 WORDS) Following serologic markers are often tested: Hepatitis B surface antigen (HBsAg), antibody to Hepatitis B surface antigen (anti-HBs), Hepatitis B core Ab (Anti-HBc) IgM, Hepatitis B core Ab (Anti-HBc) IgG, Hepatitis B e antigen (HBeAg), and Hepatitis B e antibody (anti-HBe). [10] HBsAg: Acute infection (less than 6 months) or chronic infection (more than 6 months). Anti-HBs: Recovery from acute infection or immunity from vaccination. HBeAg: Mostly associated with high viral load. Anti-HBe: Low replicative phase. Anti-HBc IgM: Acute infection, an only marker present in the window period, can be present during exacerbation of chronic infection. Anti-HBc IgG: Exposure to infection, chronic infection (if present along with HBsAg), recovery from acute infection (if present with anti-HBs), if isolated presence, may represent occult infection. Shortly after the appearance of the HBsAg, another antigen called e antigen (HBeAg) will appear. Traditionally, the presence of HBeAg in a host's serum is associated with much higher rates of viral replication and enhanced infectivity; however, variants of the virus do not produce the 'e' antigen, so this rule does not always hold true. During the natural course of an infection, the HBeAg may be cleared, and antibodies to the 'e' antigen (anti-HBe) will arise immediately afterwards. This conversion is usually associated with a dramatic decline in viral replication. If the host is able to clear the infection, eventually the HBsAg will become undetectable and will be followed by IgG antibodies to the surface antigen and core antigen (anti-HBs and anti HBc IgG). The time between the removal of the HBsAg and the appearance of anti-HBs is called the window period. A person negative for HBsAg but positive for anti-HBs either has cleared an infection or has been vaccinated previously. Hepatitis B Two periods may be referred to as window period in hepatitis B infection: (1) the period that elapses during HBsAg to HBsAb seroconversion, i.e. between the disappearance of surface antigen (HBsAg) from serum and the appearance of HBsAb (anti-HBs), and (2) the period between infection and appearance of HBsAg. During the window of HBsAg to HBsAb seroconversion, IgM anti-core (HBc-IgM) is the only detectable antibody. HBV DNA may be positive as well. This window period does not occur in persons who develop chronic hepatitis B, i.e. who continue to have detectable HBV DNA for greater than 6 months (HbsAg remains positive), or in people who develop isolated HBcAb positivity, i.e. who lose HBsAg, but do not develop HBsAb (HBV DNA may or may not remain positive). See also Incubation period, the time between infection and the appearance of symptoms References HIV/AIDS Serology individual with an acute HBV infection would test positive for HBsAg and anti-HBc (total and IgM) while negative for anti-HBs. An individual with a chronic infection would test positive for HBsAg and total anti-HBc (IgM and IgG), but negative for IgM anti-HBc and anti-HBs. An individual who has successfully resolved their HBV infection will test negative for HBsAg, positive for anti-HBc, and may test negative or positive for anti-HBs, although most will test positive. In the typical disease course for hepatitis B, the individual will first seroconvert for hepatitis B surface antigen (HBsAg). While some can convert within one week, most individuals take about four weeks after initial infection to convert. Anti-core antibodies (anti-HBc) are the first antibodies produced by the body, first in short-term IgM (anti-HBc IgM), and subsequently in long-term IgG; while levels of IgM anti-HBc will peak around sixteen weeks after exposure and fall within about seven to eight months, IgG anti-HBc will remain detectable in the serum as a sign of chronic infection for years. IgM anti-HBc concentration will fall regardless of whether or not the individual clears the infection. The window period for HBsAg/anti-HBs testing occurs as concentration of HBsAg falls and before the body develops anti-HBs antibodies, lasting approximately six to eight weeks in most individuals. During this time, serology assays can test for total anti-HBc. Levels of anti-surface antibody Hepatitis B When a person gets a hepatitis B vaccine then the most common test for hepatitis B will show them to be positive. The usual course of action, in this case, is to give the person a panel of tests for HBsAg, anti-HBc, and anti-HBs (hepatitis B surface antigen, anti-hepatitis B core, and anti-hepatitis B surface). A person who has never been exposed to hepatitis B but has gotten the vaccine will be positive for anti-HBs but negative for the other two tests in the panel. Other combinations of positive and negative in this test can mean other things, such as acute, chronic, or past infection. Viral hepatitis Viral hepatitis is primarily diagnosed through blood tests for levels of viral antigens (such as the hepatitis B surface or core antigen), anti-viral antibodies (such as the anti-hepatitis B surface antibody or anti-hepatitis A antibody), or viral DNA/RNA. In early infection (i.e. within 1 week), IgM antibodies are found in the blood. In late infection and after recovery, IgG antibodies are present and remain in the body for up to years. Therefore, when a patient is positive for IgG antibody but negative for IgM antibody, he is considered immune from the virus via either prior infection and recovery or prior vaccination. In the case of hepatitis B, blood tests exist for multiple virus antigens (which are different components of the virion particle) and antibodies. The combination of antigen and antibody positivity can provide information about the stage of infection (acute or chronic), the degree of viral replication, and the infectivity of the virus. Hepatitis B e antigen (HBeAg) is a marker to indicate active replication of hepatitis B virus (HBV). Occult HBV infection (OBI), referred to persistence of HBV DNA in serum and/or liver without detectable serum hepatitis B surface (HBsAg), usually has low HBV DNA levels. The presence of HBeAg in OBI is unusual. We report 2 patients who presented negative for HBsAg but positive for HBeAg and HBV DNA. HBV markers were quantified in the longitudinal sera in a period of 1-2years. The HBV DNA sequences were analyzed in 2 patients' sera and 1 patient's liver. Both patients were also positive for total anti-HBs and anti-HBc but negative for anti-HBe and anti-HBc IgM. HBV DNA levels were 234-567IU/ml in case 1 and 42-1130IU/ml in case 2. The alignment analysis of the S gene showed that HBV in both patients was genotype C, serotype adr. Cloning analysis of the a determinant of HBsAg showed that the immune escape mutants were predominant in both patients over the follow-up period. The HBV had double mutations (A1762T and G1764A) in the basal core promoter but had no mutation in the pre C/C gene in both patients. The patients with negative HBsAg but positive HBeAg may represent a unique type of OBI. Test for HBeAg would be critical to identifying such type of OBI. Figure 55-2 details the sequence of the various HBV antigens and antibodies in acute infection. The first serological marker to be detected is the hepatitis B surface antigen (HBsAg) , often preceding the increase in transaminase levels. As HBsAg disappears, antibodies to the surface antigen develop (anti-HBs), marking complete resolution of disease. Hepatitis B core antigen is an intracellular antigen and not detectable in serum. However, anti -HBc is detectable wi thin weeks of HBsAg appearance. The hepatitis Be antigen (HBeAg) is present during times of high viral replication and often correlates with detectable HBV DNA. After acute hepatitis, approximately 90 percent of adults recover completely. The 10 percent who remain chronically infected are considered to have chronic hepatitis B. Chronic HBV infection is oten asymptomatic but may be clinically suggested by persistent anorexia, weight loss, fatigue, and The surface antigen (HBsAg) is most frequently used to screen for the presence of this infection. It is the first detectable viral antigen to appear during infection. However, early in an infection, this antigen may not be present and it may be undetectable later in the infection as it is being cleared by the host. The infectious virion contains an inner \"core particle\" enclosing viral genome. The icosahedral core particle is made of 180 or 240 copies of the core protein, alternatively known as core antigen, or HBcAg. During this 'window' in which the host remains infected but is successfully clearing the virus, IgM antibodies specific to the core antigen (anti-HBc IgM) may be the only serological evidence of disease. Therefore, most diagnostic panels contain HBsAg and total anti-HBc (both IgM and IgG). Thirty-four persistent healthy carriers of HBsAg (serum HBsAg detectable for longer than 3 months with normal liver function tests and normal liver histology or slight aspecific abnormalities) were discovered by routine testing of household relatives of B virus hepatitis patients. The carriers were followed-up for 11 to 37 months by clinical control, liver function tests and liver needle biopsy. None carrier had previous jaundice. During the follow-up period, in 17 of the 34 subjects, was there no evidence of deterioration in either clinical state, liver function of pathological findings. In 5 of the 34 carriers, HBsAg disappeared from serum after a period ranging from 6 to 12 months. The remaining 12 cases developed clinical and histological picture of acute viral hepatitis after 6 to 29 months (mean 12 months). Of these 12 patients, 6 recovered and become HBsAg; 2 remained HBsAg healthy carriers despite normalization of biochemical and histological abnormalities; 3 progressed from the acute stage to antigen positive CAH. The remaining one case could not be followed-up after the acute hepatitis. Our data indicate that the outcome of the HBsAg carrier state is unpredictable and stress the need of long-term follow-up surveillance. We evaluated the clinical and epidemiological data of 142 HBsAg carriers. This prospective trial is part of a program of study and follow-up in HVB patients. The median age was 34.58 years old, males 56.3%. The average follow-up was 32.4 months. Complete clinical history, routine analysis, liver function tests, alfa-fetoprotein, serology for HVB, HCV and HDV and abdominal ecography were done in all patients. DNA-HVB was done only in special cases. Patients with less than 6 months of follow-up were excluded. The 118 remaining carriers were classified into two groups, depending on ALT values. Group 1 (normal ALT): included 98 carriers, 3 of them developed an active chronic hepatitis that was treated with interferon. A small CHC was diagnosed in another patient and it was resected. Group 2 (elevated ALT): included 20 carriers, only 9 of them agreed to biopsy and we found severe hepatic lesions in 4 of them. No group presented coinfection with HCV or HDV. No patient died. We conclude that the study and follow-up of asymptomatic HBsAg carriers permits an early diagnosis and treatment of the complications of this pathology (chronic hepatitis, CHC, etc); in our study, three patients developed chronic hepatitis, successfully treated with interferon, and one small size CHC was diagnosed in another patient. The study of relatives permits also detect subclinic liver disease and facilitates vaccination to prevention transmission of this infection. The study tries to clarify the affliction of liver as a consequence of the permanent HB antigenemy in apparently healthy persons. The study proves beyond doubt that in the majority of the HB antigen carriers such histological changes of the liver can be found that can be attributed only to an infection by the hepatitis virus. The majority of the HB antigen carriers are suffering either from the chronic focal (58%) or from the diffuse (21%) persistent hepatitis. A smaller percentage is suffering from more dangerous hepatopathies (acute viral hepatitis 4,2%, hepatitis chron. aggressiva 4.2%, cirrhosis 1,4%). The kind of the illness can be determined with the histological examination only because of the absence of the clinical symptomatology and because of the liver function tests are in such cases frequently normal. Our investigations indicate that the diffuse and focal forms of persistent hepatitis can remain unchanged overlong periods and the same histological findings over a number of years. The chronic persistent hepatitis, however, may develop through clinically imperceptible changes into a chronic aggressive hepatitis, and the inapparent acute hepatitis can even pass over directly into cirrhosis. The identification of various forms of hepatitis, from light instances to the most severe cases, among the HB antigen carriers proves that the acute viral hepatitis of the type B may have in all the phases of its development a clinically asymptomatic course; it may even asymptomatically pass over into hepatopathies of the most severe kinds. The state of health of persons with HB antigenemy must be systematically followed up. For these reasons the histological examinations of the bioptic liver material that are made from time to time during the follow up of the illness have a decisive role. Evaluation of hepatitis B virus infection can be complicated, and some uncommon but possible scenarios should be kept in mind while investigating. Patients can test negative for HBsAg and anti-HBs but can have the presence of anti-HBc. This situation is possible when the result is false positive but can also happen in patients who are in the time window where they have cleared HBsAg from the blood, but anti-HBs has not yet appeared. Some patients who have cleared hepatitis B virus infection but have lost the anti-HBs over the years can test negative both for HBsAg and anti-HBs but positive for anti-HBc.  Also, patients infected with the hepatitis B virus many years ago can sometimes develop a core mutant variant of the hepatitis B virus where they can test negative for HBeAg and positive for anti-HBe even though the virus may still be active and is replicating. When lab findings like these are detected, the hepatitis B virus DNA PCR assay to check for viral replication is recommended. Among the six species of hepatitis viruses, HBV (hepatitis B virus) and HCV (hepatitis C virus) can induce persistent infection. HBV and HCV are transmitted parenterally, of which maternal transmission and transfusion-associated infection is a major route respectively. We opened the special clinic for carriers detected through blood donation, and followed them at regular intervals for their health care. The prevalence rate of HBV carriers decreased from 3.0% to 1.2% in these 10 years, and that of HCV decreased from 0.9 to 0.4% in these 4 years. Prevalence rate of HBV peaks at 50s and that of HCV peaks at 60s. Due to nearly complete screening of donated blood, post-transfusion hepatitis almost disappeared. HBV vaccine for neonates born from infected mothers reduced the new incidence of HBV carriers. In HBV carriers seroconversion of HBeAg to HBeAb occurs at teens with transient hepatitis and appearance of mutant virus. Ninety percent of the carriers remains healthy for the lifetime but some of them aggravate into chronic hepatitis leading to HCC (hepatocellular carcinoma). In HCV acute infection at adult age succeeds to chronic infection and eventually to liver cirrhosis with sporadic appearance of HCC. On the other hand, less than 50% of HCV carriers seem to be asymptomatic and do not lead to grave disease. In HBV carriers tendency to reject the virus occurs and eventually HBV is cleared in some percentage of the population. In contrast HCV does not tend to be cleared. HBsAb is a defensive antibody. In contrast HCVAb is not a defensive antibody but an infective antibody like HBcAb. DNA polymerase is a good marker of disease state in HBV, and HCV RNA is a good marker of HCV proliferation. Treatment with IFN is sometimes effective for seroconversion in HBV, and for eradication of virus in HCV. Primary infection with Epstein-Barr virus (EBV) often occurs subclinically during childhood, resulting in a latent infection of B lymphocytes. In this report, a chronic hepatitis B case who presented with a serologic profile mimicking acute hepatitis B virus (HBV) infection and exhibiting transient autoantibody positivities because of the polyclonal activation of B cells due to EBV reactivation has been presented. The test results of 56 years old male patient who suffered from fatigue and pain on the right upper quadrant, revealed high levels of liver enzymes (AST: 187 U/L, ALT: 569 U/L), positivity of HBsAg, anti-HBc IgG and anti-HBe, and negativity of anti-HBc IgM, HBeAg and anti-HBs. Since HBV-DNA level was found 405,974 copies/mL by quantitative real time polymerase chain reaction (PCR), the patient was taken into follow-up. At the 6th month AST and ALT levels further elevated (352 U/L and 609 U/L, respectively), and anti-HBc IgM and anti-HBs became positive in addition to the previous positive markers of HBV. With the suspicion of superinfection, further laboratory investigations yielded negative results in CMV-IgM and Paul Bunnel test, while positive results in EBV anti-VCA IgM and IgG, anti-EBNA IgM and IgG, anti-p22 IgM and IgG and anti-EA IgM. In the follow-up period high levels of autoantibody positivities [rheumatoid factor (42.200 U/ml), anti-nuclear antibody (1/100) and anti-Ro-52] together with increased levels of total IgG, IgM and IgA were detected. In the following months, the levels of transaminases, total immunoglobulins and HBV-DNA have distinctively decreased, and in the 20th month the previous HBV profile regained (HBsAg, anti-HBc IgG and anti-HBe positive, anti-HBc IgM and anti-HBs negative, HBV-DNA: 6984 copies/ml) and the other pathological test results returned to normal. As a result, ALT increases seen during the course of chronic hepatitis B should not always be considered as HBV manifestations and the unusual serologic patterns should be evaluated as a consequence of superinfection with various viral agents. A 81 day old male infant developed an acute hepatitic failure and died shortly thereafter. Determinations of HBs antigen and antibody (AB) and HBeAg and AB were performed in the parents and sibling of the infected child. The mother and a sister were an asymptomatic carrier of HBsAg, the first HBeAg positive and the second HBeAB positive. An elder sibling was HBsAg and HBeAg positive in this serum. The father was anti-HBs positive. In the family of the sister, the man and two childs were HBsAg and anti-HBsAB negative. A new baby in the family of the propositus born and a combination of HB vaccine and HBIg (hepatite B immuno-globulin) was started at birth. Unfortunately the child died of S.D.I.S. (Sudden Death Infant Syndrome). The HB vaccine was immuno-genetic in this infant and the anti-HBs in the immuno-globulin M (IgM) was positive as in several adults controls. This case allow us to discuss vertical transmission of hepatitis B, the clinical aspect of neonatal hepatitis and the preventing HB infection by combinaison of HB vaccine and HBIg. Two groups of immigrants from Ethiopia, one of 86 and the other of 165 individuals, aged 0-40, were examined for hepatitis B virus (HBV) infection in 1987-88, 3-7 years after their arrival in Israel. The results were compared with those obtained in the same age-group among Ethiopians who immigrated to Israel in 1980-82. The immigrants were found to be in good physical condition, their liver function tests were normal and no clinical evidence of chronic liver disease was found. Of the 22 children aged 0-4, 16 had anti-HBs as a result of vaccination at birth against HBV and they were excluded from the comparative study. In the age-groups 5-40 there was no significant change in the percentage of individuals positive for HBsAg, anti-HBs or anti-HBc only, compared with the group examined in 1980-82. There were two significant findings in this study: a) In 1987-88 [corrected], 8-9% of HBsAg-positive individuals had HBeAg and 64-81% had anti-HBe, while in 1980-82, 36% of those positive for HBsAg had HBeAg and only 25% had anti-HBe. b) At the time of arrival recent infection by HBV was indicated by the presence of IgM anti-HBc in 57% of those positive for HBsAg and 21% in whom anti-HBc was the sole serological HBV marker. In 1987-88 no IgM anti-HBc was found in HBsAg-positive persons or in those with anti-HBc only. These results indicate that most HBV infections in this population had occurred before their arrival in Israel. There is a profound change in the epidemiology of HBV infection in this Ethiopian population following immigration, which is probably due to environmental changes as well as to vaccination against HBV of all young children aged less than or equal to 3 years.\nHere is the question:\nDIGESTIVE SYSTEM: Indicate the clinical situation in relation to hepatitis B virus infection in a 5-year-old patient from Nigeria, with normal physical examination and the following serology for hepatitis B: HBsAg + / ANTI-HBs - / HbeAg - / ANTI-HBe + / ANTI-HBc IgM - / ANTI-HBc IgG + / DNA HBV +:\nHere are the potential choices:\n1. Acute infection.\n2. Chronic infection.\n3. Vaccinated patient.\n4. Asymptomatic carrier.\nThe correct answer is: 2. Chronic infection."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Although refeeding syndrome has been well documented in starved patients, obese patients, those with anorexia nervosa, malnourished elderly individuals, and certain postoperative patients, little is known about the presence and the importance of refeeding syndrome in patients with gastrointestinal fistula and insufficient nutrition support over the long term. The objective of this study was to estimate the morbidity of this syndrome in these patients, to assess the safety and efficacy of our graduated refeeding regimen, and to emphasize the importance of this syndrome. One hundred fifty-eight patients with gastrointestinal fistula during the past 2 y were reviewed. Fifteen of these patients were diagnosed as having refeeding syndrome. They were started on the refeeding procedure according to our regimen, and changes in their serum levels of electrolytes were recorded. The symptoms and signs they presented were noted. All patients were successfully advanced to full nutrition support. During the refeeding procedure, patients presented with weakness, paralysis of limbs, slight dyspnea, paresthesia, tachycardia, edema, and diarrhea. Serum phosphorus concentration decreased in all patients within 24 h of refeeding, reaching a mean nadir after 3.3 +/- 1.5 d and another 6.1 +/- 2.1 d to return to above 0.70 mM/L upon phosphorus supplementation. Three patients treated with growth hormone presented more severe hypophosphatemia (&lt;0.20 mM/L) than the others. 1) Refeeding syndrome occurs commonly in patients with malnutrition secondary to gastrointestinal fistula. 2) Alterations in phosphate metabolism are central to the refeeding syndrome. 3) Supplementation with electrolytes (including especially phosphate) and vitamins is the focal point of the treatment of this syndrome. 4) Growth hormone treatment may aggravate hypophosphatemia. The Refeeding Syndrome is conformed by a series of clinical manifestations related to electrolytic alterations associated with the restarting of the nutritive contribution both enteral and parenteral. To detect the Refeeding Syndrome incidence in malnourished patients who required nutritional, enteral or endovenous support and its relationship with mortality. A cohort study was performed in the service of Nutritional Support of the IMSS (Social Security Mexican Institute) Specialties Hospital CMN León, from June 1995 to May 1996. All patients with mild and severe malnutrition were included, they received endovenous or enteral nutritious support for more than 7 days, without presenting previous electrolytic unbalance. Serum potassium, phosphorous, and magnesium levels were determined before starting the nutritious support and also on the 3rd, 7th, and 10th days. Descriptive statistics, Student's t and Z test were used, with a 5% significance level. 148 patients with total nutritional support, 23 (16%) of them with restrained malnutrition and 65 (44%) with severe deficit. 54 men and 34 women with an average age of 51.6 +/- 19.4 years. Nineteen patients were eliminated due to a nutrition period of less than 7 days, and other 19 were also eliminated for presenting electrolytic alterations before the nutritive support started. An incidence of 48% of electrolytic alterations compatible with the refeeding syndrome was the result in the remaining 50 patients. The alterations were: hypomagnesemia 13/24, hypokalemia 12/24 and hypophosphatemia 4/24; in 55% of the cases the syndrome appeared at the third day of administration. Hospital sojourn of patients with the syndrome was 26.7 +/- 18 days vs 15.3 +/- 7 (p &lt; 0.05) of those who did not present it. 15 patients died, 5 of them had electrolytic alterations before nutrition, 7 (29%) with refeeding syndrome and 3 (12%) did not presented it (p = 0.059). Refeeding Syndrome is a frequent entity in malnourished patients submitted to enteral or parenteral nutrition; at least in this study it was of 48%; its presence was followed by a longer hospital stay and a higher mortality rate. Refeeding syndrome is a potentially life-threatening condition characterised by severe intracellular electrolyte shifts, acute circulatory fluid overload and organ failure. The initial symptoms are non-specific but early clinical features are severely low-serum electrolyte concentrations of potassium, phosphate or magnesium. Risk factors for the syndrome include starvation, chronic alcoholism, anorexia nervosa and surgical interventions that require lengthy periods of fasting. The causes of the refeeding syndrome are excess or unbalanced enteral, parenteral or oral nutritional intake. Prevention of the syndrome includes identification of individuals at risk, controlled hypocaloric nutritional intake and supplementary electrolyte replacement. To determine the occurrence of refeeding syndrome in adults commenced on artificial nutrition support. Prospective cohort study. Large, single site university teaching hospital. Recruitment period 2007-2009. 243 adults started on artificial nutrition support for the first time during that admission recruited from wards and intensive care.  occurrence of the refeeding syndrome. Secondary outcome: analysis of the risk factors which predict the refeeding syndrome. Tertiary outcome: mortality due to refeeding syndrome and all-cause mortality. 133 participants had one or more of the following risk factors: body mass index &lt;16-18.5≥(kg/m(2)), unintentional weight loss &gt;15% in the preceding 3-6 months, very little or no nutritional intake &gt;10 days, history of alcohol or drug abuse and low baseline levels of serum potassium, phosphate or magnesium prior to recruitment. Poor nutritional intake for more than 10 days, weight loss &gt;15% prior to recruitment and low-serum magnesium level at baseline predicted the refeeding syndrome with a sensitivity of 66.7%: specificity was &gt;80% apart from weight loss of &gt;15% which was 59.1%. Baseline low-serum magnesium was an independent predictor of the refeeding syndrome (p=0.021). Three participants (2% 3/243) developed severe electrolyte shifts, acute circulatory fluid overload and disturbance to organ function following artificial nutrition support and were diagnosed with refeeding syndrome. There were no deaths attributable to the refeeding syndrome, but (5.3% 13/243) participants died during the feeding period and (28% 68/243) died during hospital admission. Death of these participants was due to cerebrovascular accident, traumatic injury, respiratory failure, organ failure or end-of-life causes. Refeeding syndrome was a rare, survivable phenomenon that occurred during hypocaloric nutrition support in participants identified at risk. Independent predictors for refeeding syndrome were starvation and baseline low-serum magnesium concentration. Intravenous carbohydrate infusion prior to artificial nutrition support may have precipitated the onset of the syndrome. Refeeding syndrome (RFS) can be a severe and life-threatening complication of anorexia nervosa (AN) associated with electrolyte abnormalities and organ damage, and occurs with the transition from a prolonged catabolic to anabolic state, particularly with an overzealous nutrient supply. There is no unequivocal definition of RFS, although hypophosphatemia is recognized as a crucial factor in its pathogenesis. RFS can be responsible for cardiovascular complications, such as heart failure, left ventricular damage, and arrhythmias, because of different potential mechanisms: electrolyte imbalances, increased retention of sodium and liquids secondary to insulin secretion, and excessive fat emulsion supplementation. We report on the case of a 13-y-old male patient with severe AN in whom a delayed and reversible myocardial dysfunction was documented during cautious nutritional replenishment, even in the absence of serum electrolyte imbalances. Seven days after the inception of integrative enteral nutrition, heart failure was unexpectedly documented as follows: reduction in fraction ejection, presence of mild bilateral perimalleolar edema, and increased n-terminal prohormone of brain natriuretic peptide. A more pronounced water restriction protocol and delayed achievement of goal feeding rate, resulting also in lower sodium intake, were implemented to reduce cardiac overload with a full resolution of the complication in approximately 2 mo. Refeeding patients with AN could be complicated by heart failure despite cautious nutritional replenishment and regardless of electrolyte imbalance, even in a later phase of recovery. Therefore, strict adherence to recommendations for nutritional replenishment and close monitoring of cardiac function should always be considered when refeeding patients with AN. Clinical situations The syndrome can occur at the beginning of treatment for anorexia nervosa when patients have an increase in calorie intake and can be fatal. It can also occur after the onset of a severe illness or major surgery. The shifting of electrolytes and fluid balance increases cardiac workload and heart rate. This can lead to acute heart failure. Oxygen consumption is increased which strains the respiratory system and can make weaning from ventilation more difficult. Diagnosis Refeeding syndrome can be fatal if not recognized and treated properly. An awareness of the condition and a high index of suspicion are required in order to make the diagnosis. The electrolyte disturbances of the refeeding syndrome can occur within the first few days of refeeding. Close monitoring of blood biochemistry is therefore necessary in the early refeeding period. Anorexia nervosa exhibits one of the highest death rates among psychiatric patients and a relevant fraction of it is derived from undernutrition. Nutritional and medical treatment of extreme undernutrition present two very complex and conflicting tasks: (1) to avoid \"refeeding syndrome\" caused by a too fast correction of malnutrition; and (2) to avoid \"underfeeding\" caused by a too cautious refeeding. To obtain optimal treatment results, the caloric intake should be planned starting with indirect calorimetry measurements and electrolyte abnormalities accurately controlled and treated. This article reports the case of an anorexia nervosa young female affected by extreme undernutrition (BMI 9.6 kg/m(2)) who doubled her admission body weight (from 22.5 kg to 44 kg) in a reasonable time with the use of enteral tube feeding for gradual correction of undernutrition. Refeeding syndrome was avoided through a specialized and flexible program according to clinical, laboratory, and physiological findings. Commentary is provided on the pivotal paper by Weinsier and Krumdieck from 1981 describing 2 patients who developed profound and fatal refeeding syndrome following initiation of aggressive total parenteral nutrition. This classic description was among the first to describe the overwhelming cardiovascular and pulmonary manifestations that can accompany parenteral refeeding with carbohydrate in chronically malnourished patients. The syndrome has also been described with oral and enteral nutrition. One of the hallmarks of the syndrome is hypophosphatemia. Since 1981, dosing schemes for addressing hypophosphatemia have been refined. Other manifestations of the syndrome include other electrolyte abnormalities such as hypokalemia and hypomagnesemia, hyperglycemia, fluid and sodium retention, and neurologic and hematologic complications. Case reports of refeeding syndrome continue to be published, particularly in the anorexia nervosa population. Stressed, critically ill patients may be at risk of refeeding following short periods of fasting; hypophosphatemia is commonly encountered in this situation. It behooves the current nutrition support practitioner to keep in mind the types of patients at risk of refeeding syndrome and to approach refeeding of such patients with caution and careful monitoring. Severe undernutrition nearly always leads to marked changes in body spaces (e.g., alterations of intra-extracellular water) and in body masses and composition (e.g., overall and compartmental stores of phosphate, potassium, and magnesium). In patients with severe undernutrition it is almost always necessary to use oral nutrition support and/or artificial nutrition, besides ordinary food; enteral nutrition should be a preferred route of feeding if there is a functional accessible gastrointestinal tract. Refeeding of severely malnourished patients represents two very complex and conflicting tasks: (1) to avoid \"refeeding syndrome\" caused by a too fast correction of malnutrition; (2) to avoid \"underfeeding\" caused by a too cautious rate of refeeding. The aim of this paper is to discuss the modality of refeeding severely underfed patients and to present our experience with the use of enteral tube feeding for gradual correction of very severe undernutrition whilst avoiding refeeding syndrome, in 10 patients aged 22 ± 11.4 years and with mean initial body mass index (BMI) of 11.2 ± 0.7 kg/m(2). The mean BMI increased from 11.2 ± 0.7 kg/m(2) to 17.3 ± 1.6 kg/m(2) and the mean body weight from 27.9 ± 3.3 to 43.0 ± 5.7 kg after 90 days of intensive in-patient treatment (p &lt; 0.0001). Caloric intake levels were established after measuring resting energy expenditure by indirect calorimetry, and nutritional support was performed with enteral feeding. Vitamins, phosphate, and potassium supplements were administered during refeeding. All patients achieved a significant modification of BMI; none developed refeeding syndrome. In conclusion, our findings show that, even in cases of extreme undernutrition, enteral feeding may be a well-tolerated way of feeding. The clinical nutrition-eating disorders-unit in Raymond Poincaré Hospital is a reference center for the management of severe malnutrition and its complications in patients with anorexia nervosa (AN). The purpose of this study is to specify socio-demographic, anamnesic and clinical characteristics of AN patients hospitalized for extreme malnutrition, to identify types and prevalence of medical complications presented during their hospitalization for refeeding and the evolution of patients nutritional status. Demographic, clinical and paraclinical data of 354 severely malnourished AN patients were collected, during their first hospitalization in the unit, between November 1997 and January 2014, through medical records. The prevalence of medical complications was compared between the 2 AN subtypes (restricting and binging-purging). 339 patients were female and mean age was 28.7 ± 10.7 years old. Duration of AN was 9.5 ± 9 years, 173 (48.9%) patients had a restricting AN subtype. BMI at admission was 12.2 ± 1.6 kg/m<sup2</sup, 280 (79.3%) patients had already been hospitalized for AN in other hospitals before. Psychiatric comorbidities were present in 168 (47.5%) patients. Associated somatic comorbidities concerned 70 (19.8%) patients. Outcomes during hospitalization were marked by 4.1 ± 3.9 kg weight gain on 36.9 ± 30.5 days. Enteral nutrition was provided in 304 (85.9%) patients. Main medical complications during hospitalization were: anemia (79%), neutropenia (53.9%), hypertransaminasemia (53.7%), osteoporosis (46.3%), hypokalemia (39.5%), hypophosphatemia (26%), hypoglycemia (13.8%), infectious complications (24.3%), cardiac dysfunction (7.1%), and proven gelatinous bone marrow transformation (6.5%). Hypokalemia was more frequent in binging-purging subtype. Lympho-neutropenia and hypertransaminasemia were more frequent in restricting subtype. During their hospitalization, 35 (10%) patients were referred to medical intensive care unit and 5 patients died. AN patients hospitalized for severe malnutrition in a specialized clinical nutrition unit have severe and frequent medical complications. Psychiatric comorbidities are also frequent and could complicate medical care. A specialized and multidisciplinary management of these patients is therefore essential. Anorexia nervosa is associated with several serious medical complications related to malnutrition, severe weight loss, and low levels of micronutrients. The refeeding phase of these high-risk patients bears a further threat to health and potentially fatal complications. The objective of this study was to examine complications due to refeeding of patients with anorexia nervosa, as well as their mortality rate after the implementation of guidelines from the European Society of Clinical Nutrition and Metabolism. We analyzed retrospective, observational data of a consecutive, unselected anorexia nervosa cohort during a 5-y period. The sample consisted of 65 inpatients, 14 were admitted more than once within the study period, resulting in 86 analyzed cases. Minor complications associated with refeeding during the first 10 d (replenishing phase) were recorded in nine cases (10.5%), four with transient pretibial edemas and three with organ dysfunction. In two cases, a severe hypokalemia occurred. During the observational phase of 30 d, 16 minor complications occurred in 14 cases (16.3%). Six infectious and 10 non-infectious complications occurred. None of the patients with anorexia nervosa died within a follow-up period of 3 mo. Our data demonstrate that the seriousness and rate of complications during the replenishment phase in this high-risk population can be kept to a minimum. The findings indicate that evidence-based refeeding regimens, such as our guidelines are able to reduce complications and prevent mortality. Despite anorexia nervosa, our sample were affected by serious comorbidities, no case met the full diagnostic criteria for refeeding syndrome. Treatment In critically ill patients admitted to an intensive care unit, if phosphate drops to below 0.65 mmol/L (2.0 mg/dL) from a previously normal level within three days of starting enteral or parenteral nutrition, caloric intake should be reduced to 480 kcals per day for at least two days while electrolytes are replaced. Daily doses of thiamine, vitamin B complex (strong) and a multivitamin and mineral preparation are strongly recommended. Blood biochemistry should be monitored regularly until it is stable. Although clinical trials are lacking in patients other than those admitted to intensive care, it is commonly recommended that energy intake should remain lower than that normally required for the first 3–5 days of treatment of refeeding syndrome for all patients. Refeeding syndrome occurs in patients with severe malnutrition when refeeding begins after a long period of starvation. This syndrome increases the risk of clinical complications and mortality. Hypophosphatemia is considered the primary characteristic of the syndrome. The aim of our study was to investigate the presence of other electrolyte alterations in patients with cancer during the early stage of refeeding. In this observational study, we enrolled 34 patients with cancer of the upper aerodigestive tract receiving upfront radiotherapy who were also enrolled in a nutrition program. A caloric intake assessment, anthropometric measurements and biochemical laboratory tests were performed. Significant weight loss (∼20%) was found in these patients. In the patients receiving artificial nutrition, we found lower levels of potassium and total protein compared with those who were fed orally (p = 0.03 for potassium and 0.02 for protein, respectively). Patients on enteral tube feeding had a higher caloric intake compared with those who were fed orally (25±5 kcal/kg/day vs. 10±2 kcal/kg/day). Hypokalemia, like hypophosphatemia, could be a complication associated with refeeding in patients with cancer. Hypokalemia was present in the early stages of high-calorie refeeding. To describe two cases of successfully prevented refeeding syndrome in a high-risk group of patients. Case 1 was a 70-y-old woman who presented with a 4-mo history of poor dietary intake and ill health due to a connective tissue disease leading to myositis and dysphagia and complicated by respiratory failure needing mechanical ventilation. Twelve hours after starting nasogastric tube feeding, she developed a cardiac arrest from which she was successfully resuscitated. Repeated attempts to wean her from the ventilator failed. Case 2 was a 15-y-old girl who was readmitted after a total colectomy for severe ulcerative colitis with diarrhea and vomiting leading to significant weight loss. Her body mass index was 11.4 kg/m(2). In case 1, after consultation by the clinical nutrition team, the diagnosis of refeeding syndrome was made and the patient was duly started on a high-protein, high-fat, low-carbohydrate diet, multivitamin and trace-element supplements, and electrolyte infusion. Subsequently she was successfully weaned from the ventilator. In case 2, further investigation by the clinical nutrition team revealed low baseline electrolyte concentrations including potassium, magnesium, calcium, and phosphate and low serum albumin. Her low body mass index and baseline electrolyte concentrations put her at high risk of developing refeeding syndrome. She was initially started on low-calorie feeding, multivitamin and minerals, and her electrolytes were carefully monitored. She made a good recovery. Refeeding syndrome is a life-threatening, underdiagnosed, treatable condition but there is a need for a wider awareness of the condition among health professionals. Feedback syndrome is characterized clinically by neurological alterations, respiratory symptoms, arrhythmias and heart failure few days after refeeding. It happens due to severe electrolyte changes, such as hypophosphatemia, hypomagnesemia and hypokalemia associated with metabolic abnormalities that may occur as a result of nutritional support (oral, enteral or parenteral) in severely malnourished patients. To evaluate its causes and the preventive dietary measures aiming to reduce the morbimortality. Was conducted literature review in SciELO, LILACS, Medline / PUBMED, Cochrane Library and government websites in Portuguese, English and Spanish. The survey was about the last 15 years, selecting the headings: refeeding syndrome, malnutrition, hypophosphatemia, hypokalemia, hypomagnesemia. The monitoring of metabolic parameters and electrolyte levels before starting nutritional support and periodically during feeding should be based on protocols and the duration of therapy. Patients at high risk and other metabolic complications should be followed closely, and depletion of minerals and electrolytes should be replaced before starting the diet. A multidisciplinary team of nutrition therapy can guide and educate other health professionals in prevention, diagnosis and treatment of the syndrome. We determine the incidence of the malnutrition syndrome and its relation with probable risk factors, in 106 patients, with a mean age of 53.3 +/- 15.4 years, with a diagnosis of cancer confirmed histologically, and who received artificial nutrition either enterally or endovenously, during an average of 16.8 +/- 2 days, which included a supply of 60 to 100 mmol/day of phosphorus. We considered there to be a renutrition syndrome when there as hypophosphatemia; &lt; 2.5 mmol/l, which took place during the nutritional treatment phase, and previous to which, the patients had normal serum levels of phosphorus. The serum electrolyte concentrations were measured prior to the start of the treatment, and daily during the first week, and later every 3 days until the end. The study variables were: age, sex, type of cancer, degree of malnutrition, degree of hypophosphatemia, day on which in occurred, and clinical manifestations associated to this. The relative risk was calculated for the variables of age, sex, malnutrition and cancer. The incidence of the renutrition syndrome was 24.5%; it was more frequent in the enteral group than in the endovenous group (37.5% vs. 18.9%, p &lt; 0.005); and it took place 72 hours after starting the nutritional support, in 61.5% of the cases, with a mean phosphorus concentrations of 1.9 mmol/l; the most frequent clinical manifestations were the neuromuscular ones (30%), and the most frequent type of cancer was lymphoma (15.4%). The risk factors were age greater than 60 years (RR = 1.7), and moderate or severe malnutrition 8RR = 2.0). We conclude that the prevalence of the renutrition syndrome is high in the cancer patients, despite an intense preventive treatment with phosphorus. Overzealous refeeding in chronically malnourished anorexia nervosa patients may cause life-threatening complications. We describe a 14-year-old girl with anorexia nervosa who had a decrease in body weight from 45 kg to 25.5 kg over an 18-month period. She received 40 kcal.kg-1.d-1 carbohydrate-rich nutrition via enteral and parenteral routes. Her serum phosphate concentration dropped from a baseline of 1.39 mmol/L (4.3 mg/dL) to 0.19 mmol/L (0.6 mg/dL) on Day 4 of refeeding. Concurrent with the development of hypophosphatemia, she became drowsy and developed generalized muscle weakness, impaired myocardial contractility, thrombocytopenia, and gastrointestinal bleeding. Fluid overload with pulmonary edema complicated her recovery from these adverse events. After intravenous phosphate supplementation and fluid restriction, the symptoms of refeeding syndrome gradually resolved within 2 weeks. In chronically malnourished anorexia nervosa patients, nutritional support should be instituted gradually to avoid rapid electrolyte shifts and fluid overload. Serum phosphate concentrations, fluid status, and blood cell counts should be closely monitored. Sudden cardiac death Anorexia is a relatively common condition that can lead patients to have dangerous electrolyte imbalances, leading to acquired long QT syndrome which can result in sudden cardiac death. This can develop over a prolonged period of time, and the risk is further heightened when feeding resumes after a period of abstaining from consumption. Refeeding syndrome Care must be taken when a patient begins to eat after prolonged starvation to avoid the potentially fatal complications of refeeding syndrome. The initial signs of refeeding syndrome are minimal, but can rapidly progress to death. Thus, the reinitiation of food or oral intake is usually started slowly and requires close observation under supervision by trained healthcare professionals. This is usually done in a hospital or nutritional rehabilitation center. Management Anorexia can be treated with the help of orexigenic drugs. The nutritional rehabilitation of malnourished patients hospitalised with anorexia nervosa is essential. The provision of adequate nutrition must occur, while simultaneously, minimising the risk of refeeding complications, such as electrolyte, metabolic, and organ dysfunction. The aim of this study was to compare the efficacy and safety of an iso-caloric lower carbohydrate/high fat enteral formula (28% carbohydrate, 56% fat) against a standard enteral formula (54% carbohydrate, 29% fat). Patients (aged 15-25 years) hospitalised with anorexia nervosa were recruited into this double blinded randomised controlled trial. An interim analysis was completed at midpoint, when 24 participants, mean age 17.5 years (± 1.1), had been randomly allocated to lower carbohydrate/high fat (n = 14) or standard (n = 10) feeds. At baseline, there was no significant difference in degree of malnutrition, medical instability, history of purging or serum phosphate levels between the two treatment arms. A significantly lower rate of hypophosphatemia developed in patients who received the lower carbohydrate/high fat formula compared to standard formula (5/14 vs 9/10, p = 0.013). The serum phosphate level decreased in both feeds, however it decreased to a larger extent in the standard feed compared to the lower carbohydrate/high fat feed (standard feed 1.11 ± 0.13 mmol/L at baseline vs 0.88 ± 0.12 mmol/L at week 1; lower carbohydrate/high fat feed 1.18 ± 0.19 mmol/L at baseline vs 1.06 ± 0.15 mmol/L at week 1). Overall, serum phosphate levels were significantly higher in the lower carbohydrate/high fat feed compared with standard feed treatment arm at Week 1 (1.06 ± 0.15 mmol/L vs 0.88 ± 0.12 mmol/L, p &lt; 0.001). There was no significant difference in weight gain, number of days to reach medical stability, incidence of hypoglycaemia, or hospital length of stay. The results of this study indicate that enteral nutrition provided to hospitalised malnourished young people with anorexia nervosa using a lower carbohydrate/high fat formula (28% carbohydrate, 56% fat) seems to provide protection from hypophosphatemia in the first week compared to when using a standard enteral formula. Further research may be required to confirm this finding in other malnourished populations. ANZCTR, ACTRN12617000342314. Registered 3 March 2017, http://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000342314. Refeeding severely malnourished patients with Anorexia nervosa requires specialized in-patient treatment to reduce medical risks, to avoid refeeding syndrome and other life-threatening situations. The authors present a retrospective cohort nutritional rehabilitation study of 33 very severe Anorexia nervosa in-patients, aged 22.8 ± 7.6 years (mean ± SD) and with an initial body mass index ≤ 12 kg/m(2), treated in a specialized Eating Disorders Unit. Thirty-three female patients were included and treated. Mean BMI increased from 11.3 ± 0.7 Kg/m(2), to 13.5 ± 1 Kg/m(2), and mean body weight from 29.1 ± 3.2 Kg to 34.5 ± 3.3 Kg, after 60 days of intensive in-patient treatments (p &lt; 0.0001). Feeding was carefully instituted; caloric intake levels were established after measuring REE by indirect calorimetry. Nutritional support was initiated with temporary nasogastric feeding in 30 patients, and with oral supplementation in 3 patients. Vitamins, potassium and phosphate supplements were administered during refeeding. All patients achieved a significant increase in body weight, none developed refeeding syndrome as far as laboratory and clinical investigations were concerned. Our findings show that, even in cases of extreme undernutrition, if feeding is performed cautiously and in a specialized unit, it is possible to avoid the refeeding syndrome.\nHere is the question:\nENDOCRINOLOGY: A patient on enteral nutritional support presents 72 hours after starting enteral nutrition with a CBC showing hypophosphoremia and hypokalemia, with clinical signs of heart failure. The patient is diagnosed with refeeding syndrome. Indicate which of the following is NOT considered a risk factor for a patient presenting with this condition:\nHere are the potential choices:\n1. Previous caloric malnutrition.\n2. Anorexia nervosa.\n3. Non-morbid obesity.\n4. Elderly.\n5. Prolonged vomiting and diarrhea.\nThe correct answer is: ",
        "gold_answer": "3 Non-morbid obesity.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Although refeeding syndrome has been well documented in starved patients, obese patients, those with anorexia nervosa, malnourished elderly individuals, and certain postoperative patients, little is known about the presence and the importance of refeeding syndrome in patients with gastrointestinal fistula and insufficient nutrition support over the long term. The objective of this study was to estimate the morbidity of this syndrome in these patients, to assess the safety and efficacy of our graduated refeeding regimen, and to emphasize the importance of this syndrome. One hundred fifty-eight patients with gastrointestinal fistula during the past 2 y were reviewed. Fifteen of these patients were diagnosed as having refeeding syndrome. They were started on the refeeding procedure according to our regimen, and changes in their serum levels of electrolytes were recorded. The symptoms and signs they presented were noted. All patients were successfully advanced to full nutrition support. During the refeeding procedure, patients presented with weakness, paralysis of limbs, slight dyspnea, paresthesia, tachycardia, edema, and diarrhea. Serum phosphorus concentration decreased in all patients within 24 h of refeeding, reaching a mean nadir after 3.3 +/- 1.5 d and another 6.1 +/- 2.1 d to return to above 0.70 mM/L upon phosphorus supplementation. Three patients treated with growth hormone presented more severe hypophosphatemia (&lt;0.20 mM/L) than the others. 1) Refeeding syndrome occurs commonly in patients with malnutrition secondary to gastrointestinal fistula. 2) Alterations in phosphate metabolism are central to the refeeding syndrome. 3) Supplementation with electrolytes (including especially phosphate) and vitamins is the focal point of the treatment of this syndrome. 4) Growth hormone treatment may aggravate hypophosphatemia. The Refeeding Syndrome is conformed by a series of clinical manifestations related to electrolytic alterations associated with the restarting of the nutritive contribution both enteral and parenteral. To detect the Refeeding Syndrome incidence in malnourished patients who required nutritional, enteral or endovenous support and its relationship with mortality. A cohort study was performed in the service of Nutritional Support of the IMSS (Social Security Mexican Institute) Specialties Hospital CMN León, from June 1995 to May 1996. All patients with mild and severe malnutrition were included, they received endovenous or enteral nutritious support for more than 7 days, without presenting previous electrolytic unbalance. Serum potassium, phosphorous, and magnesium levels were determined before starting the nutritious support and also on the 3rd, 7th, and 10th days. Descriptive statistics, Student's t and Z test were used, with a 5% significance level. 148 patients with total nutritional support, 23 (16%) of them with restrained malnutrition and 65 (44%) with severe deficit. 54 men and 34 women with an average age of 51.6 +/- 19.4 years. Nineteen patients were eliminated due to a nutrition period of less than 7 days, and other 19 were also eliminated for presenting electrolytic alterations before the nutritive support started. An incidence of 48% of electrolytic alterations compatible with the refeeding syndrome was the result in the remaining 50 patients. The alterations were: hypomagnesemia 13/24, hypokalemia 12/24 and hypophosphatemia 4/24; in 55% of the cases the syndrome appeared at the third day of administration. Hospital sojourn of patients with the syndrome was 26.7 +/- 18 days vs 15.3 +/- 7 (p &lt; 0.05) of those who did not present it. 15 patients died, 5 of them had electrolytic alterations before nutrition, 7 (29%) with refeeding syndrome and 3 (12%) did not presented it (p = 0.059). Refeeding Syndrome is a frequent entity in malnourished patients submitted to enteral or parenteral nutrition; at least in this study it was of 48%; its presence was followed by a longer hospital stay and a higher mortality rate. Refeeding syndrome is a potentially life-threatening condition characterised by severe intracellular electrolyte shifts, acute circulatory fluid overload and organ failure. The initial symptoms are non-specific but early clinical features are severely low-serum electrolyte concentrations of potassium, phosphate or magnesium. Risk factors for the syndrome include starvation, chronic alcoholism, anorexia nervosa and surgical interventions that require lengthy periods of fasting. The causes of the refeeding syndrome are excess or unbalanced enteral, parenteral or oral nutritional intake. Prevention of the syndrome includes identification of individuals at risk, controlled hypocaloric nutritional intake and supplementary electrolyte replacement. To determine the occurrence of refeeding syndrome in adults commenced on artificial nutrition support. Prospective cohort study. Large, single site university teaching hospital. Recruitment period 2007-2009. 243 adults started on artificial nutrition support for the first time during that admission recruited from wards and intensive care.  occurrence of the refeeding syndrome. Secondary outcome: analysis of the risk factors which predict the refeeding syndrome. Tertiary outcome: mortality due to refeeding syndrome and all-cause mortality. 133 participants had one or more of the following risk factors: body mass index &lt;16-18.5≥(kg/m(2)), unintentional weight loss &gt;15% in the preceding 3-6 months, very little or no nutritional intake &gt;10 days, history of alcohol or drug abuse and low baseline levels of serum potassium, phosphate or magnesium prior to recruitment. Poor nutritional intake for more than 10 days, weight loss &gt;15% prior to recruitment and low-serum magnesium level at baseline predicted the refeeding syndrome with a sensitivity of 66.7%: specificity was &gt;80% apart from weight loss of &gt;15% which was 59.1%. Baseline low-serum magnesium was an independent predictor of the refeeding syndrome (p=0.021). Three participants (2% 3/243) developed severe electrolyte shifts, acute circulatory fluid overload and disturbance to organ function following artificial nutrition support and were diagnosed with refeeding syndrome. There were no deaths attributable to the refeeding syndrome, but (5.3% 13/243) participants died during the feeding period and (28% 68/243) died during hospital admission. Death of these participants was due to cerebrovascular accident, traumatic injury, respiratory failure, organ failure or end-of-life causes. Refeeding syndrome was a rare, survivable phenomenon that occurred during hypocaloric nutrition support in participants identified at risk. Independent predictors for refeeding syndrome were starvation and baseline low-serum magnesium concentration. Intravenous carbohydrate infusion prior to artificial nutrition support may have precipitated the onset of the syndrome. Refeeding syndrome (RFS) can be a severe and life-threatening complication of anorexia nervosa (AN) associated with electrolyte abnormalities and organ damage, and occurs with the transition from a prolonged catabolic to anabolic state, particularly with an overzealous nutrient supply. There is no unequivocal definition of RFS, although hypophosphatemia is recognized as a crucial factor in its pathogenesis. RFS can be responsible for cardiovascular complications, such as heart failure, left ventricular damage, and arrhythmias, because of different potential mechanisms: electrolyte imbalances, increased retention of sodium and liquids secondary to insulin secretion, and excessive fat emulsion supplementation. We report on the case of a 13-y-old male patient with severe AN in whom a delayed and reversible myocardial dysfunction was documented during cautious nutritional replenishment, even in the absence of serum electrolyte imbalances. Seven days after the inception of integrative enteral nutrition, heart failure was unexpectedly documented as follows: reduction in fraction ejection, presence of mild bilateral perimalleolar edema, and increased n-terminal prohormone of brain natriuretic peptide. A more pronounced water restriction protocol and delayed achievement of goal feeding rate, resulting also in lower sodium intake, were implemented to reduce cardiac overload with a full resolution of the complication in approximately 2 mo. Refeeding patients with AN could be complicated by heart failure despite cautious nutritional replenishment and regardless of electrolyte imbalance, even in a later phase of recovery. Therefore, strict adherence to recommendations for nutritional replenishment and close monitoring of cardiac function should always be considered when refeeding patients with AN. Clinical situations The syndrome can occur at the beginning of treatment for anorexia nervosa when patients have an increase in calorie intake and can be fatal. It can also occur after the onset of a severe illness or major surgery. The shifting of electrolytes and fluid balance increases cardiac workload and heart rate. This can lead to acute heart failure. Oxygen consumption is increased which strains the respiratory system and can make weaning from ventilation more difficult. Diagnosis Refeeding syndrome can be fatal if not recognized and treated properly. An awareness of the condition and a high index of suspicion are required in order to make the diagnosis. The electrolyte disturbances of the refeeding syndrome can occur within the first few days of refeeding. Close monitoring of blood biochemistry is therefore necessary in the early refeeding period. Anorexia nervosa exhibits one of the highest death rates among psychiatric patients and a relevant fraction of it is derived from undernutrition. Nutritional and medical treatment of extreme undernutrition present two very complex and conflicting tasks: (1) to avoid \"refeeding syndrome\" caused by a too fast correction of malnutrition; and (2) to avoid \"underfeeding\" caused by a too cautious refeeding. To obtain optimal treatment results, the caloric intake should be planned starting with indirect calorimetry measurements and electrolyte abnormalities accurately controlled and treated. This article reports the case of an anorexia nervosa young female affected by extreme undernutrition (BMI 9.6 kg/m(2)) who doubled her admission body weight (from 22.5 kg to 44 kg) in a reasonable time with the use of enteral tube feeding for gradual correction of undernutrition. Refeeding syndrome was avoided through a specialized and flexible program according to clinical, laboratory, and physiological findings. Commentary is provided on the pivotal paper by Weinsier and Krumdieck from 1981 describing 2 patients who developed profound and fatal refeeding syndrome following initiation of aggressive total parenteral nutrition. This classic description was among the first to describe the overwhelming cardiovascular and pulmonary manifestations that can accompany parenteral refeeding with carbohydrate in chronically malnourished patients. The syndrome has also been described with oral and enteral nutrition. One of the hallmarks of the syndrome is hypophosphatemia. Since 1981, dosing schemes for addressing hypophosphatemia have been refined. Other manifestations of the syndrome include other electrolyte abnormalities such as hypokalemia and hypomagnesemia, hyperglycemia, fluid and sodium retention, and neurologic and hematologic complications. Case reports of refeeding syndrome continue to be published, particularly in the anorexia nervosa population. Stressed, critically ill patients may be at risk of refeeding following short periods of fasting; hypophosphatemia is commonly encountered in this situation. It behooves the current nutrition support practitioner to keep in mind the types of patients at risk of refeeding syndrome and to approach refeeding of such patients with caution and careful monitoring. Severe undernutrition nearly always leads to marked changes in body spaces (e.g., alterations of intra-extracellular water) and in body masses and composition (e.g., overall and compartmental stores of phosphate, potassium, and magnesium). In patients with severe undernutrition it is almost always necessary to use oral nutrition support and/or artificial nutrition, besides ordinary food; enteral nutrition should be a preferred route of feeding if there is a functional accessible gastrointestinal tract. Refeeding of severely malnourished patients represents two very complex and conflicting tasks: (1) to avoid \"refeeding syndrome\" caused by a too fast correction of malnutrition; (2) to avoid \"underfeeding\" caused by a too cautious rate of refeeding. The aim of this paper is to discuss the modality of refeeding severely underfed patients and to present our experience with the use of enteral tube feeding for gradual correction of very severe undernutrition whilst avoiding refeeding syndrome, in 10 patients aged 22 ± 11.4 years and with mean initial body mass index (BMI) of 11.2 ± 0.7 kg/m(2). The mean BMI increased from 11.2 ± 0.7 kg/m(2) to 17.3 ± 1.6 kg/m(2) and the mean body weight from 27.9 ± 3.3 to 43.0 ± 5.7 kg after 90 days of intensive in-patient treatment (p &lt; 0.0001). Caloric intake levels were established after measuring resting energy expenditure by indirect calorimetry, and nutritional support was performed with enteral feeding. Vitamins, phosphate, and potassium supplements were administered during refeeding. All patients achieved a significant modification of BMI; none developed refeeding syndrome. In conclusion, our findings show that, even in cases of extreme undernutrition, enteral feeding may be a well-tolerated way of feeding. The clinical nutrition-eating disorders-unit in Raymond Poincaré Hospital is a reference center for the management of severe malnutrition and its complications in patients with anorexia nervosa (AN). The purpose of this study is to specify socio-demographic, anamnesic and clinical characteristics of AN patients hospitalized for extreme malnutrition, to identify types and prevalence of medical complications presented during their hospitalization for refeeding and the evolution of patients nutritional status. Demographic, clinical and paraclinical data of 354 severely malnourished AN patients were collected, during their first hospitalization in the unit, between November 1997 and January 2014, through medical records. The prevalence of medical complications was compared between the 2 AN subtypes (restricting and binging-purging). 339 patients were female and mean age was 28.7 ± 10.7 years old. Duration of AN was 9.5 ± 9 years, 173 (48.9%) patients had a restricting AN subtype. BMI at admission was 12.2 ± 1.6 kg/m<sup2</sup, 280 (79.3%) patients had already been hospitalized for AN in other hospitals before. Psychiatric comorbidities were present in 168 (47.5%) patients. Associated somatic comorbidities concerned 70 (19.8%) patients. Outcomes during hospitalization were marked by 4.1 ± 3.9 kg weight gain on 36.9 ± 30.5 days. Enteral nutrition was provided in 304 (85.9%) patients. Main medical complications during hospitalization were: anemia (79%), neutropenia (53.9%), hypertransaminasemia (53.7%), osteoporosis (46.3%), hypokalemia (39.5%), hypophosphatemia (26%), hypoglycemia (13.8%), infectious complications (24.3%), cardiac dysfunction (7.1%), and proven gelatinous bone marrow transformation (6.5%). Hypokalemia was more frequent in binging-purging subtype. Lympho-neutropenia and hypertransaminasemia were more frequent in restricting subtype. During their hospitalization, 35 (10%) patients were referred to medical intensive care unit and 5 patients died. AN patients hospitalized for severe malnutrition in a specialized clinical nutrition unit have severe and frequent medical complications. Psychiatric comorbidities are also frequent and could complicate medical care. A specialized and multidisciplinary management of these patients is therefore essential. Anorexia nervosa is associated with several serious medical complications related to malnutrition, severe weight loss, and low levels of micronutrients. The refeeding phase of these high-risk patients bears a further threat to health and potentially fatal complications. The objective of this study was to examine complications due to refeeding of patients with anorexia nervosa, as well as their mortality rate after the implementation of guidelines from the European Society of Clinical Nutrition and Metabolism. We analyzed retrospective, observational data of a consecutive, unselected anorexia nervosa cohort during a 5-y period. The sample consisted of 65 inpatients, 14 were admitted more than once within the study period, resulting in 86 analyzed cases. Minor complications associated with refeeding during the first 10 d (replenishing phase) were recorded in nine cases (10.5%), four with transient pretibial edemas and three with organ dysfunction. In two cases, a severe hypokalemia occurred. During the observational phase of 30 d, 16 minor complications occurred in 14 cases (16.3%). Six infectious and 10 non-infectious complications occurred. None of the patients with anorexia nervosa died within a follow-up period of 3 mo. Our data demonstrate that the seriousness and rate of complications during the replenishment phase in this high-risk population can be kept to a minimum. The findings indicate that evidence-based refeeding regimens, such as our guidelines are able to reduce complications and prevent mortality. Despite anorexia nervosa, our sample were affected by serious comorbidities, no case met the full diagnostic criteria for refeeding syndrome. Treatment In critically ill patients admitted to an intensive care unit, if phosphate drops to below 0.65 mmol/L (2.0 mg/dL) from a previously normal level within three days of starting enteral or parenteral nutrition, caloric intake should be reduced to 480 kcals per day for at least two days while electrolytes are replaced. Daily doses of thiamine, vitamin B complex (strong) and a multivitamin and mineral preparation are strongly recommended. Blood biochemistry should be monitored regularly until it is stable. Although clinical trials are lacking in patients other than those admitted to intensive care, it is commonly recommended that energy intake should remain lower than that normally required for the first 3–5 days of treatment of refeeding syndrome for all patients. Refeeding syndrome occurs in patients with severe malnutrition when refeeding begins after a long period of starvation. This syndrome increases the risk of clinical complications and mortality. Hypophosphatemia is considered the primary characteristic of the syndrome. The aim of our study was to investigate the presence of other electrolyte alterations in patients with cancer during the early stage of refeeding. In this observational study, we enrolled 34 patients with cancer of the upper aerodigestive tract receiving upfront radiotherapy who were also enrolled in a nutrition program. A caloric intake assessment, anthropometric measurements and biochemical laboratory tests were performed. Significant weight loss (∼20%) was found in these patients. In the patients receiving artificial nutrition, we found lower levels of potassium and total protein compared with those who were fed orally (p = 0.03 for potassium and 0.02 for protein, respectively). Patients on enteral tube feeding had a higher caloric intake compared with those who were fed orally (25±5 kcal/kg/day vs. 10±2 kcal/kg/day). Hypokalemia, like hypophosphatemia, could be a complication associated with refeeding in patients with cancer. Hypokalemia was present in the early stages of high-calorie refeeding. To describe two cases of successfully prevented refeeding syndrome in a high-risk group of patients. Case 1 was a 70-y-old woman who presented with a 4-mo history of poor dietary intake and ill health due to a connective tissue disease leading to myositis and dysphagia and complicated by respiratory failure needing mechanical ventilation. Twelve hours after starting nasogastric tube feeding, she developed a cardiac arrest from which she was successfully resuscitated. Repeated attempts to wean her from the ventilator failed. Case 2 was a 15-y-old girl who was readmitted after a total colectomy for severe ulcerative colitis with diarrhea and vomiting leading to significant weight loss. Her body mass index was 11.4 kg/m(2). In case 1, after consultation by the clinical nutrition team, the diagnosis of refeeding syndrome was made and the patient was duly started on a high-protein, high-fat, low-carbohydrate diet, multivitamin and trace-element supplements, and electrolyte infusion. Subsequently she was successfully weaned from the ventilator. In case 2, further investigation by the clinical nutrition team revealed low baseline electrolyte concentrations including potassium, magnesium, calcium, and phosphate and low serum albumin. Her low body mass index and baseline electrolyte concentrations put her at high risk of developing refeeding syndrome. She was initially started on low-calorie feeding, multivitamin and minerals, and her electrolytes were carefully monitored. She made a good recovery. Refeeding syndrome is a life-threatening, underdiagnosed, treatable condition but there is a need for a wider awareness of the condition among health professionals. Feedback syndrome is characterized clinically by neurological alterations, respiratory symptoms, arrhythmias and heart failure few days after refeeding. It happens due to severe electrolyte changes, such as hypophosphatemia, hypomagnesemia and hypokalemia associated with metabolic abnormalities that may occur as a result of nutritional support (oral, enteral or parenteral) in severely malnourished patients. To evaluate its causes and the preventive dietary measures aiming to reduce the morbimortality. Was conducted literature review in SciELO, LILACS, Medline / PUBMED, Cochrane Library and government websites in Portuguese, English and Spanish. The survey was about the last 15 years, selecting the headings: refeeding syndrome, malnutrition, hypophosphatemia, hypokalemia, hypomagnesemia. The monitoring of metabolic parameters and electrolyte levels before starting nutritional support and periodically during feeding should be based on protocols and the duration of therapy. Patients at high risk and other metabolic complications should be followed closely, and depletion of minerals and electrolytes should be replaced before starting the diet. A multidisciplinary team of nutrition therapy can guide and educate other health professionals in prevention, diagnosis and treatment of the syndrome. We determine the incidence of the malnutrition syndrome and its relation with probable risk factors, in 106 patients, with a mean age of 53.3 +/- 15.4 years, with a diagnosis of cancer confirmed histologically, and who received artificial nutrition either enterally or endovenously, during an average of 16.8 +/- 2 days, which included a supply of 60 to 100 mmol/day of phosphorus. We considered there to be a renutrition syndrome when there as hypophosphatemia; &lt; 2.5 mmol/l, which took place during the nutritional treatment phase, and previous to which, the patients had normal serum levels of phosphorus. The serum electrolyte concentrations were measured prior to the start of the treatment, and daily during the first week, and later every 3 days until the end. The study variables were: age, sex, type of cancer, degree of malnutrition, degree of hypophosphatemia, day on which in occurred, and clinical manifestations associated to this. The relative risk was calculated for the variables of age, sex, malnutrition and cancer. The incidence of the renutrition syndrome was 24.5%; it was more frequent in the enteral group than in the endovenous group (37.5% vs. 18.9%, p &lt; 0.005); and it took place 72 hours after starting the nutritional support, in 61.5% of the cases, with a mean phosphorus concentrations of 1.9 mmol/l; the most frequent clinical manifestations were the neuromuscular ones (30%), and the most frequent type of cancer was lymphoma (15.4%). The risk factors were age greater than 60 years (RR = 1.7), and moderate or severe malnutrition 8RR = 2.0). We conclude that the prevalence of the renutrition syndrome is high in the cancer patients, despite an intense preventive treatment with phosphorus. Overzealous refeeding in chronically malnourished anorexia nervosa patients may cause life-threatening complications. We describe a 14-year-old girl with anorexia nervosa who had a decrease in body weight from 45 kg to 25.5 kg over an 18-month period. She received 40 kcal.kg-1.d-1 carbohydrate-rich nutrition via enteral and parenteral routes. Her serum phosphate concentration dropped from a baseline of 1.39 mmol/L (4.3 mg/dL) to 0.19 mmol/L (0.6 mg/dL) on Day 4 of refeeding. Concurrent with the development of hypophosphatemia, she became drowsy and developed generalized muscle weakness, impaired myocardial contractility, thrombocytopenia, and gastrointestinal bleeding. Fluid overload with pulmonary edema complicated her recovery from these adverse events. After intravenous phosphate supplementation and fluid restriction, the symptoms of refeeding syndrome gradually resolved within 2 weeks. In chronically malnourished anorexia nervosa patients, nutritional support should be instituted gradually to avoid rapid electrolyte shifts and fluid overload. Serum phosphate concentrations, fluid status, and blood cell counts should be closely monitored. Sudden cardiac death Anorexia is a relatively common condition that can lead patients to have dangerous electrolyte imbalances, leading to acquired long QT syndrome which can result in sudden cardiac death. This can develop over a prolonged period of time, and the risk is further heightened when feeding resumes after a period of abstaining from consumption. Refeeding syndrome Care must be taken when a patient begins to eat after prolonged starvation to avoid the potentially fatal complications of refeeding syndrome. The initial signs of refeeding syndrome are minimal, but can rapidly progress to death. Thus, the reinitiation of food or oral intake is usually started slowly and requires close observation under supervision by trained healthcare professionals. This is usually done in a hospital or nutritional rehabilitation center. Management Anorexia can be treated with the help of orexigenic drugs. The nutritional rehabilitation of malnourished patients hospitalised with anorexia nervosa is essential. The provision of adequate nutrition must occur, while simultaneously, minimising the risk of refeeding complications, such as electrolyte, metabolic, and organ dysfunction. The aim of this study was to compare the efficacy and safety of an iso-caloric lower carbohydrate/high fat enteral formula (28% carbohydrate, 56% fat) against a standard enteral formula (54% carbohydrate, 29% fat). Patients (aged 15-25 years) hospitalised with anorexia nervosa were recruited into this double blinded randomised controlled trial. An interim analysis was completed at midpoint, when 24 participants, mean age 17.5 years (± 1.1), had been randomly allocated to lower carbohydrate/high fat (n = 14) or standard (n = 10) feeds. At baseline, there was no significant difference in degree of malnutrition, medical instability, history of purging or serum phosphate levels between the two treatment arms. A significantly lower rate of hypophosphatemia developed in patients who received the lower carbohydrate/high fat formula compared to standard formula (5/14 vs 9/10, p = 0.013). The serum phosphate level decreased in both feeds, however it decreased to a larger extent in the standard feed compared to the lower carbohydrate/high fat feed (standard feed 1.11 ± 0.13 mmol/L at baseline vs 0.88 ± 0.12 mmol/L at week 1; lower carbohydrate/high fat feed 1.18 ± 0.19 mmol/L at baseline vs 1.06 ± 0.15 mmol/L at week 1). Overall, serum phosphate levels were significantly higher in the lower carbohydrate/high fat feed compared with standard feed treatment arm at Week 1 (1.06 ± 0.15 mmol/L vs 0.88 ± 0.12 mmol/L, p &lt; 0.001). There was no significant difference in weight gain, number of days to reach medical stability, incidence of hypoglycaemia, or hospital length of stay. The results of this study indicate that enteral nutrition provided to hospitalised malnourished young people with anorexia nervosa using a lower carbohydrate/high fat formula (28% carbohydrate, 56% fat) seems to provide protection from hypophosphatemia in the first week compared to when using a standard enteral formula. Further research may be required to confirm this finding in other malnourished populations. ANZCTR, ACTRN12617000342314. Registered 3 March 2017, http://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000342314. Refeeding severely malnourished patients with Anorexia nervosa requires specialized in-patient treatment to reduce medical risks, to avoid refeeding syndrome and other life-threatening situations. The authors present a retrospective cohort nutritional rehabilitation study of 33 very severe Anorexia nervosa in-patients, aged 22.8 ± 7.6 years (mean ± SD) and with an initial body mass index ≤ 12 kg/m(2), treated in a specialized Eating Disorders Unit. Thirty-three female patients were included and treated. Mean BMI increased from 11.3 ± 0.7 Kg/m(2), to 13.5 ± 1 Kg/m(2), and mean body weight from 29.1 ± 3.2 Kg to 34.5 ± 3.3 Kg, after 60 days of intensive in-patient treatments (p &lt; 0.0001). Feeding was carefully instituted; caloric intake levels were established after measuring REE by indirect calorimetry. Nutritional support was initiated with temporary nasogastric feeding in 30 patients, and with oral supplementation in 3 patients. Vitamins, potassium and phosphate supplements were administered during refeeding. All patients achieved a significant increase in body weight, none developed refeeding syndrome as far as laboratory and clinical investigations were concerned. Our findings show that, even in cases of extreme undernutrition, if feeding is performed cautiously and in a specialized unit, it is possible to avoid the refeeding syndrome.\nHere is the question:\nENDOCRINOLOGY: A patient on enteral nutritional support presents 72 hours after starting enteral nutrition with a CBC showing hypophosphoremia and hypokalemia, with clinical signs of heart failure. The patient is diagnosed with refeeding syndrome. Indicate which of the following is NOT considered a risk factor for a patient presenting with this condition:\nHere are the potential choices:\n1. Previous caloric malnutrition.\n2. Anorexia nervosa.\n3. Non-morbid obesity.\n4. Elderly.\n5. Prolonged vomiting and diarrhea.\nThe correct answer is: 3. Non-morbid obesity."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Autoimmune Hemolytic anemia (AIHA) a relatively uncommon form of hemolytic anemia in children, occurs due to the premature destruction of red blood cells caused by presence of autoantibodies directed against antigens on RBCs. Warm reactive AIHA is the most common form due to IgG isotype of immunoglobulin class binding to autologous RBCs at 37<sup0</supC and confirmed with a positive DAT screening. We present a case of DAT-negative primary warm AIHA in an infant due to IgA antibody. A 10 month old male infant presented with dark colored urine and irritability for past two months, with associated history of fever, diarrhea and vomiting. He had received one red cell transfusion 10 days prior. On physical examination he had pallor with tachycardia without splenomegaly. On investigation his hemoglobin was 5.8 g/dl, WBC 25.9 × 10<sup3</sup/mm<sup3</sup and normal platelets counts. Peripheral blood smear had spherocytes and biochemical values showed high bilirubin and LDH. Immunohematological work up revelaed polyspecific DAT was negative but monospecific DAT screening showed strong (4+) positivity for IgA and a weak IgG positivity. The patient was diagnosed as IgA-mediated Warm AIHA and was started on prednisolone at 2 mg/kg/day following which hemoglobin improved over the next 2 months. After 2 weeks, prednisolone was tapered and stopped by the end of 3 months. Patients with clinical and laboratory evidence of acute hemolysis, an additional screening for IgA antibody may be done even in cases where poly-specific DAT is negative. Early detection helps in avoiding further investigations and provide efficient management. A 49-year-old woman with type 2 diabetes mellitus (T2DM) presented to the emergency department. Her examination showed marked pallor, exhaustion, lethargy, yellowish eyes, anorexia, nausea and vomiting. Hematuria; negative standard direct antiglobulin test (DAT); normal glucose 6 phosphate dehydrogenase (G6PD); hemoglobin (Hb), 4.8 g/dl; Mean cell volume (MCV), 91fl; platelet count, 233 × 10<sup6</sup/L; Total bilirubin, 7.0 mg/dl; Glucose, 316 mg/dl; lactate dehydrogenase (LDH), 1750U/L. Undoubtedly, therapeutic panel should have been used for hemolytic anemia. Intravenous (IV) fluids and 2 units of packed cell were transfused. Methylprednisolone with rituximab were started for the patient. After 3 weeks of the patient admission, she was discharged home with stable vital signs and Hb, 10 g/dl. We concluded in the cases that presented along with a severe drop in Hb and evidence of hemolysis which non immune hemolytic anemia is excluded in spite of negative standard DAT limited transfusion besides corticosteroids combined with rituximab, could be helpful in saving the patient. A 16-year-old male patient who was on oral iron treatment for iron deficiency anemia for the last one year was seen at the Haematology clinic with complaints of weakness, pallor, and jaundice. A complete blood count revealed Hb of 4.2 mmol/L, Hct of 0.14, and MCV of 76 fl. A blood smear showed 50% neutrophils, 40% lymphocytes, and 10% monocytes with anisocytosis, poikilocytosis, polichromasia in erythrocytes and normoblasts. Reticulocyte count was under 1%. There was a slight erythroid hyperplasia in the bone marrow aspiration. Biochemical examinations showed total bilirubin of 3.9 mg/dL, indirect bilirubin of 3.4 mg/dL, and lactate dehydrogenase (LDH) of 6085 U/L (220-450). In re-evaluating the history of the patient, he was seen to be complaining of dark discoloration of morning urine. Perl's reaction was found to be positive for hemosiderin in the urine sediment. Because Ham's test was positive, the levels of CD55, 58, and 59 proteins on erythrocyte membranes were found to be lower. The patient was started 32 mg of methylprednisolone and his anaemia was improved by the 14th day of treatment. When evaluating iron deficiency anemia resistant to iron supplementation, PNH should be kept in mind.  Thymomas are often associated with autoimmune disorders. We report on a 45-year-old female patient with thymoma and hypogammaglobulinemia (Good's syndrome) who developed symptomatic macrocytic anemia (Hb 4.4 g/dl, MCV 112 fl) and thrombocytosis (Plt 442 G/l). Besides hypogammaglobulinemia (IgG 589 mg/dl), an inverted ratio of CD4(+)/CD8(+) cells was seen. The bone marrow biopsy showed a slightly hypercellular bone marrow with normal granulopoiesis, normal megakaryopoiesis and a mild dyserythropoiesis without any ring-sideroblasts. The in-vitro stem cell culture from the bone marrow revealed an atypical growth of macroclusters, reduced BFU-E and CFU-GEMM colony growth, whereas the CFU-GM colony growth was within the normal range. The chromosomal analysis showed a normal karyotype. The plasma vitamin B(12) and folate levels were within normal ranges, and we could not detect any autoantibodies. These findings excluded the differential diagnoses pure red cell aplasia (PRCA) and pernicious anemia. After resection of the thymoma of mixed cell type, the macrocytic anemia and thrombocytosis disappeared. The clinical course was complicated by a cerebral palsy and a life-threatening fungal septicemia after surgery. In the third year after thymectomy, hyporegenerative macrocytic anemia and thrombocytosis reappeared and an immunosuppressive treatment with prednisolone (1 mg/kg BW) was started. After initiation of the prednisolone therapy, reticulocyte counts increased and macrocytic anemia as well as thrombocytosis disappeared. The normalization of these laboratory parameters during glucocorticoid therapy suggests that in rare cases the constellation of macrocytic anemia, thrombocytosis and hypogammaglobulinemia may be due to an underlying immunologic mechanism. To summarize the clinical characteristics, diagnosis and treatment of a case with autoimmune lymphoproliferative syndrome (ALPS) . The patient was diagnosed as autoimmune lymphoproliferactive syndrome (ALPS) after being admitted to the Department of Rheumatism and Immunology of Tianjin Children's Hospital in February 20, 2014. The clinical characteristics, physical examination, laboratory tests, gene tests, and treatment process were analyzed and related literature was reviewed. The patient was a 16-month- old boy.Since the first month of life, he started to have repeatedly fever, diarrhea, shortness of breath, lymphadenopathy, hepatosplenomegaly, anemia (HGBmin 50 g/L) and thrombocytopenia (min 35 × 10⁹/L) . But multiple exams showed a normal peripheral blood leukocyte count, hypergammaglobulinemia (IgG 19 800 mg/L, IgA 1 710 mg/L, IgM 2 590 mg/L) and significantly increased serum vitamin B12. Flow cytometric measures showed that CD3⁺ CD4⁻ CD8⁻ T lymphocytes significantly increased ( &gt; 10%) at four times. The count of CD3⁺ TCRαβ⁺ CD4⁻ CD8⁻T lymphocytes (double negative T cells; DNTs) &gt;3% twice. The genetic test showed that 309th FAS gene area showed heterozygous mutations, the boy was diagnosed as ALPS. Added examinations of lymphocytes apoptosis induced by FAS was positive. He was treated with prednisone 15 mg once daily and immunomodulator 150 mg three times a day, while in maintaining period with normal levels of hemoglobin and platelet, the dose of prednisone was reduced gradually. Till now, the patient has been treated and observed for 8 months. We retrieved the reports of ALPS in the databases at home and abroad published in recent 10 years, more than 400 cases reported from foreign countries, but there were only 5 domestic cases. Among those, 4 had onset in infancy and 1 at 6-years of age. All the cases presented servere lymphadenopathy and hepatosplenomegaly with anemia (4 of them with hemolytic anemia) and thrombocytopenia. Three cases had a history of frequent infection, one of them had glomerulonephritis. All patient with significant high level of serum immunoglobulin ( &gt; 1.5 times upper limit of normal range), in 3 of them serum vitamin B12 was &gt; 1.5 pg/L (the other 2 cases missed the exam). In 5 cases CD3⁺ CD4⁻ CD8⁻T cells &gt; 10%, and in 2 case DNTs were 8.9% and 15.7% respectively (the other 3 cases missed the exam). Three cases were clearly detected with FAS mutations. All patients were treated with corticosteroid, 2 of them were added with mycophenolate mofetil. The therapy presented effective result in early 1-3 months, but no long-term follow-up reports were available. ALPS is a disorder of disrupted lymphocyte homeostasis caused by defective Fas-mediated apoptosis, and it is one of the primary immunodeficiency diseases. The onset of the disease occurs during infancy mainly. Clinical lymphoid hyperplasia and autoimmune phenomena are outstanding signs, which can be associated with frequent infections and allergies. The level of serum vitamin B12 &gt; 1.5 pg/L and the count of CD3⁺ CD4⁻ CD8⁻ T cell show important significance. Exact diagnosis should depend on detecting DNTs and FAS gene. A 70-year-old woman was admitted to our hospital in November 1992 for evaluation of anemia. Physical examination revealed anemia, jaundice, swelling of axial and inguinal lymph nodes, and splenomegaly. Abnormal hematological findings were as follows: Hb of 3.9 g/dl, reticulocyte count of 58.2% (61.7 x 10(4)/microliters), hyperplasia of normal erythroblasts in bone marrow, and eosinophilia (21.0%, 2352/microliters) in peripheral blood. Routine laboratory examinations revealed polycolonal hypergammaglobulinemia 3.0 g/dl, a high level of serum LDH (797 IU/I) and a total bilirubin of 2.4 mg/dl (indirect, 1.6 mg/dl). The serum haptoglobin level was very low (&lt; 5 mg/dl). Results of serological examinations were as follows: IgG of 3366 mg/dl, CH50 of 16.0 U/ml, positive Coombs test 2+, and positive tests for antinuclear antibody, rheumatoid factor, and cold agglutinin. CRP was negative. PHA-stimulated lymphocyte blast formation, NK activity, and ADCC activity were found to be suppressed, and the percentage of CD4-positive lymphocytes in peripheral blood was also low. An axillary lymph node biopsy revealed reactive lymphadenitis. No signs or history suggested allergy, collagen disease, or parasitic infection. Autoimmune hemolytic anemia (AIHA) complicated by immunologic abnormalities and eosinophilia was diagnosed. Oral prednisolone markedly reduced the hemolytic anemia, eosinophilia, lymph node swelling, and splenomegaly, but NK activity remained low. Spherocytosis is the presence of spherocytes in the blood, i.e erythrocytes (red blood cells) that are sphere-shaped rather than bi-concave disk shaped as normal. Spherocytes are found in all hemolytic anemias to some degree. Hereditary spherocytosis and autoimmune hemolytic anemia are characterized by having only spherocytes. Causes Spherocytes are found in immunologically-mediated hemolytic anemias and in hereditary spherocytosis, but the former would have a positive direct Coombs test and the latter would not. The misshapen but otherwise healthy red blood cells are mistaken by the spleen for old or damaged red blood cells and it thus constantly breaks them down, causing a cycle whereby the body destroys its own blood supply (auto-hemolysis). A complete blood count (CBC) may show increased reticulocytes, a sign of increased red blood cell production, and decreased hemoglobin and hematocrit. The term \"non-hereditary spherocytosis\" is occasionally used, albeit rarely. A 78-year-old woman was admitted to our hospital because of disorientation and fever on January 21, 1992. Two days before admission she experienced vomiting, anorexia and general malaise. Laboratory examinations on admission disclosed a hemoglobin level of 11.1 g/dl and a platelet count of 8,000/microliters. The peripheral blood smear revealed anisocytosis with numerous schistocytes and poikilocytes. Polychromatophilic and nucleated red blood cells were also seen, and the reticulocyte count was 38/1000. Her serum lactate dehydrogenase (LDH) value was 2,977 WU and the total serum bilirubin level was 3.5 mg/dl with 2.7 mg/dl indirect reacting fraction. Serum creatinine was 4.7 mg/dl. Her consciousness became semicomatose after a systemic seizure which lasted approximately 15 seconds and her hemoglobin level decreased to 8.5 g/dl on hospital day 2. Therefore, we diagnosed her as having thrombotic thrombocytopenic purpura (TTP) because of the presence of all 5 features, that is, thrombocytopenia, microangiopathic hemolytic anemia, fluctuating neurologic abnormalities, renal dysfunction and fever. A plasmapheresis with fresh frozen plasma (FFP) replacement was begun on that day. She was also treated with anti-platelet agents, 80 mg/day aspirin, and 300 mg/day dipyridamole. Moreover, packed red blood cells (PRC) were infused. While also receiving diphenylhydantoin and phenobarbital to prevent convulsions, status epilepticus developed on day 3. Because of inhibited spontaneous respiration which was an adverse effect derived from diazepam and sodium thiamylal administered intravenously to treat the status epilepticus, an artificial respiration was initiated.(ABSTRACT TRUNCATED AT 250 WORDS) Diagnosis Pancytopenia usually requires a bone marrow biopsy in order to distinguish among different causes. anemia: hemoglobin < 13.5 g/dL (male) or 12 g/dL (female). leukopenia: total white cell count < 4.0 x 109/L. Decrease in all types of white blood cells (revealed by doing a differential count). thrombocytopenia: platelet count < 150×109/L. Treatment Treatment is done to address the underlying cause. To tide over immediate crisis Blood transfusion with packed red blood cells (PRBC) or platelet transfusion may be done. Sometimes there are obvious clinical clues to suggest underlying B12 deficiency for a cause of pancytopenia. In this selected cases even with severe anemia blood product transfusions can be avoided and vitamin B12 treatment itself suffice. In other situations like acute leukemia, Myelodysplastic syndrome, aplastic anemia etc. disease specific therapy is needed. References External links EID Journal (Volume 6, Number 6), CDC, December 2000. Myeloid Hemoglobinopathies (congenital abnormality of the hemoglobin molecule or of the rate of hemoglobin synthesis) Sickle cell disease Thalassemia Methemoglobinemia Anemias (lack of red blood cells or hemoglobin) Iron-deficiency anemia Megaloblastic anemia Vitamin B12 deficiency Pernicious anemia Folate deficiency Hemolytic anemias (destruction of red blood cells) Genetic disorders of RBC membrane Hereditary spherocytosis Hereditary elliptocytosis Congenital dyserythropoietic anemia Genetic disorders of RBC metabolism Glucose-6-phosphate dehydrogenase deficiency (G6PD) Pyruvate kinase deficiency Immune mediated hemolytic anemia (direct Coombs test is positive) Autoimmune hemolytic anemia Warm antibody autoimmune hemolytic anemia Idiopathic Systemic lupus erythematosus (SLE) Evans syndrome (antiplatelet antibodies and hemolytic antibodies) Cold autoimmune hemolytic anemia Cold agglutinin disease Paroxysmal cold hemoglobinuria (rare) The aim of this study is to evaluate the clinical, biological and hematological profiles of autoimmune hemolytic anemia (AIHA) in children and to specify its etiologies, therapeutic modalities, and treatment responses. This is a 14-year retrospective study of AIHA cases collected at the department of pediatric emergency and reanimation of Hedi Chaker University Hospital in Sfax. We included patients under 14 years old with clinical and biological features of hemolysis and a positive direct antiglobulin test (DAT). The selected patients' demographic characteristics, physical signs, laboratory findings, and treatment responses were recorded. Thirteen cases of AIHA were collected, including 8 girls and 5 boys. The median age at diagnosis was 4 years and 6 months (range: 8 months to 13 years). Consanguinity was reported in 6 cases and 4 patients had a previous infection history. The onset of AIHA was progressive in 9 cases, marked by an anemic syndrome and hemolysis symptoms in 6 and 8 cases, respectively. The clinical triad (pallor, jaundice and splenomegaly) was found in only 4 cases. At the time of diagnosis, the median hemoglobin (Hb) level was 6g/dL (range: 4.2 to 9.2g/dL), anemia was non-regenerative in 2 patients. Thrombocytopenia and neutropenia were noted in 5 and 1 patient, respectively. Peripheral smear examination showed spherocytosis in 2 cases. All the patients had a positive DAT. Of these, 10 were positive with IgG and 3 with both IgG and C3d. AIHA was secondary to other conditions in 9 patients: infection (3 cases), autoimmune disease (4 cases), and immunodeficiency (2 cases). All the patients received first-line corticosteroid therapy but only 8 of them required blood transfusions due to severe anemia. Complete remission was obtained in 7 cases. Corticosteroid resistance and dependence were noted in 1 and 2 cases, respectively. During evolution, additional therapy was indicated in 4 patients and it included cyclosporine A, azathioprine, and mycophenolate mofetil (MMF). After a median follow-up of 4.5 years, the cure rate was 80% and only 1 patient (a boy) died due to his underlying pathology. Our study highlights the rarity, severity, and heterogeneity of etiological contexts of AIHA in children. The therapeutic difficulties justify specific expertise in pediatric hematology. Diagnosis Diagnosis is made by a positive direct Coombs test, other lab tests, and clinical examination and history. The direct Coombs test looks for antibodies attached to the surface of red blood cells. Clinical findings Laboratory findings include severe anemia, normal MCV (mean corpuscular volume) , and hyperbilirubinemia (from increased red cell destruction) that can be of the conjugated or unconjugated type. Treatment Corticosteroids and immunoglobulins are two commonly used treatments for warm antibody AIHA. Initial medical treatment consists of prednisone. If ineffective, splenectomy should be considered. If refractory to both these therapies, other options include rituximab, danazol, cyclosphosphamide, azathioprine, or ciclosporin. High-dose intravenous immune globulin may be effective in controlling hemolysis, but the benefit is short lived (1–4 weeks), and the therapy is very expensive. See also List of circulatory system conditions References Crimean-Congo hemorrhagic fever (CCHF) is a zoonotic disease that can be presented with fever, fatigue, generalized joint/body pain, diarrhea and bleeding in various parts of the body. The risk of developing a severe fatal disease in humans, the possibility of being infected with aerosols and the risk of being used as a biological weapon make the disease still an important health problem all over the world as there is no a specific treatment and vaccine that has proven effective againt the virus today. The pathogenesis of the disease is not known, but vascular endothelial damage is prominent. Therefore, it progresses with thrombocytopenia, anemia, leukopenia and this hematological findings can be confused with hematological malignancies. Acute lymphoblastic leukemia (ALL) is a malignancy included in differential diagnoses and occurs as a result of mutations occuring at a stage of differentiation in the lymphoid precursor cells in the bone marrow. In this study, we present a case of ALL who was diagnosed with CCHF simultaneously. A 43-year old female patient who works in the library and does not have a chronic disease other than asthma and thyroid disorder, has admitted to our hospital with the complaints of intermittent fever, weakness, generalized joint and body pain for about 3 weeks. She had fever and the physical examination revealed bilateral cervical and right postauricular lymphadenopathies. Her aspartate aminotransferase: 77 U/L, alanine aminotransferase: 117 U/L, lactate dehydrogenase: 616 U/L, hemoglobin: 8.27 g/dl, leukocyte count: 15.690/mm3 , neutrophil count: 550/mm3 (%3.5), lymphocyte count: 6690/mm3 (%42.6), platelet count: 102.100/mm3 , C-reactive protein: 163.6 mg/L was detected and the patient was hospitalized on 5 August 2019 for further examination and treatment. Considering that the patient may have viral infection in the foreground the requested test results were detected as; anti-CMV IgM negative, anti-CMV IgG positive, anti-toxoplasma IgM negative, anti-toxoplasma IgG positive, anti-rubella IgM negative, anti-rubella IgG positive, HBsAg negative, anti-HBc IgM negative, antiHBs positive, anti-HAV IgM negative, anti-HAV IgG positive, anti-HCV negative, anti-HIV negative, EpsteinBarr virus (EBV) VCA IgM negative, EBV VCA IgG positive, EBV EBNA IgG positive. Brucella Rose Bengal and Coombs tube agglutination was found be negative. As the cytopenia of the patient deepened, the patient was accepted to have neutropenic fever and it was planned to start piperacillin-tazobactam 4 x 4.5 g/day and two units of erythrocyte replacement therapy. When the patient's history was questioned again, it was learned that she had a tick on her neck about three weeks ago and she had removed the tick herself; 4-5 days later she had the complaints of fever and flu like symptoms and also diarrhea complaints lasting for 3-4 days. Considering the current anamnesis and laboratory findings, the patient was thought to have CCHF and the patient was isolated. The serum sample taken from patient with an initial diagnosis of CCHF and sent to Department of Microbiology Reference Laboratory Public Health Agency of Turkey. The patient was referred to the Antalya Training and Research Hospital. The patient's CCHF serum result was positive. Ribavirin treatment was not initiated in the patient who was accepted to be in the convalescence period, piperacillin-tazobactam 4 x 4.5 g/day treatment was continued and supportive treatment was given. In the follow-up, as the patient's neutropenia, thrombocytopenia and lymphocytopenia still continuing, she was transferred to hematology clinic for malignancy examination and bone marrow biopsy performed by hematology and B cell ALL was diagnosed. She was accepted to be convalescent in terms of CCHF and chemotherapy was started for ALL treatment by hematology. The patient is still being followed up by the hematology clinic and allogenic hematopoietic stem cell tranplantation is planned for the patient. As a result, CCHF is a disease that can be confused with many differential diagnosis. With this case, it is aimed to draw attention to the diagnostic difficulties of CCHF and ALL and to be the first case in the literature. Laboratory Diagnosis. The peripheral blood smear in autoimmune hemolytic anemia usually reveals spherocytes and occasionally nucleated RBCs. The reticulocyte count varies because some patients have relatively low reticulocyte counts as a result of autoantibodies that cross-react with RBC precursors. Treatment and Prognosis. Transfusion for the treatment of autoimmune hemolysis is challenging because crossmatching is difficult, as the autoantibodies react with virtually all RBCs. In addition to transfusion, which may be lifesaving, management of autoimmune hemolytic anemia depends on antibody type. Management may involve administration of corticosteroids and, at times, intravenous immunoglobulin. Corticosteroids reduce the clearance of sensitized RBCs in the spleen. In drug-induced hemolysis, withdrawal of the drug usually leads to resolution of the hemolytic process. More than 80% of children with autoimmune hemolytic anemia recover spontaneously. Approval for treatment of autoimmune hemolytic anemia (AIHA) is in Stage 1 of Phase II trials. This study is a Phase 2, multi-center, open label, Simon two-stage study to evaluate the safety and efficacy of fostamatinib disodium in the treatment of warm antibody autoimmune hemolytic anemia. Primary outcome measures examined include a hemoglobin response measured by levels higher than 10 g/dL and 2 g/dL higher than the baseline hemoglobin. Responses were studied for a period of 12 weeks and for a dose of 150 mg in the morning and evening. The study began in April 2016 and is estimated to conclude in September 2017. The study is currently recruiting participants from U.S. states including Arizona, California, D.C., Massachusetts, New York, North Carolina, and Texas. Subjects must have had a diagnosis of primary or secondary warm antibody AIHA, and must have failed at least 1 prior treatment regimen for AIHA. Subjects cannot have a platelet count less than 30,000/μL, have AIHA secondary We report a Childhood case of hereditary spherocytosis (HS) first diagnosed upon the development of aplastic crisis. A 6-year-old boy presented with fever and anemia. Although there was neither icterus nor splenomegaly at first, mild icterus and splenomegaly gradually developed with improvement of anemia. The diagnosis of HS was made on the basis of the presence of numerous spherocytes on the peripheral smear, increased osmotic fragility and the auto-hemolysis test result. The severe anemia in the early course with a marked decrease in the bone marrow erythroid cells and the absence of icterus and splenomegaly indicate that it was due to aplastic crisis. In the virological study, anti-human parvovirus (HPV) antibody titers were increased: the values of anti-HPV IgM were high and those of anti-HPV IgG were suddenly elevated. We thus considered that this HS case developed aplastic crisis by HPV infection.\nHere is the question:\nHEMATOLOGY: A 32-year-old woman with cerebral palsy from childbirth comes to the emergency department for a few days of dark urine associated with an episode of high fever and dry cough. On admission, the CBC showed 16900 leukocytes/mm3 (85% S, 11% L, 4% M), hemoglobin 6.3 g/dL; MCV 109 fl, 360000 platelets/mm3. In the biochemistry LDH 2408; bilirubin 6.8 mg/dl, (unconjugated bilirubin 6.1 mg/dl), normal GOT and GPT. The morphological study of blood showed macrocytic anisocytosis with frequent spherocytic forms and polychromatophilia without blasts. The irregular antibody study is positive for panagglutinin, making crossmatching difficult. What would be your suspicion and the most appropriate treatment?\nHere are the potential choices:\n1. Medullary aplasia and immunotherapy with thymoglobulin and cyclosporine.\n2. Hereditary spherocytosis and splenectomy.\n3. Autoimmune hemolytic anemia associated with respiratory infection and corticosteroids.\n4. Pernicious anemia and periodic injections of vitamin B12.\n5. Acute leukemia and chemotherapy.\nThe correct answer is: ",
        "gold_answer": "3 Autoimmune hemolytic anemia associated with respiratory infection and corticosteroids.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Autoimmune Hemolytic anemia (AIHA) a relatively uncommon form of hemolytic anemia in children, occurs due to the premature destruction of red blood cells caused by presence of autoantibodies directed against antigens on RBCs. Warm reactive AIHA is the most common form due to IgG isotype of immunoglobulin class binding to autologous RBCs at 37<sup0</supC and confirmed with a positive DAT screening. We present a case of DAT-negative primary warm AIHA in an infant due to IgA antibody. A 10 month old male infant presented with dark colored urine and irritability for past two months, with associated history of fever, diarrhea and vomiting. He had received one red cell transfusion 10 days prior. On physical examination he had pallor with tachycardia without splenomegaly. On investigation his hemoglobin was 5.8 g/dl, WBC 25.9 × 10<sup3</sup/mm<sup3</sup and normal platelets counts. Peripheral blood smear had spherocytes and biochemical values showed high bilirubin and LDH. Immunohematological work up revelaed polyspecific DAT was negative but monospecific DAT screening showed strong (4+) positivity for IgA and a weak IgG positivity. The patient was diagnosed as IgA-mediated Warm AIHA and was started on prednisolone at 2 mg/kg/day following which hemoglobin improved over the next 2 months. After 2 weeks, prednisolone was tapered and stopped by the end of 3 months. Patients with clinical and laboratory evidence of acute hemolysis, an additional screening for IgA antibody may be done even in cases where poly-specific DAT is negative. Early detection helps in avoiding further investigations and provide efficient management. A 49-year-old woman with type 2 diabetes mellitus (T2DM) presented to the emergency department. Her examination showed marked pallor, exhaustion, lethargy, yellowish eyes, anorexia, nausea and vomiting. Hematuria; negative standard direct antiglobulin test (DAT); normal glucose 6 phosphate dehydrogenase (G6PD); hemoglobin (Hb), 4.8 g/dl; Mean cell volume (MCV), 91fl; platelet count, 233 × 10<sup6</sup/L; Total bilirubin, 7.0 mg/dl; Glucose, 316 mg/dl; lactate dehydrogenase (LDH), 1750U/L. Undoubtedly, therapeutic panel should have been used for hemolytic anemia. Intravenous (IV) fluids and 2 units of packed cell were transfused. Methylprednisolone with rituximab were started for the patient. After 3 weeks of the patient admission, she was discharged home with stable vital signs and Hb, 10 g/dl. We concluded in the cases that presented along with a severe drop in Hb and evidence of hemolysis which non immune hemolytic anemia is excluded in spite of negative standard DAT limited transfusion besides corticosteroids combined with rituximab, could be helpful in saving the patient. A 16-year-old male patient who was on oral iron treatment for iron deficiency anemia for the last one year was seen at the Haematology clinic with complaints of weakness, pallor, and jaundice. A complete blood count revealed Hb of 4.2 mmol/L, Hct of 0.14, and MCV of 76 fl. A blood smear showed 50% neutrophils, 40% lymphocytes, and 10% monocytes with anisocytosis, poikilocytosis, polichromasia in erythrocytes and normoblasts. Reticulocyte count was under 1%. There was a slight erythroid hyperplasia in the bone marrow aspiration. Biochemical examinations showed total bilirubin of 3.9 mg/dL, indirect bilirubin of 3.4 mg/dL, and lactate dehydrogenase (LDH) of 6085 U/L (220-450). In re-evaluating the history of the patient, he was seen to be complaining of dark discoloration of morning urine. Perl's reaction was found to be positive for hemosiderin in the urine sediment. Because Ham's test was positive, the levels of CD55, 58, and 59 proteins on erythrocyte membranes were found to be lower. The patient was started 32 mg of methylprednisolone and his anaemia was improved by the 14th day of treatment. When evaluating iron deficiency anemia resistant to iron supplementation, PNH should be kept in mind.  Thymomas are often associated with autoimmune disorders. We report on a 45-year-old female patient with thymoma and hypogammaglobulinemia (Good's syndrome) who developed symptomatic macrocytic anemia (Hb 4.4 g/dl, MCV 112 fl) and thrombocytosis (Plt 442 G/l). Besides hypogammaglobulinemia (IgG 589 mg/dl), an inverted ratio of CD4(+)/CD8(+) cells was seen. The bone marrow biopsy showed a slightly hypercellular bone marrow with normal granulopoiesis, normal megakaryopoiesis and a mild dyserythropoiesis without any ring-sideroblasts. The in-vitro stem cell culture from the bone marrow revealed an atypical growth of macroclusters, reduced BFU-E and CFU-GEMM colony growth, whereas the CFU-GM colony growth was within the normal range. The chromosomal analysis showed a normal karyotype. The plasma vitamin B(12) and folate levels were within normal ranges, and we could not detect any autoantibodies. These findings excluded the differential diagnoses pure red cell aplasia (PRCA) and pernicious anemia. After resection of the thymoma of mixed cell type, the macrocytic anemia and thrombocytosis disappeared. The clinical course was complicated by a cerebral palsy and a life-threatening fungal septicemia after surgery. In the third year after thymectomy, hyporegenerative macrocytic anemia and thrombocytosis reappeared and an immunosuppressive treatment with prednisolone (1 mg/kg BW) was started. After initiation of the prednisolone therapy, reticulocyte counts increased and macrocytic anemia as well as thrombocytosis disappeared. The normalization of these laboratory parameters during glucocorticoid therapy suggests that in rare cases the constellation of macrocytic anemia, thrombocytosis and hypogammaglobulinemia may be due to an underlying immunologic mechanism. To summarize the clinical characteristics, diagnosis and treatment of a case with autoimmune lymphoproliferative syndrome (ALPS) . The patient was diagnosed as autoimmune lymphoproliferactive syndrome (ALPS) after being admitted to the Department of Rheumatism and Immunology of Tianjin Children's Hospital in February 20, 2014. The clinical characteristics, physical examination, laboratory tests, gene tests, and treatment process were analyzed and related literature was reviewed. The patient was a 16-month- old boy.Since the first month of life, he started to have repeatedly fever, diarrhea, shortness of breath, lymphadenopathy, hepatosplenomegaly, anemia (HGBmin 50 g/L) and thrombocytopenia (min 35 × 10⁹/L) . But multiple exams showed a normal peripheral blood leukocyte count, hypergammaglobulinemia (IgG 19 800 mg/L, IgA 1 710 mg/L, IgM 2 590 mg/L) and significantly increased serum vitamin B12. Flow cytometric measures showed that CD3⁺ CD4⁻ CD8⁻ T lymphocytes significantly increased ( &gt; 10%) at four times. The count of CD3⁺ TCRαβ⁺ CD4⁻ CD8⁻T lymphocytes (double negative T cells; DNTs) &gt;3% twice. The genetic test showed that 309th FAS gene area showed heterozygous mutations, the boy was diagnosed as ALPS. Added examinations of lymphocytes apoptosis induced by FAS was positive. He was treated with prednisone 15 mg once daily and immunomodulator 150 mg three times a day, while in maintaining period with normal levels of hemoglobin and platelet, the dose of prednisone was reduced gradually. Till now, the patient has been treated and observed for 8 months. We retrieved the reports of ALPS in the databases at home and abroad published in recent 10 years, more than 400 cases reported from foreign countries, but there were only 5 domestic cases. Among those, 4 had onset in infancy and 1 at 6-years of age. All the cases presented servere lymphadenopathy and hepatosplenomegaly with anemia (4 of them with hemolytic anemia) and thrombocytopenia. Three cases had a history of frequent infection, one of them had glomerulonephritis. All patient with significant high level of serum immunoglobulin ( &gt; 1.5 times upper limit of normal range), in 3 of them serum vitamin B12 was &gt; 1.5 pg/L (the other 2 cases missed the exam). In 5 cases CD3⁺ CD4⁻ CD8⁻T cells &gt; 10%, and in 2 case DNTs were 8.9% and 15.7% respectively (the other 3 cases missed the exam). Three cases were clearly detected with FAS mutations. All patients were treated with corticosteroid, 2 of them were added with mycophenolate mofetil. The therapy presented effective result in early 1-3 months, but no long-term follow-up reports were available. ALPS is a disorder of disrupted lymphocyte homeostasis caused by defective Fas-mediated apoptosis, and it is one of the primary immunodeficiency diseases. The onset of the disease occurs during infancy mainly. Clinical lymphoid hyperplasia and autoimmune phenomena are outstanding signs, which can be associated with frequent infections and allergies. The level of serum vitamin B12 &gt; 1.5 pg/L and the count of CD3⁺ CD4⁻ CD8⁻ T cell show important significance. Exact diagnosis should depend on detecting DNTs and FAS gene. A 70-year-old woman was admitted to our hospital in November 1992 for evaluation of anemia. Physical examination revealed anemia, jaundice, swelling of axial and inguinal lymph nodes, and splenomegaly. Abnormal hematological findings were as follows: Hb of 3.9 g/dl, reticulocyte count of 58.2% (61.7 x 10(4)/microliters), hyperplasia of normal erythroblasts in bone marrow, and eosinophilia (21.0%, 2352/microliters) in peripheral blood. Routine laboratory examinations revealed polycolonal hypergammaglobulinemia 3.0 g/dl, a high level of serum LDH (797 IU/I) and a total bilirubin of 2.4 mg/dl (indirect, 1.6 mg/dl). The serum haptoglobin level was very low (&lt; 5 mg/dl). Results of serological examinations were as follows: IgG of 3366 mg/dl, CH50 of 16.0 U/ml, positive Coombs test 2+, and positive tests for antinuclear antibody, rheumatoid factor, and cold agglutinin. CRP was negative. PHA-stimulated lymphocyte blast formation, NK activity, and ADCC activity were found to be suppressed, and the percentage of CD4-positive lymphocytes in peripheral blood was also low. An axillary lymph node biopsy revealed reactive lymphadenitis. No signs or history suggested allergy, collagen disease, or parasitic infection. Autoimmune hemolytic anemia (AIHA) complicated by immunologic abnormalities and eosinophilia was diagnosed. Oral prednisolone markedly reduced the hemolytic anemia, eosinophilia, lymph node swelling, and splenomegaly, but NK activity remained low. Spherocytosis is the presence of spherocytes in the blood, i.e erythrocytes (red blood cells) that are sphere-shaped rather than bi-concave disk shaped as normal. Spherocytes are found in all hemolytic anemias to some degree. Hereditary spherocytosis and autoimmune hemolytic anemia are characterized by having only spherocytes. Causes Spherocytes are found in immunologically-mediated hemolytic anemias and in hereditary spherocytosis, but the former would have a positive direct Coombs test and the latter would not. The misshapen but otherwise healthy red blood cells are mistaken by the spleen for old or damaged red blood cells and it thus constantly breaks them down, causing a cycle whereby the body destroys its own blood supply (auto-hemolysis). A complete blood count (CBC) may show increased reticulocytes, a sign of increased red blood cell production, and decreased hemoglobin and hematocrit. The term \"non-hereditary spherocytosis\" is occasionally used, albeit rarely. A 78-year-old woman was admitted to our hospital because of disorientation and fever on January 21, 1992. Two days before admission she experienced vomiting, anorexia and general malaise. Laboratory examinations on admission disclosed a hemoglobin level of 11.1 g/dl and a platelet count of 8,000/microliters. The peripheral blood smear revealed anisocytosis with numerous schistocytes and poikilocytes. Polychromatophilic and nucleated red blood cells were also seen, and the reticulocyte count was 38/1000. Her serum lactate dehydrogenase (LDH) value was 2,977 WU and the total serum bilirubin level was 3.5 mg/dl with 2.7 mg/dl indirect reacting fraction. Serum creatinine was 4.7 mg/dl. Her consciousness became semicomatose after a systemic seizure which lasted approximately 15 seconds and her hemoglobin level decreased to 8.5 g/dl on hospital day 2. Therefore, we diagnosed her as having thrombotic thrombocytopenic purpura (TTP) because of the presence of all 5 features, that is, thrombocytopenia, microangiopathic hemolytic anemia, fluctuating neurologic abnormalities, renal dysfunction and fever. A plasmapheresis with fresh frozen plasma (FFP) replacement was begun on that day. She was also treated with anti-platelet agents, 80 mg/day aspirin, and 300 mg/day dipyridamole. Moreover, packed red blood cells (PRC) were infused. While also receiving diphenylhydantoin and phenobarbital to prevent convulsions, status epilepticus developed on day 3. Because of inhibited spontaneous respiration which was an adverse effect derived from diazepam and sodium thiamylal administered intravenously to treat the status epilepticus, an artificial respiration was initiated.(ABSTRACT TRUNCATED AT 250 WORDS) Diagnosis Pancytopenia usually requires a bone marrow biopsy in order to distinguish among different causes. anemia: hemoglobin < 13.5 g/dL (male) or 12 g/dL (female). leukopenia: total white cell count < 4.0 x 109/L. Decrease in all types of white blood cells (revealed by doing a differential count). thrombocytopenia: platelet count < 150×109/L. Treatment Treatment is done to address the underlying cause. To tide over immediate crisis Blood transfusion with packed red blood cells (PRBC) or platelet transfusion may be done. Sometimes there are obvious clinical clues to suggest underlying B12 deficiency for a cause of pancytopenia. In this selected cases even with severe anemia blood product transfusions can be avoided and vitamin B12 treatment itself suffice. In other situations like acute leukemia, Myelodysplastic syndrome, aplastic anemia etc. disease specific therapy is needed. References External links EID Journal (Volume 6, Number 6), CDC, December 2000. Myeloid Hemoglobinopathies (congenital abnormality of the hemoglobin molecule or of the rate of hemoglobin synthesis) Sickle cell disease Thalassemia Methemoglobinemia Anemias (lack of red blood cells or hemoglobin) Iron-deficiency anemia Megaloblastic anemia Vitamin B12 deficiency Pernicious anemia Folate deficiency Hemolytic anemias (destruction of red blood cells) Genetic disorders of RBC membrane Hereditary spherocytosis Hereditary elliptocytosis Congenital dyserythropoietic anemia Genetic disorders of RBC metabolism Glucose-6-phosphate dehydrogenase deficiency (G6PD) Pyruvate kinase deficiency Immune mediated hemolytic anemia (direct Coombs test is positive) Autoimmune hemolytic anemia Warm antibody autoimmune hemolytic anemia Idiopathic Systemic lupus erythematosus (SLE) Evans syndrome (antiplatelet antibodies and hemolytic antibodies) Cold autoimmune hemolytic anemia Cold agglutinin disease Paroxysmal cold hemoglobinuria (rare) The aim of this study is to evaluate the clinical, biological and hematological profiles of autoimmune hemolytic anemia (AIHA) in children and to specify its etiologies, therapeutic modalities, and treatment responses. This is a 14-year retrospective study of AIHA cases collected at the department of pediatric emergency and reanimation of Hedi Chaker University Hospital in Sfax. We included patients under 14 years old with clinical and biological features of hemolysis and a positive direct antiglobulin test (DAT). The selected patients' demographic characteristics, physical signs, laboratory findings, and treatment responses were recorded. Thirteen cases of AIHA were collected, including 8 girls and 5 boys. The median age at diagnosis was 4 years and 6 months (range: 8 months to 13 years). Consanguinity was reported in 6 cases and 4 patients had a previous infection history. The onset of AIHA was progressive in 9 cases, marked by an anemic syndrome and hemolysis symptoms in 6 and 8 cases, respectively. The clinical triad (pallor, jaundice and splenomegaly) was found in only 4 cases. At the time of diagnosis, the median hemoglobin (Hb) level was 6g/dL (range: 4.2 to 9.2g/dL), anemia was non-regenerative in 2 patients. Thrombocytopenia and neutropenia were noted in 5 and 1 patient, respectively. Peripheral smear examination showed spherocytosis in 2 cases. All the patients had a positive DAT. Of these, 10 were positive with IgG and 3 with both IgG and C3d. AIHA was secondary to other conditions in 9 patients: infection (3 cases), autoimmune disease (4 cases), and immunodeficiency (2 cases). All the patients received first-line corticosteroid therapy but only 8 of them required blood transfusions due to severe anemia. Complete remission was obtained in 7 cases. Corticosteroid resistance and dependence were noted in 1 and 2 cases, respectively. During evolution, additional therapy was indicated in 4 patients and it included cyclosporine A, azathioprine, and mycophenolate mofetil (MMF). After a median follow-up of 4.5 years, the cure rate was 80% and only 1 patient (a boy) died due to his underlying pathology. Our study highlights the rarity, severity, and heterogeneity of etiological contexts of AIHA in children. The therapeutic difficulties justify specific expertise in pediatric hematology. Diagnosis Diagnosis is made by a positive direct Coombs test, other lab tests, and clinical examination and history. The direct Coombs test looks for antibodies attached to the surface of red blood cells. Clinical findings Laboratory findings include severe anemia, normal MCV (mean corpuscular volume) , and hyperbilirubinemia (from increased red cell destruction) that can be of the conjugated or unconjugated type. Treatment Corticosteroids and immunoglobulins are two commonly used treatments for warm antibody AIHA. Initial medical treatment consists of prednisone. If ineffective, splenectomy should be considered. If refractory to both these therapies, other options include rituximab, danazol, cyclosphosphamide, azathioprine, or ciclosporin. High-dose intravenous immune globulin may be effective in controlling hemolysis, but the benefit is short lived (1–4 weeks), and the therapy is very expensive. See also List of circulatory system conditions References Crimean-Congo hemorrhagic fever (CCHF) is a zoonotic disease that can be presented with fever, fatigue, generalized joint/body pain, diarrhea and bleeding in various parts of the body. The risk of developing a severe fatal disease in humans, the possibility of being infected with aerosols and the risk of being used as a biological weapon make the disease still an important health problem all over the world as there is no a specific treatment and vaccine that has proven effective againt the virus today. The pathogenesis of the disease is not known, but vascular endothelial damage is prominent. Therefore, it progresses with thrombocytopenia, anemia, leukopenia and this hematological findings can be confused with hematological malignancies. Acute lymphoblastic leukemia (ALL) is a malignancy included in differential diagnoses and occurs as a result of mutations occuring at a stage of differentiation in the lymphoid precursor cells in the bone marrow. In this study, we present a case of ALL who was diagnosed with CCHF simultaneously. A 43-year old female patient who works in the library and does not have a chronic disease other than asthma and thyroid disorder, has admitted to our hospital with the complaints of intermittent fever, weakness, generalized joint and body pain for about 3 weeks. She had fever and the physical examination revealed bilateral cervical and right postauricular lymphadenopathies. Her aspartate aminotransferase: 77 U/L, alanine aminotransferase: 117 U/L, lactate dehydrogenase: 616 U/L, hemoglobin: 8.27 g/dl, leukocyte count: 15.690/mm3 , neutrophil count: 550/mm3 (%3.5), lymphocyte count: 6690/mm3 (%42.6), platelet count: 102.100/mm3 , C-reactive protein: 163.6 mg/L was detected and the patient was hospitalized on 5 August 2019 for further examination and treatment. Considering that the patient may have viral infection in the foreground the requested test results were detected as; anti-CMV IgM negative, anti-CMV IgG positive, anti-toxoplasma IgM negative, anti-toxoplasma IgG positive, anti-rubella IgM negative, anti-rubella IgG positive, HBsAg negative, anti-HBc IgM negative, antiHBs positive, anti-HAV IgM negative, anti-HAV IgG positive, anti-HCV negative, anti-HIV negative, EpsteinBarr virus (EBV) VCA IgM negative, EBV VCA IgG positive, EBV EBNA IgG positive. Brucella Rose Bengal and Coombs tube agglutination was found be negative. As the cytopenia of the patient deepened, the patient was accepted to have neutropenic fever and it was planned to start piperacillin-tazobactam 4 x 4.5 g/day and two units of erythrocyte replacement therapy. When the patient's history was questioned again, it was learned that she had a tick on her neck about three weeks ago and she had removed the tick herself; 4-5 days later she had the complaints of fever and flu like symptoms and also diarrhea complaints lasting for 3-4 days. Considering the current anamnesis and laboratory findings, the patient was thought to have CCHF and the patient was isolated. The serum sample taken from patient with an initial diagnosis of CCHF and sent to Department of Microbiology Reference Laboratory Public Health Agency of Turkey. The patient was referred to the Antalya Training and Research Hospital. The patient's CCHF serum result was positive. Ribavirin treatment was not initiated in the patient who was accepted to be in the convalescence period, piperacillin-tazobactam 4 x 4.5 g/day treatment was continued and supportive treatment was given. In the follow-up, as the patient's neutropenia, thrombocytopenia and lymphocytopenia still continuing, she was transferred to hematology clinic for malignancy examination and bone marrow biopsy performed by hematology and B cell ALL was diagnosed. She was accepted to be convalescent in terms of CCHF and chemotherapy was started for ALL treatment by hematology. The patient is still being followed up by the hematology clinic and allogenic hematopoietic stem cell tranplantation is planned for the patient. As a result, CCHF is a disease that can be confused with many differential diagnosis. With this case, it is aimed to draw attention to the diagnostic difficulties of CCHF and ALL and to be the first case in the literature. Laboratory Diagnosis. The peripheral blood smear in autoimmune hemolytic anemia usually reveals spherocytes and occasionally nucleated RBCs. The reticulocyte count varies because some patients have relatively low reticulocyte counts as a result of autoantibodies that cross-react with RBC precursors. Treatment and Prognosis. Transfusion for the treatment of autoimmune hemolysis is challenging because crossmatching is difficult, as the autoantibodies react with virtually all RBCs. In addition to transfusion, which may be lifesaving, management of autoimmune hemolytic anemia depends on antibody type. Management may involve administration of corticosteroids and, at times, intravenous immunoglobulin. Corticosteroids reduce the clearance of sensitized RBCs in the spleen. In drug-induced hemolysis, withdrawal of the drug usually leads to resolution of the hemolytic process. More than 80% of children with autoimmune hemolytic anemia recover spontaneously. Approval for treatment of autoimmune hemolytic anemia (AIHA) is in Stage 1 of Phase II trials. This study is a Phase 2, multi-center, open label, Simon two-stage study to evaluate the safety and efficacy of fostamatinib disodium in the treatment of warm antibody autoimmune hemolytic anemia. Primary outcome measures examined include a hemoglobin response measured by levels higher than 10 g/dL and 2 g/dL higher than the baseline hemoglobin. Responses were studied for a period of 12 weeks and for a dose of 150 mg in the morning and evening. The study began in April 2016 and is estimated to conclude in September 2017. The study is currently recruiting participants from U.S. states including Arizona, California, D.C., Massachusetts, New York, North Carolina, and Texas. Subjects must have had a diagnosis of primary or secondary warm antibody AIHA, and must have failed at least 1 prior treatment regimen for AIHA. Subjects cannot have a platelet count less than 30,000/μL, have AIHA secondary We report a Childhood case of hereditary spherocytosis (HS) first diagnosed upon the development of aplastic crisis. A 6-year-old boy presented with fever and anemia. Although there was neither icterus nor splenomegaly at first, mild icterus and splenomegaly gradually developed with improvement of anemia. The diagnosis of HS was made on the basis of the presence of numerous spherocytes on the peripheral smear, increased osmotic fragility and the auto-hemolysis test result. The severe anemia in the early course with a marked decrease in the bone marrow erythroid cells and the absence of icterus and splenomegaly indicate that it was due to aplastic crisis. In the virological study, anti-human parvovirus (HPV) antibody titers were increased: the values of anti-HPV IgM were high and those of anti-HPV IgG were suddenly elevated. We thus considered that this HS case developed aplastic crisis by HPV infection.\nHere is the question:\nHEMATOLOGY: A 32-year-old woman with cerebral palsy from childbirth comes to the emergency department for a few days of dark urine associated with an episode of high fever and dry cough. On admission, the CBC showed 16900 leukocytes/mm3 (85% S, 11% L, 4% M), hemoglobin 6.3 g/dL; MCV 109 fl, 360000 platelets/mm3. In the biochemistry LDH 2408; bilirubin 6.8 mg/dl, (unconjugated bilirubin 6.1 mg/dl), normal GOT and GPT. The morphological study of blood showed macrocytic anisocytosis with frequent spherocytic forms and polychromatophilia without blasts. The irregular antibody study is positive for panagglutinin, making crossmatching difficult. What would be your suspicion and the most appropriate treatment?\nHere are the potential choices:\n1. Medullary aplasia and immunotherapy with thymoglobulin and cyclosporine.\n2. Hereditary spherocytosis and splenectomy.\n3. Autoimmune hemolytic anemia associated with respiratory infection and corticosteroids.\n4. Pernicious anemia and periodic injections of vitamin B12.\n5. Acute leukemia and chemotherapy.\nThe correct answer is: 2. Hereditary spherocytosis and splenectomy."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n In contrast to pulmonary parenchyma metastases or lymphangitic carcinomatosis, neoplastic emboli of small pulmonary arteries and capillaries frequently go unrecognized and are only discovered at autopsy. Five patients (48 +/- 12 years old) were admitted to 3 intensive care units for severe acute respiratory failure and died between the first and the tenth day following hospitalization. Each patient had a history of rapidly progressive dyspnea, and physical examination showed clinical evidence of right ventricular failure. The lungs were clear on chest X-rays and the ECG revealed sinus tachycardia with a right QRS axis. The mean partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2) were, respectively, 50.8 +/- 9.1 mm Hg and 22.2 +/- 2.4 mm Hg. A swan-Ganz catheter, inserted into 4 patients, revealed pulmonary arterial hypertension (55, 43, 37, 28) with capillary wedge pressure within the normal limits and cardiac output normal or low (3.0, 3.8, 4.4, 5.0 l/min). Pulmonary angiograms from each patient showed decreased distal lung perfusion without any proximal defects suggestive of pulmonary embolism. The inferior vena cava always appeared clear. Malignant cells were found upon autopsy (4 cases) in the lumina of the pulmonary arterioles and the primary site of the cancer was determined in 3 patients (2 hepatomas and 1 pancreatic carcinoma). The last patient had a known breast cancer with bone marrow metastases and clinical, hemodynamic and angiographic evidence of neoplastic emboli. The clinical course of neoplastic emboli can suggest acute pulmonary embolism, but the diagnosis can only be advanced after pulmonary angiography, especially if the patient is to have a cancer.(ABSTRACT TRUNCATED AT 250 WORDS) To report clinical application of Extracorporeal membrane oxygenation for severe acute respiratory and heart failure in a child with severe pneumonia. A seven-year old male patient with severe pneumonia complicated with heart and lung function failure was admitted to PICU in 28th of December, 2008.Veno-artery access was set up via euthyphoria cannulation in operative incision. Blood was drained from the right atrium through a cannula introduced via femoral veins, and returned via femoral artery. The inter-surface of the ECMO equipment system was completely coated with heparin-coating technique. Anticoagulation was maintained with heparin to keep the activated clotting time (ACT) between 150 and 200 seconds and heparin usage dose was 10 U/(kg.h), mean blood flow was 1/2-2/3 of 80-120 ml/(kg.min) during ECMO assistant period. During ECMO, ventilator settings were gradually reduced to allow lung rest, i.e. peak inspiratory pressure less than 25 cm H2O (1 cm H2O=0.098 kPa), end expiratory pressure 8-10 cm H2O, rate 10-15 breaths per minute and FiO2 30%-40%. In management of ECMO, the incipient blood flow was set at 0.8 L/min, the radio of oxygen and blood flow was 1:1, FiO2 60%. After ten minutes of ECMO working, the blood oxygen saturation of radial artery increased from 40 mm Hg (1 mm Hg=0.133 kPa) to 177 mm Hg, Lac decreased from 3.5 mmol/L to 2.8 mmol/L. Four hours later, blood gas analysis of radial artery showed PaO2 202 mm Hg, PCO2 44 mm Hg, Lac 1.5 mmol/L, blood flow was set at 0.6 L/min, FiO2 60%, PaO2 kept above 150 mm Hg. 96 hours after ECMO supporting, the blood flow was set at 0.4 L/min [20 ml/(kg.min)], the results of blood gas analysis of radial artery was PaO2 190 mm Hg, PaCO2 36 mm Hg, SaO2 100%, Lac 0.9 mmol/L, then the child weaned off successfully from ECMO. Two days later, the child was successfully extubated. After two weeks treatment, the patient was discharged. The main complication associated with extracorporeal membrane oxygenation were bleeding. ECMO is an effective mechanical assistant therapy method for severe pulmonary and cardiac failure in a child. Acute Respiratory Distress Syndrome (ARDS) is a potential complication of cardiac surgery, given that patients undergoing CABG frequently have hypoxemia and pulmonary dysfunction during initial hours after surgery. Thus, ARDS criteria in these patients are more likely to be positive while these criteria may not match the patient`s clinical picture. We aimed to investigate frequency of rapid onset hypoxemia in Pressure of Arterial Oxygen to Fractional Inspired Oxygen Concentration (PaO2/FiO2) less than 200 and diffuse pulmonary infiltrates as two diagnostic criteria forwards and compared these criteria with the clinical picture of the patients after Coronary Artery Bypass Graft (CABG) in this study. The study was prospective case series which carried out in about six months. All patients admitted to intensive care unit of Tehran Heart Center, who had undergone CABG on cardiopulmonary pump (CPB) recruited in the study. After considering inclusion criteria, age, sex, duration of intubation, arterial blood gas and chest radiography, on 24 hours and 48 hours after admission to the ICU were recorded. Then, patients with rapid onset of hypoxemia (PaO2/FiO2≤200mmHg) and diffuse pulmonary infiltrates and without sign or symptoms of obvious heart failure (probable positive ARDS cases) criteria were recorded and comparison between these probable positive cases with clinician`s clinical diagnosis (blinded to the study) was performed. In this study, a total of 300 patients after on-pump coronary artery bypass surgery were included. Postoperatively, 2 (0.66 %) in the 24 hours and 4 (1.33%) patients in 48 hours after surgery were positive for the two ARDS criteria according to the checklists, but; nobody had saved persistently ARDS criteria persistently during 48 hours after surgery. At the same time, clinician did not report any case of ARDS among 300 patients. In this study patients with ARDS criteria had no significant differences in age (P.value=0.937) and sex (P.value=0.533). Duration of intubation in patients with ARDS (14.26 ± 4.25 hours) in the first 48 hours was higher but not statistically different from the group without ARDS (11.60 ± 5.45 hours) (P.value=0.236). ARDS diagnosis based on rapid onset of hypoxemia (PaO2/FiO2≤200 mmHg) and diffuse pulmonary infiltrates and without signs or symptoms of obvious heart failure criteria in patients undergoing CABG could lead to overdiagnosis or misdiagnosis in less than 24 hours follow up. We recommend following patients for more than 24 hours and revise the current ARDS criteria for CABG patients.  We evaluated the frequency and cause of acute respiratory failure in renal transplant recipients. Our single-center retrospective observational study included consecutive renal transplant recipients who were admitted to an intensive care unit for acute respiratory failure between 2011 and 2017. Acute respiratory failure was defined as oxygen saturation &lt; 92% or partial pressure of oxygen in arterial blood &lt; 60 mm Hg on room air and/or requirement of noninvasive or invasive mechanical ventilation. Of 187 renal transplant recipients, 35 (18.71%) required intensive care unit admission; 11 of these patients (31.4%) were admitted to the intensive care unit with acute respiratory failure. Six of these patients (54.5%) had pneumonia and had shown infiltrates on chest radiography, which were shown in a minimum of 3 zones of the lung (2 with Klebsiella pneumonia, 1 with Acinetobacter species, 1 with Proteus mirabilis, 2 with no microorganisms). The other reasons for acute respiratory failure were cardiogenic pulmonary edema (2 patients), acute respiratory distress syndrome (2 patients, due to acute pancreatitis and acute cerebrovascular thromboembolism), and exacerbation of chronic obstructive pulmonary disease (1 patient). Six patients (54.5%) needed invasive mechanical ventilation because of pneumonia (3 patients), cardiogenic pulmonary edema (2 patients), and cerebrovascular thromboembolism (1 patient). Hemodialysis was administered in 5 patients (45%). Six of 11 patients died due to pneumonia (3 p atients), cardiogenic pulmonary edema (2 patients), and cerebrovascular thromboembolism (1 patient). Among the 5 survivors, 3 (60%) had recovered previous graft function. Acute respiratory failure is associated with high mortality and morbidity in renal transplant recipients. Main causes of acute respiratory failure were bacterial pneumonia and cardiogenic pulmonary edema in our study population. Extended chemoprophylaxis for bacterial and fungal infection and early intensive care unit admission of patients with acute respiratory failure may improve outcomes. To assess whether patients breathing spontaneously under standard oxygen could be recognized early as acute respiratory distress syndrome patients according to the current Berlin definition. A post hoc analysis from two prospective studies. Twenty-three French ICUs. All patients admitted for acute hypoxemic respiratory failure and treated with noninvasive ventilation were analyzed. Patients with cardiogenic pulmonary edema, acute exacerbation of chronic obstructive pulmonary disease, or hypercapnia were excluded. None. The PaO2/FIO2 ratio was estimated at admission under standard oxygen and then under noninvasive ventilation 1 hour after initiation and within the first 24 hours. Among the 219 patients treated with noninvasive ventilation for acute hypoxemic respiratory failure, 180 (82%) had bilateral infiltrates including 161 patients with PaO2/FIO2 less than or equal to 300 mm Hg under standard oxygen. Among them, 127 were treated with positive end-expiratory pressure of at least 5 cm H2O, and 120 (94%) fulfilled criteria for acute respiratory distress syndrome within the first 24 hours. The mortality rate of patients with bilateral infiltrates and PaO2/FIO2 less than or equal to 300 mm Hg under standard oxygen was 29%, a rate very close to that of intubated patients with acute respiratory distress syndrome in the Berlin definition. Almost all patients with pulmonary bilateral infiltrates and a PaO2/FIO2 less than or equal to 300 mm Hg under standard oxygen fulfilled the acute respiratory distress syndrome criteria under noninvasive ventilation within the first 24 hours. Their mortality rate was similar to that reported in the Berlin definition of acute respiratory distress syndrome. Therefore, spontaneous breathing patients with the acute respiratory distress syndrome criteria could be identified early without positive pressure ventilation. Berlin Criteria: as stated on UpToDate (2020) Timing: onset of respiratory symptoms within one week of a injury/insult. Chest Imaging: either chest x-ray or CT scan, must show bilateral opacities that cannot be fully explained by other conditions such as effusion, lung/lobar collapse, or lung nodules. Origin of Edema: respiratory failure that cannot be fully explained by cardiac failure or fluid overload, this needs objective assessment such as an echocardiogram. Impaired Oxygenation: this can be determined by looking at the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2) that can be obtained based on an arterial blood gas test. Note: all PaO2/FiO2 ratios used in the determination of the severity of ARDS require that the patient be on a ventilator at a setting that includes 5 cm H2O or more of positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP). Causes may include sepsis, pancreatitis, trauma, pneumonia, and aspiration. The underlying mechanism involves diffuse injury to cells which form the barrier of the microscopic air sacs of the lungs, surfactant dysfunction, activation of the immune system, and dysfunction of the body's regulation of blood clotting. In effect, ARDS impairs the lungs' ability to exchange oxygen and carbon dioxide. Adult diagnosis is based on a PaO2/FiO2 ratio (ratio of partial pressure arterial oxygen and fraction of inspired oxygen) of less than 300 mm Hg despite a positive end-expiratory pressure (PEEP) of more than 5 cm H2O. Cardiogenic pulmonary edema, as the cause, must be excluded. To examine the relationship between age and mortality in ARDS patients and evaluate the importance of factors that increase the mortality of older ARDS patients. Prospective inception cohort study. Community-based referral hospital. Two hundred fifty-six ARDS patients identified from May 1987 to December 1990. ARDS was defined by the following: (1) PaO2/PAO2 &lt; or = 0.2; (2) pulmonary capillary wedge pressure &lt; or = 15 mm Hg; (3) total static thoracic compliance &lt; or = 50 mL/cm H2O; (4) bilateral infiltrates on chest radiograph; and (5) an appropriate clinical setting for ARDS. Comparison of organ failure, incidence of sepsis, patient demographics, arterial oxygenation, and level of support in those 55 years and younger and those older than 55 years of age. Withdrawal of support in patients who died. Seventy-two of 112 patients older than 55 years (64%) died vs 65 of 144 patients 55 years and younger (45%) (p = 0.002). Examination of patient groups using age identified older than 55 years as a \"cutpoint\" above which mortality was greater (p = 0.002). Older nonsurvivors did not differ from nonsurvivors 55 years or younger with respect to gender, smoking history, ARDS risk factors, ARDS identifying characteristics, APACHE II (acute physiology and chronic health evaluation), number of organ failures, or the incidence of sepsis. In the 48 h prior to death, nonsurvivors 55 years and younger had more organ failure (3.4 +/- 0.2 vs 2.8 +/- 0.2; p = 0.03), higher fraction of inspired oxygen (0.82 +/- 0.03 vs 0.68 +/- 0.03; p = 0.008), and higher positive end-expiratory pressure levels (13 +/- 1 vs 8 +/- 1; p = 0.001) than older nonsurvivors. Despite more severe expression of disease, only 32 (50%) nonsurvivors 55 years and younger had support withdrawn. Significantly more nonsurvivors older than 55 years (73%) had support withdrawn (p = 0.009). Even in the absence of chronic disease states, withdrawal was more likely for patients older than 55 years (21/51) than in those 55 years and younger (3/32; p &lt; 0.001). Mortality is significantly higher for patients with ARDS older than 55 years. Decisions to withdraw support are made more often in ARDS patients older than 55 years. These data suggest that age bias may influence decisions to withdraw support. Phase 1 (acute injury): Normal physical exam; possible respiratory alkalosis. Phase 2 (6–48 hours): Hyperventilation, hypocapnia, widening A-a oxygen gradient. Phase 3: Acute respiratory failure, tachypnea, dyspnea, ↓ lung compliance, scattered rales, diffuse chest infltrates on CXR (see Figure 2.15-5). F IGU R E 2.1 5-5. AP CXR showing a diffuse alveolar filling pattern 2° to ARDS. (Reproduced, with permission, from Kasper DL et al. Harrison’s Principles of Internal Medicine, 16th ed. New York: McGraw-Hill, 2005: 1497.) ■ Phase 4: Severe hypoxemia unresponsive to therapy; ↑ intrapulmonary shunting; metabolic and respiratory acidosis. The criteria for ARDS diagnosis (according to the American-European Consensus Conference defnition) are as follows: Acute onset of respiratory distress. PaO2/FiO2 ratio ≤ 200 mmHg. Bilateral pulmonary infltrates on CXR. No evidence of cardiac origin (capillary wedge pressure < 18 mmHg or no clinical evidence of elevated left atrial pressure). To define the occurrence rate of acute respiratory distress syndrome (ARDS) using established criteria in a well-defined general patient population, to study the clinical course of ARDS when patients were ventilated using a \"lung-protective\" strategy, and to define the total costs of care. A 3-yr (1993 through 1995) retrospective descriptive analysis of all patients with ARDS treated in Kuopio University Hospital. Intensive care unit in the university hospital. Fifty-nine patients fulfilled the definition of ARDS: Pao2/Fio2 &lt;200 mm Hg (33.3 kPa) during mechanical ventilation and bilateral infiltrates on chest radiograph. None. With a patient data management system, the day-by-day data of hemodynamics, ventilation, respiratory mechanics, gas exchange, and organ failures were collected during the period that Pao2/Fio2 ratio was &lt;200 mm Hg (33.3 kPa). The frequency of ARDS was 4.9 cases/100,000 inhabitants/yr. Pneumonia and sepsis were the most common causes of ARDS. Mean age was 43+/-2 yrs. At the time of lowest Pao2/Fio2, the nonsurvivors had lower arterial and venous oxygen saturations and higher arterial lactate than survivors, whereas there were no differences between the groups in other parameters. Multiple organ dysfunction preceded the worst oxygenation in both the survivors and nonsurvivors. The intensive care mortality was 37%; hospital mortality and mortality after a minimum 8 months of follow-up was 42%. The most frequent cause of death was multiple organ failure. The effective costs of intensive care per survivor were US $73,000. The outcome of ARDS is unpredictable at the time of onset and also at the time of the worst oxygenation. Keeping the inspiratory pressures low (30-35 cm H2O [2.94 to 3.43 kPa]) reduces the frequency of pneumothorax, and might lower the mortality. Most patients are young, and therefore the costs per saved year of life are low. MAJOR COMPLICATIONS Cardiopulmonary Complications Ventilation-perfusion mismatching produces a fall in arterial Po2 early in the course. Increasing alveolar epithelial injury and capillary permeability result in increased pulmonary water content, which decreases pulmonary compliance and interferes with oxygen exchange. In the absence of pneumonia or heart failure, progressive diffuse pulmonary infiltrates and arterial hypoxemia occurring within 1 week of a known insult indicate the development of mild acute respiratory distress syndrome (ARDS) (200 mmHg < Pao2/Fio2 ≤ 300 mmHg), moderate ARDS (100 mmHg < Pao2/Fio2 ≤ 200 mmHg), or severe ARDS (Pao2/Fio2 ≤100 mmHg). Acute lung injury or ARDS develops in ~50% of patients with severe sepsis or septic shock. Respiratory muscle fatigue can exacerbate hypoxemia and hypercapnia. An elevated pulmonary capillary wedge pressure (>18 mmHg) suggests fluid volume overload or cardiac failure rather than ARDS. Pneumonia caused by viruses or by This type of respiratory failure is caused by conditions that affect oxygenation, such as: Low ambient oxygen (e.g. at high altitude) Ventilation-perfusion mismatch (parts of the lung receive oxygen but not enough blood to absorb it, e.g. pulmonary embolism) Alveolar hypoventilation (decreased minute volume due to reduced respiratory muscle activity, e.g. in acute neuromuscular disease); this form can also cause type 2 respiratory failure if severe. Diffusion problem (oxygen cannot enter the capillaries due to parenchymal disease, e.g. in pneumonia or ARDS) Shunt (oxygenated blood mixes with non-oxygenated blood from the venous system, e.g. right to left shunt) Type 2 Hypoxemia (PaO2 <8kPa or normal) with hypercapnia (PaCO2 >6.0kPa). The basic defect in type 2 respiratory failure is characterized by: {| class=\"wikitable\" |PaO2 || decreased (< )or normal |- | PaCO2 || increased (> ) |- | PA-aO2 || normal |- |pH || <7.35 |} This type of respiratory failure occurs with alveolar flooding and subsequent intrapulmonary shunt physiology. Alveolar flooding may be a consequence of pulmonary edema, pneumonia, or alveolar hemorrhage. Pulmonary edema can be further categorized as occurring due to elevated pulmonary microvascular pressures, as seen in heart failure and intravascular volume overload or ARDS (“low-pressure pulmonary edema,” Chap. 322). This syndrome is defined by acute onset (≤1 week) of bilateral opacities on chest imaging that are not fully explained by cardiac failure or fluid overload and of shunt physiology requiring positive end-expiratory pressure (PEEP). Type I respiratory failure occurs in clinical settings such as sepsis, gastric aspiration, pneumonia, near-drowning, multiple blood transfusions, and pancreatitis. The mortality rate among patients with ARDS was traditionally very high (50–70%), although changes in patient care have led to mortality rates closer to 30% (see below). Equations Abbreviated alveolar air equation PAO2, PEO2, and PIO2 are the partial pressures of oxygen in alveolar, expired, and inspired gas, respectively, and VD/Vt is the ratio of physiologic dead space over tidal volume. Medicine In medicine, the FIO2 is the assumed percentage of oxygen concentration participating in gas exchange in the alveoli. Uses The FIO2 is used in the APACHE II (Acute Physiology and Chronic Health Evaluation II) severity of disease classification system for intensive care unit patients. For FIO2 values equal to or greater than 0.5, the alveolar–arterial gradient value should be used in the APACHE II score calculation. Otherwise, the PaO2 will suffice. The ratio between partial pressure of oxygen in arterial blood (PaO2) and FIO2 is used as an indicator of hypoxemia per the American-European Consensus Conference on lung injury. A high FIO2 has been shown to alter the ratio of PaO2/FIO2. Cardiovascular dysfunction a) Shock b) Cardiac Arrest c) Severe hypoperfusion (lactate >5 mmol/L or >45 mg/dL) d) Severe acidosis (pH<7.1) e) Use of continuous vasoactive drugs f) Cardio-pulmonary resuscitation Respiratory dysfunction g) Acute cyanosis h) Gasping i) Severe tachypnea (respiratory rate>40 breaths per minute) j) Severe bradypnea (respiratory rate<6 breaths per minute) k) Severe hypoxemia (O2 saturation <90% for ≥60min or PAO2/FiO2<200) l) Intubation and ventilation not related to anaesthesia Renal dysfunction m) Oliguria non responsive to fluids or diuretics n) Severe acute azotemia (creatinine >300 μmol/ml or >3.5 mg/dL) o) Dialysis for acute renal failure Coagulation dysfunction p) Failure to form clots q) Severe acute thrombocytopenia (<50,000 platelets/ml) r) Massive transfusion of blood or red cells (≥ 5 units) Hepatic dysfunction s) Jaundice in the presence of pre-eclampsia Noninvasive estimation techniques have been proposed. Clinical significance Because of the large compliance of pulmonary circulation, it provides an indirect measure of the left atrial pressure. For example, it is considered the gold standard for determining the cause of acute pulmonary edema; this is likely to be present at a PWP of >20mmHg. It has also been used to diagnose severity of left ventricular failure and mitral stenosis, given that elevated pulmonary capillary wedge pressure strongly suggests failure of left ventricular output. Traditionally, it was believed that pulmonary edema with normal PWP suggested a diagnosis of acute respiratory distress syndrome (ARDS) or non cardiogenic pulmonary edema (as in opiate poisoning). However, since capillary hydrostatic pressure exceeds wedge pressure once the balloon is deflated (to promote a gradient for forward flow), a normal wedge pressure cannot conclusively differentiate between hydrostatic pulmonary edema and ARDS. Removal of the extrinsic cause or treatment of underlying infection if identifed. Corticosteroid treatment may be used if no cause is identif ed. Causes include ventilation-perfusion (V/Q) mismatch, right-to-left shunt, hypoventilation, low inspired O2 content (important at altitudes), and diffusion impairment. Findings depend on the etiology. ↓HbO2 saturation, cyanosis, tachypnea, shortness of breath, pleuritic chest pain, and altered mental status may be seen. Pulse oximetry: Demonstrates ↓ HbO2 saturation. CXR: To rule out ARDS, atelectasis, or an infltrative process (e.g., pneumonia) and to look for signs of pulmonary embolism. ABGs: To evaluate PaO2 and to calculate the alveolar-arterial (A-a) oxygen gradient ([(Patm − 47) × FiO2 − (PaCO2/0.8)] − PaO2). An ↑ A-a gradient suggests a V/Q mismatch or a diffusion impairment. Figure 2.15-4 summarizes the approach toward hypoxemic patients. Is PaCO2 increased? Hypoventilation Yes Yes No No Is PAO2 − PaO2 increased? Twenty-nine patients, divided into three groups: 1) chronic obstructive pulmonary disease; 2) acute or chronic pulmonary disease with left heart failure; 3) respiratory insufficiency after peritonitis, pancreatitis, and/or sepsis, were studied during respirator treatment with regard to gas exchange, breathing mechanics and central circulation. The dead space ventilation was somewhat greater in group 1 than in the other groups. The alveolar-arterial oxygen tension difference was least in group 1, greater in group 2 and extremely high in group 3. Neither dynamic compliance of the thorax nor inspiratory resistance showed any significant differences between the groups. The cardiac output had the highest values in group 3. The venous admixture was generally small in group 1 and extremely large in group 3. The pulmonary artery pressures were highest in group 2. Three variables proved to be valuable when assessing the prognosis of a patient: a large venous admixture; a large alveolar-arterial oxygen tension difference, and a high pulmonary artery pressure indicated a less favourable prognosis. 1. The use of an oxygen chamber in the treatment of pneumonia patients makes it possible to administer this gas for long periods of time under exactly known conditions. The medical and nursing care of the patient is greatly facilitated. 2. Prolonged inhalation of oxygen varying from 40 to 60 per cent appears to be without harm. 3. Oxygen administered to intensely anoxemic patients almost immediately clears up this anoxemia. Cyanosis disappears with the anoxemia. 4. The removal of patients from the high oxygen while they are still sick and while examination shows that there are still extensive edema and infiltration of the lung results in a return of the intense anoxemia. 5. It is sometimes impossible to clear up the anoxemia, even when as high as 60 per cent of oxygen is given, especially when there are considerable edema and infiltration of the lungs. 6. Five cases in which the prognosis was grave recovered. Three cases, one of tuberculosis, one with a Pneumococcus Type III infection, and a third with a pneumonia superimposed on a chronic pulmonary condition, died. 7. In all cases there appeared to be an improvement in the patient's condition. In one case, particularly, with an intense degree of anoxemia, the patient became moribund and pulseless. Following the administration of 60 per cent of oxygen there was a lowering of the heart rate from 160 to 120, the return of the pulse to the radial artery, the color became bright pink, and there was a remarkable change in the clinical condition. 8. The anoxemia of pneumonia is due, in large measure, to an impairment of the respiratory surface of the lungs. The greater the lung involvement the greater the anoxemia. Especially is this so when the pneumonic process extends throughout the lungs so that there are many patches of bronchopneumonia, with accompanying bronchitis and edema, as evidenced by the presence of râles throughout the lungs. 9. Rapid and shallow breathing of the degree observed in pneumonia is, as far as present evidence shows, of less importance in the production of anoxemia.\nHere is the question:\nANESTHESIOLOGY, CRITICAL CARE AND EMERGENCIES: A patient admitted for acute pancreatitis starts with tachypnea, tachycardia, sweating and progressive cyanosis. PaO2 is 55 mm Hg (PaO2/FiO2 ratio<200). CXR shows bilateral alveolar pulmonary infiltrates. Pulmonary capillary wedge pressure is normal. Oxygen therapy does not improve the situation. What is the most probable diagnosis:\nHere are the potential choices:\n1. Nosocomial pneumonia.\n2. Cardiac failure.\n3. Carcinomatous lymphangitis.\n4. Pulmonary thromboembolism.\n5. Respiratory distress.\nThe correct answer is: ",
        "gold_answer": "5 Respiratory distress.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n In contrast to pulmonary parenchyma metastases or lymphangitic carcinomatosis, neoplastic emboli of small pulmonary arteries and capillaries frequently go unrecognized and are only discovered at autopsy. Five patients (48 +/- 12 years old) were admitted to 3 intensive care units for severe acute respiratory failure and died between the first and the tenth day following hospitalization. Each patient had a history of rapidly progressive dyspnea, and physical examination showed clinical evidence of right ventricular failure. The lungs were clear on chest X-rays and the ECG revealed sinus tachycardia with a right QRS axis. The mean partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2) were, respectively, 50.8 +/- 9.1 mm Hg and 22.2 +/- 2.4 mm Hg. A swan-Ganz catheter, inserted into 4 patients, revealed pulmonary arterial hypertension (55, 43, 37, 28) with capillary wedge pressure within the normal limits and cardiac output normal or low (3.0, 3.8, 4.4, 5.0 l/min). Pulmonary angiograms from each patient showed decreased distal lung perfusion without any proximal defects suggestive of pulmonary embolism. The inferior vena cava always appeared clear. Malignant cells were found upon autopsy (4 cases) in the lumina of the pulmonary arterioles and the primary site of the cancer was determined in 3 patients (2 hepatomas and 1 pancreatic carcinoma). The last patient had a known breast cancer with bone marrow metastases and clinical, hemodynamic and angiographic evidence of neoplastic emboli. The clinical course of neoplastic emboli can suggest acute pulmonary embolism, but the diagnosis can only be advanced after pulmonary angiography, especially if the patient is to have a cancer.(ABSTRACT TRUNCATED AT 250 WORDS) To report clinical application of Extracorporeal membrane oxygenation for severe acute respiratory and heart failure in a child with severe pneumonia. A seven-year old male patient with severe pneumonia complicated with heart and lung function failure was admitted to PICU in 28th of December, 2008.Veno-artery access was set up via euthyphoria cannulation in operative incision. Blood was drained from the right atrium through a cannula introduced via femoral veins, and returned via femoral artery. The inter-surface of the ECMO equipment system was completely coated with heparin-coating technique. Anticoagulation was maintained with heparin to keep the activated clotting time (ACT) between 150 and 200 seconds and heparin usage dose was 10 U/(kg.h), mean blood flow was 1/2-2/3 of 80-120 ml/(kg.min) during ECMO assistant period. During ECMO, ventilator settings were gradually reduced to allow lung rest, i.e. peak inspiratory pressure less than 25 cm H2O (1 cm H2O=0.098 kPa), end expiratory pressure 8-10 cm H2O, rate 10-15 breaths per minute and FiO2 30%-40%. In management of ECMO, the incipient blood flow was set at 0.8 L/min, the radio of oxygen and blood flow was 1:1, FiO2 60%. After ten minutes of ECMO working, the blood oxygen saturation of radial artery increased from 40 mm Hg (1 mm Hg=0.133 kPa) to 177 mm Hg, Lac decreased from 3.5 mmol/L to 2.8 mmol/L. Four hours later, blood gas analysis of radial artery showed PaO2 202 mm Hg, PCO2 44 mm Hg, Lac 1.5 mmol/L, blood flow was set at 0.6 L/min, FiO2 60%, PaO2 kept above 150 mm Hg. 96 hours after ECMO supporting, the blood flow was set at 0.4 L/min [20 ml/(kg.min)], the results of blood gas analysis of radial artery was PaO2 190 mm Hg, PaCO2 36 mm Hg, SaO2 100%, Lac 0.9 mmol/L, then the child weaned off successfully from ECMO. Two days later, the child was successfully extubated. After two weeks treatment, the patient was discharged. The main complication associated with extracorporeal membrane oxygenation were bleeding. ECMO is an effective mechanical assistant therapy method for severe pulmonary and cardiac failure in a child. Acute Respiratory Distress Syndrome (ARDS) is a potential complication of cardiac surgery, given that patients undergoing CABG frequently have hypoxemia and pulmonary dysfunction during initial hours after surgery. Thus, ARDS criteria in these patients are more likely to be positive while these criteria may not match the patient`s clinical picture. We aimed to investigate frequency of rapid onset hypoxemia in Pressure of Arterial Oxygen to Fractional Inspired Oxygen Concentration (PaO2/FiO2) less than 200 and diffuse pulmonary infiltrates as two diagnostic criteria forwards and compared these criteria with the clinical picture of the patients after Coronary Artery Bypass Graft (CABG) in this study. The study was prospective case series which carried out in about six months. All patients admitted to intensive care unit of Tehran Heart Center, who had undergone CABG on cardiopulmonary pump (CPB) recruited in the study. After considering inclusion criteria, age, sex, duration of intubation, arterial blood gas and chest radiography, on 24 hours and 48 hours after admission to the ICU were recorded. Then, patients with rapid onset of hypoxemia (PaO2/FiO2≤200mmHg) and diffuse pulmonary infiltrates and without sign or symptoms of obvious heart failure (probable positive ARDS cases) criteria were recorded and comparison between these probable positive cases with clinician`s clinical diagnosis (blinded to the study) was performed. In this study, a total of 300 patients after on-pump coronary artery bypass surgery were included. Postoperatively, 2 (0.66 %) in the 24 hours and 4 (1.33%) patients in 48 hours after surgery were positive for the two ARDS criteria according to the checklists, but; nobody had saved persistently ARDS criteria persistently during 48 hours after surgery. At the same time, clinician did not report any case of ARDS among 300 patients. In this study patients with ARDS criteria had no significant differences in age (P.value=0.937) and sex (P.value=0.533). Duration of intubation in patients with ARDS (14.26 ± 4.25 hours) in the first 48 hours was higher but not statistically different from the group without ARDS (11.60 ± 5.45 hours) (P.value=0.236). ARDS diagnosis based on rapid onset of hypoxemia (PaO2/FiO2≤200 mmHg) and diffuse pulmonary infiltrates and without signs or symptoms of obvious heart failure criteria in patients undergoing CABG could lead to overdiagnosis or misdiagnosis in less than 24 hours follow up. We recommend following patients for more than 24 hours and revise the current ARDS criteria for CABG patients.  We evaluated the frequency and cause of acute respiratory failure in renal transplant recipients. Our single-center retrospective observational study included consecutive renal transplant recipients who were admitted to an intensive care unit for acute respiratory failure between 2011 and 2017. Acute respiratory failure was defined as oxygen saturation &lt; 92% or partial pressure of oxygen in arterial blood &lt; 60 mm Hg on room air and/or requirement of noninvasive or invasive mechanical ventilation. Of 187 renal transplant recipients, 35 (18.71%) required intensive care unit admission; 11 of these patients (31.4%) were admitted to the intensive care unit with acute respiratory failure. Six of these patients (54.5%) had pneumonia and had shown infiltrates on chest radiography, which were shown in a minimum of 3 zones of the lung (2 with Klebsiella pneumonia, 1 with Acinetobacter species, 1 with Proteus mirabilis, 2 with no microorganisms). The other reasons for acute respiratory failure were cardiogenic pulmonary edema (2 patients), acute respiratory distress syndrome (2 patients, due to acute pancreatitis and acute cerebrovascular thromboembolism), and exacerbation of chronic obstructive pulmonary disease (1 patient). Six patients (54.5%) needed invasive mechanical ventilation because of pneumonia (3 patients), cardiogenic pulmonary edema (2 patients), and cerebrovascular thromboembolism (1 patient). Hemodialysis was administered in 5 patients (45%). Six of 11 patients died due to pneumonia (3 p atients), cardiogenic pulmonary edema (2 patients), and cerebrovascular thromboembolism (1 patient). Among the 5 survivors, 3 (60%) had recovered previous graft function. Acute respiratory failure is associated with high mortality and morbidity in renal transplant recipients. Main causes of acute respiratory failure were bacterial pneumonia and cardiogenic pulmonary edema in our study population. Extended chemoprophylaxis for bacterial and fungal infection and early intensive care unit admission of patients with acute respiratory failure may improve outcomes. To assess whether patients breathing spontaneously under standard oxygen could be recognized early as acute respiratory distress syndrome patients according to the current Berlin definition. A post hoc analysis from two prospective studies. Twenty-three French ICUs. All patients admitted for acute hypoxemic respiratory failure and treated with noninvasive ventilation were analyzed. Patients with cardiogenic pulmonary edema, acute exacerbation of chronic obstructive pulmonary disease, or hypercapnia were excluded. None. The PaO2/FIO2 ratio was estimated at admission under standard oxygen and then under noninvasive ventilation 1 hour after initiation and within the first 24 hours. Among the 219 patients treated with noninvasive ventilation for acute hypoxemic respiratory failure, 180 (82%) had bilateral infiltrates including 161 patients with PaO2/FIO2 less than or equal to 300 mm Hg under standard oxygen. Among them, 127 were treated with positive end-expiratory pressure of at least 5 cm H2O, and 120 (94%) fulfilled criteria for acute respiratory distress syndrome within the first 24 hours. The mortality rate of patients with bilateral infiltrates and PaO2/FIO2 less than or equal to 300 mm Hg under standard oxygen was 29%, a rate very close to that of intubated patients with acute respiratory distress syndrome in the Berlin definition. Almost all patients with pulmonary bilateral infiltrates and a PaO2/FIO2 less than or equal to 300 mm Hg under standard oxygen fulfilled the acute respiratory distress syndrome criteria under noninvasive ventilation within the first 24 hours. Their mortality rate was similar to that reported in the Berlin definition of acute respiratory distress syndrome. Therefore, spontaneous breathing patients with the acute respiratory distress syndrome criteria could be identified early without positive pressure ventilation. Berlin Criteria: as stated on UpToDate (2020) Timing: onset of respiratory symptoms within one week of a injury/insult. Chest Imaging: either chest x-ray or CT scan, must show bilateral opacities that cannot be fully explained by other conditions such as effusion, lung/lobar collapse, or lung nodules. Origin of Edema: respiratory failure that cannot be fully explained by cardiac failure or fluid overload, this needs objective assessment such as an echocardiogram. Impaired Oxygenation: this can be determined by looking at the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2) that can be obtained based on an arterial blood gas test. Note: all PaO2/FiO2 ratios used in the determination of the severity of ARDS require that the patient be on a ventilator at a setting that includes 5 cm H2O or more of positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP). Causes may include sepsis, pancreatitis, trauma, pneumonia, and aspiration. The underlying mechanism involves diffuse injury to cells which form the barrier of the microscopic air sacs of the lungs, surfactant dysfunction, activation of the immune system, and dysfunction of the body's regulation of blood clotting. In effect, ARDS impairs the lungs' ability to exchange oxygen and carbon dioxide. Adult diagnosis is based on a PaO2/FiO2 ratio (ratio of partial pressure arterial oxygen and fraction of inspired oxygen) of less than 300 mm Hg despite a positive end-expiratory pressure (PEEP) of more than 5 cm H2O. Cardiogenic pulmonary edema, as the cause, must be excluded. To examine the relationship between age and mortality in ARDS patients and evaluate the importance of factors that increase the mortality of older ARDS patients. Prospective inception cohort study. Community-based referral hospital. Two hundred fifty-six ARDS patients identified from May 1987 to December 1990. ARDS was defined by the following: (1) PaO2/PAO2 &lt; or = 0.2; (2) pulmonary capillary wedge pressure &lt; or = 15 mm Hg; (3) total static thoracic compliance &lt; or = 50 mL/cm H2O; (4) bilateral infiltrates on chest radiograph; and (5) an appropriate clinical setting for ARDS. Comparison of organ failure, incidence of sepsis, patient demographics, arterial oxygenation, and level of support in those 55 years and younger and those older than 55 years of age. Withdrawal of support in patients who died. Seventy-two of 112 patients older than 55 years (64%) died vs 65 of 144 patients 55 years and younger (45%) (p = 0.002). Examination of patient groups using age identified older than 55 years as a \"cutpoint\" above which mortality was greater (p = 0.002). Older nonsurvivors did not differ from nonsurvivors 55 years or younger with respect to gender, smoking history, ARDS risk factors, ARDS identifying characteristics, APACHE II (acute physiology and chronic health evaluation), number of organ failures, or the incidence of sepsis. In the 48 h prior to death, nonsurvivors 55 years and younger had more organ failure (3.4 +/- 0.2 vs 2.8 +/- 0.2; p = 0.03), higher fraction of inspired oxygen (0.82 +/- 0.03 vs 0.68 +/- 0.03; p = 0.008), and higher positive end-expiratory pressure levels (13 +/- 1 vs 8 +/- 1; p = 0.001) than older nonsurvivors. Despite more severe expression of disease, only 32 (50%) nonsurvivors 55 years and younger had support withdrawn. Significantly more nonsurvivors older than 55 years (73%) had support withdrawn (p = 0.009). Even in the absence of chronic disease states, withdrawal was more likely for patients older than 55 years (21/51) than in those 55 years and younger (3/32; p &lt; 0.001). Mortality is significantly higher for patients with ARDS older than 55 years. Decisions to withdraw support are made more often in ARDS patients older than 55 years. These data suggest that age bias may influence decisions to withdraw support. Phase 1 (acute injury): Normal physical exam; possible respiratory alkalosis. Phase 2 (6–48 hours): Hyperventilation, hypocapnia, widening A-a oxygen gradient. Phase 3: Acute respiratory failure, tachypnea, dyspnea, ↓ lung compliance, scattered rales, diffuse chest infltrates on CXR (see Figure 2.15-5). F IGU R E 2.1 5-5. AP CXR showing a diffuse alveolar filling pattern 2° to ARDS. (Reproduced, with permission, from Kasper DL et al. Harrison’s Principles of Internal Medicine, 16th ed. New York: McGraw-Hill, 2005: 1497.) ■ Phase 4: Severe hypoxemia unresponsive to therapy; ↑ intrapulmonary shunting; metabolic and respiratory acidosis. The criteria for ARDS diagnosis (according to the American-European Consensus Conference defnition) are as follows: Acute onset of respiratory distress. PaO2/FiO2 ratio ≤ 200 mmHg. Bilateral pulmonary infltrates on CXR. No evidence of cardiac origin (capillary wedge pressure < 18 mmHg or no clinical evidence of elevated left atrial pressure). To define the occurrence rate of acute respiratory distress syndrome (ARDS) using established criteria in a well-defined general patient population, to study the clinical course of ARDS when patients were ventilated using a \"lung-protective\" strategy, and to define the total costs of care. A 3-yr (1993 through 1995) retrospective descriptive analysis of all patients with ARDS treated in Kuopio University Hospital. Intensive care unit in the university hospital. Fifty-nine patients fulfilled the definition of ARDS: Pao2/Fio2 &lt;200 mm Hg (33.3 kPa) during mechanical ventilation and bilateral infiltrates on chest radiograph. None. With a patient data management system, the day-by-day data of hemodynamics, ventilation, respiratory mechanics, gas exchange, and organ failures were collected during the period that Pao2/Fio2 ratio was &lt;200 mm Hg (33.3 kPa). The frequency of ARDS was 4.9 cases/100,000 inhabitants/yr. Pneumonia and sepsis were the most common causes of ARDS. Mean age was 43+/-2 yrs. At the time of lowest Pao2/Fio2, the nonsurvivors had lower arterial and venous oxygen saturations and higher arterial lactate than survivors, whereas there were no differences between the groups in other parameters. Multiple organ dysfunction preceded the worst oxygenation in both the survivors and nonsurvivors. The intensive care mortality was 37%; hospital mortality and mortality after a minimum 8 months of follow-up was 42%. The most frequent cause of death was multiple organ failure. The effective costs of intensive care per survivor were US $73,000. The outcome of ARDS is unpredictable at the time of onset and also at the time of the worst oxygenation. Keeping the inspiratory pressures low (30-35 cm H2O [2.94 to 3.43 kPa]) reduces the frequency of pneumothorax, and might lower the mortality. Most patients are young, and therefore the costs per saved year of life are low. MAJOR COMPLICATIONS Cardiopulmonary Complications Ventilation-perfusion mismatching produces a fall in arterial Po2 early in the course. Increasing alveolar epithelial injury and capillary permeability result in increased pulmonary water content, which decreases pulmonary compliance and interferes with oxygen exchange. In the absence of pneumonia or heart failure, progressive diffuse pulmonary infiltrates and arterial hypoxemia occurring within 1 week of a known insult indicate the development of mild acute respiratory distress syndrome (ARDS) (200 mmHg < Pao2/Fio2 ≤ 300 mmHg), moderate ARDS (100 mmHg < Pao2/Fio2 ≤ 200 mmHg), or severe ARDS (Pao2/Fio2 ≤100 mmHg). Acute lung injury or ARDS develops in ~50% of patients with severe sepsis or septic shock. Respiratory muscle fatigue can exacerbate hypoxemia and hypercapnia. An elevated pulmonary capillary wedge pressure (>18 mmHg) suggests fluid volume overload or cardiac failure rather than ARDS. Pneumonia caused by viruses or by This type of respiratory failure is caused by conditions that affect oxygenation, such as: Low ambient oxygen (e.g. at high altitude) Ventilation-perfusion mismatch (parts of the lung receive oxygen but not enough blood to absorb it, e.g. pulmonary embolism) Alveolar hypoventilation (decreased minute volume due to reduced respiratory muscle activity, e.g. in acute neuromuscular disease); this form can also cause type 2 respiratory failure if severe. Diffusion problem (oxygen cannot enter the capillaries due to parenchymal disease, e.g. in pneumonia or ARDS) Shunt (oxygenated blood mixes with non-oxygenated blood from the venous system, e.g. right to left shunt) Type 2 Hypoxemia (PaO2 <8kPa or normal) with hypercapnia (PaCO2 >6.0kPa). The basic defect in type 2 respiratory failure is characterized by: {| class=\"wikitable\" |PaO2 || decreased (< )or normal |- | PaCO2 || increased (> ) |- | PA-aO2 || normal |- |pH || <7.35 |} This type of respiratory failure occurs with alveolar flooding and subsequent intrapulmonary shunt physiology. Alveolar flooding may be a consequence of pulmonary edema, pneumonia, or alveolar hemorrhage. Pulmonary edema can be further categorized as occurring due to elevated pulmonary microvascular pressures, as seen in heart failure and intravascular volume overload or ARDS (“low-pressure pulmonary edema,” Chap. 322). This syndrome is defined by acute onset (≤1 week) of bilateral opacities on chest imaging that are not fully explained by cardiac failure or fluid overload and of shunt physiology requiring positive end-expiratory pressure (PEEP). Type I respiratory failure occurs in clinical settings such as sepsis, gastric aspiration, pneumonia, near-drowning, multiple blood transfusions, and pancreatitis. The mortality rate among patients with ARDS was traditionally very high (50–70%), although changes in patient care have led to mortality rates closer to 30% (see below). Equations Abbreviated alveolar air equation PAO2, PEO2, and PIO2 are the partial pressures of oxygen in alveolar, expired, and inspired gas, respectively, and VD/Vt is the ratio of physiologic dead space over tidal volume. Medicine In medicine, the FIO2 is the assumed percentage of oxygen concentration participating in gas exchange in the alveoli. Uses The FIO2 is used in the APACHE II (Acute Physiology and Chronic Health Evaluation II) severity of disease classification system for intensive care unit patients. For FIO2 values equal to or greater than 0.5, the alveolar–arterial gradient value should be used in the APACHE II score calculation. Otherwise, the PaO2 will suffice. The ratio between partial pressure of oxygen in arterial blood (PaO2) and FIO2 is used as an indicator of hypoxemia per the American-European Consensus Conference on lung injury. A high FIO2 has been shown to alter the ratio of PaO2/FIO2. Cardiovascular dysfunction a) Shock b) Cardiac Arrest c) Severe hypoperfusion (lactate >5 mmol/L or >45 mg/dL) d) Severe acidosis (pH<7.1) e) Use of continuous vasoactive drugs f) Cardio-pulmonary resuscitation Respiratory dysfunction g) Acute cyanosis h) Gasping i) Severe tachypnea (respiratory rate>40 breaths per minute) j) Severe bradypnea (respiratory rate<6 breaths per minute) k) Severe hypoxemia (O2 saturation <90% for ≥60min or PAO2/FiO2<200) l) Intubation and ventilation not related to anaesthesia Renal dysfunction m) Oliguria non responsive to fluids or diuretics n) Severe acute azotemia (creatinine >300 μmol/ml or >3.5 mg/dL) o) Dialysis for acute renal failure Coagulation dysfunction p) Failure to form clots q) Severe acute thrombocytopenia (<50,000 platelets/ml) r) Massive transfusion of blood or red cells (≥ 5 units) Hepatic dysfunction s) Jaundice in the presence of pre-eclampsia Noninvasive estimation techniques have been proposed. Clinical significance Because of the large compliance of pulmonary circulation, it provides an indirect measure of the left atrial pressure. For example, it is considered the gold standard for determining the cause of acute pulmonary edema; this is likely to be present at a PWP of >20mmHg. It has also been used to diagnose severity of left ventricular failure and mitral stenosis, given that elevated pulmonary capillary wedge pressure strongly suggests failure of left ventricular output. Traditionally, it was believed that pulmonary edema with normal PWP suggested a diagnosis of acute respiratory distress syndrome (ARDS) or non cardiogenic pulmonary edema (as in opiate poisoning). However, since capillary hydrostatic pressure exceeds wedge pressure once the balloon is deflated (to promote a gradient for forward flow), a normal wedge pressure cannot conclusively differentiate between hydrostatic pulmonary edema and ARDS. Removal of the extrinsic cause or treatment of underlying infection if identifed. Corticosteroid treatment may be used if no cause is identif ed. Causes include ventilation-perfusion (V/Q) mismatch, right-to-left shunt, hypoventilation, low inspired O2 content (important at altitudes), and diffusion impairment. Findings depend on the etiology. ↓HbO2 saturation, cyanosis, tachypnea, shortness of breath, pleuritic chest pain, and altered mental status may be seen. Pulse oximetry: Demonstrates ↓ HbO2 saturation. CXR: To rule out ARDS, atelectasis, or an infltrative process (e.g., pneumonia) and to look for signs of pulmonary embolism. ABGs: To evaluate PaO2 and to calculate the alveolar-arterial (A-a) oxygen gradient ([(Patm − 47) × FiO2 − (PaCO2/0.8)] − PaO2). An ↑ A-a gradient suggests a V/Q mismatch or a diffusion impairment. Figure 2.15-4 summarizes the approach toward hypoxemic patients. Is PaCO2 increased? Hypoventilation Yes Yes No No Is PAO2 − PaO2 increased? Twenty-nine patients, divided into three groups: 1) chronic obstructive pulmonary disease; 2) acute or chronic pulmonary disease with left heart failure; 3) respiratory insufficiency after peritonitis, pancreatitis, and/or sepsis, were studied during respirator treatment with regard to gas exchange, breathing mechanics and central circulation. The dead space ventilation was somewhat greater in group 1 than in the other groups. The alveolar-arterial oxygen tension difference was least in group 1, greater in group 2 and extremely high in group 3. Neither dynamic compliance of the thorax nor inspiratory resistance showed any significant differences between the groups. The cardiac output had the highest values in group 3. The venous admixture was generally small in group 1 and extremely large in group 3. The pulmonary artery pressures were highest in group 2. Three variables proved to be valuable when assessing the prognosis of a patient: a large venous admixture; a large alveolar-arterial oxygen tension difference, and a high pulmonary artery pressure indicated a less favourable prognosis. 1. The use of an oxygen chamber in the treatment of pneumonia patients makes it possible to administer this gas for long periods of time under exactly known conditions. The medical and nursing care of the patient is greatly facilitated. 2. Prolonged inhalation of oxygen varying from 40 to 60 per cent appears to be without harm. 3. Oxygen administered to intensely anoxemic patients almost immediately clears up this anoxemia. Cyanosis disappears with the anoxemia. 4. The removal of patients from the high oxygen while they are still sick and while examination shows that there are still extensive edema and infiltration of the lung results in a return of the intense anoxemia. 5. It is sometimes impossible to clear up the anoxemia, even when as high as 60 per cent of oxygen is given, especially when there are considerable edema and infiltration of the lungs. 6. Five cases in which the prognosis was grave recovered. Three cases, one of tuberculosis, one with a Pneumococcus Type III infection, and a third with a pneumonia superimposed on a chronic pulmonary condition, died. 7. In all cases there appeared to be an improvement in the patient's condition. In one case, particularly, with an intense degree of anoxemia, the patient became moribund and pulseless. Following the administration of 60 per cent of oxygen there was a lowering of the heart rate from 160 to 120, the return of the pulse to the radial artery, the color became bright pink, and there was a remarkable change in the clinical condition. 8. The anoxemia of pneumonia is due, in large measure, to an impairment of the respiratory surface of the lungs. The greater the lung involvement the greater the anoxemia. Especially is this so when the pneumonic process extends throughout the lungs so that there are many patches of bronchopneumonia, with accompanying bronchitis and edema, as evidenced by the presence of râles throughout the lungs. 9. Rapid and shallow breathing of the degree observed in pneumonia is, as far as present evidence shows, of less importance in the production of anoxemia.\nHere is the question:\nANESTHESIOLOGY, CRITICAL CARE AND EMERGENCIES: A patient admitted for acute pancreatitis starts with tachypnea, tachycardia, sweating and progressive cyanosis. PaO2 is 55 mm Hg (PaO2/FiO2 ratio<200). CXR shows bilateral alveolar pulmonary infiltrates. Pulmonary capillary wedge pressure is normal. Oxygen therapy does not improve the situation. What is the most probable diagnosis:\nHere are the potential choices:\n1. Nosocomial pneumonia.\n2. Cardiac failure.\n3. Carcinomatous lymphangitis.\n4. Pulmonary thromboembolism.\n5. Respiratory distress.\nThe correct answer is: 5. Respiratory distress."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Assessment of the etiology of urinary tract infections and pathogen drug sensitivity in hospitalized children. We analyzed 156 medical records of patients admitted to the Clinical Department of Pediatrics, Bielański Hospital in Warsaw in 2012, with a suspected UTI. Positive urine culture results were found in 113 (72.4%) children (68; 60.2% of girls and 45; 39.8% of boys), aged from 2 months to 17.9 years (the average age was 2 years and 3 months). E. coli was the most frequent isolated pathogen - 92.0% of patients (104/113). The greatest sensitivity of pathogens showed to cephalosporins of the second and third generation (80.5-90.3%). The sensitivity to amoxicillin with clavulanic acid was 71.7% and 41.6% for ampicillin. The length of hospital stay and treatment ranged from 2 to 16 days (average 8.6 days). In 60.2% (68/113) of patients were treated with second cephalosporin, in 17.7% (20/113) with third generation cephalosporins. Only 11.5% of them (13/113) received amoxicillin with clavulanic acid. Before the treatment, 69.9% (79/113) of children had a fever from 38 up to 41,7ºC, and the fever persisted for the average of 2.5 days (1-8 days). We found significantly higher levels of CRP in children aged between 2-4 in comparison to other age groups (p= 0.0290). In 44.2% (50/113) of children the cystourethrography was performed and in 22% (11/50) cases we recognized a unilateral or bilateral vesicoureteral-ureter of a I to IV degree, on one or both sides. The most common etiological agent of UTIs in children remains E. coli. The sensitivity of urinary pathogens to the commonly used antibiotics is still high, however, finds a large percentage of strains resistant to ampicillin and to amoxicillin with clavulanic acid. The antibiotic recommended for empiric therapy of UTIs in children should be cephalosporins, if there is such a possibility, the treatment should be based on drug sensitivity tests of the organisms grown. Because of the relatively long hospitalization of children with UTIs and the possibility of hospital complications, sequential treatment should also be considered sequential. A first urinary tract infection (UTI) in childhood is more prevalent in females &lt; 5-years-old. Circumcision generally protects males from UTI, however, during the month following the procedure, the prevalence of infection increases up to 12 times in circumcised boys when compared with those not circumcised. Almost all the infections are caused by aerobic Gram-negative bacteria of which E. coli are responsible for 70-90% of the cases. Signs and symptoms of UTI vary in different age groups. Factors associated with the likelihood of UTI are: non-circumcised male, fever &gt; 40 degrees C, and a fever &gt; 39 degrees C for more than 48 hours with no other focus of infection on physical examination. Urinalysis and urine microscopy are screening tests for UTI. In children with clinical symptoms and signs suggesting UTI, the results of these tests have a positive predictive value (if both are positive), or negative predictive value (if both are negative) approximating 100%. The definitive diagnosis of UTI is based on the urine culture. Bag urine culture is associated with a very high rate of contamination. Therefore, in non-toilet trained children, urine culture should be obtained directly from the urinary bladder either by supra pubic aspiration or in and out transurethral catheterization. Mid stream clean voided urine specimens obtained from circumcised males in the first months of life are also acceptable. Depending on the clinical presentation, oral therapy can begin from as early as two months of age, and the recommended empiric drugs for first febrile UTI are cefuroxime axetil, or amoxicillin clavulanate. Cephlexin is recommended for cystitis. During the course of antibiotic treatment, serial white blood cell count and temperature are closely monitored. Typically, the intravenous antibiotics are continued until the person has no fever for at least 24 to 48hours, then equivalent antibiotics by mouth can be given for a total of twoweek duration of treatment. Intravenous fluids may be administered to compensate for the reduced oral intake, insensible losses (due to the raised temperature) and vasodilation and to optimize urine output. Percutaneous nephrostomy or ureteral stent placement may be indicated to relieve obstruction caused by a stone. Children with acute pyelonephritis can be treated effectively with oral antibiotics (cefixime, ceftibuten and amoxicillin/clavulanic acid) or with short courses (2 to 4days) of intravenous therapy followed by oral therapy. If intravenous therapy is chosen, single daily dosing with aminoglycosides is safe and effective. Infants less than 3 months of age with urinary tract infection are usually hospitalized. Recent studies show that a less aggressive management for those patients aged ≥ 29 days may be feasible. To determine the complication rate in infants&lt;3 months of age with urinary tract infection, and to identify the causative agents and their antibiotic susceptibility. A retrospective study was conducted on infants&lt;3 months of age with positive urinalysis results, together with a positive urine culture from a catheterized specimen and seen in the Emergency Department from 2007 to 2012. Demographics, clinical and microbiology (microorganism isolated and antibiotic susceptibility) data were collected. The complications rate (bacteremia, bacterial meningitis, renal abscess, surgical intervention, Intensive Care Unit admission, or death) were calculated for the overall sample and for different age groups (&lt;29, 29-60, and 61-90 days). A total of 460 patients are included; 137 (29.8%)&lt;29, 166 (36.1%) 29-60, and 157 (34.1%) 61-90 days of age. Twenty four (5.4%; 95% CI: 3.6-7.8) had bacteremia; 15 (10.9%; 95% CI: 6.7-17.3) were&lt;29 days; 8 (4.9%; 95% CI: 2.5-9.4) were 29-60 days, and one (0.7%; 95% CI: 0.1-3.7) was 61-90 days of age (P&lt;.001). One neonate (0.8%; 95% CI: 0.1-4.1) had bacterial meningitis, and 2, renal abscess. Escherichia coli was the common pathogen identified (87.2%) in the urine culture, with a susceptibility to amoxicillin-clavulanate, gentamicin, and cefixime of 89.2, 97.0, and 96.0%, respectively. Complications are low in infants&lt;3 months of age with UTI, especially in those ≥ 29 days of age. The identification of patients at very low risk for complications would allow a less aggressive management. Escherichia coli antibiotic susceptibility remains stable, but continuing careful surveillance is essential to optimize empirical antibiotic treatment. The infectious disease is the main source of care demand in Pediatric Emergency Departments (PED) and is a frequent cause of hospital admission with antibiotics. Our objectives are: 1) to determine the diseases that are seen in PED that required admission with antibiotics; 2) to determine the microbiological methods used and, 3) to analyze the characteristics of the indicated treatment. A prospective multicenter study was conducted in 22 Spanish hospitals. We included patients younger than 18 years seen in PED on day 14 of each month between June 2009 and May 2010 who required hospitalization with systemic antibiotics. Patients admitted to Intensive Care Unit were excluded. There were 30,632 consultations in the PED during the study period. A total of 1,446 (4.7%) patients were hospitalized, 395 (27.3%) of them with antibiotics. Ninety-five patients (24.1%) had received antibiotics before admission. Three hundred twenty (81%) children underwent at least one microbiological test, with blood culture (69.9%) and urine culture (30.9%) being the most requested ones. The main diagnoses at admission were pneumonia (29.4%), urinary tract infection (15.4%), and fever without source (12.1%). Twenty five different antibiotics were prescribed, with cefotaxime (27.8%) and amoxicillin-clavulanate (23.4%) being the most prescribed ones. A single antibiotic was prescribed to 80.8% of patients, and parenteral administration was the most indicated (93.7%). Antibiotic therapy was prescribed in one in every 4 patients who required admission to hospital. Pneumonia was the most common source. Blood culture was the most frequent microbiological test requested in the PED. A limited number of beta-lactam antibiotics represented the majority of antibiotic prescriptions. Urinary tract infections (UTIs) are a common diagnosis within the pediatric emergency department (ED). Because of the necessary delay in obtaining urine culture results, clinicians must decide whether to prescribe antibiotics for a suspected UTI before urine culture results. The primary objective of this study was to identify the proportion of children given empiric antibiotics who subsequently did not meet consensus definition of an UTI. The secondary objective was to identify factors associated with return visits to the ED after an index visit for UTI. We also attempted to identify predictors of prescription of empiric antibiotics for children who did not have a UTI. This was a retrospective chart review of all patients between the ages of 2 months and 18 years diagnosed with a UTI between July 2016 and June 2017 in the ED of a single urban quaternary care center. Patients were excluded for the following reasons: use of bag for urine collection, subsequent admission to the hospital, receipt of antibiotics within the previous 3 days, use of antibiotics for an indication other than a UTI, and urine culture obtained at an outside facility. Of 404 included patients, 389 (96.2%) were discharged on antibiotics and 243 (62.4%) did not have a UTI. On the multivariate analysis, age ≧ 36 months was associated with increased odds of receiving antibiotics and not having a UTI while both ≥1+ leukocyte esterase and ≥1+ nitrites on urinalysis were associated with decreased odds of receiving antibiotics and not meeting UTI criteria. Sixty-two patients revisited the ED within 30 days of the initial visit, 24 (38.7%) of which met criteria for UTI during the index visit. Prescription of antibiotics at the time of the index visit was associated with decreased odds of reutilization, whereas an extended-spectrum β-lactamase producing organism cultured from urine at the index visit was associated with increased odds of reutilization. A high number of patients discharged on empiric antibiotics did not meet criteria for a UTI. We did not identify clinically useful factors that predicted prescription of empiric antibiotics for children who do not have a UTI. We believe that unnecessary antibiotic prescriptions could be substantially decreased by decreasing empiric use of antibiotics coupled with reliable follow-up for positive urine cultures. Diagnosis Laboratory examination Analysis of the urine may show signs of urinary tract infection. Specifically, the presence of nitrite and white blood cells on a urine test strip in patients with typical symptoms are sufficient for the diagnosis of pyelonephritis, and are an indication for empirical treatment. Blood tests such as a complete blood count may show neutrophilia. Microbiological culture of the urine, with or without blood cultures and antibiotic sensitivity testing are useful for establishing a formal diagnosis, and are considered mandatory. Diagnosis In straightforward cases, a diagnosis may be made and treatment given based on symptoms alone without further laboratory confirmation. In complicated or questionable cases, it may be useful to confirm the diagnosis via urinalysis, looking for the presence of urinary nitrites, white blood cells (leukocytes), or leukocyte esterase. Another test, urine microscopy, looks for the presence of red blood cells, white blood cells, or bacteria. Urine culture is deemed positive if it shows a bacterial colony count of greater than or equal to 103 colony-forming units per mL of a typical urinary tract organism. Antibiotic sensitivity can also be tested with these cultures, making them useful in the selection of antibiotic treatment. However, women with negative cultures may still improve with antibiotic treatment. As symptoms can be vague and without reliable tests for urinary tract infections, diagnosis can be difficult in the elderly. Assess H and P for “low risk” status Age? <1 mo >1 mo Low risk Not low risk CBC with differential, blood culture, urine culture All parameters normal? No Yes All parameters normal? NoYes outpatients without empirical antibiotic treatment or, alternatively, treated with intramuscular ceftriaxone. Regardless of antibiotic treatment, close follow-up for at least 72 hours, including re-evaluation in 24 hours or immediately with any clinical change, is essential. Children with a positive blood culture require immediate re-evaluation, repeat blood culture, consideration for lumbar puncture, and empirical antibiotic treatment. Urine dipsticks have to be used more frequently for the screening of urinary tract infections (UTI) in febrile infants and children (grade A). Confirmation of the UTI by urine culture should prefer other methods of sampling than the urine bag: sampling jet, urethral catheterization, or pubic puncture (grade A). The percentage of Escherichia coli producing extended-spectrum beta-lactamases (ESBL) in children accounts for less than 10 % in France and does not justify revising the 2007 recommendations (grade B). An increase in the use of carbapenems in first-line treatment is a major environmental hazard and exposes the patient to the risk of untreatable infections. For febrile UTI, the expert group recommended: (1) recover the results of susceptibility testing as soon as possible to quickly adapt treatment for possible resistant strains; (2) favor initial treatment with aminoglycosides (particularly amikacin) which remain active in the majority of ESBL strains for patients seen in the pediatric emergency department and/or hospital; (3) ceftriaxone (IV or IM) remains an appropriate treatment for patients seen in the emergency department or outpatient clinic because the percentage of ESBL-producing enterobacteria strains remains low; (4) use oral cefixime (grade B) in nonsevere cases and low-risk patients defined as age&gt;3 months, general condition preserved, disease duration of fever&lt;4 days, no associated comorbidity, and no history of urinary tract infection, uropathy, or prior antibiotic therapy in the last 3 months; (5) oral relay for parenteral treatment is guided by in vitro susceptibility testing, in an attempt to reduce the use of oral cephalosporins to limit the selection of resistant bacterial strains. The total duration of treatment recommended is usually 10 days. Except for special circumstances, there is no need to prescribe retrograde cystography or antibiotic prophylaxis after a first febrile urinary tract infection. For cystitis, the panel recommends systematic urinalysis and initial prescription before the results of the urine culture of one of the three following oral antibiotics: amoxicillin-clavulanate, cotrimoxazole, cefixime. The total duration of antibiotic treatment is 5days to tailor treatment based on clinical progression and antibiotic susceptibility. Urinary tract infection is a common cause of serious bacterial infection in young children. The non-specific presentation has implications for misdiagnosis and the potential for long-term complications. To determine if a negative dipstick urinalysis is adequate to exclude urinary tract infection in children aged 0-10 years. Data was subdivided into two age groups: 0-2 years and 2-10 years. Retrospective case note review over an 8-month period. Cases included required a printed urinalysis recorded from the Clinitek 50 (Bayer) machine and a printed microscopy and culture result. We defined a negative urinalysis as being negative for all of blood, protein, leucocytes and nitrites. A total of 375 cases were included for statistical calculation. Three hundred and seventy-five cases gave a prevalence of 10.7% with a sensitivity of 92.5%, specificity of 39.4% and a negative predictive value of 97.8%. In the 0-2-year-old group, we demonstrated a prevalence of 15%, a sensitivity of 87.5%, specificity of 39.7% and a negative predictive value of 94.7%. This compares to the older group (2-10 years) with a prevalence of 7.0%, a sensitivity of 100%, specificity of 39.7% and a negative predictive value of 100%. Prevalence of urinary tract infection varied with age with a higher prevalence in the 0-2 years age group. The lower negative predictive value and the higher clinical importance in this age group means that dipstick urinalysis is inadequate to exclude urinary tract infection. Conversely, we believe that children in the 2-10 years age group can adequately have urinary tract infection excluded with a negative dipstick urinalysis. Acute fever of unknown origin (FUO) in children under 29 days is a worrying situation because of the risk of serious bacterial infection (SBI). to study the main clinical and laboratory characteristics of a group of hospitalized children under 29 days with diagnosis of FUO. Retrospective study of children under 29 days hospitalized due to FUO. The clinical records of the patients were reviewed, recording age, sex, history of fever before consultation, temperature at admission, estimated severity at admission and discharge, discharge diagnoses, laboratory tests, and indicated treatments. Patients were classified according to the severity of the discharge diagnosis, as severe (S) and non-severe (NS). The inclusion criteria were term newborn, age less than 29 days, fe ver &gt; 38°C registered at home or admission, and history of &lt; 4 days. 468 children with FUO were admitted. Concordance between severity at admission and discharge was low (Kappa = 0.125; p = 0.0007). 26.1% of children were S and 73.9% NS. In the S group, urinary tract infection domínate (70.5%) and in the NS, FUO (67.6%). The cut-off levels for leukocytes/mm3, C-reactive protein, and neutrophils/mm3 showed negative predictive values to rule out severe bacterial infection. Conclu sions: Most of the newborns presented mild severity at admission, but 24% of them had SBI, thus hospitalization and close clinical observation are always necessary. Laboratory tests, such as CRP, white blood cell and neutrophils count are not good predictors of SBI. Early treatment with antibio tics for patients who meet the low-risk criteria is debatable. Most episodes of fever in children younger than 3 years of age have a demonstrable source of infection elicited by history, physical examination, or a simple laboratory test. In this age group, the most commonly identified serious bacterial infection is a UTI. A blood culture to evaluate for occult bacteremia, and urinalysis and urine culture to evaluate for a UTI, should be considered for all children younger than 3 years of age with fever without localizing signs. Stool culture should be obtained in those with diarrhea marked by blood or mucous. Ill-appearing children should be admitted to the hospital and treated with empirical antibiotics. Approximately 0.2% of well-appearing febrile children 3 to 36 months of age vaccinated against S. pneumoniae and To investigate antibiotic resistance among pathogens isolated from urines in a tertiary care children's hospital in Italy. Retrospective analysis of prospectively collected data on antibiotic susceptibility of Gram-negatives isolated from urines at the Istituto Giannina Gaslini, Genoa - Italy from 2007 to 2014. Antibiotic susceptibility was evaluated. By means of CLSI criteria from 2007 to 2010, while from 2011 EUCAST criteria were adopted. Data on susceptibility to amoxicillin-clavulanate, co-trimoxazole, cefuroxime, nitrofurantoin, fosfomycin and ciprofloxacin were evaluated for Escherichia coli, while for other Enterobacteriaceae data were collected for amoxicillin-clavulanate, co-trimoxazole and ciprofloxacin and for ciprofloxacin against Pseudomonas aeruginosa. Univariate and multivariable analyses were performed for risk factors associated with resistance. A total of 4596 Gram-negative strains were observed in 3364 patients. A significant increase in the proportion of resistant strains was observed for E.coli against amoxicillin-clavulanate, cefuroxime and ciprofloxacin and for others Enterobacteriaceae against co-trimoxazole and ciprofloxacin. Resistance to nitrofurantoin and fosfomycin was very infrequent in E.coli. Logistic regression analysis showed that repeated episode of urinary tract infections was a risk factor for E.coli resistance to amoxicillin-clavulanate, co-trimoxazole and cefuroxime, while admission in one of the Units usually managing children with urinary tract malformations was significantly associated to resistance to amoxicillin-clavulanate and cefuroxime. In conclusion the present study shows an increase in antibiotic resistance in pediatric bacteria isolated from urines in children, especially in presence of repeated episodes and/or urinary tract malformations. This resistance is worrisome for beta-lactams and cotrimoxazole, and start to increase also for fluoroquinolones while nitrofurantoin and fosfomycin still could represent useful drugs for oral treatment of these infections. • Infections are frequent in patients with urinary tract malformations • Antibiotic prophylaxis can select for resistant pathogens What is New: • The increase in the resistance to β-lactams, co-trimoxazole or fluoroquinolones in pathogens causing urinary tract infections cause a reduction of drugs with oral formulations available for therapy • Old drugs like nitrofurantoin and fosfomycin can represent attractive compounds for oral treatment of urinary tract infections in children presence of resistance to other drug classes. Acute fever of unknown origin (AFUO) is established when the anamnesis and physical examination cannot identify the cause. In infants less than 3 months-old this is situation for concern, due to the risk of a serious bacterial infection. To describe the clinical and laboratory variable of patients with AFUO, in order to look for clues in order to base studies on the decisions arising drom this problem. A report is presented on a retrospective study conducted on a cohort of children less than three months-old admitted to the Hospital Roberto del Río (2007-2011) due to an AFUO. Clinical histories were reviewed and the patients were grouped, according to the severity of the admission diagnosis, into severe and non-severe. They were compared in strata determined by the variables of clinical interest. A total of 550 children were admitted with AFUO during the study period. There was low agreement between the severity on admission and at discharge (kappa=0.079; P=.26). There were 23.8% of children in the severe group and 76.2% in the non-severe group. Urinary tract infection predominated in the severe group (68.7%) and 40.7% with acute febrile syndrome in the non-severe group. The cut-off levels for C-reactive protein, white cells, and neutrophils per mm(3), to calculate the fixed and variable indices, only showed negative predictive values of some use for ruling out serious bacterial infection. The ROC curves with white cell and neutrophil counts and C-reactive protein, did not provide andy fixed indices of clinical use. More than one-third (34.6%) of lumbar punctures were traumatic or failures. According to the results of this study, there is an obvious excess of hospital admissions, little usefulness in the examinations to identify serious bacterial infection, a high percentage lumbar punctures traumatic and lumbar punctures failures, and an excess of antibiotic treatments. A review of clinical criteria and procedures is needed. Ewingella americana (Ea) is a Gram-negative, lactose-fermenting, oxidase-negative and catalase-positive bacterium that was first described in 1983 as a new genus and species in the family Enterobacteriaceae. It is not known whether Ea is a true pathogen or simply an opportunistic infectious agent, as most of the cases have been described in patients at risk. A 4-year-old girl described here was hospitalized due to a productive cough over the previous 3 weeks and a fever &gt; 38 °C associated with tachypnea over the previous 2 days. Her familial and personal medical histories were negative for relevant diseases, including respiratory infections. At admission, she was febrile (axillary temperature 39.2 °C) and had dyspnea with retractions, grunting and nasal flaring. A chest examination revealed fine crackling rales in the left upper field associated with bilateral wheezing. A chest X-ray revealed segmental consolidation of the lingula of the left lung. Laboratory tests revealed leukocytosis (15.,800 white blood cells/mm<sup3</sup with 50.3% neutrophils), a slight increase in serum C-reactive protein (11.9 mg/L) and normal procalcitonin values (&lt; 0.12 ng/mL). A nasopharyngeal swab culture did not reveal viral or bacterial respiratory pathogens, including atypical bacteria. A blood culture revealed the presence of a Gram-negative, lactose-fermenting rod that was oxidase negative and catalase positive. The isolate was identified by means of the VITEK®2 identification system (bioMérieux, Firenze, Italy) as Ea. This identification was confirmed by sequencing the 16 s ribosomal deoxyribonucleic acid (rDNA). The pathogen was sensitive to aminoglycoside, fluoroquinolones, carbapenems, cefotaxime, and ceftazidime but was intermediate against sulfametoxazole/trimethoprim and resistant to amoxicillin-clavulanic acid, fosfomycin, and oxacillin. The child was immediately treated orally with amoxicillin-clavulanic acid and erythromycin. Based on the results of a blood culture and sensitivity tests, the amoxicillin-clavulanic acid medication was stopped after 3 days. Erythromycin was continued for a total of 10 days, and the child was discharged after 3 days in the hospital. Follow-up visit 1 month later did not reveal any respiratory problems. This case shows that Ea infections in healthy subjects are mild even in pediatric age, and the need for antibiotic therapy is debated. Cases occurring in subjects with underlying chronic disease can be significantly more complicated and require appropriate antibiotic therapy. Since infections of the urinary tract in children often present diagnostic difficulties, it is essential to be able to identify these patients with simple, reliable methods. After a clinical-laboratory study on 4176 urine cultures, the Authors affirm that the reliability of this test is much greater when the parents have been instructed in the correct way of collection the urine specimen, and when in the laboratory the \"slide\" is carried out within three hours of taking the sample. To evaluate clinical and analytic numeric data that may help the emergency departments to identify bacterial infections in infants. A retrospective study of 430 infants with bacterial growth in cultures (culture from blood, 30; urine, 207; stools, 193, and/or cerebrospinal fluid, n 25) was performed. These patients were compared with a control group (n 430), randomly selected from patients aged less than 12 months with negative cultures who were hospitalized with suspected infection. Neonates and surgical patients were excluded from both groups. Statistical analysis was performed using Student's t-test for independent samples, Levene's test for the study of equality of variances, bivariate correlation and one-factor ANOVA, and receiver-operating characteristic (ROC) curves and odds ratios were calculated when statistically significant (p &lt; 0.05) results were obtained. These analyses were performed using the SPSS 10.0 statistical software package. Of the infants admitted to the pediatric unit, 11.7 % had at least one positive bacterial culture. Temperature (p 0.005), leucocyte count (p 0.003), percentage of neutrophils (p &lt; 0.0001) and C-reactive protein (p &lt; 0.0001) were significantly higher in infants with positive cultures. In invasive infections significant differences were found in sex (more frequent in males) (p 0.03), heart rate (p &lt; 0.0001) and respiratory rate (p 0.003). In the ROC curves, the best diagnostic yield was obtained for C-reactive protein (0.93 for a cutoff value of 29 mg/l, 86 % specificity and 91 % sensitivity). C-reactive protein is essential for diagnosis of bacterial infection in infants in the emergency department.\nHere is the question:\nPEDIATRICS: A 13-month-old infant comes to the emergency department with fever up to 39ºC of 48h of evolution with no other associated symptoms. Examination by organs and devices with no significant findings, highlighting good general condition. You were going to discharge him home but the Pediatrics attending on duty asks for a systematic urine and urine culture by catheterization. The urine shows leukocyturia ++, hematuria + and nitrites ++ and the urine Gram-negative bacilli are observed. In the blood analysis there is no leukocytosis and the C-reactive protein is 50 mg/l. The attending now tells you that the child does not need to be admitted and to prescribe an oral antibiotic. State the least appropriate empirical antibiotic treatment in this case:\nHere are the potential choices:\n1. Amoxicillin.\n2. Amoxicillin-clavulanic acid.\n3. Cefuroxime-axetil.\n4. Cotrimoxazole.\n5. Cefixime.\nThe correct answer is: ",
        "gold_answer": "1 Amoxicillin.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Assessment of the etiology of urinary tract infections and pathogen drug sensitivity in hospitalized children. We analyzed 156 medical records of patients admitted to the Clinical Department of Pediatrics, Bielański Hospital in Warsaw in 2012, with a suspected UTI. Positive urine culture results were found in 113 (72.4%) children (68; 60.2% of girls and 45; 39.8% of boys), aged from 2 months to 17.9 years (the average age was 2 years and 3 months). E. coli was the most frequent isolated pathogen - 92.0% of patients (104/113). The greatest sensitivity of pathogens showed to cephalosporins of the second and third generation (80.5-90.3%). The sensitivity to amoxicillin with clavulanic acid was 71.7% and 41.6% for ampicillin. The length of hospital stay and treatment ranged from 2 to 16 days (average 8.6 days). In 60.2% (68/113) of patients were treated with second cephalosporin, in 17.7% (20/113) with third generation cephalosporins. Only 11.5% of them (13/113) received amoxicillin with clavulanic acid. Before the treatment, 69.9% (79/113) of children had a fever from 38 up to 41,7ºC, and the fever persisted for the average of 2.5 days (1-8 days). We found significantly higher levels of CRP in children aged between 2-4 in comparison to other age groups (p= 0.0290). In 44.2% (50/113) of children the cystourethrography was performed and in 22% (11/50) cases we recognized a unilateral or bilateral vesicoureteral-ureter of a I to IV degree, on one or both sides. The most common etiological agent of UTIs in children remains E. coli. The sensitivity of urinary pathogens to the commonly used antibiotics is still high, however, finds a large percentage of strains resistant to ampicillin and to amoxicillin with clavulanic acid. The antibiotic recommended for empiric therapy of UTIs in children should be cephalosporins, if there is such a possibility, the treatment should be based on drug sensitivity tests of the organisms grown. Because of the relatively long hospitalization of children with UTIs and the possibility of hospital complications, sequential treatment should also be considered sequential. A first urinary tract infection (UTI) in childhood is more prevalent in females &lt; 5-years-old. Circumcision generally protects males from UTI, however, during the month following the procedure, the prevalence of infection increases up to 12 times in circumcised boys when compared with those not circumcised. Almost all the infections are caused by aerobic Gram-negative bacteria of which E. coli are responsible for 70-90% of the cases. Signs and symptoms of UTI vary in different age groups. Factors associated with the likelihood of UTI are: non-circumcised male, fever &gt; 40 degrees C, and a fever &gt; 39 degrees C for more than 48 hours with no other focus of infection on physical examination. Urinalysis and urine microscopy are screening tests for UTI. In children with clinical symptoms and signs suggesting UTI, the results of these tests have a positive predictive value (if both are positive), or negative predictive value (if both are negative) approximating 100%. The definitive diagnosis of UTI is based on the urine culture. Bag urine culture is associated with a very high rate of contamination. Therefore, in non-toilet trained children, urine culture should be obtained directly from the urinary bladder either by supra pubic aspiration or in and out transurethral catheterization. Mid stream clean voided urine specimens obtained from circumcised males in the first months of life are also acceptable. Depending on the clinical presentation, oral therapy can begin from as early as two months of age, and the recommended empiric drugs for first febrile UTI are cefuroxime axetil, or amoxicillin clavulanate. Cephlexin is recommended for cystitis. During the course of antibiotic treatment, serial white blood cell count and temperature are closely monitored. Typically, the intravenous antibiotics are continued until the person has no fever for at least 24 to 48hours, then equivalent antibiotics by mouth can be given for a total of twoweek duration of treatment. Intravenous fluids may be administered to compensate for the reduced oral intake, insensible losses (due to the raised temperature) and vasodilation and to optimize urine output. Percutaneous nephrostomy or ureteral stent placement may be indicated to relieve obstruction caused by a stone. Children with acute pyelonephritis can be treated effectively with oral antibiotics (cefixime, ceftibuten and amoxicillin/clavulanic acid) or with short courses (2 to 4days) of intravenous therapy followed by oral therapy. If intravenous therapy is chosen, single daily dosing with aminoglycosides is safe and effective. Infants less than 3 months of age with urinary tract infection are usually hospitalized. Recent studies show that a less aggressive management for those patients aged ≥ 29 days may be feasible. To determine the complication rate in infants&lt;3 months of age with urinary tract infection, and to identify the causative agents and their antibiotic susceptibility. A retrospective study was conducted on infants&lt;3 months of age with positive urinalysis results, together with a positive urine culture from a catheterized specimen and seen in the Emergency Department from 2007 to 2012. Demographics, clinical and microbiology (microorganism isolated and antibiotic susceptibility) data were collected. The complications rate (bacteremia, bacterial meningitis, renal abscess, surgical intervention, Intensive Care Unit admission, or death) were calculated for the overall sample and for different age groups (&lt;29, 29-60, and 61-90 days). A total of 460 patients are included; 137 (29.8%)&lt;29, 166 (36.1%) 29-60, and 157 (34.1%) 61-90 days of age. Twenty four (5.4%; 95% CI: 3.6-7.8) had bacteremia; 15 (10.9%; 95% CI: 6.7-17.3) were&lt;29 days; 8 (4.9%; 95% CI: 2.5-9.4) were 29-60 days, and one (0.7%; 95% CI: 0.1-3.7) was 61-90 days of age (P&lt;.001). One neonate (0.8%; 95% CI: 0.1-4.1) had bacterial meningitis, and 2, renal abscess. Escherichia coli was the common pathogen identified (87.2%) in the urine culture, with a susceptibility to amoxicillin-clavulanate, gentamicin, and cefixime of 89.2, 97.0, and 96.0%, respectively. Complications are low in infants&lt;3 months of age with UTI, especially in those ≥ 29 days of age. The identification of patients at very low risk for complications would allow a less aggressive management. Escherichia coli antibiotic susceptibility remains stable, but continuing careful surveillance is essential to optimize empirical antibiotic treatment. The infectious disease is the main source of care demand in Pediatric Emergency Departments (PED) and is a frequent cause of hospital admission with antibiotics. Our objectives are: 1) to determine the diseases that are seen in PED that required admission with antibiotics; 2) to determine the microbiological methods used and, 3) to analyze the characteristics of the indicated treatment. A prospective multicenter study was conducted in 22 Spanish hospitals. We included patients younger than 18 years seen in PED on day 14 of each month between June 2009 and May 2010 who required hospitalization with systemic antibiotics. Patients admitted to Intensive Care Unit were excluded. There were 30,632 consultations in the PED during the study period. A total of 1,446 (4.7%) patients were hospitalized, 395 (27.3%) of them with antibiotics. Ninety-five patients (24.1%) had received antibiotics before admission. Three hundred twenty (81%) children underwent at least one microbiological test, with blood culture (69.9%) and urine culture (30.9%) being the most requested ones. The main diagnoses at admission were pneumonia (29.4%), urinary tract infection (15.4%), and fever without source (12.1%). Twenty five different antibiotics were prescribed, with cefotaxime (27.8%) and amoxicillin-clavulanate (23.4%) being the most prescribed ones. A single antibiotic was prescribed to 80.8% of patients, and parenteral administration was the most indicated (93.7%). Antibiotic therapy was prescribed in one in every 4 patients who required admission to hospital. Pneumonia was the most common source. Blood culture was the most frequent microbiological test requested in the PED. A limited number of beta-lactam antibiotics represented the majority of antibiotic prescriptions. Urinary tract infections (UTIs) are a common diagnosis within the pediatric emergency department (ED). Because of the necessary delay in obtaining urine culture results, clinicians must decide whether to prescribe antibiotics for a suspected UTI before urine culture results. The primary objective of this study was to identify the proportion of children given empiric antibiotics who subsequently did not meet consensus definition of an UTI. The secondary objective was to identify factors associated with return visits to the ED after an index visit for UTI. We also attempted to identify predictors of prescription of empiric antibiotics for children who did not have a UTI. This was a retrospective chart review of all patients between the ages of 2 months and 18 years diagnosed with a UTI between July 2016 and June 2017 in the ED of a single urban quaternary care center. Patients were excluded for the following reasons: use of bag for urine collection, subsequent admission to the hospital, receipt of antibiotics within the previous 3 days, use of antibiotics for an indication other than a UTI, and urine culture obtained at an outside facility. Of 404 included patients, 389 (96.2%) were discharged on antibiotics and 243 (62.4%) did not have a UTI. On the multivariate analysis, age ≧ 36 months was associated with increased odds of receiving antibiotics and not having a UTI while both ≥1+ leukocyte esterase and ≥1+ nitrites on urinalysis were associated with decreased odds of receiving antibiotics and not meeting UTI criteria. Sixty-two patients revisited the ED within 30 days of the initial visit, 24 (38.7%) of which met criteria for UTI during the index visit. Prescription of antibiotics at the time of the index visit was associated with decreased odds of reutilization, whereas an extended-spectrum β-lactamase producing organism cultured from urine at the index visit was associated with increased odds of reutilization. A high number of patients discharged on empiric antibiotics did not meet criteria for a UTI. We did not identify clinically useful factors that predicted prescription of empiric antibiotics for children who do not have a UTI. We believe that unnecessary antibiotic prescriptions could be substantially decreased by decreasing empiric use of antibiotics coupled with reliable follow-up for positive urine cultures. Diagnosis Laboratory examination Analysis of the urine may show signs of urinary tract infection. Specifically, the presence of nitrite and white blood cells on a urine test strip in patients with typical symptoms are sufficient for the diagnosis of pyelonephritis, and are an indication for empirical treatment. Blood tests such as a complete blood count may show neutrophilia. Microbiological culture of the urine, with or without blood cultures and antibiotic sensitivity testing are useful for establishing a formal diagnosis, and are considered mandatory. Diagnosis In straightforward cases, a diagnosis may be made and treatment given based on symptoms alone without further laboratory confirmation. In complicated or questionable cases, it may be useful to confirm the diagnosis via urinalysis, looking for the presence of urinary nitrites, white blood cells (leukocytes), or leukocyte esterase. Another test, urine microscopy, looks for the presence of red blood cells, white blood cells, or bacteria. Urine culture is deemed positive if it shows a bacterial colony count of greater than or equal to 103 colony-forming units per mL of a typical urinary tract organism. Antibiotic sensitivity can also be tested with these cultures, making them useful in the selection of antibiotic treatment. However, women with negative cultures may still improve with antibiotic treatment. As symptoms can be vague and without reliable tests for urinary tract infections, diagnosis can be difficult in the elderly. Assess H and P for “low risk” status Age? <1 mo >1 mo Low risk Not low risk CBC with differential, blood culture, urine culture All parameters normal? No Yes All parameters normal? NoYes outpatients without empirical antibiotic treatment or, alternatively, treated with intramuscular ceftriaxone. Regardless of antibiotic treatment, close follow-up for at least 72 hours, including re-evaluation in 24 hours or immediately with any clinical change, is essential. Children with a positive blood culture require immediate re-evaluation, repeat blood culture, consideration for lumbar puncture, and empirical antibiotic treatment. Urine dipsticks have to be used more frequently for the screening of urinary tract infections (UTI) in febrile infants and children (grade A). Confirmation of the UTI by urine culture should prefer other methods of sampling than the urine bag: sampling jet, urethral catheterization, or pubic puncture (grade A). The percentage of Escherichia coli producing extended-spectrum beta-lactamases (ESBL) in children accounts for less than 10 % in France and does not justify revising the 2007 recommendations (grade B). An increase in the use of carbapenems in first-line treatment is a major environmental hazard and exposes the patient to the risk of untreatable infections. For febrile UTI, the expert group recommended: (1) recover the results of susceptibility testing as soon as possible to quickly adapt treatment for possible resistant strains; (2) favor initial treatment with aminoglycosides (particularly amikacin) which remain active in the majority of ESBL strains for patients seen in the pediatric emergency department and/or hospital; (3) ceftriaxone (IV or IM) remains an appropriate treatment for patients seen in the emergency department or outpatient clinic because the percentage of ESBL-producing enterobacteria strains remains low; (4) use oral cefixime (grade B) in nonsevere cases and low-risk patients defined as age&gt;3 months, general condition preserved, disease duration of fever&lt;4 days, no associated comorbidity, and no history of urinary tract infection, uropathy, or prior antibiotic therapy in the last 3 months; (5) oral relay for parenteral treatment is guided by in vitro susceptibility testing, in an attempt to reduce the use of oral cephalosporins to limit the selection of resistant bacterial strains. The total duration of treatment recommended is usually 10 days. Except for special circumstances, there is no need to prescribe retrograde cystography or antibiotic prophylaxis after a first febrile urinary tract infection. For cystitis, the panel recommends systematic urinalysis and initial prescription before the results of the urine culture of one of the three following oral antibiotics: amoxicillin-clavulanate, cotrimoxazole, cefixime. The total duration of antibiotic treatment is 5days to tailor treatment based on clinical progression and antibiotic susceptibility. Urinary tract infection is a common cause of serious bacterial infection in young children. The non-specific presentation has implications for misdiagnosis and the potential for long-term complications. To determine if a negative dipstick urinalysis is adequate to exclude urinary tract infection in children aged 0-10 years. Data was subdivided into two age groups: 0-2 years and 2-10 years. Retrospective case note review over an 8-month period. Cases included required a printed urinalysis recorded from the Clinitek 50 (Bayer) machine and a printed microscopy and culture result. We defined a negative urinalysis as being negative for all of blood, protein, leucocytes and nitrites. A total of 375 cases were included for statistical calculation. Three hundred and seventy-five cases gave a prevalence of 10.7% with a sensitivity of 92.5%, specificity of 39.4% and a negative predictive value of 97.8%. In the 0-2-year-old group, we demonstrated a prevalence of 15%, a sensitivity of 87.5%, specificity of 39.7% and a negative predictive value of 94.7%. This compares to the older group (2-10 years) with a prevalence of 7.0%, a sensitivity of 100%, specificity of 39.7% and a negative predictive value of 100%. Prevalence of urinary tract infection varied with age with a higher prevalence in the 0-2 years age group. The lower negative predictive value and the higher clinical importance in this age group means that dipstick urinalysis is inadequate to exclude urinary tract infection. Conversely, we believe that children in the 2-10 years age group can adequately have urinary tract infection excluded with a negative dipstick urinalysis. Acute fever of unknown origin (FUO) in children under 29 days is a worrying situation because of the risk of serious bacterial infection (SBI). to study the main clinical and laboratory characteristics of a group of hospitalized children under 29 days with diagnosis of FUO. Retrospective study of children under 29 days hospitalized due to FUO. The clinical records of the patients were reviewed, recording age, sex, history of fever before consultation, temperature at admission, estimated severity at admission and discharge, discharge diagnoses, laboratory tests, and indicated treatments. Patients were classified according to the severity of the discharge diagnosis, as severe (S) and non-severe (NS). The inclusion criteria were term newborn, age less than 29 days, fe ver &gt; 38°C registered at home or admission, and history of &lt; 4 days. 468 children with FUO were admitted. Concordance between severity at admission and discharge was low (Kappa = 0.125; p = 0.0007). 26.1% of children were S and 73.9% NS. In the S group, urinary tract infection domínate (70.5%) and in the NS, FUO (67.6%). The cut-off levels for leukocytes/mm3, C-reactive protein, and neutrophils/mm3 showed negative predictive values to rule out severe bacterial infection. Conclu sions: Most of the newborns presented mild severity at admission, but 24% of them had SBI, thus hospitalization and close clinical observation are always necessary. Laboratory tests, such as CRP, white blood cell and neutrophils count are not good predictors of SBI. Early treatment with antibio tics for patients who meet the low-risk criteria is debatable. Most episodes of fever in children younger than 3 years of age have a demonstrable source of infection elicited by history, physical examination, or a simple laboratory test. In this age group, the most commonly identified serious bacterial infection is a UTI. A blood culture to evaluate for occult bacteremia, and urinalysis and urine culture to evaluate for a UTI, should be considered for all children younger than 3 years of age with fever without localizing signs. Stool culture should be obtained in those with diarrhea marked by blood or mucous. Ill-appearing children should be admitted to the hospital and treated with empirical antibiotics. Approximately 0.2% of well-appearing febrile children 3 to 36 months of age vaccinated against S. pneumoniae and To investigate antibiotic resistance among pathogens isolated from urines in a tertiary care children's hospital in Italy. Retrospective analysis of prospectively collected data on antibiotic susceptibility of Gram-negatives isolated from urines at the Istituto Giannina Gaslini, Genoa - Italy from 2007 to 2014. Antibiotic susceptibility was evaluated. By means of CLSI criteria from 2007 to 2010, while from 2011 EUCAST criteria were adopted. Data on susceptibility to amoxicillin-clavulanate, co-trimoxazole, cefuroxime, nitrofurantoin, fosfomycin and ciprofloxacin were evaluated for Escherichia coli, while for other Enterobacteriaceae data were collected for amoxicillin-clavulanate, co-trimoxazole and ciprofloxacin and for ciprofloxacin against Pseudomonas aeruginosa. Univariate and multivariable analyses were performed for risk factors associated with resistance. A total of 4596 Gram-negative strains were observed in 3364 patients. A significant increase in the proportion of resistant strains was observed for E.coli against amoxicillin-clavulanate, cefuroxime and ciprofloxacin and for others Enterobacteriaceae against co-trimoxazole and ciprofloxacin. Resistance to nitrofurantoin and fosfomycin was very infrequent in E.coli. Logistic regression analysis showed that repeated episode of urinary tract infections was a risk factor for E.coli resistance to amoxicillin-clavulanate, co-trimoxazole and cefuroxime, while admission in one of the Units usually managing children with urinary tract malformations was significantly associated to resistance to amoxicillin-clavulanate and cefuroxime. In conclusion the present study shows an increase in antibiotic resistance in pediatric bacteria isolated from urines in children, especially in presence of repeated episodes and/or urinary tract malformations. This resistance is worrisome for beta-lactams and cotrimoxazole, and start to increase also for fluoroquinolones while nitrofurantoin and fosfomycin still could represent useful drugs for oral treatment of these infections. • Infections are frequent in patients with urinary tract malformations • Antibiotic prophylaxis can select for resistant pathogens What is New: • The increase in the resistance to β-lactams, co-trimoxazole or fluoroquinolones in pathogens causing urinary tract infections cause a reduction of drugs with oral formulations available for therapy • Old drugs like nitrofurantoin and fosfomycin can represent attractive compounds for oral treatment of urinary tract infections in children presence of resistance to other drug classes. Acute fever of unknown origin (AFUO) is established when the anamnesis and physical examination cannot identify the cause. In infants less than 3 months-old this is situation for concern, due to the risk of a serious bacterial infection. To describe the clinical and laboratory variable of patients with AFUO, in order to look for clues in order to base studies on the decisions arising drom this problem. A report is presented on a retrospective study conducted on a cohort of children less than three months-old admitted to the Hospital Roberto del Río (2007-2011) due to an AFUO. Clinical histories were reviewed and the patients were grouped, according to the severity of the admission diagnosis, into severe and non-severe. They were compared in strata determined by the variables of clinical interest. A total of 550 children were admitted with AFUO during the study period. There was low agreement between the severity on admission and at discharge (kappa=0.079; P=.26). There were 23.8% of children in the severe group and 76.2% in the non-severe group. Urinary tract infection predominated in the severe group (68.7%) and 40.7% with acute febrile syndrome in the non-severe group. The cut-off levels for C-reactive protein, white cells, and neutrophils per mm(3), to calculate the fixed and variable indices, only showed negative predictive values of some use for ruling out serious bacterial infection. The ROC curves with white cell and neutrophil counts and C-reactive protein, did not provide andy fixed indices of clinical use. More than one-third (34.6%) of lumbar punctures were traumatic or failures. According to the results of this study, there is an obvious excess of hospital admissions, little usefulness in the examinations to identify serious bacterial infection, a high percentage lumbar punctures traumatic and lumbar punctures failures, and an excess of antibiotic treatments. A review of clinical criteria and procedures is needed. Ewingella americana (Ea) is a Gram-negative, lactose-fermenting, oxidase-negative and catalase-positive bacterium that was first described in 1983 as a new genus and species in the family Enterobacteriaceae. It is not known whether Ea is a true pathogen or simply an opportunistic infectious agent, as most of the cases have been described in patients at risk. A 4-year-old girl described here was hospitalized due to a productive cough over the previous 3 weeks and a fever &gt; 38 °C associated with tachypnea over the previous 2 days. Her familial and personal medical histories were negative for relevant diseases, including respiratory infections. At admission, she was febrile (axillary temperature 39.2 °C) and had dyspnea with retractions, grunting and nasal flaring. A chest examination revealed fine crackling rales in the left upper field associated with bilateral wheezing. A chest X-ray revealed segmental consolidation of the lingula of the left lung. Laboratory tests revealed leukocytosis (15.,800 white blood cells/mm<sup3</sup with 50.3% neutrophils), a slight increase in serum C-reactive protein (11.9 mg/L) and normal procalcitonin values (&lt; 0.12 ng/mL). A nasopharyngeal swab culture did not reveal viral or bacterial respiratory pathogens, including atypical bacteria. A blood culture revealed the presence of a Gram-negative, lactose-fermenting rod that was oxidase negative and catalase positive. The isolate was identified by means of the VITEK®2 identification system (bioMérieux, Firenze, Italy) as Ea. This identification was confirmed by sequencing the 16 s ribosomal deoxyribonucleic acid (rDNA). The pathogen was sensitive to aminoglycoside, fluoroquinolones, carbapenems, cefotaxime, and ceftazidime but was intermediate against sulfametoxazole/trimethoprim and resistant to amoxicillin-clavulanic acid, fosfomycin, and oxacillin. The child was immediately treated orally with amoxicillin-clavulanic acid and erythromycin. Based on the results of a blood culture and sensitivity tests, the amoxicillin-clavulanic acid medication was stopped after 3 days. Erythromycin was continued for a total of 10 days, and the child was discharged after 3 days in the hospital. Follow-up visit 1 month later did not reveal any respiratory problems. This case shows that Ea infections in healthy subjects are mild even in pediatric age, and the need for antibiotic therapy is debated. Cases occurring in subjects with underlying chronic disease can be significantly more complicated and require appropriate antibiotic therapy. Since infections of the urinary tract in children often present diagnostic difficulties, it is essential to be able to identify these patients with simple, reliable methods. After a clinical-laboratory study on 4176 urine cultures, the Authors affirm that the reliability of this test is much greater when the parents have been instructed in the correct way of collection the urine specimen, and when in the laboratory the \"slide\" is carried out within three hours of taking the sample. To evaluate clinical and analytic numeric data that may help the emergency departments to identify bacterial infections in infants. A retrospective study of 430 infants with bacterial growth in cultures (culture from blood, 30; urine, 207; stools, 193, and/or cerebrospinal fluid, n 25) was performed. These patients were compared with a control group (n 430), randomly selected from patients aged less than 12 months with negative cultures who were hospitalized with suspected infection. Neonates and surgical patients were excluded from both groups. Statistical analysis was performed using Student's t-test for independent samples, Levene's test for the study of equality of variances, bivariate correlation and one-factor ANOVA, and receiver-operating characteristic (ROC) curves and odds ratios were calculated when statistically significant (p &lt; 0.05) results were obtained. These analyses were performed using the SPSS 10.0 statistical software package. Of the infants admitted to the pediatric unit, 11.7 % had at least one positive bacterial culture. Temperature (p 0.005), leucocyte count (p 0.003), percentage of neutrophils (p &lt; 0.0001) and C-reactive protein (p &lt; 0.0001) were significantly higher in infants with positive cultures. In invasive infections significant differences were found in sex (more frequent in males) (p 0.03), heart rate (p &lt; 0.0001) and respiratory rate (p 0.003). In the ROC curves, the best diagnostic yield was obtained for C-reactive protein (0.93 for a cutoff value of 29 mg/l, 86 % specificity and 91 % sensitivity). C-reactive protein is essential for diagnosis of bacterial infection in infants in the emergency department.\nHere is the question:\nPEDIATRICS: A 13-month-old infant comes to the emergency department with fever up to 39ºC of 48h of evolution with no other associated symptoms. Examination by organs and devices with no significant findings, highlighting good general condition. You were going to discharge him home but the Pediatrics attending on duty asks for a systematic urine and urine culture by catheterization. The urine shows leukocyturia ++, hematuria + and nitrites ++ and the urine Gram-negative bacilli are observed. In the blood analysis there is no leukocytosis and the C-reactive protein is 50 mg/l. The attending now tells you that the child does not need to be admitted and to prescribe an oral antibiotic. State the least appropriate empirical antibiotic treatment in this case:\nHere are the potential choices:\n1. Amoxicillin.\n2. Amoxicillin-clavulanic acid.\n3. Cefuroxime-axetil.\n4. Cotrimoxazole.\n5. Cefixime.\nThe correct answer is: 1. Amoxicillin."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n To evaluate the efficacy of hCG therapy on retractile testis in various testicular locations and age groups. This study comprised 123 boys whose diagnosis were retractile testis with scrotal base, high scrotal and superficial inguinal localizations with an average age of 4,2 (1-8) years. 123 boys with retractile testes were given a total dose of 9000 hCG and its effect on scrotal base, high scrotal and superficial inguinal located testes were evaluated after 2 weeks and 6 months of completing hCG course. The patients were evaluated in four age groups such as less than 2 years of age, between 2-4, 4-6 years and more than 6 years of age and the response rates were also noted in these age groups. In unilateral cases, the response in base, high scrotal and superficial inguinal levels were found as 100%, 83,3%, 72,7% respectively where as these rates were found as 100%, 92,6%, 76,3% respectively in bilateral cases after 2 weeks of hCG therapy. The response rates in less than 2 year old group, 2-4, 4-6 and more than 6 years group were found as 0%, 80%, 78,7%, 100% respectively in unilateral cases and 33,3%, 90%, 86,9% and 83,3% respectively in bilateral cases. After 6 months, reascend was observed in 12,4% in unilateral group and 6,7% in bilateral group. 72,7-100% of retractile testes respond to hCG administration with the highest response in the age of more than six year group. High response rates observed in retractile testes after hCG therapy in more than 2 years old age group indicate that hCG must be given as a primary treatment in retractile testes and orchiopexy for the failures. Also patients must be followed up closely for reascend cases. A total of 7 boys 4 to 10 years old was evaluated for undescended testes. All patients had been seen previously by a pediatric urologist and diagnosed as having a retractile testis. In fact 4 boys had undergone surgical correction of a contralateral undescended testis at an earlier date at which time the testis in question could be manipulated into the scrotum. Another boy was examined under anesthesia and the operation was canceled because the testis could be brought into the scrotum. Subsequently, on followup evaluation 2 to 8 years later the ipsilateral testis could not be manipulated into the scrotum. Of the boys 6 then were treated with a short course of human chorionic gonadotropin. Four patients had a positive response but in 3 the testis was undescended again at examination 6 months later. Of the boys 6 ultimately underwent orchiopexy. Boys with highly retractile testes require periodic examination until puberty to ensure that those testes do not ascend secondarily. In a recent study, the effect of human chorionic gonadotropin (HCG) in the treatment of children with cryptorchidism aged less than four years was questioned. The purpose of the present study was to determine, on the basis of a retrospective examination of patients' records, the effect of HCG treatment, whether outcomes are age-dependent and whether the effects of treatment are related to the position of the testis. Patients diagnosed with undescended testis who had been treated at the Department of Urology at Gentofte Hospital (Copenhagen) in the period from 1 November 1998 to 31 May 2003 were identified. Patients who had been treated with HCG were included in the sample. Boys who at an earlier stage had been operated on in the inguinal or scrotal region, or who had suffered from inguinal hernia, were excluded, and clinical retractile testes were separated from true undescended testes. The criterion of success for efficient treatment was complete descent to the bottom of the scrotum. In the 306 records examined, 121 patients met the inclusion criteria. In total, there were 170 undescended testes. The patients' median age at time of treatment was 3.6 years. The overall success rate was 34.7%. The success rates in the individual age categories were: 1-2 years, 36.7%; 3-4 years, 33.4%; and 5-13 years, 35%. The position of the testis at the beginning of treatment showed that the lower the pretreatment position, the better the success rate. The overall success of HCG treatment of cryptorchidism was 34.7%. No age dependency of HCG effects was found, but the position of the testis before treatment influenced the success rate. Failure to replace the testes in the scrotum during hernia repair leads to iatrogenic undescended testes. At other times, the testes may spontaneously move back to the inguinal area after being placed in the scrotum, thus resulting in ascending testes. The cases in this study were assessed. Records of 910 boys operated due to inguinal hernia were assessed retrospectively. Following hernia repair, the testes were placed in the scrotum. After the operation, all the testes were checked for being in the scrotum. They were called for follow-up after the operation. Their testes were checked for remaining in the scrotum. Ascending testes were detected in 4 (0.43%) of the patients. These patients had scrotal hypoplasia and/or retractile testes. Their age ranged between 1-3 years. Ascending testes were bilateral in 2 patients, and on the right side in 2. Human chorionic gonodotropin (hCG) was initiated in 3 patients. Two of them improved. Two underwent scrotal orchiopexy. These patients may benefit from hCG in the early postoperative period. Later, scrotal orchiopexy may be needed. Patients who have retractile testes or scrotal hypoplasia in addition to inguinal hernia need orchiopexy together with herniorrhaphy. For non-scrotal testes a distinction can be made between retractile testes (completely descended and normally developed but sometimes situated subcutaneously in the groin area), retained testes (testes cannot be brought into the scrotum or this can only be achieved using light manual pressure) and ectopic testes (lying outside of the descent trajectory). It is estimated that 0.7-0.8% of all boys have as yet undescended testes. The first few days after the birth are the most suitable for testing and registration, as then the cremaster reflex is absent. Registration should take place in both the youth healthcare file and in the 'growth book' for the parents. Retractile testes do not require treatment. There is no consensus concerning the treatment of (possible) acquired nonscrotal testes. For undescended testes the management depends on previous testes localisations. For ectopic testes and testes that have never been scrotal, a referral for surgical treatment should be made prior to the second birthday. Orchidopexy (a better description is orchidofuniculolysis followed by orchidopexy) is only justified in the case of testes which have never descended. In the case of a clear indication, the general practitioner should make a prompt referral (before the second birthday) and in other cases assurance should be provided and an expectant policy adopted until puberty. We prospectively evaluated the efficacy of human chorionic gonadotropin (HCG) in the treatment of undescended testis and sought to determine whether HCG assists in the differentiation of undescended testis from retractile testis. Patients with undescended testes were offered HCG. Testis position, laterality and the presence or absence of a hypoplastic scrotum were noted. The same physician (G. W. K.) recorded physical findings prospectively and stated clinical impression of descent. A total of 67 patients with 90 undescended or retractile testes were treated and evaluated with HCG. Of the 64 undescended testes 13 (20%) descended with HCG therapy, with none requiring subsequent surgery. Of the 26 retractile testes 15 (58%) descended with HCG (p &lt;0.001). Based on physical examination, 100% of retractile testes descended if the testis was in the high scrotal position but only 40% descended if the testis was in the superficial pouch or inguinal area. In the undescended testes group no ectopic or nonpalpable testis descended with HCG. Evaluation of HCG with age demonstrated minimal response (15%) to HCG at less than 24 months, and a peak response between ages 2 and 6 years (75%) with response decreasing thereafter. HCG may have a limited role in the evaluation of undescended testis in patients younger than 2 years. HCG can serve as an adjunct in the clinical diagnosis of retractile testis in older children. Among 509 boys referred with undescended testicles, 112 had true undescended testicles unilaterally and 62 bilaterally. Patients with true undescended testicles were offered hormonal treatment unless the condition was associated with hernia or previous operations. Boys less than 5 years old were primarily treated with gonadotrophin releasing hormone (GnRH), while boys more than 5 years old were primarily treated with human chorionic gonadotrophin (hCG). If the effect of the primary treatment was insufficient the other hormone was given. Testicular descent was obtained for 64% (23/36) of the intraabdominally located testicles in boys with bilaterally undescended testicles versus only 14% (3/21) in boys with unilaterally undescended testicles (p &lt; .001). Treating 1 to 4 years old boys with GnRH resulted in descent in 16 of 95 testicles and secondary treatment with hCG yielded an additional 34, whereas secondary treatment of 5 to 13 years old boys with GnRH added only 10 descended testicles to 51 of 101 testicles. Reading the maternity records of 272 of the boys support other studies showing that testicles may reascend. Boys with endocrinological or \"surgical\" causes of incomplete testicular descent were relatively more likely to have had one or two undescended testicles during the first postnatal week compared with boys found to have only retractile testicles (p &lt; .001). Treatment with hormones resulted in descent in 56% of boys whose testicles were both descended within one week after birth. Conversely, only 1 of 20 boys with unilateral testicular undescent postnatally was sufficiently treated with hormones (p &lt; .001). The hormonal effect in boys with bilaterally undescended testicles at delivery did not differ significantly from boys with either one or none undescended testicle postnatally. In 35 of 51 boys (69%) in whom the hormonal effect was insufficient, operation revealed a \"surgical cause\" of the incomplete testicular descent. --Guidelines for the treatment ofundescended testis (UDT) are sparse. Often an operation in the second year of life is advised. --Recent data indicate that the normal maturation process, which will ultimately lead to a normal quantity and quality of germ cells, is impaired as early as in the first half year of a newborn's life. None of the guidelines take this into account. Spontaneous descent after the fourth month following birth, of testes that have previously not descended, hardly ever occurs. --No differences have been shown in complication numbers between surgery before and after the first birthday. Orchidopexy prior to the 13th birthday reduces the risk of testicular cancer. --Therefore, based on these data, it is advised to perform orchidopexy in the second half of the first year of a newborn's life. In older boys a UDT must be treated before the 13th birthday. --In the Netherlands a lot more orchidopexies are done despite what may be expected based on prevalence numbers of UDT: testes retaining a normal volume that would most probably have descended spontaneously come puberty. --It remains important to carry out a careful physical examination and document the position of the testes soon after birth, and later on if UDT is suspected, to avoid unnecessary operations on retractile testes and acquired UDT. Diagnosis The most common diagnostic dilemma in otherwise normal boys is distinguishing a retractile testis from a testis that will not descend spontaneously into the scrotum. Retractile testes are more common than truly undescended testes and do not need to be operated on. In normal males, as the cremaster muscle relaxes or contracts, the testis moves lower or higher (\"retracts\") in the scrotum. This cremasteric reflex is much more active in infant boys than older men. A retractile testis high in the scrotum can be difficult to distinguish from a position in the lower inguinal canal. Though various maneuvers are used to do so, such as using a cross-legged position, soaping the examiner's fingers, or examining in a warm bath, the benefit of surgery in these cases can be a matter of clinical judgment. We retrospectively evaluated the ability of human chorionic gonadotropin (HCG) to make the nonpalpable cryptorchid testis become palpable and promote testicular descent. Through surgical bookings we identified 94 patients younger than 11 years who received HCG between 1984 and 1994 for the diagnosis or treatment of a nonpalpable undescended testis. The dose of HCG was 1,500 IU/m.2 intramuscularly 2 times weekly for 4 weeks. Testis location was determined by physical examination before and after hormone administration, and confirmed at surgical exploration. Of the 99 nonpalpable testes identified in 94 patients 39 (39%) became palpable following HCG administration and only 2 (2%) completely descended. A total of 60 testes remained nonpalpable with the most common reason being an absent or severely atrophic testis (40, 67%). Of the testes remaining nonpalpable after hormonal stimulation 73% were surgically located at or distal to the internal ring. HCG is preoperatively efficacious in causing the nonpalpable undescended testis to become palpable. For patients failing to respond to hormonal stimulation we recommend preliminary inguinal exploration, since most testes or testicular remnants are located within the inguinal canal or immediately below the internal ring. The undescended testis is usually histologically normal at birth. Atrophy and dysplasia are found after the first year of life. Some boys have congenital dysplasia in the contralateral descended testis. Surgical correction at an early age results in greater chance of adult fertility. Administration of human chorionic gonadotropin causes testosterone release from functioning testes and may result in descent of retractile testes. Orchidopexy is usually done in the second year of life. Most extra-abdominal testes can be brought into the scrotum with correction of the associated hernia. If the testis is not palpable, ultrasound or magnetic resonance imaging may determine its location. The closer the testis is to the internal inguinal ring, the better the chance of successful orchidopexy. With an incidence of 0.7-3% in male infants, undescended testicles is one of the most common congenital anomalies. In the first 6 months of life, the testicles may spontaneously descend in up to 70% of individuals. If the testicle is not in a scrotal position afterwards, fertility can gradually be reduced and the risk of a testicular tumor increases. Therefore, the current German guideline for undescended testis recommends that therapy should be take place between 6 and 12 months of life. After extensive information on the advantages and disadvantages, hormone therapy with the aim of a descensus or in those with bilateral anomaly with the aim of improving the germ cell pool can be offered. After the first year of life, hormone therapy is obsolete. Otherwise, surgical intervention is the treatment of choice. In the case of gliding or deep inguinal testis via scrotal or inguinal access, in the case of nonpalpable and sonographically undetectable testis, laparoscopy is carried out for diagnosis and simultaneous therapy. In the first postoperative year, adequate follow-up should be done to detect a re-ascensus and/or insufficient growth. Regular self-examinations from the age of 15 serve for the early detection of a testicular tumor that occurs only very rarely (approximately 0.003%). Cryptorchidism or undescended testis is the single most common genitourinary disease in male neonates. In most cases, the testes will descend spontaneously by 3 months of age. If the testes do not descend by 6 months of age, the probability of spontaneous descent thereafter is low. About 1%-2% of boys older than 6 months have undescended testes after their early postnatal descent. In some cases, a testis vanishes in the abdomen or reascends after birth which was present in the scrotum at birth. An inguinal undescended testis is sometimes mistaken for an inguinal hernia. A surgical specialist referral is recommended if descent does not occur by 6 months, undescended testis is newly diagnosed after 6 months of age, or testicular torsion is suspected. International guidelines do not recommend ultrasonography or other diagnostic imaging because they cannot add diagnostic accuracy or change treatment. Routine hormonal therapy is not recommended for undescended testis due to a lack of evidence. Orchiopexy is recommended between 6 and 18 months at the latest to protect the fertility potential and decrease the risk of malignant changes. Patients with unilateral undescended testis have an infertility rate of up to 10%. This rate is even higher in patients with bilateral undescended testes, with intra-abdominal undescended testis, or who underwent delayed orchiopexy. Patients with undescended testis have a threefold increased risk of testicular cancer later in life compared to the general population. Self-examination after puberty is recommended to facilitate early cancer detection. A timely referral to a surgical specialist and timely surgical correction are the most important factors for decreasing infertility and testicular cancer rates. Cryptorchidism results from a complex hereditary series of incompletely understood events involving the HPG axis. The incidence is indirectly related to birth weight and dramatically decreases during the first 3 months after birth. Many nonscrotal testes are retractile and require no therapy whatsoever. True cryptorchid testes develop identifiable histologic alterations within 2 years of parturition, and endocrine abnormalities are often detectable during infancy. Hormonal therapy with hCG is effective in causing descent in only a small percent of children with cryptorchidism. GnRH nasal spray is no different from placebo in double-blind studies in which retractile testes have been excluded. The results are best in low-lying testes and in older children, but a recognized late-failure rate requires continued surveillance. HCG therapy appears to be of little use in nonpalpable cryptorchid testes. The risk of testicular cancer is increased in men with a history of cryptorchidism and even includes the contralateral descended testes. This risk may be reduced by early orchidopexy. Fertility is impaired in men with cryptorchidism and is reported to be no better than 75% and 50%, respectively, in men who have undergone successful unilateral or bilateral orchidopexy. There is unconfirmed evidence that orchidopexy carried out before the age of 2 years may improve these fertility rates. It is recommended that all children with cryptorchid testes undergo treatment by the age of 1 or 2 years. The parents of children with a nonpalpable testis should be informed of the high rate of testicular absence. If hormonal therapy is to be used, it must be initiated at 10 months of age. Treatment failures must be identified quickly to allow prompt referral of these children to a pediatric urologist or surgeon for orchidopexy. The term cryptorchidism indicates a testis, which has failed to descend to the scrotum and is located at any point along the normal path of descent or at an ectopic site. Hormones play a pivotal role in testicular descent except during the migration to the level of internal inguinal ring. Cryptorchidism is present in about 4.5% of newborns with a higher incidence in preterms. The incidence decreases to 1.2% by the first year. It is classified as palpable and impalpable. The most common site of an ectopic testis is superficial inguinal pouch. Retractile testis is often bilateral and most common in boys between 5 and 6 years of age. Hypospadias and inguinal hernias are the most common associated anomalies seen with undescended testis. A thorough clinical examination helps in arriving at the etiology. A short hCG stimulation test helps to exclude anorchia. Different imaging techniques are of little help in diagnosis and require the help of an experienced radiologist. Laparoscopy has an important role in the diagnosis and management of undescended testis. The common complications include torsion and atrophy of testis. Infertility is seen in about 40% of unilateral and 70% of bilateral cryptorchidism. Undescended testis is 20 to 40 times more likely to undergo malignant transformation than normal testis. Both hCG and GnRH have been used with limited success in these children. All boys with cryptorchidism should be referred to a pediatric surgeon before 2 years of age. These children should be followed up every year after surgery to identify testicular tumors. To review the differences between normal, retractile, ectopic, ascended, and undescended testes and to describe the optimal way to perform a testicular examination to distinguish one from the other, as well as to demonstrate that ultrasound imaging is not necessary and to clarify when to consider specialist referral. This paper is based on selected findings from a MEDLINE search on undescended testes and orchiopexy referrals, and on our experience at the Urology Clinic at the Children's Hospital of Eastern Ontario in Ottawa, including review of referrals to our clinic for undescended testes and the resultant findings of normal variants versus surgical cases. The MeSH headings used in our MEDLINE search included <iundescended testicle, retractile testicle, ectopic testicle, ascended testicle, referral and consultation,</i and <iorchiopexy</i. An <iundescended testis</i is defined as the true absence of one testis (or both testes) from normal scrotal position. Ectopic and ascended testes will likewise be absent from the scrotum, the latter having been present at one point in development. Differentiating among testicular examination findings is important, as descended and retractile testes are managed conservatively, while prompt surgical intervention should be offered for ascended, ectopic, and undescended testes. Uncertainty surrounding the diagnosis of an undescended testis causes anxiety, might lead to unwarranted imaging, and might increase the wait list for specialty assessment. For this reason, avoidance of ultrasound in the evaluation of undescended testes was included in the recent Choosing Wisely Canada campaign. We seek to clarify the physical examination findings in the evaluation of possible undescended testes, the suggested referral parameters, and the subsequent management. Undescended testes and their variants are common. As decision for referral is based on the primary care physician's physical examination findings, we clarify distinguishing between normal and abnormal findings on testicular examination to aid in appropriate referral for subspecialist evaluation. Consultation, if needed, should be sought at 6 months' corrected gestational age, or at detection if later than 6 months, without delay for ultrasound imaging, as surgical management is recommended for those patients with undescended, ectopic, or ascended testes. Seventy one patients with ectopic testis of age between 2 and 11.5 years were treated with human chorionic gonadotropin (HCG) at doses recommended by the International Health Foundation. The descent of testis to the scrotum was achieved in almost half of the treated boys (49.3%). The descent was successful mainly in cases of lower inguinal position of the undescended testicle, and only rarely when the testicle was situated higher. The descent was never successful in cases when the scrotum was small and underdeveloped. The medical treatment of retentio testis remains controversial because of ineffectiveness and/or adverse events. Follicle-stimulating hormone (FSH) seems to influence the spontaneous descent of the testis; furthermore, it induces luteinizing hormone (LH) receptors. Therefore, we performed a double-blind placebo-controlled study to investigate the effect of FSH with human chorionic gonadotrophin (hCG) versus hCG alone in retentio testis patients. Twenty-two boys with retentio testis were investigated, excluding retractile testis. Group A (N = 14: four with bilateral and 10 with unilateral retentio testis; mean age 3.15 years) was treated with 150 IU of FSH twice a week for 2 weeks followed by 150 IU of FSH and 250 IU of hCG (half the recommended World Health Organization dose) twice a week for another 4 weeks. Group B (N = 8: two with bilateral and six with unilateral retentito testis; mean age 3.3 years) was treated with 250 IU of hCG twice a week for 6 weeks. Testicular position, volume and consistency as well as the appearance of the scrotum and the penile length were determined at the start of the treatment as well as at weeks 2, 4, 6 and 12 by two independent investigators. Blood investigation consisted of measurements of LH, FSH, testosterone and sex hormone-binding globulin. Successful descent was considered when the testis reached a mid- or low scrotal position. In group A, 6/18 testes descended successfully. In group B, 6/10 testes descended. Of the unsuccessfully treated patients, six of group A and three of group B underwent surgery.(ABSTRACT TRUNCATED AT 250 WORDS) The aim of the study was to compare the effects of human chorionic gonadotropin (hCG) therapy with those of surgical or combined therapy on testicular volume (TV) in boys at different ages with unilateral canalicular undescended testis (UDT). In total, 155 boys aged 1 to 12 years were treated: either surgically (ST), or by 50 IU/kg body weight hCG administration every three days for five weeks (HT), or by a combination of the two. The patients underwent ultrasound examination of TV before the treatment, 9-12 (median 10) and 24-39 months (median 32) after therapy. The testicular atrophy index (TAI) of the affected testicle was calculated. The success rate was 94.7% for ST, 39.2% for HT and 98% for HST patients. The atrophy rate was 5.3% for ST, 0% for HT and 2% for HST. Neither treatment type nor patient age significantly influenced gonadal atrophy. No significant differences in TV of the affected testis were observed after treatment between the groups. The TAI values were significantly the lowest in HT group (p = 0.0006). Both TV and TAI changes from the baseline values did not differ between the treatment groups. At the 24- to 39-month follow-up, no significant differences were observed in the change in baseline TV and baseline TAI between age groups. TV of the affected testis increased significantly (p = 0.0000), and TAI decreased significantly over time (p = 0.01), with no significant differences depending on the age group, treatment type or the interaction of the two factors. The hCG therapy did not impair the development of affected and healthy testes, neither as single nor as neoadjuvant therapy, both during early assessment and after 2-3 years. Patients' age at the initiation of treatment seems irrelevant. Testes follow the \"path of descent\" from high in the posterior fetal abdomen to the inguinal ring and beyond to the inguinal canal and into the scrotum. In most cases (97% full-term, 70% preterm), both testes have descended by birth. In most other cases, only one testis fails to descend (cryptorchidism) and that will probably express itself within a year. Pubertal The testes grow in response to the start of spermatogenesis. Size depends on lytic function, sperm production (amount of spermatogenesis present in testis), interstitial fluid, and Sertoli cell fluid production. After puberty, the volume of the testes can be increased by over 500% as compared to the pre-pubertal size. Testicles are fully descended before one reaches puberty. Clinical significance Protection and injury In a population of 8500 men attending the andrology outpatient clinic, 200 men (2.35%) were recorded as having some disturbances with the descent of the testes into the scrotum. Medical history of the patients revealed that 51 underwent unilateral orchidopexy; 40 bilateral orchidopexy; and 24 were treated with human chorionic gonadotropin in order to induce descent of their testes. In addition, 6 patients reported spontaneous descent of the testes, and 13 others were found to be unilaterally cryptorchid upon physical examination. Results of semen analysis, hormonal profile, testes position, and testicular volume were compared to those of 105 proven fertile men. The major finding of this study shows that post-partum undescended testes suffer from primary Sertoli cell malfunction as reflected by elevated serum follicle stimulating hormone levels. Serum luteinizing hormone and testosterone levels were within the normal range. Surgical descent of the testes did not improve sperm production, proved by low sperm quality of all the study groups, compared to the cryptorchid group. Among the patients who were operated on, no correlation was found between age at operation and semen variables. All groups showed poor sperm quality which can be defined as oligoteratoasthenozoospermia. The degree of spermatogenic damage was in the following order of diagnosis or treatment: bilateral orchidopexy greater than cryptorchid testes greater than hormonal treatment greater than unilateral orchidopexy greater than late spontaneous descent of the testes. Thus, it is advisable to postpone surgical treatment of cryptorchidism and apply this only after a waiting period, and if the hormonal approach has failed to descend the testis.\nHere is the question:\nUROLOGY: 12-month-old boy, who in the health examinations practiced since birth presents right testicle in inguinal canal that is not possible to descend to the scrotum. Mark the CORRECT answer:\nHere are the potential choices:\n1. The most likely diagnosis is retractile testis.\n2. Wait until two years of age for spontaneous decrease of the synovial fluid.\n3. Human chorionic gonadotropin is the treatment of first choice.\n4. The indication for orchidopexy should not be deferred.\nThe correct answer is: ",
        "gold_answer": "4 The indication for orchidopexy should not be deferred.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n To evaluate the efficacy of hCG therapy on retractile testis in various testicular locations and age groups. This study comprised 123 boys whose diagnosis were retractile testis with scrotal base, high scrotal and superficial inguinal localizations with an average age of 4,2 (1-8) years. 123 boys with retractile testes were given a total dose of 9000 hCG and its effect on scrotal base, high scrotal and superficial inguinal located testes were evaluated after 2 weeks and 6 months of completing hCG course. The patients were evaluated in four age groups such as less than 2 years of age, between 2-4, 4-6 years and more than 6 years of age and the response rates were also noted in these age groups. In unilateral cases, the response in base, high scrotal and superficial inguinal levels were found as 100%, 83,3%, 72,7% respectively where as these rates were found as 100%, 92,6%, 76,3% respectively in bilateral cases after 2 weeks of hCG therapy. The response rates in less than 2 year old group, 2-4, 4-6 and more than 6 years group were found as 0%, 80%, 78,7%, 100% respectively in unilateral cases and 33,3%, 90%, 86,9% and 83,3% respectively in bilateral cases. After 6 months, reascend was observed in 12,4% in unilateral group and 6,7% in bilateral group. 72,7-100% of retractile testes respond to hCG administration with the highest response in the age of more than six year group. High response rates observed in retractile testes after hCG therapy in more than 2 years old age group indicate that hCG must be given as a primary treatment in retractile testes and orchiopexy for the failures. Also patients must be followed up closely for reascend cases. A total of 7 boys 4 to 10 years old was evaluated for undescended testes. All patients had been seen previously by a pediatric urologist and diagnosed as having a retractile testis. In fact 4 boys had undergone surgical correction of a contralateral undescended testis at an earlier date at which time the testis in question could be manipulated into the scrotum. Another boy was examined under anesthesia and the operation was canceled because the testis could be brought into the scrotum. Subsequently, on followup evaluation 2 to 8 years later the ipsilateral testis could not be manipulated into the scrotum. Of the boys 6 then were treated with a short course of human chorionic gonadotropin. Four patients had a positive response but in 3 the testis was undescended again at examination 6 months later. Of the boys 6 ultimately underwent orchiopexy. Boys with highly retractile testes require periodic examination until puberty to ensure that those testes do not ascend secondarily. In a recent study, the effect of human chorionic gonadotropin (HCG) in the treatment of children with cryptorchidism aged less than four years was questioned. The purpose of the present study was to determine, on the basis of a retrospective examination of patients' records, the effect of HCG treatment, whether outcomes are age-dependent and whether the effects of treatment are related to the position of the testis. Patients diagnosed with undescended testis who had been treated at the Department of Urology at Gentofte Hospital (Copenhagen) in the period from 1 November 1998 to 31 May 2003 were identified. Patients who had been treated with HCG were included in the sample. Boys who at an earlier stage had been operated on in the inguinal or scrotal region, or who had suffered from inguinal hernia, were excluded, and clinical retractile testes were separated from true undescended testes. The criterion of success for efficient treatment was complete descent to the bottom of the scrotum. In the 306 records examined, 121 patients met the inclusion criteria. In total, there were 170 undescended testes. The patients' median age at time of treatment was 3.6 years. The overall success rate was 34.7%. The success rates in the individual age categories were: 1-2 years, 36.7%; 3-4 years, 33.4%; and 5-13 years, 35%. The position of the testis at the beginning of treatment showed that the lower the pretreatment position, the better the success rate. The overall success of HCG treatment of cryptorchidism was 34.7%. No age dependency of HCG effects was found, but the position of the testis before treatment influenced the success rate. Failure to replace the testes in the scrotum during hernia repair leads to iatrogenic undescended testes. At other times, the testes may spontaneously move back to the inguinal area after being placed in the scrotum, thus resulting in ascending testes. The cases in this study were assessed. Records of 910 boys operated due to inguinal hernia were assessed retrospectively. Following hernia repair, the testes were placed in the scrotum. After the operation, all the testes were checked for being in the scrotum. They were called for follow-up after the operation. Their testes were checked for remaining in the scrotum. Ascending testes were detected in 4 (0.43%) of the patients. These patients had scrotal hypoplasia and/or retractile testes. Their age ranged between 1-3 years. Ascending testes were bilateral in 2 patients, and on the right side in 2. Human chorionic gonodotropin (hCG) was initiated in 3 patients. Two of them improved. Two underwent scrotal orchiopexy. These patients may benefit from hCG in the early postoperative period. Later, scrotal orchiopexy may be needed. Patients who have retractile testes or scrotal hypoplasia in addition to inguinal hernia need orchiopexy together with herniorrhaphy. For non-scrotal testes a distinction can be made between retractile testes (completely descended and normally developed but sometimes situated subcutaneously in the groin area), retained testes (testes cannot be brought into the scrotum or this can only be achieved using light manual pressure) and ectopic testes (lying outside of the descent trajectory). It is estimated that 0.7-0.8% of all boys have as yet undescended testes. The first few days after the birth are the most suitable for testing and registration, as then the cremaster reflex is absent. Registration should take place in both the youth healthcare file and in the 'growth book' for the parents. Retractile testes do not require treatment. There is no consensus concerning the treatment of (possible) acquired nonscrotal testes. For undescended testes the management depends on previous testes localisations. For ectopic testes and testes that have never been scrotal, a referral for surgical treatment should be made prior to the second birthday. Orchidopexy (a better description is orchidofuniculolysis followed by orchidopexy) is only justified in the case of testes which have never descended. In the case of a clear indication, the general practitioner should make a prompt referral (before the second birthday) and in other cases assurance should be provided and an expectant policy adopted until puberty. We prospectively evaluated the efficacy of human chorionic gonadotropin (HCG) in the treatment of undescended testis and sought to determine whether HCG assists in the differentiation of undescended testis from retractile testis. Patients with undescended testes were offered HCG. Testis position, laterality and the presence or absence of a hypoplastic scrotum were noted. The same physician (G. W. K.) recorded physical findings prospectively and stated clinical impression of descent. A total of 67 patients with 90 undescended or retractile testes were treated and evaluated with HCG. Of the 64 undescended testes 13 (20%) descended with HCG therapy, with none requiring subsequent surgery. Of the 26 retractile testes 15 (58%) descended with HCG (p &lt;0.001). Based on physical examination, 100% of retractile testes descended if the testis was in the high scrotal position but only 40% descended if the testis was in the superficial pouch or inguinal area. In the undescended testes group no ectopic or nonpalpable testis descended with HCG. Evaluation of HCG with age demonstrated minimal response (15%) to HCG at less than 24 months, and a peak response between ages 2 and 6 years (75%) with response decreasing thereafter. HCG may have a limited role in the evaluation of undescended testis in patients younger than 2 years. HCG can serve as an adjunct in the clinical diagnosis of retractile testis in older children. Among 509 boys referred with undescended testicles, 112 had true undescended testicles unilaterally and 62 bilaterally. Patients with true undescended testicles were offered hormonal treatment unless the condition was associated with hernia or previous operations. Boys less than 5 years old were primarily treated with gonadotrophin releasing hormone (GnRH), while boys more than 5 years old were primarily treated with human chorionic gonadotrophin (hCG). If the effect of the primary treatment was insufficient the other hormone was given. Testicular descent was obtained for 64% (23/36) of the intraabdominally located testicles in boys with bilaterally undescended testicles versus only 14% (3/21) in boys with unilaterally undescended testicles (p &lt; .001). Treating 1 to 4 years old boys with GnRH resulted in descent in 16 of 95 testicles and secondary treatment with hCG yielded an additional 34, whereas secondary treatment of 5 to 13 years old boys with GnRH added only 10 descended testicles to 51 of 101 testicles. Reading the maternity records of 272 of the boys support other studies showing that testicles may reascend. Boys with endocrinological or \"surgical\" causes of incomplete testicular descent were relatively more likely to have had one or two undescended testicles during the first postnatal week compared with boys found to have only retractile testicles (p &lt; .001). Treatment with hormones resulted in descent in 56% of boys whose testicles were both descended within one week after birth. Conversely, only 1 of 20 boys with unilateral testicular undescent postnatally was sufficiently treated with hormones (p &lt; .001). The hormonal effect in boys with bilaterally undescended testicles at delivery did not differ significantly from boys with either one or none undescended testicle postnatally. In 35 of 51 boys (69%) in whom the hormonal effect was insufficient, operation revealed a \"surgical cause\" of the incomplete testicular descent. --Guidelines for the treatment ofundescended testis (UDT) are sparse. Often an operation in the second year of life is advised. --Recent data indicate that the normal maturation process, which will ultimately lead to a normal quantity and quality of germ cells, is impaired as early as in the first half year of a newborn's life. None of the guidelines take this into account. Spontaneous descent after the fourth month following birth, of testes that have previously not descended, hardly ever occurs. --No differences have been shown in complication numbers between surgery before and after the first birthday. Orchidopexy prior to the 13th birthday reduces the risk of testicular cancer. --Therefore, based on these data, it is advised to perform orchidopexy in the second half of the first year of a newborn's life. In older boys a UDT must be treated before the 13th birthday. --In the Netherlands a lot more orchidopexies are done despite what may be expected based on prevalence numbers of UDT: testes retaining a normal volume that would most probably have descended spontaneously come puberty. --It remains important to carry out a careful physical examination and document the position of the testes soon after birth, and later on if UDT is suspected, to avoid unnecessary operations on retractile testes and acquired UDT. Diagnosis The most common diagnostic dilemma in otherwise normal boys is distinguishing a retractile testis from a testis that will not descend spontaneously into the scrotum. Retractile testes are more common than truly undescended testes and do not need to be operated on. In normal males, as the cremaster muscle relaxes or contracts, the testis moves lower or higher (\"retracts\") in the scrotum. This cremasteric reflex is much more active in infant boys than older men. A retractile testis high in the scrotum can be difficult to distinguish from a position in the lower inguinal canal. Though various maneuvers are used to do so, such as using a cross-legged position, soaping the examiner's fingers, or examining in a warm bath, the benefit of surgery in these cases can be a matter of clinical judgment. We retrospectively evaluated the ability of human chorionic gonadotropin (HCG) to make the nonpalpable cryptorchid testis become palpable and promote testicular descent. Through surgical bookings we identified 94 patients younger than 11 years who received HCG between 1984 and 1994 for the diagnosis or treatment of a nonpalpable undescended testis. The dose of HCG was 1,500 IU/m.2 intramuscularly 2 times weekly for 4 weeks. Testis location was determined by physical examination before and after hormone administration, and confirmed at surgical exploration. Of the 99 nonpalpable testes identified in 94 patients 39 (39%) became palpable following HCG administration and only 2 (2%) completely descended. A total of 60 testes remained nonpalpable with the most common reason being an absent or severely atrophic testis (40, 67%). Of the testes remaining nonpalpable after hormonal stimulation 73% were surgically located at or distal to the internal ring. HCG is preoperatively efficacious in causing the nonpalpable undescended testis to become palpable. For patients failing to respond to hormonal stimulation we recommend preliminary inguinal exploration, since most testes or testicular remnants are located within the inguinal canal or immediately below the internal ring. The undescended testis is usually histologically normal at birth. Atrophy and dysplasia are found after the first year of life. Some boys have congenital dysplasia in the contralateral descended testis. Surgical correction at an early age results in greater chance of adult fertility. Administration of human chorionic gonadotropin causes testosterone release from functioning testes and may result in descent of retractile testes. Orchidopexy is usually done in the second year of life. Most extra-abdominal testes can be brought into the scrotum with correction of the associated hernia. If the testis is not palpable, ultrasound or magnetic resonance imaging may determine its location. The closer the testis is to the internal inguinal ring, the better the chance of successful orchidopexy. With an incidence of 0.7-3% in male infants, undescended testicles is one of the most common congenital anomalies. In the first 6 months of life, the testicles may spontaneously descend in up to 70% of individuals. If the testicle is not in a scrotal position afterwards, fertility can gradually be reduced and the risk of a testicular tumor increases. Therefore, the current German guideline for undescended testis recommends that therapy should be take place between 6 and 12 months of life. After extensive information on the advantages and disadvantages, hormone therapy with the aim of a descensus or in those with bilateral anomaly with the aim of improving the germ cell pool can be offered. After the first year of life, hormone therapy is obsolete. Otherwise, surgical intervention is the treatment of choice. In the case of gliding or deep inguinal testis via scrotal or inguinal access, in the case of nonpalpable and sonographically undetectable testis, laparoscopy is carried out for diagnosis and simultaneous therapy. In the first postoperative year, adequate follow-up should be done to detect a re-ascensus and/or insufficient growth. Regular self-examinations from the age of 15 serve for the early detection of a testicular tumor that occurs only very rarely (approximately 0.003%). Cryptorchidism or undescended testis is the single most common genitourinary disease in male neonates. In most cases, the testes will descend spontaneously by 3 months of age. If the testes do not descend by 6 months of age, the probability of spontaneous descent thereafter is low. About 1%-2% of boys older than 6 months have undescended testes after their early postnatal descent. In some cases, a testis vanishes in the abdomen or reascends after birth which was present in the scrotum at birth. An inguinal undescended testis is sometimes mistaken for an inguinal hernia. A surgical specialist referral is recommended if descent does not occur by 6 months, undescended testis is newly diagnosed after 6 months of age, or testicular torsion is suspected. International guidelines do not recommend ultrasonography or other diagnostic imaging because they cannot add diagnostic accuracy or change treatment. Routine hormonal therapy is not recommended for undescended testis due to a lack of evidence. Orchiopexy is recommended between 6 and 18 months at the latest to protect the fertility potential and decrease the risk of malignant changes. Patients with unilateral undescended testis have an infertility rate of up to 10%. This rate is even higher in patients with bilateral undescended testes, with intra-abdominal undescended testis, or who underwent delayed orchiopexy. Patients with undescended testis have a threefold increased risk of testicular cancer later in life compared to the general population. Self-examination after puberty is recommended to facilitate early cancer detection. A timely referral to a surgical specialist and timely surgical correction are the most important factors for decreasing infertility and testicular cancer rates. Cryptorchidism results from a complex hereditary series of incompletely understood events involving the HPG axis. The incidence is indirectly related to birth weight and dramatically decreases during the first 3 months after birth. Many nonscrotal testes are retractile and require no therapy whatsoever. True cryptorchid testes develop identifiable histologic alterations within 2 years of parturition, and endocrine abnormalities are often detectable during infancy. Hormonal therapy with hCG is effective in causing descent in only a small percent of children with cryptorchidism. GnRH nasal spray is no different from placebo in double-blind studies in which retractile testes have been excluded. The results are best in low-lying testes and in older children, but a recognized late-failure rate requires continued surveillance. HCG therapy appears to be of little use in nonpalpable cryptorchid testes. The risk of testicular cancer is increased in men with a history of cryptorchidism and even includes the contralateral descended testes. This risk may be reduced by early orchidopexy. Fertility is impaired in men with cryptorchidism and is reported to be no better than 75% and 50%, respectively, in men who have undergone successful unilateral or bilateral orchidopexy. There is unconfirmed evidence that orchidopexy carried out before the age of 2 years may improve these fertility rates. It is recommended that all children with cryptorchid testes undergo treatment by the age of 1 or 2 years. The parents of children with a nonpalpable testis should be informed of the high rate of testicular absence. If hormonal therapy is to be used, it must be initiated at 10 months of age. Treatment failures must be identified quickly to allow prompt referral of these children to a pediatric urologist or surgeon for orchidopexy. The term cryptorchidism indicates a testis, which has failed to descend to the scrotum and is located at any point along the normal path of descent or at an ectopic site. Hormones play a pivotal role in testicular descent except during the migration to the level of internal inguinal ring. Cryptorchidism is present in about 4.5% of newborns with a higher incidence in preterms. The incidence decreases to 1.2% by the first year. It is classified as palpable and impalpable. The most common site of an ectopic testis is superficial inguinal pouch. Retractile testis is often bilateral and most common in boys between 5 and 6 years of age. Hypospadias and inguinal hernias are the most common associated anomalies seen with undescended testis. A thorough clinical examination helps in arriving at the etiology. A short hCG stimulation test helps to exclude anorchia. Different imaging techniques are of little help in diagnosis and require the help of an experienced radiologist. Laparoscopy has an important role in the diagnosis and management of undescended testis. The common complications include torsion and atrophy of testis. Infertility is seen in about 40% of unilateral and 70% of bilateral cryptorchidism. Undescended testis is 20 to 40 times more likely to undergo malignant transformation than normal testis. Both hCG and GnRH have been used with limited success in these children. All boys with cryptorchidism should be referred to a pediatric surgeon before 2 years of age. These children should be followed up every year after surgery to identify testicular tumors. To review the differences between normal, retractile, ectopic, ascended, and undescended testes and to describe the optimal way to perform a testicular examination to distinguish one from the other, as well as to demonstrate that ultrasound imaging is not necessary and to clarify when to consider specialist referral. This paper is based on selected findings from a MEDLINE search on undescended testes and orchiopexy referrals, and on our experience at the Urology Clinic at the Children's Hospital of Eastern Ontario in Ottawa, including review of referrals to our clinic for undescended testes and the resultant findings of normal variants versus surgical cases. The MeSH headings used in our MEDLINE search included <iundescended testicle, retractile testicle, ectopic testicle, ascended testicle, referral and consultation,</i and <iorchiopexy</i. An <iundescended testis</i is defined as the true absence of one testis (or both testes) from normal scrotal position. Ectopic and ascended testes will likewise be absent from the scrotum, the latter having been present at one point in development. Differentiating among testicular examination findings is important, as descended and retractile testes are managed conservatively, while prompt surgical intervention should be offered for ascended, ectopic, and undescended testes. Uncertainty surrounding the diagnosis of an undescended testis causes anxiety, might lead to unwarranted imaging, and might increase the wait list for specialty assessment. For this reason, avoidance of ultrasound in the evaluation of undescended testes was included in the recent Choosing Wisely Canada campaign. We seek to clarify the physical examination findings in the evaluation of possible undescended testes, the suggested referral parameters, and the subsequent management. Undescended testes and their variants are common. As decision for referral is based on the primary care physician's physical examination findings, we clarify distinguishing between normal and abnormal findings on testicular examination to aid in appropriate referral for subspecialist evaluation. Consultation, if needed, should be sought at 6 months' corrected gestational age, or at detection if later than 6 months, without delay for ultrasound imaging, as surgical management is recommended for those patients with undescended, ectopic, or ascended testes. Seventy one patients with ectopic testis of age between 2 and 11.5 years were treated with human chorionic gonadotropin (HCG) at doses recommended by the International Health Foundation. The descent of testis to the scrotum was achieved in almost half of the treated boys (49.3%). The descent was successful mainly in cases of lower inguinal position of the undescended testicle, and only rarely when the testicle was situated higher. The descent was never successful in cases when the scrotum was small and underdeveloped. The medical treatment of retentio testis remains controversial because of ineffectiveness and/or adverse events. Follicle-stimulating hormone (FSH) seems to influence the spontaneous descent of the testis; furthermore, it induces luteinizing hormone (LH) receptors. Therefore, we performed a double-blind placebo-controlled study to investigate the effect of FSH with human chorionic gonadotrophin (hCG) versus hCG alone in retentio testis patients. Twenty-two boys with retentio testis were investigated, excluding retractile testis. Group A (N = 14: four with bilateral and 10 with unilateral retentio testis; mean age 3.15 years) was treated with 150 IU of FSH twice a week for 2 weeks followed by 150 IU of FSH and 250 IU of hCG (half the recommended World Health Organization dose) twice a week for another 4 weeks. Group B (N = 8: two with bilateral and six with unilateral retentito testis; mean age 3.3 years) was treated with 250 IU of hCG twice a week for 6 weeks. Testicular position, volume and consistency as well as the appearance of the scrotum and the penile length were determined at the start of the treatment as well as at weeks 2, 4, 6 and 12 by two independent investigators. Blood investigation consisted of measurements of LH, FSH, testosterone and sex hormone-binding globulin. Successful descent was considered when the testis reached a mid- or low scrotal position. In group A, 6/18 testes descended successfully. In group B, 6/10 testes descended. Of the unsuccessfully treated patients, six of group A and three of group B underwent surgery.(ABSTRACT TRUNCATED AT 250 WORDS) The aim of the study was to compare the effects of human chorionic gonadotropin (hCG) therapy with those of surgical or combined therapy on testicular volume (TV) in boys at different ages with unilateral canalicular undescended testis (UDT). In total, 155 boys aged 1 to 12 years were treated: either surgically (ST), or by 50 IU/kg body weight hCG administration every three days for five weeks (HT), or by a combination of the two. The patients underwent ultrasound examination of TV before the treatment, 9-12 (median 10) and 24-39 months (median 32) after therapy. The testicular atrophy index (TAI) of the affected testicle was calculated. The success rate was 94.7% for ST, 39.2% for HT and 98% for HST patients. The atrophy rate was 5.3% for ST, 0% for HT and 2% for HST. Neither treatment type nor patient age significantly influenced gonadal atrophy. No significant differences in TV of the affected testis were observed after treatment between the groups. The TAI values were significantly the lowest in HT group (p = 0.0006). Both TV and TAI changes from the baseline values did not differ between the treatment groups. At the 24- to 39-month follow-up, no significant differences were observed in the change in baseline TV and baseline TAI between age groups. TV of the affected testis increased significantly (p = 0.0000), and TAI decreased significantly over time (p = 0.01), with no significant differences depending on the age group, treatment type or the interaction of the two factors. The hCG therapy did not impair the development of affected and healthy testes, neither as single nor as neoadjuvant therapy, both during early assessment and after 2-3 years. Patients' age at the initiation of treatment seems irrelevant. Testes follow the \"path of descent\" from high in the posterior fetal abdomen to the inguinal ring and beyond to the inguinal canal and into the scrotum. In most cases (97% full-term, 70% preterm), both testes have descended by birth. In most other cases, only one testis fails to descend (cryptorchidism) and that will probably express itself within a year. Pubertal The testes grow in response to the start of spermatogenesis. Size depends on lytic function, sperm production (amount of spermatogenesis present in testis), interstitial fluid, and Sertoli cell fluid production. After puberty, the volume of the testes can be increased by over 500% as compared to the pre-pubertal size. Testicles are fully descended before one reaches puberty. Clinical significance Protection and injury In a population of 8500 men attending the andrology outpatient clinic, 200 men (2.35%) were recorded as having some disturbances with the descent of the testes into the scrotum. Medical history of the patients revealed that 51 underwent unilateral orchidopexy; 40 bilateral orchidopexy; and 24 were treated with human chorionic gonadotropin in order to induce descent of their testes. In addition, 6 patients reported spontaneous descent of the testes, and 13 others were found to be unilaterally cryptorchid upon physical examination. Results of semen analysis, hormonal profile, testes position, and testicular volume were compared to those of 105 proven fertile men. The major finding of this study shows that post-partum undescended testes suffer from primary Sertoli cell malfunction as reflected by elevated serum follicle stimulating hormone levels. Serum luteinizing hormone and testosterone levels were within the normal range. Surgical descent of the testes did not improve sperm production, proved by low sperm quality of all the study groups, compared to the cryptorchid group. Among the patients who were operated on, no correlation was found between age at operation and semen variables. All groups showed poor sperm quality which can be defined as oligoteratoasthenozoospermia. The degree of spermatogenic damage was in the following order of diagnosis or treatment: bilateral orchidopexy greater than cryptorchid testes greater than hormonal treatment greater than unilateral orchidopexy greater than late spontaneous descent of the testes. Thus, it is advisable to postpone surgical treatment of cryptorchidism and apply this only after a waiting period, and if the hormonal approach has failed to descend the testis.\nHere is the question:\nUROLOGY: 12-month-old boy, who in the health examinations practiced since birth presents right testicle in inguinal canal that is not possible to descend to the scrotum. Mark the CORRECT answer:\nHere are the potential choices:\n1. The most likely diagnosis is retractile testis.\n2. Wait until two years of age for spontaneous decrease of the synovial fluid.\n3. Human chorionic gonadotropin is the treatment of first choice.\n4. The indication for orchidopexy should not be deferred.\nThe correct answer is: 4. The indication for orchidopexy should not be deferred."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Since 1982, and with informed patient consent, we have photocoagulated confluent drusen and limited serous pigment epithelium detachment (SPED) in the fellow eye of ten patients suffering from advanced, disciform type, age-related macula degeneration (ARMD). This treatment was only carried out on appearance of metamorphopsia. Photocoagulation was performed with either the green ray of the argon laser, or the yellow ray of a dye laser. Spots of about 200 microns were placed in a grid-like fashion among the drusen. No complications were observed due to the treatment. The follow-up period on these ten patients, eight women and two men, mean age 77 years, was two to eight years, and the three patients have died. The drusen disappeared completely in three patients and partially in one. The functional results seemed favorable in three cases. In one case of confluent drusen associated with SPED and serous retinal detachment, vision improved remarkably from 0.3 to 0.5 with a Parinaud 2, with a follow-up of five years. In another case, the improvement was from 0.4 to 0.7 but the patient died after only a few months. In another case, vision has been stable for five years. The vision of the seven remaining patients deteriorated; three cases showed central areolar sclerosis, and one case a localised new vessel with vision less than 0.1. In three cases vision dropped to 0.2 and Parinaud 6, but they have been stable for at least four years (eight years for one patient).(ABSTRACT TRUNCATED AT 250 WORDS) To investigate the causes of hyperreflective dots (HRDs) in spectral domain optical coherence tomography (OCT) excluding diabetic macular edema (DME) and RVO (retinal vein occlusion). The medical records of 56 patients with HRDs documented by OCT were reviewed retrospectively. The patients with DME and RVO were excluded from the study in order to prevent misdiagnosing hard exudates or HRDs. The causes, unilaterality or bilaterality of HRD and demographic properties of the patients with HRD were evaluated. Sixty four eyes of 56 patients having HRDs were included in this study. Of the patients with HRD, 17 (30.36%) were women and 39 (69.64%) were men. The ages of patients were between 13 to 84 years (median 60.18 years). The causes of HRD were as follows: papilledema in 4 eyes (6.25%), active neovascular age related macular degeneration (AMD) in 33 eyes (51.56%), familial dominant drusen in 2 eyes (3.13%), central serous chorioretinopathy in 19 eyes (29.69%) and commotio retina in 2 eyes (3.13%), choroidal folds in one eye (1.56%), branch retinal artery occlusion in one eye (1.56%), central retinal artery occlusion in one patient (1.56%) and Best vitelliform macular dystrophy in one eye (1.56%). The most common cause of HRD was AMD. The causes of HRDs in both eyes were AMD and papilledema. The most common causes of HRDs excluding DME and RVO seem as active exudative AMD. The presence of HRDs in retinal diseases might affect the decisions and the results of the treatment and the prognosis of diseases. To investigate the prevalence and clinical significance of small retinal haemorrhages accompanied by macular soft drusen in exudative age-related macular degeneration (AMD). This observational case series included patients who had first been diagnosed with exudative AMD. Small retinal haemorrhages were defined as preretinal or intraretinal haemorrhages, no larger than half the disc diameter in size and located within 3000 μm of the fovea centre. If there was more than one haemorrhage, the entire affected area was less than two-thirds of the disc diameter. Macular soft drusen was defined as the presence of soft drusen (≥125 μm in diameter) within the macular area. The presence of retinal angiomatous proliferation (RAP) was estimated based on the results of indocyanine green angiography (ICGA). The prevalence of reticular pseudodrusen was also estimated. Among the 1921 eyes from 1604 patients who were newly diagnosed with exudative AMD during the 40 months prior to the study, 101 eyes (5.3%) from 79 patients presented with the fundus characteristics described above. ICGA images were available for 69 eyes. Among these eyes, 28 eyes (43.1%) and 25 eyes (38.5%) were found to have type 1 and 2 RAP, respectively. A chorioretinal anastomosis (type 3 RAP) was identified in 12 (18.5%) eyes. Reticular pseudodrusen were noted in 78 eyes (77.2%). The presence of small retinal haemorrhages accompanied by macular soft drusen was highly predictive of RAP. The high prevalence of both soft drusen and reticular pseudodrusen in these eyes may suggest a profound decrease in choroidal perfusion in these eyes. Drusen, from the German word for node or geode (singular, \"Druse\"), are tiny yellow or white accumulations of extracellular material that build up between Bruch's membrane and the retinal pigment epithelium of the eye. The presence of a few small (\"hard\") drusen is normal with advancing age, and most people over 40 have some hard drusen. However, the presence of larger and more numerous drusen in the macula is a common early sign of age-related macular degeneration (AMD). Classification Drusen are associated with aging and macular degeneration are distinct from another clinical entity, optic disc drusen, which is present on the optic nerve head. Both age-related drusen and optic disc drusen can be observed by ophthalmoscopy. Optical coherence tomography scans of the orbits or head, calcification at the head of the optic nerve without change in size of globe strongly suggests drusen in a middle-age or elderly patient. On examination, patients frequently have decreased best-corrected visual acuity (BCVA), and Amsler grid evaluation may reveal areas of central or paracentral scotoma or visual distortion. Ophthalmic examination of the anterior segment of the eye is usually normal. ARMD-related CNV has several different appearances on the dilated funduscopic exam. [17] These include: A gray-green membrane deep into the retina is usually associated with an overlying neurosensory retinal detachment. There may be the presence of blood, lipid, or subretinal fluid. RPE detachments appear clinically as dome-shaped, sharply demarcated elevations of the RPE; these may also be serous, fibrovascular, drusenoid, or hemorrhagic. [18] There may be massive subretinal hemorrhage with central vision loss or, less commonly, breakthrough vitreous hemorrhage with peripheral vision loss. RPE tears. Disciform scars may be present, which may appear as white or yellow subretinal membranes with or without RPE hyperplasia. To describe the 15-year cumulative incidence of signs of early and late age-related macular degeneration (AMD). Population-based cohort study. We included 3917 persons, 43 to 86 years of age at the time of a baseline examination in 1988 through 1990 and with information collected in follow-up in 1993 through 1995, and/or 1998 through 2000, and/or 2003 through 2005. Grading of stereoscopic fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. Cumulative incidence of drusen type and size, pigmentary abnormalities, geographic atrophy, and exudative AMD accounting for competing risk of death. The 15-year cumulative incidence was 14.3% for early AMD (the presence of either soft indistinct drusen or the presence of pigmentary abnormalities together with any type of drusen) and 3.1% for late AMD (presence of exudative AMD or geographic atrophy). There was an increased incidence of AMD lesions with age (P&lt;0.05). Individuals &gt; or = 75 years of age at baseline had significantly (P&lt;0.01) higher 15-year incidences of the following characteristics than people 43 to 54 years of age: larger drusen (125 mum in diameter, 24.1% vs 10.6%), soft indistinct drusen (18.7% vs 6.5%), retinal pigmentary abnormalities (20.2% vs 3.7%), exudative macular degeneration (4.4% vs 0.4%), and pure geographic atrophy (3.2% vs 0%). Controlling for age, compared with those with small numbers of only small hard drusen (1-2), those with large numbers of only hard drusen (&gt; or =8) had an increased 15-year age-adjusted incidence of both soft indistinct drusen (16.3% vs 4.7%) and pigmentary abnormalities (10.6% vs 2.7%). Eyes with soft indistinct drusen or pigmentary abnormalities at baseline were more likely to develop late AMD at follow-up than eyes without these lesions (17.8% vs 1.2% and 12.9% vs 1.7%, respectively). We document the long-term incidence of signs of AMD and a continuum from small hard drusen to late AMD in older persons in the population. The 15-year cumulative incidence of late AMD in people &gt; or = 75 years of age (8%) indicates a public health problem of significant proportions because the United States population this age is expected to increase by 54% between 2005 and 2025. AMD-like pathology begins with small yellow deposits (drusen) in the macula, between the retinal pigment epithelium and the underlying choroid. Most people with these early changes (referred to as age-related maculopathy) still have good vision. People with drusen may or may not develop AMD. In fact, the majority of people over age 60 have drusen with no adverse effects. The risk of developing symptoms is higher when the drusen are large and numerous, and associated with the disturbance in the pigmented cell layer under the macula. Large and soft drusen are thought to be related to elevated cholesterol deposits. Early AMD Early AMD is diagnosed based on the presence of medium-sized drusen, about the width of an average human hair. Early AMD is usually asymptomatic. Intermediate AMD Intermediate AMD is diagnosed by large drusen and/or any retinal pigment abnormalities. Intermediate AMD may cause some vision loss, but, like early AMD, it is usually asymptomatic. A maculopathy is any pathological condition of the macula, an area at the centre of the retina that is associated with highly sensitive, accurate vision. Forms of maculopathies Age-Related Macular Degeneration is a degenerative maculopathy associated with progressive sight loss. It is characterised by changes in pigmentation in the Retinal Pigment Epithelium, the appearance of drusen on the retina of the eye and choroidal neovascularization. AMD has two forms; 'dry' or atrophic/non-exudative AMD, and 'wet' or exudative/neovascular AMD. Malattia Leventinese (or Doyne’s honeycomb retinal dystrophy) is another maculopathy with a similar pathology to wet AMD. Cellophane Maculopathy A fine glistening membrane forms over the macula, obscuring the vision. To study time patterns in bilateral exudative age-related macular degeneration (AMD) and the pattern of drusen before and after the onset of exudative AMD. Out of 2220 individuals in the Icelandic genetic study of AMD, 151 had bilateral exudative AMD. We searched for previous records in the Icelandic University Retina Unit. For the 65 patients with a fluorescein angiography record of both eyes, we established the time between the onset of disease in each eye. For the 53 patients with colour fundus photographs of the latter eye taken prior to the occurrence of exudative disease, we graded the drusen before and after the onset of exudative AMD in the second eye. The time interval between the onset of exudative AMD in the first and second eyes was 2.5 years (95% CI: 1.8-3.2; n = 65) and the median was 1.8 years. In 82% of cases the second eye was affected within 4 years. Soft drusen in the macula were found in 95% of eyes that later developed exudative disease (n = 53). Soft and hard drusen decreased in number in the central macula following the development of exudative disease. Bilateral exudative AMD develops within a few years in both eyes. Drusen are less visible following the onset of exudative AMD in the second eye. Breakthrough vitreous hemorrhage can also occur in wet ARMD, and diagnosis may be challenging if there is a poor view on dilated funduscopic examination. Diagnosis may be established by evaluating the patient’s fellow eye or obtaining a thorough history. Other potential causes of vitreous hemorrhage include: Proliferative diabetic retinopathy Retinal tear or retinal detachment Hemorrhagic posterior vitreous detachment Neovascularization from other causes, including vein occlusions, radiation retinopathy, or sickle cell retinopathy Age-related macular degeneration (AMD) is the leading cause of irreversible severe visual loss in the United States in people over 50 years of age. The nonexudative stage includes hard drusen (associated with localized dysfunction of the retinal pigment epithelium [RPE]), soft drusen (associated with diffuse dysfunction of the RPE), and geographic (areolar) atrophy. These fundus changes may predispose the eye to develop the neovascular/exudative stages of AMD. Most patients who develop severe visual loss from AMD have this exudative stage. Treatment for AMD has been shown to be effective for only a small proportion of patients who have a well-defined choroidal neovascular membrane (CNVM) more than 200 microns from the foveal center. Even in successfully treated cases, severe visual loss is postponed only for about 18 months because of the high rate of recurrent CNVMs that extend into the fovea. Thus, despite recent breakthroughs in laser treatment for AMD, most patients who develop the exudative form of AMD will develop central visual impairment. At the present time, the only available treatments for the majority of patients who develop the exudative form of AMD are low vision aids. Investigators are currently evaluating whether treatment is effective for membranes within 200 microns of the foveal center. Future studies need to be directed toward further understanding of the pathogenesis, treatment and prevention of the blinding complications of AMD. The usefulness of automated static perimetry and optical coherence tomography in the management of macular diseases has been described. Scotomata in eyes with central serous chorioretinopathy could be evaluated with central 10-degree automated static perimetry. The degree of visual field defects in eyes with the disease varied greatly with mean deviation of -10 dB or less in as many as 10% of the subjects. Although retinitis pigmentosa is a diffuse retinal dystrophy, eyes with a moderately advanced stage of retinitis pigmentosa should be managed as a macular disease, because the functioning retina is confined within the vascular arcade. The progressive nature in this stage of the disease could be demonstrated with a central 10-degree automated static perimetry measured once or twice a year and the use of univariate linear regression of mean deviation, in half of the patients with a mean follow-up period of 5 years. Functional recovery in eyes with exudative age-related macular degeneration after laser surgery or submacular surgery could be evaluated with central 10-degree automated static perimetry. Eyes with increased mean deviation in spite of reduced visual acuity after therapeutic intervention should also be evaluated. Macular function could also be evaluated using a color test. A newly developed color saturation discrimination test was applied to patients with age-related macular degeneration, retinitis pigmentosa, and cone dystrophy. The degree of dyschromatopsia was less in eyes with age-related macular degeneration than in those with retinitis pigmentosa or cone dystrophy with the same level of acuity loss. The highly protrusive nature of the orange-red nodule in eyes with idiopathic polypoidal choroidal vasculopathy was demonstrated with dimensional measurement with OCT. The degree of protrusion was greater than in eyes with serous pigment epithelial detachment, which suggests that the polypoidal lesion is covered with rigid tissues including Bruch's membrane. Parafoveal retinal sensitivity obtained with automated static perimetry was studied in correlation with retinal thickness measured using OCT in eyes with branch retinal vein occlusion showing macular edema without macular non-perfusion or massive retinal hemorrhages. The increased retinal thickness due to macular edema is closely correlated with retinal sensitivity both at the fovea and in the parafoveal area. Eighty-nine phakic eyes of 46 patients with retinitis pigmentosa patients were studied to detect cystoid macular edema using OCT. Cystoid lesions were observed in the macula in 12 eyes in 6 (13%) of 46 patients. Some eyes with OCT-proven cystoid macular edema did not show dye pooling in the fluorescein angiogram. The width of the total area of cystoid lesions was positively correlated with best-corrected visual acuity but the thickness of the neurosensory retina at the center of the fovea was not. OCT findings of successfully repaired macular holes were categorized into 3 groups. Eyes with U-type showed a normal foveal contour and a dark layer corresponding to the outer segment of photoreceptors. Eyes with V-type showed a notch in the surface of repaired neurosensory retina without a dark layer on the retinal pigment epithelium. Those with W-type showed a defect of the neurosensory retina, where the retinal pigment epithelium was exposed. The visual results were excellent in eyes with U-type, but poor in those with W-type. Acute visual loss is a rapid loss of the ability to see. It is caused by many ocular conditions like retinal detachment, glaucoma, macular degeneration, and giant cell arteritis, etc. Main causes Retinal detachment Retinal detachment should be considered if there were preceding flashes or floaters, or if there is a new visual field defect in one eye. If treated early enough, retinal tear and detachment can have a good outcome. Glaucoma Angle-closure glaucoma should be considered if there is painful loss of vision with a red eye, nausea or vomiting. The eye pressure will be very high typically greater than 40 mmHg. Emergent laser treatment to the iris may prevent blindness. Macular degeneration Wet macular degeneration should be considered in older people with new distortion of their vision with bleeding in the macula. Vision can often be regained with prompt eye injections with anti-VEGF agents. Giant cell arteritis Age-related macular degeneration (AMD) in the Japanese often shows different clinical features from those described in Caucasians. For example, we often observe choroidal neovascularization (CNV) in elderly patients without drusen in the fundus. The high incidence of polypoidal choroidal vasculopathy (PCV) in AMD among Japanese is well-known. The reason why such differences occur in clinical manifestations of AMD has been one of my main interests. In this review article, I will discuss the characteristics of AMD in the Japanese population, as found in our recent study. I. Prevalence and clinical characteristics of AMD in the Japanese population. Cohort studies are important to determine the prevalence and incidence of diseases. In Japan, cohort studies began to be carried out rather late compared with Western countries. Although good cohort studies from Japan are reported in the literature, the size of the cohorts was not sufficiently large to determine the prevalence of AMD. However, a recent meta-analysis of Asian cohorts has shown that the prevalence of late AMD in Asians is not different from that reported in Caucasians. On the other hand, the prevalence of early AMD appears lower in the Japanese than in Caucasians. Recently, we have published the results of the Nagahama Cohort study. In this cohort study, we found a high prevalence of drusen. It seems that the incidence of dry AMD is likely to increase among Japanese. In Japan, most retina specialists classify AMD into three categories : typical AMD, PCV, and retinal angiomatous proliferation (RAP). However, there are no definite diagnostic criteria to distinguish between the three conditions. To compare the clinical features of Japanese and Western cases of AMD, and to determine the incidence of the three types of AMD, we exchanged data about 100 consecutive cases between Kyoto University and Centre d'Ophtalmologie de Paris, France. Interestingly, the diagnoses made by the two institutes were not always in agreement. We also found more cases of PCV among the Japanese than among the French. II. PCV. About 50% of exudative AMD cases in the Japanese population are PCV. Because of its peculiar angiographic findings, PCV has long been considered to be a distinct clinical entity different from the usual exudative AMD. Also, there have been serious discussions on the nature of PCV. In our analyses, about 20% of PCV cases show rather large lesion sizes that exceed the vascular arcade. Scar formation in the macula and compromised vision are frequent findings in such cases. The occurrence of PCV in the inferior staphyloma or in angioid streaks shows heterogeneity in PCV. These findings suggest that PCV may be a finding on indocyanine green angiography rather than a distinct clinical entity. Spectral domain OCT examination shows that the branching vascular network of PCV is located between the retinal pigment epithelium and Bruch's membrane. In cases with retinal pigment epithelial detachment, CNV from the branching vascular network was found to extend along the roof of the detached retinal pigment epithelium. Such findings show that the branching vascular network of PCV is type 1 CNV. Complement factor H (CFH) and age-related maculopathy 2 (ARMS2)/High temperature requirement 1 (HTRA1) located on chromosome 10 (10q26) are well-established disease susceptible genes of AMD. In the Japanese, the prevalence of CFH Y402H gene polymorphism is low and ARMS2/HITRA1 plays a more important role in the development of AMD. In ARMS2 A69S polymorphism, a large deletion/insertion (443de1/54ins) that is reported in Caucasians was also found in Japanese. Thus, the genetic background of Caucasian and Japanese AMD is quite similar, as is also the case with exudative AMD and PCV. Our findings show that PCV is not a distinct clinical entity but is a subtype of exudative AMD. III. Exudative AMD with choroidal vascular hyperpermeability. Choroidal vascular hyperpermeability observed in central serous chorioretinopathy can be found in about 20% to 30% of exudative AMD cases in Japanese. Such cases often show a thick choroid, lack of drusen, and rather good visual prognosis with slow progression of the disease. Recently, \"pachychoroid neovasculopathy\" has been described by a group from New York. Such cases of AMD with choroidal vascular hyperpermeability, a thick choroid, and lack of drusen appears to belong to pachychoroid neovasculopathy. We studied the risk allele frequencies of CFH I62V and ARMS2 A69S gene polymorphisms in three groups : usual exudative AMD, pachychoroid neovasculopathy, and normal controls. Interestingly, cases of pachychoroid neovasculopathy show different gene polymorphisms of CFH I62V and ARMS2 A69S from the usual cases of exudative AMD and a more similar pattern to normal controls. Therefore, the possible mechanisms of the CNV development in such cases may differ from the classic well-documented drusen-dependent pathways. IV. Atrophic AMD in Japanese. Data from the Nagahama Cohort study show an increasing prevalence of drusen in Japanese. Recently, more extensive information on drusen has become available and the redefinition of drusen is currently in progress. In particular, the importance of reticular pseudodrusen (RPD) is more widely appreciated. This type of drusen is often found in Japanese AMD. Although the nature and location of RPD are still debatable, many investigators believe that this type of drusen is located under the sensory retina rather than under Bruch's membrane. In our analyses, RPD was found in 18.4% of late AMD cases in Japanese. It was more common in eyes with RAP or atrophic AMD and was seldom found in PCV. ARMS2 A69S gene polymorphism was found more frequently in cases of exudative AMD with RPD, than in cases of exudative AMD without RPD. Eyes with RPD show a thin choroid and diminished vascular densities of choroidal vessels. Since, in most eyes with retinal diseases quality of vision is greatly affected by visual field defects including paracentral scotoma and inferior field defects, visual function should be assessed by central 30- or 10-degrree automated static perimetry as well as visual acuity testing. The reduction of light sensitivity, demonstrated in the results of Humphrey central 10-2 perimetry, is more apparent than visual acuity loss in eyes with central serous chorioretinopathy (CSC), in which patients complain of dimness in the visual field of the affected eye. While reduced light sensitivity in eyes with acute CSC is well correlated with the height of subretinal fluid, marked and irreversible light sensitivity loss is demonstrated in the absence of subretinal fluid in eyes with chronic CSC due to structural damage in the photoreceptors. Various degrees of light sensitivity loss are seen in eyes wih age-related macular degeneration corresponding to intraretinal or subretinal pathology including intra- or subretinal fluid, fibrous scarring containing choroidal neovascularization and atrophic changes. The mean deviation (MD) of Humphrey central 10-2 perimetry is useful in predicting the visual outcome in eyes with exudative AMD after photodynamic therapy or intravitreal injection of anti-vascular endothelial growth factor. The progression of retinitis pigmentosa is well assssed with MD of Humphrey central 10-2 perimetry, which decreases linearly in the stage of residual visual field of 10 degrees or less. The age of patients with visual loss below 0.5 is delayed in eyes showing pencil-like configuration of \"Traquair's island of visual field\", in which a small area of normal light sensitivity around the fixation point is surrounded by absolute scotoma. With less visual acuity loss compared with that seen in eyes with central retinal artery occlusion; eyes with branch retinal artery occlusion show marked visual field defects, which are permanent and profound simulating the nasal-step pattern seen in eyes with glaucoma. Non-perfusion areas in fluorescein angiograms of eyes with branch retinal vein occlusion generally demonstrate reduced light sensitivity in the results of Humphrey central 30-2 perimetry, the degree of which tends to correlate with severity of non-perfusion. The light sensitivity in the area of detached retina in eyes with rhegmatogenous retinal detachment is generally reduced to show absolute scotoma, yet these eyes recover greatly after successful surgical repair. • Next, examine the macula. The macula is the area between the superior and inferior temporal vascular arcades, and its center is the fovea. You can examine the macula by pointing your ophthalmoscope about 15° temporal to the optic disc. Alternatively, ask the patient to look into the center of the light. Note the foveal reflex and the presence of any hemorrhage, exudate, abnormal blood vessels, scars, deposits, or other abnormalities. • Examine the retinal blood vessels by re-identifying the optic disc and following each of the four main branches away from the disc. The veins are dark red and relatively large. The arteries are narrower and bright red. • Ask the patient to look in the eight cardinal directions to allow you to view the peripheral fundus. In a patient with a well-dilated pupil, it is possible to visualize as far as the equator. We report a novel case of vitreous hemorrhage associated with suspected rupture of 2-disc-diameter retinal arterial macroaneurysm on the optic disc. A 90-year-old woman presented with blurred vision (sudden onset) in her left eye. Examination of the fundus revealed acute onset vitreous hemorrhage of unknown origin without retinal detachment. She underwent vitrectomy, but after excision of the dense vitreous hemorrhage, a 2-disc-diameter hematoma appeared on the optic disc and was removed promptly. Because the bleeding at the base of the hematoma was of arterial origin and pulsating, the first vitrectomy could not achieve hemostasis. Five days after the first surgery, we performed a second vitrectomy. This revealed a subretinal hemorrhage along the superior and inferior arcade vessels and a macular hole, which was almost completely closed with an inverted internal limiting membrane flap. Unfortunately, the macular hole reopened 41 days after the second surgery. In patients presenting with only a large hematoma on the optic disc, it might be prudent to leave the hematoma. However, this large retinal arterial macroaneurysm was on a rare location on the optic disc, making it doubly difficult for the surgeons to diagnose and choose the best option intraoperatively. The differential diagnosis for dense vitreous hemorrhage of unknown origin should include a large retinal arterial macroaneurysm on the optic disc. Optic Disc Drusen These are refractile deposits within the substance of the optic nerve head (Fig. 39-13). They are unrelated to drusen of the retina, which occur in age-related macular degeneration. Optic disc drusen are most common in people of northern European descent. Their diagnosis is obvious when they are visible as glittering particles on the surface of the optic disc. However, in many patients they are hidden beneath the surface, producing pseudopapilledema. It is important to recognize optic disc drusen to avoid an unnecessary evaluation for papilledema. Ultrasound or computed tomography (CT) scanning is sensitive for detection of buried optic disc drusen because they contain calcium. In most patients, optic disc drusen are an incidental, innocuous finding, but they can produce visual obscurations. On perimetry they give rise to enlarged blind spots and arcuate CHAPTER 39 Disorders of the Eye\nHere is the question:\nOPHTHALMOLOGY: An 84-year-old woman presents with loss of vision in the left eye of 4 days of evolution accompanied by metamorphopsia. The macula shows abundant hard exudates, two small deep hemorrhages and a localized neurosensory retinal detachment. In the contralateral eye there are abundant soft drusen. Which of the following diagnoses do you think is the most likely?\nHere are the potential choices:\n1. Acute posterior vitreous detachment.\n2. Exudative age-related macular degeneration (AMD).\n3. Central retinal artery obstruction.\n4. Non-arteritic anterior ischemic optic neuropathy.\nThe correct answer is: ",
        "gold_answer": "2 Exudative age-related macular degeneration (AMD).",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Since 1982, and with informed patient consent, we have photocoagulated confluent drusen and limited serous pigment epithelium detachment (SPED) in the fellow eye of ten patients suffering from advanced, disciform type, age-related macula degeneration (ARMD). This treatment was only carried out on appearance of metamorphopsia. Photocoagulation was performed with either the green ray of the argon laser, or the yellow ray of a dye laser. Spots of about 200 microns were placed in a grid-like fashion among the drusen. No complications were observed due to the treatment. The follow-up period on these ten patients, eight women and two men, mean age 77 years, was two to eight years, and the three patients have died. The drusen disappeared completely in three patients and partially in one. The functional results seemed favorable in three cases. In one case of confluent drusen associated with SPED and serous retinal detachment, vision improved remarkably from 0.3 to 0.5 with a Parinaud 2, with a follow-up of five years. In another case, the improvement was from 0.4 to 0.7 but the patient died after only a few months. In another case, vision has been stable for five years. The vision of the seven remaining patients deteriorated; three cases showed central areolar sclerosis, and one case a localised new vessel with vision less than 0.1. In three cases vision dropped to 0.2 and Parinaud 6, but they have been stable for at least four years (eight years for one patient).(ABSTRACT TRUNCATED AT 250 WORDS) To investigate the causes of hyperreflective dots (HRDs) in spectral domain optical coherence tomography (OCT) excluding diabetic macular edema (DME) and RVO (retinal vein occlusion). The medical records of 56 patients with HRDs documented by OCT were reviewed retrospectively. The patients with DME and RVO were excluded from the study in order to prevent misdiagnosing hard exudates or HRDs. The causes, unilaterality or bilaterality of HRD and demographic properties of the patients with HRD were evaluated. Sixty four eyes of 56 patients having HRDs were included in this study. Of the patients with HRD, 17 (30.36%) were women and 39 (69.64%) were men. The ages of patients were between 13 to 84 years (median 60.18 years). The causes of HRD were as follows: papilledema in 4 eyes (6.25%), active neovascular age related macular degeneration (AMD) in 33 eyes (51.56%), familial dominant drusen in 2 eyes (3.13%), central serous chorioretinopathy in 19 eyes (29.69%) and commotio retina in 2 eyes (3.13%), choroidal folds in one eye (1.56%), branch retinal artery occlusion in one eye (1.56%), central retinal artery occlusion in one patient (1.56%) and Best vitelliform macular dystrophy in one eye (1.56%). The most common cause of HRD was AMD. The causes of HRDs in both eyes were AMD and papilledema. The most common causes of HRDs excluding DME and RVO seem as active exudative AMD. The presence of HRDs in retinal diseases might affect the decisions and the results of the treatment and the prognosis of diseases. To investigate the prevalence and clinical significance of small retinal haemorrhages accompanied by macular soft drusen in exudative age-related macular degeneration (AMD). This observational case series included patients who had first been diagnosed with exudative AMD. Small retinal haemorrhages were defined as preretinal or intraretinal haemorrhages, no larger than half the disc diameter in size and located within 3000 μm of the fovea centre. If there was more than one haemorrhage, the entire affected area was less than two-thirds of the disc diameter. Macular soft drusen was defined as the presence of soft drusen (≥125 μm in diameter) within the macular area. The presence of retinal angiomatous proliferation (RAP) was estimated based on the results of indocyanine green angiography (ICGA). The prevalence of reticular pseudodrusen was also estimated. Among the 1921 eyes from 1604 patients who were newly diagnosed with exudative AMD during the 40 months prior to the study, 101 eyes (5.3%) from 79 patients presented with the fundus characteristics described above. ICGA images were available for 69 eyes. Among these eyes, 28 eyes (43.1%) and 25 eyes (38.5%) were found to have type 1 and 2 RAP, respectively. A chorioretinal anastomosis (type 3 RAP) was identified in 12 (18.5%) eyes. Reticular pseudodrusen were noted in 78 eyes (77.2%). The presence of small retinal haemorrhages accompanied by macular soft drusen was highly predictive of RAP. The high prevalence of both soft drusen and reticular pseudodrusen in these eyes may suggest a profound decrease in choroidal perfusion in these eyes. Drusen, from the German word for node or geode (singular, \"Druse\"), are tiny yellow or white accumulations of extracellular material that build up between Bruch's membrane and the retinal pigment epithelium of the eye. The presence of a few small (\"hard\") drusen is normal with advancing age, and most people over 40 have some hard drusen. However, the presence of larger and more numerous drusen in the macula is a common early sign of age-related macular degeneration (AMD). Classification Drusen are associated with aging and macular degeneration are distinct from another clinical entity, optic disc drusen, which is present on the optic nerve head. Both age-related drusen and optic disc drusen can be observed by ophthalmoscopy. Optical coherence tomography scans of the orbits or head, calcification at the head of the optic nerve without change in size of globe strongly suggests drusen in a middle-age or elderly patient. On examination, patients frequently have decreased best-corrected visual acuity (BCVA), and Amsler grid evaluation may reveal areas of central or paracentral scotoma or visual distortion. Ophthalmic examination of the anterior segment of the eye is usually normal. ARMD-related CNV has several different appearances on the dilated funduscopic exam. [17] These include: A gray-green membrane deep into the retina is usually associated with an overlying neurosensory retinal detachment. There may be the presence of blood, lipid, or subretinal fluid. RPE detachments appear clinically as dome-shaped, sharply demarcated elevations of the RPE; these may also be serous, fibrovascular, drusenoid, or hemorrhagic. [18] There may be massive subretinal hemorrhage with central vision loss or, less commonly, breakthrough vitreous hemorrhage with peripheral vision loss. RPE tears. Disciform scars may be present, which may appear as white or yellow subretinal membranes with or without RPE hyperplasia. To describe the 15-year cumulative incidence of signs of early and late age-related macular degeneration (AMD). Population-based cohort study. We included 3917 persons, 43 to 86 years of age at the time of a baseline examination in 1988 through 1990 and with information collected in follow-up in 1993 through 1995, and/or 1998 through 2000, and/or 2003 through 2005. Grading of stereoscopic fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. Cumulative incidence of drusen type and size, pigmentary abnormalities, geographic atrophy, and exudative AMD accounting for competing risk of death. The 15-year cumulative incidence was 14.3% for early AMD (the presence of either soft indistinct drusen or the presence of pigmentary abnormalities together with any type of drusen) and 3.1% for late AMD (presence of exudative AMD or geographic atrophy). There was an increased incidence of AMD lesions with age (P&lt;0.05). Individuals &gt; or = 75 years of age at baseline had significantly (P&lt;0.01) higher 15-year incidences of the following characteristics than people 43 to 54 years of age: larger drusen (125 mum in diameter, 24.1% vs 10.6%), soft indistinct drusen (18.7% vs 6.5%), retinal pigmentary abnormalities (20.2% vs 3.7%), exudative macular degeneration (4.4% vs 0.4%), and pure geographic atrophy (3.2% vs 0%). Controlling for age, compared with those with small numbers of only small hard drusen (1-2), those with large numbers of only hard drusen (&gt; or =8) had an increased 15-year age-adjusted incidence of both soft indistinct drusen (16.3% vs 4.7%) and pigmentary abnormalities (10.6% vs 2.7%). Eyes with soft indistinct drusen or pigmentary abnormalities at baseline were more likely to develop late AMD at follow-up than eyes without these lesions (17.8% vs 1.2% and 12.9% vs 1.7%, respectively). We document the long-term incidence of signs of AMD and a continuum from small hard drusen to late AMD in older persons in the population. The 15-year cumulative incidence of late AMD in people &gt; or = 75 years of age (8%) indicates a public health problem of significant proportions because the United States population this age is expected to increase by 54% between 2005 and 2025. AMD-like pathology begins with small yellow deposits (drusen) in the macula, between the retinal pigment epithelium and the underlying choroid. Most people with these early changes (referred to as age-related maculopathy) still have good vision. People with drusen may or may not develop AMD. In fact, the majority of people over age 60 have drusen with no adverse effects. The risk of developing symptoms is higher when the drusen are large and numerous, and associated with the disturbance in the pigmented cell layer under the macula. Large and soft drusen are thought to be related to elevated cholesterol deposits. Early AMD Early AMD is diagnosed based on the presence of medium-sized drusen, about the width of an average human hair. Early AMD is usually asymptomatic. Intermediate AMD Intermediate AMD is diagnosed by large drusen and/or any retinal pigment abnormalities. Intermediate AMD may cause some vision loss, but, like early AMD, it is usually asymptomatic. A maculopathy is any pathological condition of the macula, an area at the centre of the retina that is associated with highly sensitive, accurate vision. Forms of maculopathies Age-Related Macular Degeneration is a degenerative maculopathy associated with progressive sight loss. It is characterised by changes in pigmentation in the Retinal Pigment Epithelium, the appearance of drusen on the retina of the eye and choroidal neovascularization. AMD has two forms; 'dry' or atrophic/non-exudative AMD, and 'wet' or exudative/neovascular AMD. Malattia Leventinese (or Doyne’s honeycomb retinal dystrophy) is another maculopathy with a similar pathology to wet AMD. Cellophane Maculopathy A fine glistening membrane forms over the macula, obscuring the vision. To study time patterns in bilateral exudative age-related macular degeneration (AMD) and the pattern of drusen before and after the onset of exudative AMD. Out of 2220 individuals in the Icelandic genetic study of AMD, 151 had bilateral exudative AMD. We searched for previous records in the Icelandic University Retina Unit. For the 65 patients with a fluorescein angiography record of both eyes, we established the time between the onset of disease in each eye. For the 53 patients with colour fundus photographs of the latter eye taken prior to the occurrence of exudative disease, we graded the drusen before and after the onset of exudative AMD in the second eye. The time interval between the onset of exudative AMD in the first and second eyes was 2.5 years (95% CI: 1.8-3.2; n = 65) and the median was 1.8 years. In 82% of cases the second eye was affected within 4 years. Soft drusen in the macula were found in 95% of eyes that later developed exudative disease (n = 53). Soft and hard drusen decreased in number in the central macula following the development of exudative disease. Bilateral exudative AMD develops within a few years in both eyes. Drusen are less visible following the onset of exudative AMD in the second eye. Breakthrough vitreous hemorrhage can also occur in wet ARMD, and diagnosis may be challenging if there is a poor view on dilated funduscopic examination. Diagnosis may be established by evaluating the patient’s fellow eye or obtaining a thorough history. Other potential causes of vitreous hemorrhage include: Proliferative diabetic retinopathy Retinal tear or retinal detachment Hemorrhagic posterior vitreous detachment Neovascularization from other causes, including vein occlusions, radiation retinopathy, or sickle cell retinopathy Age-related macular degeneration (AMD) is the leading cause of irreversible severe visual loss in the United States in people over 50 years of age. The nonexudative stage includes hard drusen (associated with localized dysfunction of the retinal pigment epithelium [RPE]), soft drusen (associated with diffuse dysfunction of the RPE), and geographic (areolar) atrophy. These fundus changes may predispose the eye to develop the neovascular/exudative stages of AMD. Most patients who develop severe visual loss from AMD have this exudative stage. Treatment for AMD has been shown to be effective for only a small proportion of patients who have a well-defined choroidal neovascular membrane (CNVM) more than 200 microns from the foveal center. Even in successfully treated cases, severe visual loss is postponed only for about 18 months because of the high rate of recurrent CNVMs that extend into the fovea. Thus, despite recent breakthroughs in laser treatment for AMD, most patients who develop the exudative form of AMD will develop central visual impairment. At the present time, the only available treatments for the majority of patients who develop the exudative form of AMD are low vision aids. Investigators are currently evaluating whether treatment is effective for membranes within 200 microns of the foveal center. Future studies need to be directed toward further understanding of the pathogenesis, treatment and prevention of the blinding complications of AMD. The usefulness of automated static perimetry and optical coherence tomography in the management of macular diseases has been described. Scotomata in eyes with central serous chorioretinopathy could be evaluated with central 10-degree automated static perimetry. The degree of visual field defects in eyes with the disease varied greatly with mean deviation of -10 dB or less in as many as 10% of the subjects. Although retinitis pigmentosa is a diffuse retinal dystrophy, eyes with a moderately advanced stage of retinitis pigmentosa should be managed as a macular disease, because the functioning retina is confined within the vascular arcade. The progressive nature in this stage of the disease could be demonstrated with a central 10-degree automated static perimetry measured once or twice a year and the use of univariate linear regression of mean deviation, in half of the patients with a mean follow-up period of 5 years. Functional recovery in eyes with exudative age-related macular degeneration after laser surgery or submacular surgery could be evaluated with central 10-degree automated static perimetry. Eyes with increased mean deviation in spite of reduced visual acuity after therapeutic intervention should also be evaluated. Macular function could also be evaluated using a color test. A newly developed color saturation discrimination test was applied to patients with age-related macular degeneration, retinitis pigmentosa, and cone dystrophy. The degree of dyschromatopsia was less in eyes with age-related macular degeneration than in those with retinitis pigmentosa or cone dystrophy with the same level of acuity loss. The highly protrusive nature of the orange-red nodule in eyes with idiopathic polypoidal choroidal vasculopathy was demonstrated with dimensional measurement with OCT. The degree of protrusion was greater than in eyes with serous pigment epithelial detachment, which suggests that the polypoidal lesion is covered with rigid tissues including Bruch's membrane. Parafoveal retinal sensitivity obtained with automated static perimetry was studied in correlation with retinal thickness measured using OCT in eyes with branch retinal vein occlusion showing macular edema without macular non-perfusion or massive retinal hemorrhages. The increased retinal thickness due to macular edema is closely correlated with retinal sensitivity both at the fovea and in the parafoveal area. Eighty-nine phakic eyes of 46 patients with retinitis pigmentosa patients were studied to detect cystoid macular edema using OCT. Cystoid lesions were observed in the macula in 12 eyes in 6 (13%) of 46 patients. Some eyes with OCT-proven cystoid macular edema did not show dye pooling in the fluorescein angiogram. The width of the total area of cystoid lesions was positively correlated with best-corrected visual acuity but the thickness of the neurosensory retina at the center of the fovea was not. OCT findings of successfully repaired macular holes were categorized into 3 groups. Eyes with U-type showed a normal foveal contour and a dark layer corresponding to the outer segment of photoreceptors. Eyes with V-type showed a notch in the surface of repaired neurosensory retina without a dark layer on the retinal pigment epithelium. Those with W-type showed a defect of the neurosensory retina, where the retinal pigment epithelium was exposed. The visual results were excellent in eyes with U-type, but poor in those with W-type. Acute visual loss is a rapid loss of the ability to see. It is caused by many ocular conditions like retinal detachment, glaucoma, macular degeneration, and giant cell arteritis, etc. Main causes Retinal detachment Retinal detachment should be considered if there were preceding flashes or floaters, or if there is a new visual field defect in one eye. If treated early enough, retinal tear and detachment can have a good outcome. Glaucoma Angle-closure glaucoma should be considered if there is painful loss of vision with a red eye, nausea or vomiting. The eye pressure will be very high typically greater than 40 mmHg. Emergent laser treatment to the iris may prevent blindness. Macular degeneration Wet macular degeneration should be considered in older people with new distortion of their vision with bleeding in the macula. Vision can often be regained with prompt eye injections with anti-VEGF agents. Giant cell arteritis Age-related macular degeneration (AMD) in the Japanese often shows different clinical features from those described in Caucasians. For example, we often observe choroidal neovascularization (CNV) in elderly patients without drusen in the fundus. The high incidence of polypoidal choroidal vasculopathy (PCV) in AMD among Japanese is well-known. The reason why such differences occur in clinical manifestations of AMD has been one of my main interests. In this review article, I will discuss the characteristics of AMD in the Japanese population, as found in our recent study. I. Prevalence and clinical characteristics of AMD in the Japanese population. Cohort studies are important to determine the prevalence and incidence of diseases. In Japan, cohort studies began to be carried out rather late compared with Western countries. Although good cohort studies from Japan are reported in the literature, the size of the cohorts was not sufficiently large to determine the prevalence of AMD. However, a recent meta-analysis of Asian cohorts has shown that the prevalence of late AMD in Asians is not different from that reported in Caucasians. On the other hand, the prevalence of early AMD appears lower in the Japanese than in Caucasians. Recently, we have published the results of the Nagahama Cohort study. In this cohort study, we found a high prevalence of drusen. It seems that the incidence of dry AMD is likely to increase among Japanese. In Japan, most retina specialists classify AMD into three categories : typical AMD, PCV, and retinal angiomatous proliferation (RAP). However, there are no definite diagnostic criteria to distinguish between the three conditions. To compare the clinical features of Japanese and Western cases of AMD, and to determine the incidence of the three types of AMD, we exchanged data about 100 consecutive cases between Kyoto University and Centre d'Ophtalmologie de Paris, France. Interestingly, the diagnoses made by the two institutes were not always in agreement. We also found more cases of PCV among the Japanese than among the French. II. PCV. About 50% of exudative AMD cases in the Japanese population are PCV. Because of its peculiar angiographic findings, PCV has long been considered to be a distinct clinical entity different from the usual exudative AMD. Also, there have been serious discussions on the nature of PCV. In our analyses, about 20% of PCV cases show rather large lesion sizes that exceed the vascular arcade. Scar formation in the macula and compromised vision are frequent findings in such cases. The occurrence of PCV in the inferior staphyloma or in angioid streaks shows heterogeneity in PCV. These findings suggest that PCV may be a finding on indocyanine green angiography rather than a distinct clinical entity. Spectral domain OCT examination shows that the branching vascular network of PCV is located between the retinal pigment epithelium and Bruch's membrane. In cases with retinal pigment epithelial detachment, CNV from the branching vascular network was found to extend along the roof of the detached retinal pigment epithelium. Such findings show that the branching vascular network of PCV is type 1 CNV. Complement factor H (CFH) and age-related maculopathy 2 (ARMS2)/High temperature requirement 1 (HTRA1) located on chromosome 10 (10q26) are well-established disease susceptible genes of AMD. In the Japanese, the prevalence of CFH Y402H gene polymorphism is low and ARMS2/HITRA1 plays a more important role in the development of AMD. In ARMS2 A69S polymorphism, a large deletion/insertion (443de1/54ins) that is reported in Caucasians was also found in Japanese. Thus, the genetic background of Caucasian and Japanese AMD is quite similar, as is also the case with exudative AMD and PCV. Our findings show that PCV is not a distinct clinical entity but is a subtype of exudative AMD. III. Exudative AMD with choroidal vascular hyperpermeability. Choroidal vascular hyperpermeability observed in central serous chorioretinopathy can be found in about 20% to 30% of exudative AMD cases in Japanese. Such cases often show a thick choroid, lack of drusen, and rather good visual prognosis with slow progression of the disease. Recently, \"pachychoroid neovasculopathy\" has been described by a group from New York. Such cases of AMD with choroidal vascular hyperpermeability, a thick choroid, and lack of drusen appears to belong to pachychoroid neovasculopathy. We studied the risk allele frequencies of CFH I62V and ARMS2 A69S gene polymorphisms in three groups : usual exudative AMD, pachychoroid neovasculopathy, and normal controls. Interestingly, cases of pachychoroid neovasculopathy show different gene polymorphisms of CFH I62V and ARMS2 A69S from the usual cases of exudative AMD and a more similar pattern to normal controls. Therefore, the possible mechanisms of the CNV development in such cases may differ from the classic well-documented drusen-dependent pathways. IV. Atrophic AMD in Japanese. Data from the Nagahama Cohort study show an increasing prevalence of drusen in Japanese. Recently, more extensive information on drusen has become available and the redefinition of drusen is currently in progress. In particular, the importance of reticular pseudodrusen (RPD) is more widely appreciated. This type of drusen is often found in Japanese AMD. Although the nature and location of RPD are still debatable, many investigators believe that this type of drusen is located under the sensory retina rather than under Bruch's membrane. In our analyses, RPD was found in 18.4% of late AMD cases in Japanese. It was more common in eyes with RAP or atrophic AMD and was seldom found in PCV. ARMS2 A69S gene polymorphism was found more frequently in cases of exudative AMD with RPD, than in cases of exudative AMD without RPD. Eyes with RPD show a thin choroid and diminished vascular densities of choroidal vessels. Since, in most eyes with retinal diseases quality of vision is greatly affected by visual field defects including paracentral scotoma and inferior field defects, visual function should be assessed by central 30- or 10-degrree automated static perimetry as well as visual acuity testing. The reduction of light sensitivity, demonstrated in the results of Humphrey central 10-2 perimetry, is more apparent than visual acuity loss in eyes with central serous chorioretinopathy (CSC), in which patients complain of dimness in the visual field of the affected eye. While reduced light sensitivity in eyes with acute CSC is well correlated with the height of subretinal fluid, marked and irreversible light sensitivity loss is demonstrated in the absence of subretinal fluid in eyes with chronic CSC due to structural damage in the photoreceptors. Various degrees of light sensitivity loss are seen in eyes wih age-related macular degeneration corresponding to intraretinal or subretinal pathology including intra- or subretinal fluid, fibrous scarring containing choroidal neovascularization and atrophic changes. The mean deviation (MD) of Humphrey central 10-2 perimetry is useful in predicting the visual outcome in eyes with exudative AMD after photodynamic therapy or intravitreal injection of anti-vascular endothelial growth factor. The progression of retinitis pigmentosa is well assssed with MD of Humphrey central 10-2 perimetry, which decreases linearly in the stage of residual visual field of 10 degrees or less. The age of patients with visual loss below 0.5 is delayed in eyes showing pencil-like configuration of \"Traquair's island of visual field\", in which a small area of normal light sensitivity around the fixation point is surrounded by absolute scotoma. With less visual acuity loss compared with that seen in eyes with central retinal artery occlusion; eyes with branch retinal artery occlusion show marked visual field defects, which are permanent and profound simulating the nasal-step pattern seen in eyes with glaucoma. Non-perfusion areas in fluorescein angiograms of eyes with branch retinal vein occlusion generally demonstrate reduced light sensitivity in the results of Humphrey central 30-2 perimetry, the degree of which tends to correlate with severity of non-perfusion. The light sensitivity in the area of detached retina in eyes with rhegmatogenous retinal detachment is generally reduced to show absolute scotoma, yet these eyes recover greatly after successful surgical repair. • Next, examine the macula. The macula is the area between the superior and inferior temporal vascular arcades, and its center is the fovea. You can examine the macula by pointing your ophthalmoscope about 15° temporal to the optic disc. Alternatively, ask the patient to look into the center of the light. Note the foveal reflex and the presence of any hemorrhage, exudate, abnormal blood vessels, scars, deposits, or other abnormalities. • Examine the retinal blood vessels by re-identifying the optic disc and following each of the four main branches away from the disc. The veins are dark red and relatively large. The arteries are narrower and bright red. • Ask the patient to look in the eight cardinal directions to allow you to view the peripheral fundus. In a patient with a well-dilated pupil, it is possible to visualize as far as the equator. We report a novel case of vitreous hemorrhage associated with suspected rupture of 2-disc-diameter retinal arterial macroaneurysm on the optic disc. A 90-year-old woman presented with blurred vision (sudden onset) in her left eye. Examination of the fundus revealed acute onset vitreous hemorrhage of unknown origin without retinal detachment. She underwent vitrectomy, but after excision of the dense vitreous hemorrhage, a 2-disc-diameter hematoma appeared on the optic disc and was removed promptly. Because the bleeding at the base of the hematoma was of arterial origin and pulsating, the first vitrectomy could not achieve hemostasis. Five days after the first surgery, we performed a second vitrectomy. This revealed a subretinal hemorrhage along the superior and inferior arcade vessels and a macular hole, which was almost completely closed with an inverted internal limiting membrane flap. Unfortunately, the macular hole reopened 41 days after the second surgery. In patients presenting with only a large hematoma on the optic disc, it might be prudent to leave the hematoma. However, this large retinal arterial macroaneurysm was on a rare location on the optic disc, making it doubly difficult for the surgeons to diagnose and choose the best option intraoperatively. The differential diagnosis for dense vitreous hemorrhage of unknown origin should include a large retinal arterial macroaneurysm on the optic disc. Optic Disc Drusen These are refractile deposits within the substance of the optic nerve head (Fig. 39-13). They are unrelated to drusen of the retina, which occur in age-related macular degeneration. Optic disc drusen are most common in people of northern European descent. Their diagnosis is obvious when they are visible as glittering particles on the surface of the optic disc. However, in many patients they are hidden beneath the surface, producing pseudopapilledema. It is important to recognize optic disc drusen to avoid an unnecessary evaluation for papilledema. Ultrasound or computed tomography (CT) scanning is sensitive for detection of buried optic disc drusen because they contain calcium. In most patients, optic disc drusen are an incidental, innocuous finding, but they can produce visual obscurations. On perimetry they give rise to enlarged blind spots and arcuate CHAPTER 39 Disorders of the Eye\nHere is the question:\nOPHTHALMOLOGY: An 84-year-old woman presents with loss of vision in the left eye of 4 days of evolution accompanied by metamorphopsia. The macula shows abundant hard exudates, two small deep hemorrhages and a localized neurosensory retinal detachment. In the contralateral eye there are abundant soft drusen. Which of the following diagnoses do you think is the most likely?\nHere are the potential choices:\n1. Acute posterior vitreous detachment.\n2. Exudative age-related macular degeneration (AMD).\n3. Central retinal artery obstruction.\n4. Non-arteritic anterior ischemic optic neuropathy.\nThe correct answer is: 2. Exudative age-related macular degeneration (AMD)."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n that becomes progressively worse to the unaffected side). When the mouth is opened, there may be deviation of the mandible towards the fractured side. Bilateral condylar fractures may cause the above signs and symptoms, but on both sides. Malocclusion and restricted jaw movement are usually more severe. Bilateral body or parasymphysis fractures are sometimes termed \"flail mandible\", and can cause involuntary posterior movement of the tongue with subsequent obstruction of the upper airway. Displacement of the condyle through the roof of the glenoid fossa and into the middle cranial fossa is rare. Other rare complications of mandibular trauma include internal carotid artery injury, and obliteration of the ear canal due to posterior condylar dislocation. Bilateral condylar fractures combined with a symphyseal fracture is sometimes termed a guardsman's fracture. The name comes from this injury occurring in soldiers who faint on parade grounds and strike the floor with their chin. External auditory canal bleeding (EACB) after facial trauma has been strongly associated with skull base fractures; however, EACB also can occur with other craniofacial fractures. The aim of this study was to analyze the frequency and causes of EACB in different craniofacial fracture types. The investigators used a retrospective cohort study design and enrolled a sample composed of patients with craniofacial fractures evaluated and treated from April 2006 through December 2011. The predictor variable was fracture type, which was categorized into 4 types: skull base fracture, midface fracture, and mandibular fracture with and without involvement of the condyle. The frequency of EACB among fracture types was compared with SPSS 13.0 (SPSS, Inc, Chicago, IL) and χ(2) test. Computed tomographic (CT) scans were analyzed to determine the cause of EACB. EACB was found in 43 of 573 craniofacial fracture cases, with a frequency of 7.5%. There were 19 EACB sides in 123 skull base fracture cases (15.4%), 26 EACB sides in 150 mandibular fracture cases involving the 196 condyles (13.3%; of these 196 condyles, 92.3% were intracapsular condylar fractures [ICFs]), 2 EACB sides in 150 mandibular fracture cases not involving the condyle (1.3%), and 1 EACB case in 150 midface fracture cases (0.7%). Statistical analysis of EACB frequency for each fracture type showed a significant difference between skull base or mandibular fractures with condylar involvement and midface or mandibular fractures without condylar involvement (P &lt; .05). However, there was no significant difference between skull base and mandibular fractures involving the condyle and midface fracture and mandibular fractures not involving the condyle (P &gt; .05). EACB is uncommon in craniofacial fractures. The frequency varies significantly based on fracture type. Skull base fracture and mandibular ICF are the 2 main causes of EACB. To explore a method of getting good three-dimensional (3D) reconstruction images of temporomandibular joint (TMJ) by computed tomography (CT), and evaluate diagnosis value of 3DCT in condylar fractures. Of the 14 patients studied, 12 were male and 2 were female with age ranging from 4 to 37 years old. 4 were old fractures and the other 10 were fresh fractures. All patients' orthopanotomograms were taken first, and then were scanned with CT. The scanning conditions were 300-345 mAS and 120kV, and the scanning methods included cross-sectional (11/14), coronal-sectional (2/14) and spiral (1/14) (pitch: 1, thickness of layers: 2.5 mm) scanning. Scanning scopes: The cross-sectional and spiral scanning were from 1 cm above the Frankfort horizontal plane to the middle of the mandibular ramus or Menton; The coronal-sectional scanning was from the mastoid process to the anterior point of the mandibular ramus or Pogonion. The thickness of the scanning layers was 2.5 mm (12/14) or 5 mm (2/14). Finally, 3D reconstructed images were obtained by shaded surface display (SSD). The cross-sectional images were obtained by being removed the cervical vertebra, the styloid process, the occipital bone and part of the mastoid process with Subtract Manual Irroi before reconstruction to avoid interference with the observation of TMJ and skull basis. 1. The best 3D CT reconstructed images were obtained by 2.5 mm-thin-layer cross-sectional scanning by being removed parts of the adjacent structures, and the bone lines were clear and smooth without adjacent bone structures shading TMJ. The quality of images taken spirally was similar to those taken cross-sectionally. While the coronal scanning neglected some important anatomic symbols which might be valuable to diagnose condylar displacement. 2. Of the 14 patients, 7 were unilateral condylar fractures and 7 were bilateral (21 sides altogether), among which 18 sides were high fractures of condyles and 3 were fractures of condylar neck. High oblique line fractures and comminuted fractures had major condylar rotation displacement which moved forward, downward and inside, whereas, vertical fractures only had minor displacement. Inward rotation displacement occurred in medial bent fractures. 10 of 14 patients (15 sides) had been conducted operation, and the same situations as seen from 3DCT reconstructed images were found. 3DCT images can display condylar fractures accurately and directly, and are very useful for surgeons to select treating methods of condylar fractures. This type of fractured mandible can involve one condyle (unilateral) or both (bilateral). Unilateral condylar fracture may cause restricted and painful jaw movement. There may be swelling over the temporomandibular joint region and bleeding from the ear because of lacerations to the external auditory meatus. The hematoma may spread downwards and backwards behind the ear, which may be confused with Battle's sign (a sign of a base of skull fracture), although this is an uncommon finding so if present, intra-cranial injury must be ruled out. If the bones fracture and overlie each other there may be shortening of the height of the ramus. This results in gagging of the teeth on the fractured side (the teeth meet too soon on the fractured side, and not on the non fractured side, i.e. \"open bite\" that becomes progressively worse to the unaffected side). When the mouth is opened, there may be deviation of the mandible towards the fractured side. Bilateral condylar fractures may cause the The aim of this study was to analyze the acute repercussions of condylar mandibular fractures on occipital-atlanto-axial joint. Twenty-five non-consecutive cases (16 males and 9 females, mean age: 22.96/range 14-36 years), observed and treated in the Maxillofacial Surgery Department of the University of L'Aquila have been considered. Types of fractures examined included: unilateral: 19 cases (solitary: 12; associated with other mandibular fractures: 7; homolateral: 2); bilateral: 6 cases (equivalent: 2; not equivalent: 4). A control group was constituted of 10 patients, 5 males and 5 females, aged from 19 to 24 years (mean-range: 21.6) suffering from acute isolated cervical distorsion (whiplash). The study has been performed by means of the analysis of X-ray and computed tomography (CT)-CT/3D of the mandibular condylar regions, the occipital-atlanto-axial structures and the cervical region. In all the cases of fractures of the mandibular condyle an acute alteration of the junctional atlanto-axial structures was present. In case of unilateral solitary condylar fractures the authors have observed an atlas rotation, homolateral to the side of the condylar fracture, independent from the level of the fracture (intra- or extracapsular). The rotation seems to be proportional to the entity of the condylar fragments dislocation on the horizontal plane and it causes a modification of the articular relations between atlas and axis (atlanto-axial subluxation) and between the atlas and the occipital bone. The authors have observed a constant derangement of the cranio-axial joint on the three planes of the space. In particular, on the vertical plane the CT reconstructions show on the right and left side a different height between the atlanto-axial articular spaces. The largest one is homolateral to the side of the condylar fracture. In case of unilateral condylar fractures associated with other mandibular fracture (homolateral or not) the authors have observed the same alterations of the occipital-atlo-epistropheal joint, but while on the horizontal plane the rotation of the atlas is always homolateral to the condylar fracture, on the vertical plane the largest atlanto-axial articular space is homolateral to the mandibular fracture with more dislocation of the fragments of fracture (usually the associated not homolateral mandibular fracture). In case of bilateral condylar fractures the authors have observed no alteration of the cranio-cervical joint. In the non-equivalent fractures, they have observed the atlas rotation on the horizontal plane and the junctional derangement on the vertical plane, homolateral to the condylar fracture with greatest dislocation. In the control group the loss of the physiological cervical lordosis has been observed. Alterations on the horizontal and vertical planes, as the rotation of the atlas, atlanto-axial subluxation or the joint derangement, instead, has never revealed. The authors state that these results represent a new nosographic entity associated with the condylar mandibular fractures with important clinical, insurance and legal repercussions. A prospective study on mid-face fractures was carried out in the Department of Oral and Maxillofacial Surgery at College of Dentistry, Indore, from August 2007 to September 2009 to analyze etiology, incidence and patterns of midface fractures and associated ocular injuries. Two hundred patients were included in this study, amongst those who reported to the Department of OMFS, College of Dentistry, Indore. After confirmed diagnosis of mid face fracture all the patients were stratified according to age, sex, cause of the accident, influence of alcohol, location, type of fractures and associated ocular injuries. The study included 200 patients with a mean age of 29.6 years. The most frequently injured patients belonged to the 21-30 year-old age group. The male predilection was 76 %. Road traffic accident was the most common causative factor (64 %), followed by assault (21 %), cases of fall (9.5 %) and other causes (5.5 %). The most common fracture in this study was found to be zygomatic complex fractures (62.5 %) (more in the age group of 21-30 years). This was followed by Lefort II fractures (23 %), multiple fractures (10 %) and Lefort I fractures (6 %), Lefort III fractures (4.5 %) and Naso-ethmoidal fractures (4 %) in descending order. 84.5 % subjects were having ocular involvement. Subconjunctival hemorrhage was present mostly in 83.5 % followed by remaining as corneal injury 15 %, reduced acuity 11.5 %, diplopia 10.5 %, enophthalmos 8.5 %, telecanthus 5 %, hyphema 3.5 %, blindness 3 % and proptosis 0.5 %. Zygomatic complex fractures were the most frequent type of injury that was complicated by blindness or a serious eye injury (61 %). Collection of data regarding the epidemiology of maxillofacial fractures is important because it may assist healthcare providers to provide necessary information for the development and evaluation of preventive measures. Ocular injuries should have an early ophthalmological examination at the time of trauma to detect any kind of ocular dysfunction.  Mandibular condyle fractures develop frequently and show the variable type of injury and complication. New opinions have emerged from recent investigation into condylar fractures. The author investigated 246 patients with condylar fractures who visited SNUDH from January 1980 to August, 1988, 8. with regard to clinical and treatment aspects, area and displacement of fractures, associated teeth injury and other body injury, complications. At last I have got the following results. 1. The incidence to condylar fractures in a series of 765 mandibular fractures may be as high as 32.2%. 2. The male patients are 3 times more than female patients. The highest frequency was recorded in the group 21-30 years of age. (34.1%). 3. Falls caused the greatest number of condylar fractures (45.2%) and next was in assult (25.6%), traffic accidents (22.4%). 4. Unilateral condylar fractures were present in 74.8%, giving a left: right ratio of 1.2:1. In cases of unilateral fracture, subcondylar fractures were by far the commonest (32.9%) but in cases of bilateral fracture, condylar neck fractures were by far the commonest. In children under 15 years of age, condylar neck fractures were more common but in patients over 16 years of age, subcondylar fractures were common. 5. Anteromedial fracture dislocations were by far the commonest (20.3%). In children under 15 years of age, fracture deviations were common but in patients over 16 years of age, fracture displacements were common. 6. 44.7% of patients with condylar fractures sustained the teeth injuries. Teeth fractures were by far the commonest. 7. Single condylar fractures showed a frequency of 30.5%. Of the concomitant fractures elsewhere in the mandible, symphysis fractures were by far the commonest (54.1%). 8. Associated other body injuries showed a frequency of 28.0%. Of them, head injuries were by far the commonest. 9. The mean interval from injury to treatment was 14.3 days. Of the treatment of condylar fractures, open reduction was by far the commonest (70.3%). Closed reduction comprised 19.9% and functional therapy comprised 8.5%. 10. In 67 patients with possible follow up period, the following complications were developed, two ankylosis, anterior open bite, mouth opening limitation, mouth opening deviation. Research has shown that panoramic radiography is similar to computed tomography in its diagnostic accuracy for mandible fractures and both are more accurate than plain film radiograph. The indications to use CT for mandible fracture vary by region, but it does not seem to add to diagnosis or treatment planning except for comminuted or avulsive type fractures, although, there is better clinician agreement on the location and absence of fractures with CT compared to panoramic radiography. Classification There are various classification systems of mandibular fractures in use. Location This is the most useful classification, because both the signs and symptoms, and also the treatment are dependent upon the location of the fracture. The mandible is usually divided into the following zones for the purpose of describing the location of a fracture (see diagram): condylar, coronoid process, ramus, angle of mandible, body (molar and premolar areas), parasymphysis and symphysis. This prospective study was designed to record relevant characteristics of mandibular condyle fractures and to evaluate the relationship between these. Data were recorded on sex, age, cause of trauma, level of fracture, dislocation of the mandibular head, dental state and associated fractures of all patients diagnosed in our hospital during the period 1984-1996 with mandibular condyle fractures. Data were analysed in our Computer Department. The sample comprised 348 patients with 444 fractures, and a male:female ratio of 2:1. Traffic accidents were the most common cause: 103 (41%) of the unilateral and 54 (56%) of the bilateral fractures, followed by alleged assault and falls. Low fractures were the most common -n = 314 of 444 (71%). The causes that involved considerable force (traffic accidents and falls) resulted in more dislocations of the mandibular head, more bilateral fractures, a tendency to fractures higher on the condyle and significantly more intracapsular fractures. Absence of molar occlusion also gave more high and fewer low fractures, but played no part in dislocation of the mandibular head from the glenoid fossa. To assess the diagnostic accuracy of physical examination findings used to identify patients at risk for midfacial or mandibular fractures. A five-year retrospective cohort was constructed from all emergency department patients with a midfacial or mandibular trauma. The sensitivity, specificity, pre-test probability, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio data was calculated for 19 and 14 physical examination findings for midfacial and mandibular fractures respectively. Computed Tomography and panoramic radiography were used as index tests. A total of 1484 patients were identified among whom 40.4% midfacial and 33.4% mandibular fractures were diagnosed. Overall, specificity was found to be higher than sensitivity. Regarding midfacial fractures, high specificity was found for raccoon eyes, malar eminence flattening and all the findings that are related to palpation, the nasal, ocular and intra-oral assessment. Malar eminence flattening, external nasal deformity, nasal septum hematoma, change of globe position and palpable step-off had ad high positive predictive value and positive likelihood ratio. Regarding mandibular fractures high specificity was found for mouth opening restriction, auditory canal bleeding, intra-oral assessment related findings, palpable step-off, inferior alveolar nerve paresthesia, the angular compression test and chin axial pressure test. The diagnostic accuracy of relevant physical examination findings were identified for the prediction of midfacial and mandibular fractures. Mandibular fracture, also known as fracture of the jaw, is a break through the mandibular bone. In about 60% of cases the break occurs in two places. It may result in a decreased ability to fully open the mouth. Often the teeth will not feel properly aligned or there may be bleeding of the gums. Mandibular fractures occur most commonly among males in their 30s. Mandibular fractures are typically the result of trauma. This can include a fall onto the chin or a hit from the side. Rarely they may be due to osteonecrosis or tumors in the bone. The most common area of fracture is at the condyle (36%), body (21%), angle (20%) and symphysis (14%). While a diagnosis can occasionally be made with plain X-ray, modern CT scans are more accurate. A comprehensive classification of midfacial/craniofacial fractures, based on two- and three-dimensional computed tomography (2D and 3D-CT) is presented. We performed a postmortem analysis of 24 patients who had died from trauma with signs of craniofacial fractures, based on 2D and 3D-CT studies with pathoanatomical findings. In addition, CT findings for 100 patients with craniofacial injuries requiring an emergency CT were correlated with surgical findings and follow-up results. On the basis of the analysis of a total of 377 fractures a classification system is proposed. The system is based on the use of the AO/ASIF (Arbeitsgemeinschaft für Osteosynthesefragen/Association for the Study of Internal Fixation) scheme, defining three types (A, B, C), three groups within each type (e.g. A1, A2, A3) and three subgroups within each group (e.g. A1.1, A1.2, A1.3) with increasing severity from A1.1 (lowest) to C3.3 (highest). The craniofacial region is divided into three units: the lower midface (I), the upper midface (II) and the craniobasal-facial unit (III). Lateral and central fractures are also distinguished. Type A fractures are non-displaced fractures, type B are displaced fractures and type C are complex/defect fractures. Groups A1, B1 and C1 comprise fractures of an isolated unit; groups A2, B2 and C2, combined fractures without involvement of the skull base; and groups A3, B3 and C3 are those combined fractures with involvement of the skull base. A correlation between the severity of the fracture and (i). the number of posttraumatic functional limitations (Spearman rank test, correlation coefficient r=0.42), (ii). the need for bone grafting or dural plastic (r=0.39) and (iii). facial asymmetry (r=0.37), was observed. The proposed classification system allows standardised documentation of midfacial and craniofacial fractures, including those not precisely defined by the Le Fort classification scheme. A Le Fort fracture of the skull is a classic transfacial fracture of the midface, involving the maxillary bone and surrounding structures in either a horizontal, pyramidal or transverse direction. The hallmark of Lefort fractures is traumatic pterygomaxillary separation, which signifies fractures between the pterygoid plates, horseshoe shaped bony protuberances which extend from the inferior margin of the maxilla, and the maxillary sinuses. Continuity of this structure is a keystone for stability of the midface, involvement of which impacts surgical management of trauma victims, as it requires fixation to a horizontal bar of the frontal bone. The pterygoid plates lie posterior to the upper dental row, or alveolar ridge, when viewing the face from an anterior view. The fractures are named after French surgeon René Le Fort (1869–1951), who discovered the fracture patterns by examining crush injuries in cadavers. Signs and symptoms may be fractured. Superior dislocations occur after being punched below the mandibular ramus as the mouth remains half-open. Since great force occurs in a punch, the angle of the jaw will be forced upward moving towards the condylar head. This can result in a fracture of the glenoid fossa and displacement of the condyle into the middle cranial fossa, potentially injuring the facial and vestibulocochlear nerves and the temporal lobe. Lateral dislocations move the mandibular condyle away from the skull and are likely to happen together with jaw fractures. There are four different positions of jaw dislocation: posterior, anterior, superior and lateral. The most common position is anterior, while the other types are rare. Anterior dislocation shifts the lower jaw forward if the mouth excessively opens. This type of dislocation may happen bilaterally or unilaterally after yawning. The muscles that are affected during anterior jaw dislocation are the masseter and temporalis which pull up on the mandible and the lateral pterygoid which relaxes the mandibular condyle. The condyle can get locked in front of the articular eminence. Posterior dislocation is possible for people who get injured by being punched in the chin. This dislocation will push the jaw back affecting the alignment of the mandibular condyle and mastoid. The external auditory canal may be fractured. Superior dislocations occur after being punched below the mandibular ramus as the mouth remains half-open. Since great force occurs in a punch, the angle of the jaw will be forced Battle's sign, also known as mastoid ecchymosis, is an indication of fracture of middle cranial fossa of the skull. These fractures may be associated with underlying brain trauma. Battle's sign consists of bruising over the mastoid process as a result of extravasation of blood along the path of the posterior auricular artery. The sign is named after William Henry Battle. Battle's sign takes at least one day to appear after the initial traumatic basilar skull fracture, similar to raccoon eyes. It is usually seen after head injuries resulting in injury to mastoid process leading to bruising. Battle's sign may be confused with a spreading hematoma from a fracture of the mandibular condyle, which is a less serious injury. See also Basilar skull fracture Raccoon eyes Black eye References Traumatology Injuries Signs and symptoms Fractures of facial bones, like other fractures, may be associated with pain, bruising, and swelling of the surrounding tissues (such symptoms can occur in the absence of fractures as well). Fractures of the nose, base of the skull, or maxilla may be associated with profuse nosebleeds. Nasal fractures may be associated with deformity of the nose, as well as swelling and bruising. Deformity in the face, for example a sunken cheekbone or teeth which do not align properly, suggests the presence of fractures. Asymmetry can suggest facial fractures or damage to nerves. People with mandibular fractures often have pain and difficulty opening their mouths and may have numbness in the lip and chin. With Le Fort fractures, the midface may move relative to the rest of the face or skull. Ultrasonography (USG) allows to the examination of soft tissue and osseous tissues in the head-and-neck region. This study compared the accuracy of USG and computed tomography (CT) scan in the diagnosis of mandibular fractures. In this prospective observational study, spiral CT scan was prescribed for the lower face and, if necessary, midface and upper face in 42 trauma patients suspected of mandibular fractures, referring to Imam Reza Hospital in Tabriz. Two radiologists evaluated the CT scans. Then, another radiologist examined all the patients with USG with a frequency of 7-12 MHz. Ultrasonographic diagnostic results were recorded and compared with the results of the CT scan examinations. The results were reported using descriptive statistical methods. The specificity and sensitivity of USG were 100% and 91.1%, respectively. The USG sensitivities in the angle, condyle, condylar neck, and symphysis fractures were 100%, 91.6%, 85.7%, and 80%, respectively, and the specificity was 100% in all that anatomical regions. Among the confounding factors, the sensitivity of the USG (84.6%) was the lowest in the presence of hematoma; however, its specificity remained 100%. One case of symphysis fracture was not detected in the absence of any confounding factors in USG examination. Although the sensitivity, specificity, and diagnostic accuracy of the USG were at high levels, there were some limitations, making it difficult to definitively replace USG with CT scans, especially in the case of condylar fractures and in the presence of confounding factors such as hematoma and swelling. There has been a rising incidence of maxillofacial injuries during the past decade as a result of an increasing number of assaults and motor vehicle accidents. The maxillofacial region is one of the most complex areas of the human body, and the radiographic imaging of this region becomes even more difficult in traumatized patients because of their clinical condition and their inability to cooperate. Imaging modalities used in the evaluation of the traumatized maxillofacial region include conventional (plain) films, tomography, panoramic radiography, computed tomography, three-dimensional computed tomography, DentaScan, and magnetic resonance imaging. Each modality is discussed with regard to technique, advantages, and disadvantages. Plain films and computed tomography, the modalities that are used most in evaluating maxillofacial structures, are discussed in more detail. The normal anatomy and radiologic features are presented for both of these modalities. Radiographic evaluation of maxillofacial injury begins with a knowledge of the direct and indirect radiographic signs of injury seen on most imaging modalities. Computed tomography also has allowed a method of classifying facial fractures that is based on the involvement of the facial buttresses or struts. Three horizontal, two coronal, and five sagittal oriented struts are described. Limited fractures are differentiated from transfacial fractures by the lack of involvement of the pterygoid plates in the limited fractures. Limited fractures also can be subclassified as solitary (fracture of a single strut) or complex (fractures of multiple struts). A portion of the orbit is involved in almost every form of facial fracture; therefore, evaluation of facial injuries should always include the orbital structures. Although both can occur simultaneously, orbital injuries can be divided into soft tissue and bony vault injuries. Similar to midface fractures, orbital fractures also can be classified as solitary (fracture involves a single wall) or complex (fracture involves more than one wall or a part of a midface fracture). Computed tomography is of great value in evaluating both forms of injury. Magnetic resonance imaging is becoming increasingly important in the evaluation of orbital soft tissue injuries. Classification of midface injuries includes the solitary strut fractures and the complex strut fractures. Solitary strut fractures include fractures of the nasal arch, zygomatic arch, and isolated sinus wall fractures. Complex strut fractures include the nasal complex fractures, zygomatic (tripod) and zygomaticomaxillary fractures, transfacial fractures (LeFort fractures), and facial smash fractures. Each fracture type and its radiographic appearance are discussed.(ABSTRACT TRUNCATED AT 400 WORDS) At the beginning of the 20th century, René Le Fort mapped typical locations for facial fractures; these are now known as Le Fort I, II, and III fractures (right). Le Fort I fractures, also called Guérin or horizontal maxillary fractures, involve the maxilla, separating it from the palate. Le Fort II fractures, also called pyramidal fractures of the maxilla, cross the nasal bones and the orbital rim. Le Fort III fractures, also called craniofacial disjunction and transverse facial fractures, cross the front of the maxilla and involve the lacrimal bone, the lamina papyracea, and the orbital floor, and often involve the ethmoid bone, are the most serious. Le Fort fractures, which account for 10–20% of facial fractures, are often associated with other serious injuries. Le Fort made his classifications based on work with cadaver skulls, and the classification system has been criticized as imprecise and simplistic since most midface fractures involve a combination of Le Fort fractures.\nHere is the question:\nOTORHINOLARYNGOLOGY AND MAXILLOFACIAL SURGERY: Given a direct trauma to the right side of the face after which the patient presents unilateral palpebral hematoma, diplopia in the vertical gaze and difficulty in opening the mouth, which of the following statements is true?\nHere are the potential choices:\n1. We are with great probability in front of a Lefort I type fracture of the middle third of the face.\n2. This is probably a unilateral orbitomalar fracture. The diagnosis would ideally be verified by CT (computed axial tomography).\n3. It is a fracture of the base of the skull at the level of the carotid foramen.\n4. The probable diagnosis is fracture with dislocation of the mandibular condyle.\n5. A mandibular fracture is probably associated with a Lefort I type midface fracture.\nThe correct answer is: ",
        "gold_answer": "2 This is probably a unilateral orbitomalar fracture. The diagnosis would ideally be verified by CT (computed axial tomography).",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n that becomes progressively worse to the unaffected side). When the mouth is opened, there may be deviation of the mandible towards the fractured side. Bilateral condylar fractures may cause the above signs and symptoms, but on both sides. Malocclusion and restricted jaw movement are usually more severe. Bilateral body or parasymphysis fractures are sometimes termed \"flail mandible\", and can cause involuntary posterior movement of the tongue with subsequent obstruction of the upper airway. Displacement of the condyle through the roof of the glenoid fossa and into the middle cranial fossa is rare. Other rare complications of mandibular trauma include internal carotid artery injury, and obliteration of the ear canal due to posterior condylar dislocation. Bilateral condylar fractures combined with a symphyseal fracture is sometimes termed a guardsman's fracture. The name comes from this injury occurring in soldiers who faint on parade grounds and strike the floor with their chin. External auditory canal bleeding (EACB) after facial trauma has been strongly associated with skull base fractures; however, EACB also can occur with other craniofacial fractures. The aim of this study was to analyze the frequency and causes of EACB in different craniofacial fracture types. The investigators used a retrospective cohort study design and enrolled a sample composed of patients with craniofacial fractures evaluated and treated from April 2006 through December 2011. The predictor variable was fracture type, which was categorized into 4 types: skull base fracture, midface fracture, and mandibular fracture with and without involvement of the condyle. The frequency of EACB among fracture types was compared with SPSS 13.0 (SPSS, Inc, Chicago, IL) and χ(2) test. Computed tomographic (CT) scans were analyzed to determine the cause of EACB. EACB was found in 43 of 573 craniofacial fracture cases, with a frequency of 7.5%. There were 19 EACB sides in 123 skull base fracture cases (15.4%), 26 EACB sides in 150 mandibular fracture cases involving the 196 condyles (13.3%; of these 196 condyles, 92.3% were intracapsular condylar fractures [ICFs]), 2 EACB sides in 150 mandibular fracture cases not involving the condyle (1.3%), and 1 EACB case in 150 midface fracture cases (0.7%). Statistical analysis of EACB frequency for each fracture type showed a significant difference between skull base or mandibular fractures with condylar involvement and midface or mandibular fractures without condylar involvement (P &lt; .05). However, there was no significant difference between skull base and mandibular fractures involving the condyle and midface fracture and mandibular fractures not involving the condyle (P &gt; .05). EACB is uncommon in craniofacial fractures. The frequency varies significantly based on fracture type. Skull base fracture and mandibular ICF are the 2 main causes of EACB. To explore a method of getting good three-dimensional (3D) reconstruction images of temporomandibular joint (TMJ) by computed tomography (CT), and evaluate diagnosis value of 3DCT in condylar fractures. Of the 14 patients studied, 12 were male and 2 were female with age ranging from 4 to 37 years old. 4 were old fractures and the other 10 were fresh fractures. All patients' orthopanotomograms were taken first, and then were scanned with CT. The scanning conditions were 300-345 mAS and 120kV, and the scanning methods included cross-sectional (11/14), coronal-sectional (2/14) and spiral (1/14) (pitch: 1, thickness of layers: 2.5 mm) scanning. Scanning scopes: The cross-sectional and spiral scanning were from 1 cm above the Frankfort horizontal plane to the middle of the mandibular ramus or Menton; The coronal-sectional scanning was from the mastoid process to the anterior point of the mandibular ramus or Pogonion. The thickness of the scanning layers was 2.5 mm (12/14) or 5 mm (2/14). Finally, 3D reconstructed images were obtained by shaded surface display (SSD). The cross-sectional images were obtained by being removed the cervical vertebra, the styloid process, the occipital bone and part of the mastoid process with Subtract Manual Irroi before reconstruction to avoid interference with the observation of TMJ and skull basis. 1. The best 3D CT reconstructed images were obtained by 2.5 mm-thin-layer cross-sectional scanning by being removed parts of the adjacent structures, and the bone lines were clear and smooth without adjacent bone structures shading TMJ. The quality of images taken spirally was similar to those taken cross-sectionally. While the coronal scanning neglected some important anatomic symbols which might be valuable to diagnose condylar displacement. 2. Of the 14 patients, 7 were unilateral condylar fractures and 7 were bilateral (21 sides altogether), among which 18 sides were high fractures of condyles and 3 were fractures of condylar neck. High oblique line fractures and comminuted fractures had major condylar rotation displacement which moved forward, downward and inside, whereas, vertical fractures only had minor displacement. Inward rotation displacement occurred in medial bent fractures. 10 of 14 patients (15 sides) had been conducted operation, and the same situations as seen from 3DCT reconstructed images were found. 3DCT images can display condylar fractures accurately and directly, and are very useful for surgeons to select treating methods of condylar fractures. This type of fractured mandible can involve one condyle (unilateral) or both (bilateral). Unilateral condylar fracture may cause restricted and painful jaw movement. There may be swelling over the temporomandibular joint region and bleeding from the ear because of lacerations to the external auditory meatus. The hematoma may spread downwards and backwards behind the ear, which may be confused with Battle's sign (a sign of a base of skull fracture), although this is an uncommon finding so if present, intra-cranial injury must be ruled out. If the bones fracture and overlie each other there may be shortening of the height of the ramus. This results in gagging of the teeth on the fractured side (the teeth meet too soon on the fractured side, and not on the non fractured side, i.e. \"open bite\" that becomes progressively worse to the unaffected side). When the mouth is opened, there may be deviation of the mandible towards the fractured side. Bilateral condylar fractures may cause the The aim of this study was to analyze the acute repercussions of condylar mandibular fractures on occipital-atlanto-axial joint. Twenty-five non-consecutive cases (16 males and 9 females, mean age: 22.96/range 14-36 years), observed and treated in the Maxillofacial Surgery Department of the University of L'Aquila have been considered. Types of fractures examined included: unilateral: 19 cases (solitary: 12; associated with other mandibular fractures: 7; homolateral: 2); bilateral: 6 cases (equivalent: 2; not equivalent: 4). A control group was constituted of 10 patients, 5 males and 5 females, aged from 19 to 24 years (mean-range: 21.6) suffering from acute isolated cervical distorsion (whiplash). The study has been performed by means of the analysis of X-ray and computed tomography (CT)-CT/3D of the mandibular condylar regions, the occipital-atlanto-axial structures and the cervical region. In all the cases of fractures of the mandibular condyle an acute alteration of the junctional atlanto-axial structures was present. In case of unilateral solitary condylar fractures the authors have observed an atlas rotation, homolateral to the side of the condylar fracture, independent from the level of the fracture (intra- or extracapsular). The rotation seems to be proportional to the entity of the condylar fragments dislocation on the horizontal plane and it causes a modification of the articular relations between atlas and axis (atlanto-axial subluxation) and between the atlas and the occipital bone. The authors have observed a constant derangement of the cranio-axial joint on the three planes of the space. In particular, on the vertical plane the CT reconstructions show on the right and left side a different height between the atlanto-axial articular spaces. The largest one is homolateral to the side of the condylar fracture. In case of unilateral condylar fractures associated with other mandibular fracture (homolateral or not) the authors have observed the same alterations of the occipital-atlo-epistropheal joint, but while on the horizontal plane the rotation of the atlas is always homolateral to the condylar fracture, on the vertical plane the largest atlanto-axial articular space is homolateral to the mandibular fracture with more dislocation of the fragments of fracture (usually the associated not homolateral mandibular fracture). In case of bilateral condylar fractures the authors have observed no alteration of the cranio-cervical joint. In the non-equivalent fractures, they have observed the atlas rotation on the horizontal plane and the junctional derangement on the vertical plane, homolateral to the condylar fracture with greatest dislocation. In the control group the loss of the physiological cervical lordosis has been observed. Alterations on the horizontal and vertical planes, as the rotation of the atlas, atlanto-axial subluxation or the joint derangement, instead, has never revealed. The authors state that these results represent a new nosographic entity associated with the condylar mandibular fractures with important clinical, insurance and legal repercussions. A prospective study on mid-face fractures was carried out in the Department of Oral and Maxillofacial Surgery at College of Dentistry, Indore, from August 2007 to September 2009 to analyze etiology, incidence and patterns of midface fractures and associated ocular injuries. Two hundred patients were included in this study, amongst those who reported to the Department of OMFS, College of Dentistry, Indore. After confirmed diagnosis of mid face fracture all the patients were stratified according to age, sex, cause of the accident, influence of alcohol, location, type of fractures and associated ocular injuries. The study included 200 patients with a mean age of 29.6 years. The most frequently injured patients belonged to the 21-30 year-old age group. The male predilection was 76 %. Road traffic accident was the most common causative factor (64 %), followed by assault (21 %), cases of fall (9.5 %) and other causes (5.5 %). The most common fracture in this study was found to be zygomatic complex fractures (62.5 %) (more in the age group of 21-30 years). This was followed by Lefort II fractures (23 %), multiple fractures (10 %) and Lefort I fractures (6 %), Lefort III fractures (4.5 %) and Naso-ethmoidal fractures (4 %) in descending order. 84.5 % subjects were having ocular involvement. Subconjunctival hemorrhage was present mostly in 83.5 % followed by remaining as corneal injury 15 %, reduced acuity 11.5 %, diplopia 10.5 %, enophthalmos 8.5 %, telecanthus 5 %, hyphema 3.5 %, blindness 3 % and proptosis 0.5 %. Zygomatic complex fractures were the most frequent type of injury that was complicated by blindness or a serious eye injury (61 %). Collection of data regarding the epidemiology of maxillofacial fractures is important because it may assist healthcare providers to provide necessary information for the development and evaluation of preventive measures. Ocular injuries should have an early ophthalmological examination at the time of trauma to detect any kind of ocular dysfunction.  Mandibular condyle fractures develop frequently and show the variable type of injury and complication. New opinions have emerged from recent investigation into condylar fractures. The author investigated 246 patients with condylar fractures who visited SNUDH from January 1980 to August, 1988, 8. with regard to clinical and treatment aspects, area and displacement of fractures, associated teeth injury and other body injury, complications. At last I have got the following results. 1. The incidence to condylar fractures in a series of 765 mandibular fractures may be as high as 32.2%. 2. The male patients are 3 times more than female patients. The highest frequency was recorded in the group 21-30 years of age. (34.1%). 3. Falls caused the greatest number of condylar fractures (45.2%) and next was in assult (25.6%), traffic accidents (22.4%). 4. Unilateral condylar fractures were present in 74.8%, giving a left: right ratio of 1.2:1. In cases of unilateral fracture, subcondylar fractures were by far the commonest (32.9%) but in cases of bilateral fracture, condylar neck fractures were by far the commonest. In children under 15 years of age, condylar neck fractures were more common but in patients over 16 years of age, subcondylar fractures were common. 5. Anteromedial fracture dislocations were by far the commonest (20.3%). In children under 15 years of age, fracture deviations were common but in patients over 16 years of age, fracture displacements were common. 6. 44.7% of patients with condylar fractures sustained the teeth injuries. Teeth fractures were by far the commonest. 7. Single condylar fractures showed a frequency of 30.5%. Of the concomitant fractures elsewhere in the mandible, symphysis fractures were by far the commonest (54.1%). 8. Associated other body injuries showed a frequency of 28.0%. Of them, head injuries were by far the commonest. 9. The mean interval from injury to treatment was 14.3 days. Of the treatment of condylar fractures, open reduction was by far the commonest (70.3%). Closed reduction comprised 19.9% and functional therapy comprised 8.5%. 10. In 67 patients with possible follow up period, the following complications were developed, two ankylosis, anterior open bite, mouth opening limitation, mouth opening deviation. Research has shown that panoramic radiography is similar to computed tomography in its diagnostic accuracy for mandible fractures and both are more accurate than plain film radiograph. The indications to use CT for mandible fracture vary by region, but it does not seem to add to diagnosis or treatment planning except for comminuted or avulsive type fractures, although, there is better clinician agreement on the location and absence of fractures with CT compared to panoramic radiography. Classification There are various classification systems of mandibular fractures in use. Location This is the most useful classification, because both the signs and symptoms, and also the treatment are dependent upon the location of the fracture. The mandible is usually divided into the following zones for the purpose of describing the location of a fracture (see diagram): condylar, coronoid process, ramus, angle of mandible, body (molar and premolar areas), parasymphysis and symphysis. This prospective study was designed to record relevant characteristics of mandibular condyle fractures and to evaluate the relationship between these. Data were recorded on sex, age, cause of trauma, level of fracture, dislocation of the mandibular head, dental state and associated fractures of all patients diagnosed in our hospital during the period 1984-1996 with mandibular condyle fractures. Data were analysed in our Computer Department. The sample comprised 348 patients with 444 fractures, and a male:female ratio of 2:1. Traffic accidents were the most common cause: 103 (41%) of the unilateral and 54 (56%) of the bilateral fractures, followed by alleged assault and falls. Low fractures were the most common -n = 314 of 444 (71%). The causes that involved considerable force (traffic accidents and falls) resulted in more dislocations of the mandibular head, more bilateral fractures, a tendency to fractures higher on the condyle and significantly more intracapsular fractures. Absence of molar occlusion also gave more high and fewer low fractures, but played no part in dislocation of the mandibular head from the glenoid fossa. To assess the diagnostic accuracy of physical examination findings used to identify patients at risk for midfacial or mandibular fractures. A five-year retrospective cohort was constructed from all emergency department patients with a midfacial or mandibular trauma. The sensitivity, specificity, pre-test probability, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio data was calculated for 19 and 14 physical examination findings for midfacial and mandibular fractures respectively. Computed Tomography and panoramic radiography were used as index tests. A total of 1484 patients were identified among whom 40.4% midfacial and 33.4% mandibular fractures were diagnosed. Overall, specificity was found to be higher than sensitivity. Regarding midfacial fractures, high specificity was found for raccoon eyes, malar eminence flattening and all the findings that are related to palpation, the nasal, ocular and intra-oral assessment. Malar eminence flattening, external nasal deformity, nasal septum hematoma, change of globe position and palpable step-off had ad high positive predictive value and positive likelihood ratio. Regarding mandibular fractures high specificity was found for mouth opening restriction, auditory canal bleeding, intra-oral assessment related findings, palpable step-off, inferior alveolar nerve paresthesia, the angular compression test and chin axial pressure test. The diagnostic accuracy of relevant physical examination findings were identified for the prediction of midfacial and mandibular fractures. Mandibular fracture, also known as fracture of the jaw, is a break through the mandibular bone. In about 60% of cases the break occurs in two places. It may result in a decreased ability to fully open the mouth. Often the teeth will not feel properly aligned or there may be bleeding of the gums. Mandibular fractures occur most commonly among males in their 30s. Mandibular fractures are typically the result of trauma. This can include a fall onto the chin or a hit from the side. Rarely they may be due to osteonecrosis or tumors in the bone. The most common area of fracture is at the condyle (36%), body (21%), angle (20%) and symphysis (14%). While a diagnosis can occasionally be made with plain X-ray, modern CT scans are more accurate. A comprehensive classification of midfacial/craniofacial fractures, based on two- and three-dimensional computed tomography (2D and 3D-CT) is presented. We performed a postmortem analysis of 24 patients who had died from trauma with signs of craniofacial fractures, based on 2D and 3D-CT studies with pathoanatomical findings. In addition, CT findings for 100 patients with craniofacial injuries requiring an emergency CT were correlated with surgical findings and follow-up results. On the basis of the analysis of a total of 377 fractures a classification system is proposed. The system is based on the use of the AO/ASIF (Arbeitsgemeinschaft für Osteosynthesefragen/Association for the Study of Internal Fixation) scheme, defining three types (A, B, C), three groups within each type (e.g. A1, A2, A3) and three subgroups within each group (e.g. A1.1, A1.2, A1.3) with increasing severity from A1.1 (lowest) to C3.3 (highest). The craniofacial region is divided into three units: the lower midface (I), the upper midface (II) and the craniobasal-facial unit (III). Lateral and central fractures are also distinguished. Type A fractures are non-displaced fractures, type B are displaced fractures and type C are complex/defect fractures. Groups A1, B1 and C1 comprise fractures of an isolated unit; groups A2, B2 and C2, combined fractures without involvement of the skull base; and groups A3, B3 and C3 are those combined fractures with involvement of the skull base. A correlation between the severity of the fracture and (i). the number of posttraumatic functional limitations (Spearman rank test, correlation coefficient r=0.42), (ii). the need for bone grafting or dural plastic (r=0.39) and (iii). facial asymmetry (r=0.37), was observed. The proposed classification system allows standardised documentation of midfacial and craniofacial fractures, including those not precisely defined by the Le Fort classification scheme. A Le Fort fracture of the skull is a classic transfacial fracture of the midface, involving the maxillary bone and surrounding structures in either a horizontal, pyramidal or transverse direction. The hallmark of Lefort fractures is traumatic pterygomaxillary separation, which signifies fractures between the pterygoid plates, horseshoe shaped bony protuberances which extend from the inferior margin of the maxilla, and the maxillary sinuses. Continuity of this structure is a keystone for stability of the midface, involvement of which impacts surgical management of trauma victims, as it requires fixation to a horizontal bar of the frontal bone. The pterygoid plates lie posterior to the upper dental row, or alveolar ridge, when viewing the face from an anterior view. The fractures are named after French surgeon René Le Fort (1869–1951), who discovered the fracture patterns by examining crush injuries in cadavers. Signs and symptoms may be fractured. Superior dislocations occur after being punched below the mandibular ramus as the mouth remains half-open. Since great force occurs in a punch, the angle of the jaw will be forced upward moving towards the condylar head. This can result in a fracture of the glenoid fossa and displacement of the condyle into the middle cranial fossa, potentially injuring the facial and vestibulocochlear nerves and the temporal lobe. Lateral dislocations move the mandibular condyle away from the skull and are likely to happen together with jaw fractures. There are four different positions of jaw dislocation: posterior, anterior, superior and lateral. The most common position is anterior, while the other types are rare. Anterior dislocation shifts the lower jaw forward if the mouth excessively opens. This type of dislocation may happen bilaterally or unilaterally after yawning. The muscles that are affected during anterior jaw dislocation are the masseter and temporalis which pull up on the mandible and the lateral pterygoid which relaxes the mandibular condyle. The condyle can get locked in front of the articular eminence. Posterior dislocation is possible for people who get injured by being punched in the chin. This dislocation will push the jaw back affecting the alignment of the mandibular condyle and mastoid. The external auditory canal may be fractured. Superior dislocations occur after being punched below the mandibular ramus as the mouth remains half-open. Since great force occurs in a punch, the angle of the jaw will be forced Battle's sign, also known as mastoid ecchymosis, is an indication of fracture of middle cranial fossa of the skull. These fractures may be associated with underlying brain trauma. Battle's sign consists of bruising over the mastoid process as a result of extravasation of blood along the path of the posterior auricular artery. The sign is named after William Henry Battle. Battle's sign takes at least one day to appear after the initial traumatic basilar skull fracture, similar to raccoon eyes. It is usually seen after head injuries resulting in injury to mastoid process leading to bruising. Battle's sign may be confused with a spreading hematoma from a fracture of the mandibular condyle, which is a less serious injury. See also Basilar skull fracture Raccoon eyes Black eye References Traumatology Injuries Signs and symptoms Fractures of facial bones, like other fractures, may be associated with pain, bruising, and swelling of the surrounding tissues (such symptoms can occur in the absence of fractures as well). Fractures of the nose, base of the skull, or maxilla may be associated with profuse nosebleeds. Nasal fractures may be associated with deformity of the nose, as well as swelling and bruising. Deformity in the face, for example a sunken cheekbone or teeth which do not align properly, suggests the presence of fractures. Asymmetry can suggest facial fractures or damage to nerves. People with mandibular fractures often have pain and difficulty opening their mouths and may have numbness in the lip and chin. With Le Fort fractures, the midface may move relative to the rest of the face or skull. Ultrasonography (USG) allows to the examination of soft tissue and osseous tissues in the head-and-neck region. This study compared the accuracy of USG and computed tomography (CT) scan in the diagnosis of mandibular fractures. In this prospective observational study, spiral CT scan was prescribed for the lower face and, if necessary, midface and upper face in 42 trauma patients suspected of mandibular fractures, referring to Imam Reza Hospital in Tabriz. Two radiologists evaluated the CT scans. Then, another radiologist examined all the patients with USG with a frequency of 7-12 MHz. Ultrasonographic diagnostic results were recorded and compared with the results of the CT scan examinations. The results were reported using descriptive statistical methods. The specificity and sensitivity of USG were 100% and 91.1%, respectively. The USG sensitivities in the angle, condyle, condylar neck, and symphysis fractures were 100%, 91.6%, 85.7%, and 80%, respectively, and the specificity was 100% in all that anatomical regions. Among the confounding factors, the sensitivity of the USG (84.6%) was the lowest in the presence of hematoma; however, its specificity remained 100%. One case of symphysis fracture was not detected in the absence of any confounding factors in USG examination. Although the sensitivity, specificity, and diagnostic accuracy of the USG were at high levels, there were some limitations, making it difficult to definitively replace USG with CT scans, especially in the case of condylar fractures and in the presence of confounding factors such as hematoma and swelling. There has been a rising incidence of maxillofacial injuries during the past decade as a result of an increasing number of assaults and motor vehicle accidents. The maxillofacial region is one of the most complex areas of the human body, and the radiographic imaging of this region becomes even more difficult in traumatized patients because of their clinical condition and their inability to cooperate. Imaging modalities used in the evaluation of the traumatized maxillofacial region include conventional (plain) films, tomography, panoramic radiography, computed tomography, three-dimensional computed tomography, DentaScan, and magnetic resonance imaging. Each modality is discussed with regard to technique, advantages, and disadvantages. Plain films and computed tomography, the modalities that are used most in evaluating maxillofacial structures, are discussed in more detail. The normal anatomy and radiologic features are presented for both of these modalities. Radiographic evaluation of maxillofacial injury begins with a knowledge of the direct and indirect radiographic signs of injury seen on most imaging modalities. Computed tomography also has allowed a method of classifying facial fractures that is based on the involvement of the facial buttresses or struts. Three horizontal, two coronal, and five sagittal oriented struts are described. Limited fractures are differentiated from transfacial fractures by the lack of involvement of the pterygoid plates in the limited fractures. Limited fractures also can be subclassified as solitary (fracture of a single strut) or complex (fractures of multiple struts). A portion of the orbit is involved in almost every form of facial fracture; therefore, evaluation of facial injuries should always include the orbital structures. Although both can occur simultaneously, orbital injuries can be divided into soft tissue and bony vault injuries. Similar to midface fractures, orbital fractures also can be classified as solitary (fracture involves a single wall) or complex (fracture involves more than one wall or a part of a midface fracture). Computed tomography is of great value in evaluating both forms of injury. Magnetic resonance imaging is becoming increasingly important in the evaluation of orbital soft tissue injuries. Classification of midface injuries includes the solitary strut fractures and the complex strut fractures. Solitary strut fractures include fractures of the nasal arch, zygomatic arch, and isolated sinus wall fractures. Complex strut fractures include the nasal complex fractures, zygomatic (tripod) and zygomaticomaxillary fractures, transfacial fractures (LeFort fractures), and facial smash fractures. Each fracture type and its radiographic appearance are discussed.(ABSTRACT TRUNCATED AT 400 WORDS) At the beginning of the 20th century, René Le Fort mapped typical locations for facial fractures; these are now known as Le Fort I, II, and III fractures (right). Le Fort I fractures, also called Guérin or horizontal maxillary fractures, involve the maxilla, separating it from the palate. Le Fort II fractures, also called pyramidal fractures of the maxilla, cross the nasal bones and the orbital rim. Le Fort III fractures, also called craniofacial disjunction and transverse facial fractures, cross the front of the maxilla and involve the lacrimal bone, the lamina papyracea, and the orbital floor, and often involve the ethmoid bone, are the most serious. Le Fort fractures, which account for 10–20% of facial fractures, are often associated with other serious injuries. Le Fort made his classifications based on work with cadaver skulls, and the classification system has been criticized as imprecise and simplistic since most midface fractures involve a combination of Le Fort fractures.\nHere is the question:\nOTORHINOLARYNGOLOGY AND MAXILLOFACIAL SURGERY: Given a direct trauma to the right side of the face after which the patient presents unilateral palpebral hematoma, diplopia in the vertical gaze and difficulty in opening the mouth, which of the following statements is true?\nHere are the potential choices:\n1. We are with great probability in front of a Lefort I type fracture of the middle third of the face.\n2. This is probably a unilateral orbitomalar fracture. The diagnosis would ideally be verified by CT (computed axial tomography).\n3. It is a fracture of the base of the skull at the level of the carotid foramen.\n4. The probable diagnosis is fracture with dislocation of the mandibular condyle.\n5. A mandibular fracture is probably associated with a Lefort I type midface fracture.\nThe correct answer is: 4. The probable diagnosis is fracture with dislocation of the mandibular condyle."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The posterior vitreous detachment consists in the separation between the posterior vitreal cortex and internal limiting membrane of the retina. This is the peak of the vitreal para-physiological age-related modifications. This problem occurs in 6% of normal people of age between 45 and 65 years and in 65% of individuals between 65 and 85 years. Several elements can be responsible for vitreous modifications, such as senility, myopia, aphakia, pseudophakia, diabetes, degeneration vitreous retinal hereditary, traumatisms, inflammation. A 75 year old male patient has come to our attention for a left eye cataract. He has undergone to a series of OCT: the first before surgery showed a perifoveal vitreous detachmen; the following ones until six months after surgery put in evidence the DPV progression accompanied by EMC, relating it with visual symptomatology. Therefore, OCT is a useful tool for a clinical analysis but also for the contribution to research concerning the pathogenesis of diseases due to vitreo-retinal modification. Retinal detachment is more common in those with severe myopia (above 5–6 diopters), as their eyes are longer, their retina is thinner, and they more frequently have lattice degeneration. The lifetime risk increases to 1 in 20. Myopia is associated with 67% of retinal detachment cases. Patients suffering from a detachment related to myopia tend to be younger than non-myopic detachment patients. Retinal detachment can occur more frequently after surgery for cataracts. The estimated of risk of retinal detachment after cataract surgery is 5 to 16 per 1000 cataract operations. The risk may be much higher in those who are highly myopic, with a frequency of 7% reported in one study. Young age at cataract removal further increased risk in this study. Long term risk of retinal detachment after extracapsular and phacoemulsification cataract surgery at 2, 5, and 10 years was estimated in one study to be 0.36%, 0.77%, and 1.29%, respectively. Although uncommon, retinal detachments are medically urgent and can result in permanent vision loss if untreated. Bilateral retinal detachments in healthy individuals are even more rare. In addition, there are no cases to date of retinal detachment associated with either coronavirus disease 2019 (COVID-19) or after receiving the Moderna (mRNA-1273) severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine. A 22-year-old woman with myopia but no ocular trauma or other major medical history presented to the emergency department with 5 days of progressive, painless vision loss in her right eye. On examination, her visual acuity with corrective lenses was 20/70 in the right eye, 20/20 in the left eye, and 20/25 with both eyes open. Point-of-care ultrasound of the eye showed a retinal detachment in the right eye. She was subsequently seen by ophthalmology and diagnosed with bilateral retinal detachments (macula off in the right, macula on in the left), despite being asymptomatic in her left eye. She underwent bilateral vitrectomies for simultaneous rhegmatogenous retinal detachments. Although the patient denied any preceding trauma, she did note having received her second dose of the COVID-19 vaccine 10 days before the onset of symptoms.Why Should an Emergency Physician Be Aware of This? We present a rare and unusual case of simultaneous bilateral retinal detachments in a healthy, young woman with no major medical history or medications. She received the COVID-19 vaccine a few days prior. Our case outlines a possible association with the vaccine and emphasizes the importance of ultrasonography in diagnosing time-sensitive medical conditions. Modern phacoemulsification has established itself as a safe and very rewarding surgical procedure. Patients and surgeons may not associate late complications with the initial surgery. However, recent studies have demonstrated that such a causal relationship may persist for many years after the cataract procedure and that there is a significant increase in the risk for developing a retinal detachment during the postoperative years. The mean time period between cataract surgery and pseudophakic retinal detachment is between 3 and 4 years. Even uncomplicated cataract surgery alters the physiological processes within the eye and can lead to progressive destruction of the vitreous for many years after the surgery. Therefore, the risk for a retinal detachment is increased for at least 10 years after the initial procedure. In recent epidemiological studies, the most important risk factors for pseudophakic retinal detachment were myopia, younger age and male gender. If all factors are combined, the cumulative risk for developing a retinal detachment after cataract surgery may rise to 20 %. Additional factors that may increase this risk are additional intraoperative complications, for example, rupture of the posterior capsule, vitreous loss or dropped nucleus. Compared to phakic retinal detachments, pseudophakic patients on average present with a shorter history of visual symptoms, are older, more commonly male and display fewer, smaller and more anteriorly located retinal breaks that frequently are only detected during surgery. The anatomic success rates have improved significantly over the past years, in particular through the advances and increasing popularity of primary vitrectomy. However, functional results are still disappointing. Only about half of the patients will achieve reading ability without low vision aids. The increased and long-term risk for pseudophakic retinal detachment should be part of the preoperative consent process of any cataract surgery, in particular, in young myopic males. Age and refractive error play a role in determining the onset of PVD in a healthy person. PVD is rare in emmetropic people under the age of 40 years, and increases with age to 86% in the 90s. Several studies have found a broad range of incidence of PVD, from 20% of autopsy cases to 57% in a more elderly population of patients (average age was 83.4 years). People with myopia (nearsightedness) greater than 6 diopters are at higher risk of PVD at all ages. Posterior vitreous detachment does not directly threaten vision. Even so, it is of increasing interest because the interaction between the vitreous body and the retina might play a decisive role in the development of major pathologic vitreoretinal conditions, such as epiretinal membrane. PVD may also occur in cases of cataract surgery, within weeks or months of the surgery. In cases of PC-IOL implantation and ruptured capsule there will be a higher risk of the lens loosening into the vitreous, although many successful cases have been reported. Three years ago we investigated 42 eyes with PC-IOL that had experienced previous posterior capsular or zonular rents and partial vitreous loss. Three to 5.5 years after PC-IOL implantation we have now performed a second investigation on 38 of these patients to examine fixation of the lenses, visual acuity, intraocular pressure and the fundus of the eye. The 38 lenses all remained stable. The rate of patients achieving 20/40 or better visual acuity decreased from 68% at the first investigation to 55% (21/38). Excluding all patients with vision-limiting preoperative conditions such as age-related macular degeneration, we found a relation-ship of 83% to 75% (21/28). In addition to the three retinal detachments and two cases of endophthalmitis found during the first investigation, we also found another retinal detachment at the follow-up examination. Only two of these six eyes with severe complications had useful vision. We conclude from our investigation that PC-IOL implanted following a posterior capsule-zonular break during ECCE can remain stable, but still lead to serious complications. To present the 2-year outcomes of surgical removal of non-age-related macular degeneration (AMD)-related choroidal neovascular membranes and to evaluate any association between visual outcome and baseline clinical factors. Retrospective consecutive case series. All patients who had surgery for non-AMD-related choroidal neovascularisation (CNV) between November 1997 and March 2003 under the care of a single surgeon (WA) were included in the study. Baseline data including patient age, duration of subfoveal CNV, preoperative visual acuity (VA), lesion size, lesion components and aetiology were collected. The primary outcome was VA change with secondary outcomes retinal detachment, operative peripheral retinal break formation, CNV recurrence and cataract. A total of 52 eyes were included in the study. The aetiology of CNV was: punctate inner choridopathy 21 (40%); idiopathic 8 (15%); pathologic myopia 6 (12%); ocular histoplasmosis syndrome 1 (2%); and other 16 (31%). The mean age of patients was 41(range 14-72) years. 24-month follow-up was available for 41 (80%) eyes. The mean logMAR equivalent baseline acuity was 1.1 and mean lesion size 1.2 disc areas. An improvement in VA &gt;1 Snellen line was noted in 26 (63%) eyes, whereas 10 (24%) eyes remained the same (within 1 line) and 5 (12%) lost &gt;1 line of acuity. Improvement in VA was associated with worse baseline VA (84% for eyes with VA &lt;or=6/36 vs 31% for those with VA&gt;6/36, p=0.001). No evidence of association between 2-year visual outcome and any other baseline factor under study was observed. Peripheral retinal breaks were noted in 5 (10%) eyes at the time of surgery, and 3 (5.8%) eyes developed postoperative retinal detachments. Persistent/recurrent CNV was noted in 17 (33%) eyes. The median time to presentation of CNV in these eyes was 27 (range 2-172) weeks. Five eyes underwent cataract surgery during the follow-up period. The mean age of these patients was significantly higher than the mean age of those who did not require cataract surgery (57 vs 37 years, p=0.014). Surgical excision of non-AMD-related CNV resulted in improvement of VA in the majority of eyes. Worse presenting acuity was associated with better visual improvements. The age related macular degeneration (ARMD) is the most common cause of the central visual acuity loss in persons of age more than 60 years in the well developed countries. Rotation of the macula is nowadays a progressive method of choice of treatment of the exsudative form of ARMD. The aim of this surgical technique is to relocate the neuroretinal epithelium of the central region of the retina to a position situated outside the border of the subfoveolar lesion. Three eyes of three patients (2 woman and one man) were operated on during the period between March and May 2001 at the Department of Ophthalmology of the School of Medicine, Charles University in Pilsen. The method used was the scleral imbrication, which belongs to methods designated as \"limited translocation\". The mean age of the patients was 62 years and the follow up period was 2 years. After the surgery the relocation of the fovea was observed in all three eyes. In two eyes, the postoperative period was complicated by tractional retinal detachment that occurred three weeks after the surgery as a consequence of progressive proliferative vitreoretinopathy (PVR). Both eyes with the retinal detachment were re-operated. In both of them, the repeated pars plana vitrectomy, epiretinal membranes removal with relaxing retinectomy was performed and after maximal mobilization of the retina, the silicone oil implantation followed. In the second patient, the postoperative period was complicated by elevation of the intraocular pressure and a radial retinal fold running from the encircling buckle indentation up to the macula. Slightly improved function was noticed only in the first patient after following cataract surgery with intraocular lens implantation. In the two other eyes, as noticed at the last follow up check, the postoperative complications caused severe decrease of the central visual acuity although the retina remained attached. Macular translocation procedure is in stage of development and its surgical techniques are being further modified. The risk of postoperative complications with profound loss of central visual acuity corresponds to the level of the technical difficulty and extent of surgical intervention. Achievements and positions Kumar is a specialist in diseases of the retina, vitreous and uvea and their management. His academic disciplines include Vitreoretinal surgery, Ophthalmic Lasers, Uveal diseases, Macular Hole surgery, anti-VEGF injections, Age Related Macular Degeneration, Retinal Detachment surgery, Myopic Traction Maculopathy, Pathological Myopia and Macular Hole Retinal Detachment. To identity anatomic risk factors involved in the onset of retinal complications causing decrease of visual acuity (VA) in the fellow eyes of highly myopic patients operated for retinal detachment with macular hole (RDMH). Cohort study. Ninety-eight patients (mean age, 51.5+/-8.0 years) with bilateral high myopia (mean myopia of the fellow eye, 20.4+/-5.5 diopters) affected by RDMH in the other eye at baseline. Evaluation of the anatomic features at baseline and during 84+/-2.7 months of follow-up by biomicroscopic examination, indirect binocular ophthalmoscopy, B-scan ultrasonography, and optical coherence tomography. Detection of anatomic features associated with onset of retinal complications causing decrease of VA during the follow-up period. The fellow eyes were divided into 2 groups according to the clinical features of the RDMH eyes: Group 1, presence of posterior vitreous detachment (PVD); and Group 2, presence of posterior vitreous schisis (PVS). At baseline, the incidence of PVD in group 1 was 31 of 47 eyes (65.9%) and the incidence of PVS in Group 2 was 42 of 51 eyes (82.3%). At the end of follow-up, group 1 eyes had a lower incidence of retinal complications causing visual decrease than group 2 eyes (group 1, 2/47 eyes; group 2, 9/51 eyes). Fellow eyes of RDMH cases with higher degree of myopia and peculiar vitreoretinal features including PVS, posterior epiretinal membrane, severe posterior staphyloma, and chorioretinal atrophy are more likely to develop retinal complications causing decrease of VA. Acute visual loss is a rapid loss of the ability to see. It is caused by many ocular conditions like retinal detachment, glaucoma, macular degeneration, and giant cell arteritis, etc. Main causes Retinal detachment Retinal detachment should be considered if there were preceding flashes or floaters, or if there is a new visual field defect in one eye. If treated early enough, retinal tear and detachment can have a good outcome. Glaucoma Angle-closure glaucoma should be considered if there is painful loss of vision with a red eye, nausea or vomiting. The eye pressure will be very high typically greater than 40 mmHg. Emergent laser treatment to the iris may prevent blindness. Macular degeneration Wet macular degeneration should be considered in older people with new distortion of their vision with bleeding in the macula. Vision can often be regained with prompt eye injections with anti-VEGF agents. Giant cell arteritis To describe clinical features and treatment outcomes of retinal detachment (RD) in eyes with retinitis pigmentosa (RP). Single-center, retrospective, interventional case series. All RP patients with RD examined between April 2003 and December 2013 and minimum 2 months of follow-up. Medical records of RP patients were screened and 31 eyes with RD were included. Family history of RP, duration of symptoms, age at presentation, associated ocular and systemic findings, and detailed ophthalmic evaluation including presenting visual acuity, type and amount of refractive error, fundus findings, electroretinogram details, surgical details, and postoperative complications and outcomes were evaluated. Univariate analysis was done to determine risk factors associated with RD in eyes with RP and risk factors associated with poor visual outcomes after treatment. Subset analysis was also done for comparing the functional and anatomical outcomes between patients undergoing scleral buckling or vitrectomy. Final surgical reattachment rate, best-corrected visual acuity. Mean age at presentation was 22 years (median, 17; range, 4-63). Mean duration of symptoms was 12 months (median, 3 months: range, 3 days-60 months). Associated ocular findings included nyctalopia (n = 23), myopia (n = 21), and hyperopia (n = 10). Systemic associations included hearing loss (n = 5), deaf-mutism (n = 1), and Bardet-Biedel syndrome (n = 1). No association between degree of myopia and RD was noted (P = 0.63). Observed retinal breaks included horse-shoe-shaped tear (n = 15), lattice with hole (n = 7), atrophic retinal hole (n = 3), retinal dialysis (n = 3), and macular hole (n = 3). The most common location of breaks was superotemporal quadrant (n = 15). Younger age, male gender, and presence of posterior vitreous detachment were strongly associated with RD with odds ratio of 1.3 (P = 0.001), 8.3 (P = 0.010), and 6 (P = 0.003), respectively. Retinal reattachment was achieved in 13 of 13 eyes (100%) with scleral buckle and 9 of 10 eyes (90%) with vitrectomy. Vision improved from 1.63±0.52 to 0.87±0.25 logarithm of the minimum angle of resolution (P &lt; 0.001) at a mean follow-up of 33 months (median, 24, range; 1-145). Rhegmatogenous RD in eyes with RP is rare. Precocious vitreous degeneration and sparse pigmentation in younger male patients has a role in etiopathogenesis. Visual prognosis remains poor despite satisfactory surgical outcomes. Macular surgery has become an increasingly atraumatic procedure for the eye with the surgical methods that have been further developed in recent years. The most common complications include cystoid macular oedema and retinal detachment, more rarely endophthalmitis. The aim of this retrospective study is to record the number of retinal detachments following elective macular surgery. In this study we included all patients who underwent pars plana vitrectomy (ppV, 20 or 25 gauge) in the years 2009 - 2016. We then identified the patients who were hospitalised again because of retinal detachment. For the affected patients, the rate of retinal detachment, functional outcomes and possible risk factors were recorded. A total of 904 eyes were identified, of which 667 had surgery for epiretinal membrane, 188 for macular hole, and 49 for vitreomacular traction with a 20 or 25 gauge ppV. Of these 904, retinal detachment occurred in 17 (1.88%) cases. The mean time between first ppV and second ppV with retinal detachment was 248 days (3 - 1837 days). Two of the 17 patients had at least one retinal break before or during surgery. The retinal break was located inferior in six cases, superior in four; in four cases PVR retinal detachment and in three cases the foramina were distributed. Mean visual acuity was 0.27 (decimal) before macular surgery and 0.28 at the time of last presentation. Modern vitrectomy techniques reduce the complications in elective macular surgery, but do not replace the surgeon's experience. A 38-year-old man presented with sudden decreased vision in the right eye 3 years ago due to vitreous haemorrhage. During follow-up, right eye fundus showed evidence of vasculitis, non-perfusion areas and neovascularisation elsewhere. Systemic evaluation findings of positive Mantoux test, QuantiFERON Gold test and right apical pleuroparenchymal fibrosis observed on high-resolution CT of the chest were suggestive of postinfection probable tubercular aetiology. He was treated with oral steroids, antitubercular therapy, intravitreal bevacizumab and anterior retinal cryopexy, leading to resolution of vasculitis and vitreous haemorrhage. Later he developed peripheral retinal flap and posterior retinal breaks at 8-month and 11-month follow-up, respectively, which were managed by barrage laser. He maintained a stable visual acuity of 20/20, N6 for the next 2 years. He then presented with sudden decreased vision in the right eye (20/50, N10). Right eye fundus showed posterior pole retinal detachment with lifting of previously barraged posterior retinal breaks. He underwent vitreoretinal surgery with gas tamponade. Recent 1-month postoperative visit showed successful retinal reattachment and visual recovery of 20/20, N6. Rhegmatogenous retinal detachment is the most common retinological emergency threatening vision, with an incidence of 1 in 10 000 persons per year, corresponding to about 8000 new cases in Germany annually. Without treatment, blindness in the affected eye may result. Selective review of the literature. Rhegmatogenous retinal detachment typically presents with the perception of light flashes, floaters, or a \"dark curtain.\" In most cases, the retinal tear is a consequence of degeneration of the vitreous body. Epidemiologic studies have identified myopia and prior cataract surgery as the main risk factors. Persons in the sixth and seventh decades of life are most commonly affected. Rhegmatogenous retinal detachment is an emergency, and all patients should be seen by an ophthalmologist on the same day that symptoms arise. The treatment consists of scleral buckle, removal of the vitreous body (vitrectomy), or a combination of the two. Anatomical success rates are in the range of 85% to 90%. Vitrectomy is followed by lens opacification in more than 70% of cases. The earlier the patient is seen by an ophthalmologist, the greater the chance that the macula is still attached, so that visual acuity can be preserved. Rhegmatogenous retinal detachment is among the main emergency indications in ophthalmology. In all such cases, an ophthalmologist must be consulted at once. The observed increasing number of severe cases of retinal detachment was the ground of the attempt to state the causes of this phenomenon. Retrospective evaluation of 100 consecutive cases of retinal detachment operated on with conventional methods between September 1997 and October 1998 was performed. The following data were analysed: sex and age of patients, period between the first symptoms and time of diagnosis and surgery. The clinical characteristics of retinal surgery comprise: extent of detachment, macular involving, type and number of breaks, degenerations and PVR. In the majority of cases very severe retinal detachments were observed, including 3-4 quadrants, with large tears or multiple breaks, with PVR B or C. Duration of the detachment ranged from several days in very few cases to several months, on average lasting several weeks. Attachment of the retina was achieved in 80 cases, improvement of the visual acuity in 47. Our data indicate the necessity to improve the early diagnosis of retinal detachment and changes predisposing to its development. To describe a case of postoperative Mycobacterium manitobense endophthalmitis with good visual outcome that is the first report of endophthalmitis by this organism. Clinical and microbiological description of a patient with postoperative endophthalmitis. A 50-year-old chronic alcoholic man was referred to us with decreased vision in his right eye for 4 days. He had undergone cataract surgery with intraocular lens implantation in his right eye a month ago. The presenting vision in his right eye was counting fingers close to face. He was diagnosed as a case of postoperative endophthalmitis. Subsequently, the patient underwent pars plana vitrectomy and vitreous biopsy. The microbiologic investigation of the vitreous biopsy showed poorly stained gram-positive beaded bacilli that were acid fast, and growth in culture was identified as Corynebacterium pseudodiphtheriticum by Vitek 2 bacterial identification system. However, DNA analysis confirmed the organism to be M. manitobense. The patient responded well to repeat interventions with intravitreal antibiotics with a final reported visual acuity of 20/30 at 4 months after first intervention. Although known to be an organism causing soft-tissue infections, M. manitobense can also cause postsurgical endophthalmitis. The diagnosis can be confused with Corynebacterium sp. on smear and culture. Subsequent DNA sequencing of the culture provides definite identification of the organism. To study the clinical features and the pathogenesis of macular hole with and without retina detachment (RD) in high myopic eyes. It was a retrospective series case study. The charts of high myopic patients with macular hole at our hospital from June 2006 to February 2007 were retrospectively reviewed and analyzed. Patients were divided into two groups (the RD group and non-RD group) depending on the presence of RD or not. Their clinical data and optic coherence tomography (OCT) results were further analyzed. SPSS 13.0 was used for the statistic analysis. When comparing the quantitative aspects like age, axial length and refraction, t-test was used. Categorical data, such as sex ratio, occurrence of vitreous traction, posterior staphyloma and retinoschisis were compared by using χ(2) test. Fisher's test was used in comparing eye laterality, incidence of white hole, visual acuity and posterior vitreous detachment (PVD). During this period, there were 43 patients fitting the including criteria. Among them, 36 patents (37 eyes) were in the RD group and 7 patients (7 eyes) in the no-RD group. In the RD group, the average age was 56.1, 24.3% of them (9/37) were male; percentage of left and right eyes was (11/37) and 70.3% (26/37), respectively; average refraction was (-8.9 ± 2.2) D; average axial length was (28.7 ± 2.0) mm. Visual acuity was ≤ 0.05 (72.2%) in 26 eyes and 0.05 - 0.2 (27.8%) in 10 patients. The incidence of complete and non-complete PVD was 89.2% (33/37) and 10.8% (4/37), respectively. White hole presented in 35.1% (3/37) patients. Vitreous traction and retinoschisis presented in 27.0% (10/37) and 35.1% (13/37) patients, respectively. In the non-RD group, the average age was 47.6; 16.7% of them (1/7) were male; left and right eyes were involved in 42.9% (3/7) and 57.1% (4/7), respectively. Average refraction was (-9.0 ± 1.9) D; average axial length was (28.9 ± 1.5) mm. Vision acuity was ≤ 0.05 in 3 patients (42.9%); between 0.05 - 0.2 in 3 eyes (42.9%) and ≥ 0.2 in 1 eye (14.3%). Incidence of complete and non-complete PVD was 85.7% (6/7) and 14.3% (1/7), respectively. White hole was observed in 14.3% (1/7) patients; 42.9% (3/7) patients were accompanied with vitreous traction and 71.4% (5/7) with retinoschisis. B-scan ultrasonography showed posterior staphyloma in all 44 eyes. The results of statistical analysis showed that the gender (χ(2) = 0.008) and eye laterality (χ(2) = 0.449) as well as refraction (t = 0.193), axial length (t = -0.25) and visual acuity (χ(2) = 4.509) of these two groups were similar (P &gt; 0.05). The incidences of vitreous traction (χ(2) = 0.709), white hole (χ(2) = 1.179), PVD (χ(2) = 0.071) and retinoschisis (χ(2) = 3.207) were also similar (P &gt; 0.05). But the age of the non-RD group is significantly younger than the RD group (t = 1.66, P &lt; 0.05). Various pathogenesis may involved in the occurrence of retinal detachment in highly myopic eyes with macular hole. Further study is required to improve our understanding of this entity.\nHere is the question:\nOPHTHALMOLOGY: A 47-year-old man with myopia magna, who underwent cataract surgery 2 years ago, comes to the emergency room reporting a profound and painless loss of vision in his right eye. Which of the following diagnoses can cause this symptomatology?\nHere are the potential choices:\n1. Post-surgical endophthalmitis.\n2. Retinal detachment.\n3. Age-related macular degeneration, wet form.\n4. Posterior vitreous detachment.\nThe correct answer is: ",
        "gold_answer": "2 Retinal detachment.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The posterior vitreous detachment consists in the separation between the posterior vitreal cortex and internal limiting membrane of the retina. This is the peak of the vitreal para-physiological age-related modifications. This problem occurs in 6% of normal people of age between 45 and 65 years and in 65% of individuals between 65 and 85 years. Several elements can be responsible for vitreous modifications, such as senility, myopia, aphakia, pseudophakia, diabetes, degeneration vitreous retinal hereditary, traumatisms, inflammation. A 75 year old male patient has come to our attention for a left eye cataract. He has undergone to a series of OCT: the first before surgery showed a perifoveal vitreous detachmen; the following ones until six months after surgery put in evidence the DPV progression accompanied by EMC, relating it with visual symptomatology. Therefore, OCT is a useful tool for a clinical analysis but also for the contribution to research concerning the pathogenesis of diseases due to vitreo-retinal modification. Retinal detachment is more common in those with severe myopia (above 5–6 diopters), as their eyes are longer, their retina is thinner, and they more frequently have lattice degeneration. The lifetime risk increases to 1 in 20. Myopia is associated with 67% of retinal detachment cases. Patients suffering from a detachment related to myopia tend to be younger than non-myopic detachment patients. Retinal detachment can occur more frequently after surgery for cataracts. The estimated of risk of retinal detachment after cataract surgery is 5 to 16 per 1000 cataract operations. The risk may be much higher in those who are highly myopic, with a frequency of 7% reported in one study. Young age at cataract removal further increased risk in this study. Long term risk of retinal detachment after extracapsular and phacoemulsification cataract surgery at 2, 5, and 10 years was estimated in one study to be 0.36%, 0.77%, and 1.29%, respectively. Although uncommon, retinal detachments are medically urgent and can result in permanent vision loss if untreated. Bilateral retinal detachments in healthy individuals are even more rare. In addition, there are no cases to date of retinal detachment associated with either coronavirus disease 2019 (COVID-19) or after receiving the Moderna (mRNA-1273) severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine. A 22-year-old woman with myopia but no ocular trauma or other major medical history presented to the emergency department with 5 days of progressive, painless vision loss in her right eye. On examination, her visual acuity with corrective lenses was 20/70 in the right eye, 20/20 in the left eye, and 20/25 with both eyes open. Point-of-care ultrasound of the eye showed a retinal detachment in the right eye. She was subsequently seen by ophthalmology and diagnosed with bilateral retinal detachments (macula off in the right, macula on in the left), despite being asymptomatic in her left eye. She underwent bilateral vitrectomies for simultaneous rhegmatogenous retinal detachments. Although the patient denied any preceding trauma, she did note having received her second dose of the COVID-19 vaccine 10 days before the onset of symptoms.Why Should an Emergency Physician Be Aware of This? We present a rare and unusual case of simultaneous bilateral retinal detachments in a healthy, young woman with no major medical history or medications. She received the COVID-19 vaccine a few days prior. Our case outlines a possible association with the vaccine and emphasizes the importance of ultrasonography in diagnosing time-sensitive medical conditions. Modern phacoemulsification has established itself as a safe and very rewarding surgical procedure. Patients and surgeons may not associate late complications with the initial surgery. However, recent studies have demonstrated that such a causal relationship may persist for many years after the cataract procedure and that there is a significant increase in the risk for developing a retinal detachment during the postoperative years. The mean time period between cataract surgery and pseudophakic retinal detachment is between 3 and 4 years. Even uncomplicated cataract surgery alters the physiological processes within the eye and can lead to progressive destruction of the vitreous for many years after the surgery. Therefore, the risk for a retinal detachment is increased for at least 10 years after the initial procedure. In recent epidemiological studies, the most important risk factors for pseudophakic retinal detachment were myopia, younger age and male gender. If all factors are combined, the cumulative risk for developing a retinal detachment after cataract surgery may rise to 20 %. Additional factors that may increase this risk are additional intraoperative complications, for example, rupture of the posterior capsule, vitreous loss or dropped nucleus. Compared to phakic retinal detachments, pseudophakic patients on average present with a shorter history of visual symptoms, are older, more commonly male and display fewer, smaller and more anteriorly located retinal breaks that frequently are only detected during surgery. The anatomic success rates have improved significantly over the past years, in particular through the advances and increasing popularity of primary vitrectomy. However, functional results are still disappointing. Only about half of the patients will achieve reading ability without low vision aids. The increased and long-term risk for pseudophakic retinal detachment should be part of the preoperative consent process of any cataract surgery, in particular, in young myopic males. Age and refractive error play a role in determining the onset of PVD in a healthy person. PVD is rare in emmetropic people under the age of 40 years, and increases with age to 86% in the 90s. Several studies have found a broad range of incidence of PVD, from 20% of autopsy cases to 57% in a more elderly population of patients (average age was 83.4 years). People with myopia (nearsightedness) greater than 6 diopters are at higher risk of PVD at all ages. Posterior vitreous detachment does not directly threaten vision. Even so, it is of increasing interest because the interaction between the vitreous body and the retina might play a decisive role in the development of major pathologic vitreoretinal conditions, such as epiretinal membrane. PVD may also occur in cases of cataract surgery, within weeks or months of the surgery. In cases of PC-IOL implantation and ruptured capsule there will be a higher risk of the lens loosening into the vitreous, although many successful cases have been reported. Three years ago we investigated 42 eyes with PC-IOL that had experienced previous posterior capsular or zonular rents and partial vitreous loss. Three to 5.5 years after PC-IOL implantation we have now performed a second investigation on 38 of these patients to examine fixation of the lenses, visual acuity, intraocular pressure and the fundus of the eye. The 38 lenses all remained stable. The rate of patients achieving 20/40 or better visual acuity decreased from 68% at the first investigation to 55% (21/38). Excluding all patients with vision-limiting preoperative conditions such as age-related macular degeneration, we found a relation-ship of 83% to 75% (21/28). In addition to the three retinal detachments and two cases of endophthalmitis found during the first investigation, we also found another retinal detachment at the follow-up examination. Only two of these six eyes with severe complications had useful vision. We conclude from our investigation that PC-IOL implanted following a posterior capsule-zonular break during ECCE can remain stable, but still lead to serious complications. To present the 2-year outcomes of surgical removal of non-age-related macular degeneration (AMD)-related choroidal neovascular membranes and to evaluate any association between visual outcome and baseline clinical factors. Retrospective consecutive case series. All patients who had surgery for non-AMD-related choroidal neovascularisation (CNV) between November 1997 and March 2003 under the care of a single surgeon (WA) were included in the study. Baseline data including patient age, duration of subfoveal CNV, preoperative visual acuity (VA), lesion size, lesion components and aetiology were collected. The primary outcome was VA change with secondary outcomes retinal detachment, operative peripheral retinal break formation, CNV recurrence and cataract. A total of 52 eyes were included in the study. The aetiology of CNV was: punctate inner choridopathy 21 (40%); idiopathic 8 (15%); pathologic myopia 6 (12%); ocular histoplasmosis syndrome 1 (2%); and other 16 (31%). The mean age of patients was 41(range 14-72) years. 24-month follow-up was available for 41 (80%) eyes. The mean logMAR equivalent baseline acuity was 1.1 and mean lesion size 1.2 disc areas. An improvement in VA &gt;1 Snellen line was noted in 26 (63%) eyes, whereas 10 (24%) eyes remained the same (within 1 line) and 5 (12%) lost &gt;1 line of acuity. Improvement in VA was associated with worse baseline VA (84% for eyes with VA &lt;or=6/36 vs 31% for those with VA&gt;6/36, p=0.001). No evidence of association between 2-year visual outcome and any other baseline factor under study was observed. Peripheral retinal breaks were noted in 5 (10%) eyes at the time of surgery, and 3 (5.8%) eyes developed postoperative retinal detachments. Persistent/recurrent CNV was noted in 17 (33%) eyes. The median time to presentation of CNV in these eyes was 27 (range 2-172) weeks. Five eyes underwent cataract surgery during the follow-up period. The mean age of these patients was significantly higher than the mean age of those who did not require cataract surgery (57 vs 37 years, p=0.014). Surgical excision of non-AMD-related CNV resulted in improvement of VA in the majority of eyes. Worse presenting acuity was associated with better visual improvements. The age related macular degeneration (ARMD) is the most common cause of the central visual acuity loss in persons of age more than 60 years in the well developed countries. Rotation of the macula is nowadays a progressive method of choice of treatment of the exsudative form of ARMD. The aim of this surgical technique is to relocate the neuroretinal epithelium of the central region of the retina to a position situated outside the border of the subfoveolar lesion. Three eyes of three patients (2 woman and one man) were operated on during the period between March and May 2001 at the Department of Ophthalmology of the School of Medicine, Charles University in Pilsen. The method used was the scleral imbrication, which belongs to methods designated as \"limited translocation\". The mean age of the patients was 62 years and the follow up period was 2 years. After the surgery the relocation of the fovea was observed in all three eyes. In two eyes, the postoperative period was complicated by tractional retinal detachment that occurred three weeks after the surgery as a consequence of progressive proliferative vitreoretinopathy (PVR). Both eyes with the retinal detachment were re-operated. In both of them, the repeated pars plana vitrectomy, epiretinal membranes removal with relaxing retinectomy was performed and after maximal mobilization of the retina, the silicone oil implantation followed. In the second patient, the postoperative period was complicated by elevation of the intraocular pressure and a radial retinal fold running from the encircling buckle indentation up to the macula. Slightly improved function was noticed only in the first patient after following cataract surgery with intraocular lens implantation. In the two other eyes, as noticed at the last follow up check, the postoperative complications caused severe decrease of the central visual acuity although the retina remained attached. Macular translocation procedure is in stage of development and its surgical techniques are being further modified. The risk of postoperative complications with profound loss of central visual acuity corresponds to the level of the technical difficulty and extent of surgical intervention. Achievements and positions Kumar is a specialist in diseases of the retina, vitreous and uvea and their management. His academic disciplines include Vitreoretinal surgery, Ophthalmic Lasers, Uveal diseases, Macular Hole surgery, anti-VEGF injections, Age Related Macular Degeneration, Retinal Detachment surgery, Myopic Traction Maculopathy, Pathological Myopia and Macular Hole Retinal Detachment. To identity anatomic risk factors involved in the onset of retinal complications causing decrease of visual acuity (VA) in the fellow eyes of highly myopic patients operated for retinal detachment with macular hole (RDMH). Cohort study. Ninety-eight patients (mean age, 51.5+/-8.0 years) with bilateral high myopia (mean myopia of the fellow eye, 20.4+/-5.5 diopters) affected by RDMH in the other eye at baseline. Evaluation of the anatomic features at baseline and during 84+/-2.7 months of follow-up by biomicroscopic examination, indirect binocular ophthalmoscopy, B-scan ultrasonography, and optical coherence tomography. Detection of anatomic features associated with onset of retinal complications causing decrease of VA during the follow-up period. The fellow eyes were divided into 2 groups according to the clinical features of the RDMH eyes: Group 1, presence of posterior vitreous detachment (PVD); and Group 2, presence of posterior vitreous schisis (PVS). At baseline, the incidence of PVD in group 1 was 31 of 47 eyes (65.9%) and the incidence of PVS in Group 2 was 42 of 51 eyes (82.3%). At the end of follow-up, group 1 eyes had a lower incidence of retinal complications causing visual decrease than group 2 eyes (group 1, 2/47 eyes; group 2, 9/51 eyes). Fellow eyes of RDMH cases with higher degree of myopia and peculiar vitreoretinal features including PVS, posterior epiretinal membrane, severe posterior staphyloma, and chorioretinal atrophy are more likely to develop retinal complications causing decrease of VA. Acute visual loss is a rapid loss of the ability to see. It is caused by many ocular conditions like retinal detachment, glaucoma, macular degeneration, and giant cell arteritis, etc. Main causes Retinal detachment Retinal detachment should be considered if there were preceding flashes or floaters, or if there is a new visual field defect in one eye. If treated early enough, retinal tear and detachment can have a good outcome. Glaucoma Angle-closure glaucoma should be considered if there is painful loss of vision with a red eye, nausea or vomiting. The eye pressure will be very high typically greater than 40 mmHg. Emergent laser treatment to the iris may prevent blindness. Macular degeneration Wet macular degeneration should be considered in older people with new distortion of their vision with bleeding in the macula. Vision can often be regained with prompt eye injections with anti-VEGF agents. Giant cell arteritis To describe clinical features and treatment outcomes of retinal detachment (RD) in eyes with retinitis pigmentosa (RP). Single-center, retrospective, interventional case series. All RP patients with RD examined between April 2003 and December 2013 and minimum 2 months of follow-up. Medical records of RP patients were screened and 31 eyes with RD were included. Family history of RP, duration of symptoms, age at presentation, associated ocular and systemic findings, and detailed ophthalmic evaluation including presenting visual acuity, type and amount of refractive error, fundus findings, electroretinogram details, surgical details, and postoperative complications and outcomes were evaluated. Univariate analysis was done to determine risk factors associated with RD in eyes with RP and risk factors associated with poor visual outcomes after treatment. Subset analysis was also done for comparing the functional and anatomical outcomes between patients undergoing scleral buckling or vitrectomy. Final surgical reattachment rate, best-corrected visual acuity. Mean age at presentation was 22 years (median, 17; range, 4-63). Mean duration of symptoms was 12 months (median, 3 months: range, 3 days-60 months). Associated ocular findings included nyctalopia (n = 23), myopia (n = 21), and hyperopia (n = 10). Systemic associations included hearing loss (n = 5), deaf-mutism (n = 1), and Bardet-Biedel syndrome (n = 1). No association between degree of myopia and RD was noted (P = 0.63). Observed retinal breaks included horse-shoe-shaped tear (n = 15), lattice with hole (n = 7), atrophic retinal hole (n = 3), retinal dialysis (n = 3), and macular hole (n = 3). The most common location of breaks was superotemporal quadrant (n = 15). Younger age, male gender, and presence of posterior vitreous detachment were strongly associated with RD with odds ratio of 1.3 (P = 0.001), 8.3 (P = 0.010), and 6 (P = 0.003), respectively. Retinal reattachment was achieved in 13 of 13 eyes (100%) with scleral buckle and 9 of 10 eyes (90%) with vitrectomy. Vision improved from 1.63±0.52 to 0.87±0.25 logarithm of the minimum angle of resolution (P &lt; 0.001) at a mean follow-up of 33 months (median, 24, range; 1-145). Rhegmatogenous RD in eyes with RP is rare. Precocious vitreous degeneration and sparse pigmentation in younger male patients has a role in etiopathogenesis. Visual prognosis remains poor despite satisfactory surgical outcomes. Macular surgery has become an increasingly atraumatic procedure for the eye with the surgical methods that have been further developed in recent years. The most common complications include cystoid macular oedema and retinal detachment, more rarely endophthalmitis. The aim of this retrospective study is to record the number of retinal detachments following elective macular surgery. In this study we included all patients who underwent pars plana vitrectomy (ppV, 20 or 25 gauge) in the years 2009 - 2016. We then identified the patients who were hospitalised again because of retinal detachment. For the affected patients, the rate of retinal detachment, functional outcomes and possible risk factors were recorded. A total of 904 eyes were identified, of which 667 had surgery for epiretinal membrane, 188 for macular hole, and 49 for vitreomacular traction with a 20 or 25 gauge ppV. Of these 904, retinal detachment occurred in 17 (1.88%) cases. The mean time between first ppV and second ppV with retinal detachment was 248 days (3 - 1837 days). Two of the 17 patients had at least one retinal break before or during surgery. The retinal break was located inferior in six cases, superior in four; in four cases PVR retinal detachment and in three cases the foramina were distributed. Mean visual acuity was 0.27 (decimal) before macular surgery and 0.28 at the time of last presentation. Modern vitrectomy techniques reduce the complications in elective macular surgery, but do not replace the surgeon's experience. A 38-year-old man presented with sudden decreased vision in the right eye 3 years ago due to vitreous haemorrhage. During follow-up, right eye fundus showed evidence of vasculitis, non-perfusion areas and neovascularisation elsewhere. Systemic evaluation findings of positive Mantoux test, QuantiFERON Gold test and right apical pleuroparenchymal fibrosis observed on high-resolution CT of the chest were suggestive of postinfection probable tubercular aetiology. He was treated with oral steroids, antitubercular therapy, intravitreal bevacizumab and anterior retinal cryopexy, leading to resolution of vasculitis and vitreous haemorrhage. Later he developed peripheral retinal flap and posterior retinal breaks at 8-month and 11-month follow-up, respectively, which were managed by barrage laser. He maintained a stable visual acuity of 20/20, N6 for the next 2 years. He then presented with sudden decreased vision in the right eye (20/50, N10). Right eye fundus showed posterior pole retinal detachment with lifting of previously barraged posterior retinal breaks. He underwent vitreoretinal surgery with gas tamponade. Recent 1-month postoperative visit showed successful retinal reattachment and visual recovery of 20/20, N6. Rhegmatogenous retinal detachment is the most common retinological emergency threatening vision, with an incidence of 1 in 10 000 persons per year, corresponding to about 8000 new cases in Germany annually. Without treatment, blindness in the affected eye may result. Selective review of the literature. Rhegmatogenous retinal detachment typically presents with the perception of light flashes, floaters, or a \"dark curtain.\" In most cases, the retinal tear is a consequence of degeneration of the vitreous body. Epidemiologic studies have identified myopia and prior cataract surgery as the main risk factors. Persons in the sixth and seventh decades of life are most commonly affected. Rhegmatogenous retinal detachment is an emergency, and all patients should be seen by an ophthalmologist on the same day that symptoms arise. The treatment consists of scleral buckle, removal of the vitreous body (vitrectomy), or a combination of the two. Anatomical success rates are in the range of 85% to 90%. Vitrectomy is followed by lens opacification in more than 70% of cases. The earlier the patient is seen by an ophthalmologist, the greater the chance that the macula is still attached, so that visual acuity can be preserved. Rhegmatogenous retinal detachment is among the main emergency indications in ophthalmology. In all such cases, an ophthalmologist must be consulted at once. The observed increasing number of severe cases of retinal detachment was the ground of the attempt to state the causes of this phenomenon. Retrospective evaluation of 100 consecutive cases of retinal detachment operated on with conventional methods between September 1997 and October 1998 was performed. The following data were analysed: sex and age of patients, period between the first symptoms and time of diagnosis and surgery. The clinical characteristics of retinal surgery comprise: extent of detachment, macular involving, type and number of breaks, degenerations and PVR. In the majority of cases very severe retinal detachments were observed, including 3-4 quadrants, with large tears or multiple breaks, with PVR B or C. Duration of the detachment ranged from several days in very few cases to several months, on average lasting several weeks. Attachment of the retina was achieved in 80 cases, improvement of the visual acuity in 47. Our data indicate the necessity to improve the early diagnosis of retinal detachment and changes predisposing to its development. To describe a case of postoperative Mycobacterium manitobense endophthalmitis with good visual outcome that is the first report of endophthalmitis by this organism. Clinical and microbiological description of a patient with postoperative endophthalmitis. A 50-year-old chronic alcoholic man was referred to us with decreased vision in his right eye for 4 days. He had undergone cataract surgery with intraocular lens implantation in his right eye a month ago. The presenting vision in his right eye was counting fingers close to face. He was diagnosed as a case of postoperative endophthalmitis. Subsequently, the patient underwent pars plana vitrectomy and vitreous biopsy. The microbiologic investigation of the vitreous biopsy showed poorly stained gram-positive beaded bacilli that were acid fast, and growth in culture was identified as Corynebacterium pseudodiphtheriticum by Vitek 2 bacterial identification system. However, DNA analysis confirmed the organism to be M. manitobense. The patient responded well to repeat interventions with intravitreal antibiotics with a final reported visual acuity of 20/30 at 4 months after first intervention. Although known to be an organism causing soft-tissue infections, M. manitobense can also cause postsurgical endophthalmitis. The diagnosis can be confused with Corynebacterium sp. on smear and culture. Subsequent DNA sequencing of the culture provides definite identification of the organism. To study the clinical features and the pathogenesis of macular hole with and without retina detachment (RD) in high myopic eyes. It was a retrospective series case study. The charts of high myopic patients with macular hole at our hospital from June 2006 to February 2007 were retrospectively reviewed and analyzed. Patients were divided into two groups (the RD group and non-RD group) depending on the presence of RD or not. Their clinical data and optic coherence tomography (OCT) results were further analyzed. SPSS 13.0 was used for the statistic analysis. When comparing the quantitative aspects like age, axial length and refraction, t-test was used. Categorical data, such as sex ratio, occurrence of vitreous traction, posterior staphyloma and retinoschisis were compared by using χ(2) test. Fisher's test was used in comparing eye laterality, incidence of white hole, visual acuity and posterior vitreous detachment (PVD). During this period, there were 43 patients fitting the including criteria. Among them, 36 patents (37 eyes) were in the RD group and 7 patients (7 eyes) in the no-RD group. In the RD group, the average age was 56.1, 24.3% of them (9/37) were male; percentage of left and right eyes was (11/37) and 70.3% (26/37), respectively; average refraction was (-8.9 ± 2.2) D; average axial length was (28.7 ± 2.0) mm. Visual acuity was ≤ 0.05 (72.2%) in 26 eyes and 0.05 - 0.2 (27.8%) in 10 patients. The incidence of complete and non-complete PVD was 89.2% (33/37) and 10.8% (4/37), respectively. White hole presented in 35.1% (3/37) patients. Vitreous traction and retinoschisis presented in 27.0% (10/37) and 35.1% (13/37) patients, respectively. In the non-RD group, the average age was 47.6; 16.7% of them (1/7) were male; left and right eyes were involved in 42.9% (3/7) and 57.1% (4/7), respectively. Average refraction was (-9.0 ± 1.9) D; average axial length was (28.9 ± 1.5) mm. Vision acuity was ≤ 0.05 in 3 patients (42.9%); between 0.05 - 0.2 in 3 eyes (42.9%) and ≥ 0.2 in 1 eye (14.3%). Incidence of complete and non-complete PVD was 85.7% (6/7) and 14.3% (1/7), respectively. White hole was observed in 14.3% (1/7) patients; 42.9% (3/7) patients were accompanied with vitreous traction and 71.4% (5/7) with retinoschisis. B-scan ultrasonography showed posterior staphyloma in all 44 eyes. The results of statistical analysis showed that the gender (χ(2) = 0.008) and eye laterality (χ(2) = 0.449) as well as refraction (t = 0.193), axial length (t = -0.25) and visual acuity (χ(2) = 4.509) of these two groups were similar (P &gt; 0.05). The incidences of vitreous traction (χ(2) = 0.709), white hole (χ(2) = 1.179), PVD (χ(2) = 0.071) and retinoschisis (χ(2) = 3.207) were also similar (P &gt; 0.05). But the age of the non-RD group is significantly younger than the RD group (t = 1.66, P &lt; 0.05). Various pathogenesis may involved in the occurrence of retinal detachment in highly myopic eyes with macular hole. Further study is required to improve our understanding of this entity.\nHere is the question:\nOPHTHALMOLOGY: A 47-year-old man with myopia magna, who underwent cataract surgery 2 years ago, comes to the emergency room reporting a profound and painless loss of vision in his right eye. Which of the following diagnoses can cause this symptomatology?\nHere are the potential choices:\n1. Post-surgical endophthalmitis.\n2. Retinal detachment.\n3. Age-related macular degeneration, wet form.\n4. Posterior vitreous detachment.\nThe correct answer is: 2. Retinal detachment."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The literature review gives the present-day views of the definition, etiology, pathogenesis, diagnosis, and treatment of microscopic colitis (MC). In the present view, MC is an inflammatory bowel disease of unknown etiology, which is characterized by chronic watery diarrhea, no macroscopic signs of large bowel involvement in the presence of specific pathomorphological changes. There are two major forms of MC, which are similar in its clinical picture, yet, heterogeneous in histological criteria: collagenous colitis (CC) and lymphocytic colitis (LC). As of now, the prevalence of MC is about 100 cases per 100,000 population, which is similar with that in other inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. MC generally prevails in women aged over 50 years. The etiology and pathogenesis of MC have not fully investigated. Watery diarrhea is as a predominant pathognomonic symptom in all the patients with MC. The major histological criterion for the diagnosis of CC is subepithelial collagen lining thickening (more than 10 pm) and that for LC is higher intraepithelial lymphocyte counts (more than 20 intraepithelial lymphocytes/100 epitheliocytes). The topical glucocorticosteroid budesonide is currently the only agent, the efficacy of which has been proven in both inducing and maintaining remission in patients with MC in many clinical trials. Microscopic colitis (MC) is an encompassing term for two diseases; collagenous colitis and lymphocytic colitis. The colon appears normal by colonoscopy and a diagnosis is only obtained with a biopsy. The histopathology of collagenous colitis is mainly characterized by a thickening of the subepithelial basement membrane of the colonic mucosa with a band of collagen. Lymphocytic colitis is mainly characterized by an intraepithelial lymphocytosis without the collagen thickening. Even though the two diseases have a distinctive pathology their clinical symptoms are characterized by chronic watery diarrhea without bleeding. Microscopic colitis is thought to cause about 4-13% of all chronic diarrhea but their relative frequency is much higher among older people. The mean annual incidence for collagenous and lymphocytic colitis has been increasing. Steroids are the most effective treatment for microscopic colitis and budesonide is the most studied and effective therapy for MC. The aim of this paper is to give a review of two relatively new diseases which are among the most common cause of chronic diarrhea, especially among older people. Collagenous colitis and lymphocytic colitis are defined by a clinicopathologic syndrome with chronic watery diarrhea, microscopic lesions of colonic biopsies, and normal barium enema and colonoscopy. A histopathological study was performed on multiple colorectal biopsies to compare 12 cases of collagenous colitis (defined by a subepithelial collagen thicker than 10 microns) and 7 cases of lymphocytic colitis (defined by a number of intraepithelial lymphocytes more than 20 per 100 epithelial cells at least in one biopsied site). The study included a semiquantitative analysis of inflammatory infiltrate in the lamina propria, crypts distortion and epithelial detachment. The number of intraepithelial lymphocytes per 100 epithelial cells was determined in surface epithelium and crypts. The subepithelial collagen thickening was studied by computerised morphometry. The intraepithelial lymphocytes, villous atrophy and thickness of the subepithelial collagen were also determined in gastric and duodenal biopsies. In collagenous colitis, the subepithelial collagenous thickness ranged from 10 to 40 microns in the colon (median 20.99 microns). In 4 cases of collagenous colitis, no thickening of the collagen plate was seen in the rectum. We found constant epithelial detachment and mucosal distortion. In lymphocytic colitis, the thickness of the subepithelial collagen ranged from 6 to 10 microns in 4 cases and was less than 6 microns in 3 cases (median 6.24 microns). The median number of intraepithelial lymphocytes in surface epithelium was 22.35 (range 18.2 to 40) in lymphocytic colitis versus 12.22 (range 4.6 to 24.4) in collagenous colitis. In conclusion, we observed an overlap of both the collagenous plate thickness and the number of intraepithelial lymphocytes in collagenous colitis and lymphocytic colitis. This result favours a unified histogenesis for these two entities. Microscopic colitis (MC) is a chronic inflammatory process observed in colon biopsies of patients with chronic aqueous diarrhea. It is called microscopic because diagnosis is determined by histological studies since the microscopic characteristics of the colon endoscopy are normal. Two patterns exist: Lymphocytic Microscopic Colitis and Collagenous Microscopic Colitis. Etiology is unknown, and the proposed pathogenic mechanisms indicate an immunological phenomenon. Based on this, the authors of this study hypothesize that lymphocytic infiltration of the lamina propria could be related to cytotoxic lymphocytes CD8 as causative agents of colon tissue damage. Prove hypothesis of immunological pathogenesis of MC. APPARATUS AND METHODS: Thirty eight (38) patients with diagnosed MC were recruited for the last four years in the Pathology Laboratory at Ricardo Palma University. Twenty two (22) colon biopsies with the most severe histological lesions were selected. These biopsies were obtained from 17 patients: 5 patients had 2 biopsies in 2 colonoscopy sessions. Biopsies were fixed in neutral formaldehyde, processed through the paraffin inclusion method, and stained with hematoxiline-eosine and Masson trichromic to distinguish collagenous tissue. Immunohistochemistry was conducted in 4- or 5-micron-thick histological sections processed through the immunoperoxidase method. Nineteen (19) biopsies corresponded to Lymphocytic MC and 3 to Collagenous MC. Lymphocytic MC showed intraepithelial lymphocytosis, dystrophic epithelial damage in the areas of lymphocytic infiltration, lamina propria inflammation with lymphocytes and plasma cells, and normal basement membrane. Collagenous MC showed thickened basement membrane due to the presence of a collagenous band, mild to moderate intraepithelial lymphocytosis, vacuolization,and frequent detachment of protective epithelium. Twenty two (22) biopsies were positive in the immunohistochemical studies. Collagenous colitis and lymphocytic colitis are the two major conditions characterized by chronic watery diarrhoea, without endoscopic or radiological lesions, but with histological abnormalities and therefore considered as \"microscopic colitis\". The histology of colonic biopsies shows inflammation of the mucosa, and either thickening of the subepithelial collagen band or an increase of lymphocytes in the surface epithelium. Different variant forms have been reported under separate names. These are probably not specific entities. The incidence of microscopic colitis is slightly less than the incidence of chronic idiopathic inflammatory bowel diseases (IBD). Microscopic colitis and IBD are clearly different entities. The relation between both entities is weak but double. Biopsy samples from patients with IBD may mimic the features of lymphocytic or collagenous colitis, both in the initial onset and during follow-up. In the large majority of these cases, endoscopy shows or has shown mucosal lesions. In rare cases, however, a double diagnosis was made. Certain patients, usually of older age, presented first with a microscopic, usually collagenous colitis and developed subsequently genuine ulcerative colitis. A typical symptom of microscopic colitis (MC) is chronic watery diarrhea with normal endoscopic findings and characteristic inflammatory changes in histopathology. Treatment of the disease is mainly empiric. MC has two main subtypes: lymphocytic colitis and collagenous colitis. There are also untypical histopathological forms of MC: MC with giant cells, MC not otherwise specified (NOS) and cryptal lymphocytic coloproctitis. Some other histopathological changes in MC have been observed, especially Paneth cell hyperplasia or epithelial degeneration. Eosinophilic colitis, acute colitis, amyloidosis, ulcerative colitis and Crohn's disease should be taken into consideration in differential diagnosis. The most reliable biopsy material for histopathological examination are samples obtained from transverse colon. Some studies proved that treatment of MC makes it possible to reduce not only clinical, but also histopathological, manifestations. Diagnosis Colonoscopic appearances are normal or near normal. As the changes are often patchy, an examination limited to the rectum may miss cases of microscopic colitis, and so a full colonoscopy is necessary. Multiple colonic biopsies are taken in order to make the diagnosis. Histological features of colonic biopsies indicating microscopic colitis are: greater than 20 intraepithelial lymphocytes per 100 epithelial cells and, additionally, 10-20 μm of a thickened subepithelial collagen band in collagenous colitis. Inflammation of the lamina propria, with mainly mononuclear cells, may be observed in collagenous colitis. The simple clinical colitis activity index was created in 1998 and is used to assess the severity of symptoms. Endoscopic The best test for diagnosis of ulcerative colitis remains endoscopy, which is examination of the internal surface of the bowel using a flexible camera. Initially, a flexible sigmoidoscopy may be completed to establish the diagnosis. The physician may elect to limit the extent of the initial exam if severe colitis is encountered to minimize the risk of perforation of the colon. However, a complete colonoscopy with entry into the terminal ileum should be performed to rule out Crohn's disease, and assess extent and severity of disease. Endoscopic findings in ulcerative colitis include: erythema (redness of the mucosa), friability of the mucosa, superficial ulceration, and loss of the vascular appearance of the colon. When present, ulcerations may be confluent. Pseudopolyps may be observed. There are controversies about taking routine mucosal biopsy when the gross colonoscopic finding is normal. This study was conducted to determine the frequency of clinically important histological abnormalities, prospectively, in chronic diarrhea patients with grossly normal or nonspecific colonoscopic findings. One hundred and eighteen patients suffering from nonbloody diarrhea with average frequency of more than two times a day for more than 4 weeks were included. Multiple biopsies (cecum, ascending colon, mid-transverse colon, descending colon, sigmoid colon and rectum) were taken during colonoscopic examinations and each biopsy specimen was reviewed by one pathologist after H&amp;E and Masson-trichrome staining. Clinically significant abnormalities (2 collagenous colitis, 1 lymphocytic colitis, 1 eosinophilic enterocolitis, 1 ulcerative colitis and 4 melanosis coli) were observed in 9 patients (7.6%). Sixteen cases (13.6%) of borderline histological abnormalities were observed (8 cases of possible collagenous colitis and 8 cases showing some features of lymphocytic colitis). Ninety two cases (78.8%) showed nonspecific inflammation only. Clinically important histological lesions can exist in significant percentage in spite of normal or nonspecific colonoscopic findings, which can justify routine mucosal biopsy in the evaluation of chronic diarrhea patients. The clinical significance of borderline histological abnormalities needs to be determined by careful follow-up studies. Microscopic colitis (MC) is a clinical syndrome of severe watery diarrhea with few or no endoscopic abnormalities. The incidence of MC is reported similar to that of other inflammatory bowel diseases. The need for histological confirmation of MC frequently guides reimbursement health policies. With the advent of high-definition (HD) coloscopes, the incidence of reporting distinct endoscopic findings in MC has risen. This has the potential to improve timely diagnosis and cost-effective MC management and diminish the workload and costs of busy modern endoscopy units. Publications on distinct endoscopic findings in MC available until March 31st, 2017 were searched systematically (electronic and manual) in PubMed database. The following search terms/descriptors were used: collagenous colitis (CC) OR lymphocytic colitis (LC) AND endoscopy, colonoscopy, findings, macroscopic, erythema, mucosa, vasculature, scars, lacerations, fractures. An additional search for MC AND perforation was made. Eighty (n=80) articles, predominantly single case reports (n=49), were found. Overall, 1582 (1159F; 61.6±14.1 years) patients (pts) with MC and endoscopic findings were reported. The majority of articles (n=62) were on CC (pts 756; 77.5% females). We identified 16 papers comprising 779 pts (69.2% females) with LC and 7 articles describing 47 pts (72.3% females) diagnosed as MC. The youngest patient was 10 and the oldest a 97-year-old. Aside diarrhea, symptoms included abdominal pain, weight loss, bloating, flatulence, edema and others. In the study group we found 615 (38.8%) persons with macroscopic lesions in gut. Isolated linear ulcerations were identified in 7 pts (1.1%) while non-ulcerous lesions i.e. pseudomembranes, a variable degree of vasculature pruning &amp; dwindling, mucosal lacerations and abnormalities such as erythema/edema/nodularity, or surface textural alteration in 608 pts (98.1%). The location of endoscopic findings was not reported in 27 articles. The distinct endoscopic findings were described in the left (descending, sigmoid, rectum - 10/21/11 studies), right (cecum, ascending - 7/7 studies), transverse colon (n=12), as well as duodenum (n=4), and terminal ileum (n=2). In 17 (1.1%) pts colonic perforation occurred. Endoscopic findings are recognized with increased frequency in pts with MC. This could improve MC diagnosis by prompting a more extensive biopsy protocol in such cases and an earlier initiation of treatment. Procedure-related perforation has been reported in this group; therefore, cautious air insufflation is advisable when endoscopic findings are recognised. Pathology Microscopic colitis is characterized by an increase in inflammatory cells, particularly lymphocytes, in colonic biopsies with an otherwise normal appearance and architecture of the colon. Inflammatory cells are increased both in the surface epithelium (\"intraepithelial lymphocytes\") and in the lamina propria. The key feature is more than 20 intra-epithelial lymphocytes per 100 epithelial cells. These are the principal features of lymphocytic colitis. An additional distinguishing feature of collagenous colitis is a thickened subepithelial collagen layer, which may be up to 30 micrometres thick, that occurs in addition to the features found in lymphocytic colitis. The fact that the two types of microscopic colitis share many features including epidemiology, risk factors and, response to therapy has led to the suggestion that they are actually subtypes of the same disease. Lymphocytic colitis is a subtype of microscopic colitis, a condition characterized by chronic non-bloody watery diarrhea. Causes No definite cause has been determined. The peak incidence of lymphocytic colitis is in persons over age 50; the disease affects women and men equally. Some reports have implicated long-term usage of NSAIDs, proton pump inhibitors, and selective serotonin reuptake inhibitors, and other drugs. Associations with other autoimmune disorders suggests that overactive immune responses occur. Diagnosis The colonoscopy is normal but histology of the mucosal biopsy reveals an accumulation of lymphocytes in the colonic epithelium and connective tissue (lamina propria). Collagenous colitis shares this feature but additionally shows a distinctive thickening of the subepithelial collagen table. Ulcerative colitis is usually continuous from the rectum, with the rectum almost universally being involved. Perianal disease is rare. The degree of involvement endoscopically ranges from proctitis (rectal inflammation) to left sided colitis (extending to descending colon), to extensive colitis (extending proximal to descending colon). Histologic Biopsies of the mucosa are taken during endoscopy to confirm the diagnosis of UC and differentiate it from Crohn's disease, which is managed differently clinically. Histologic findings in ulcerative colitis includes: distortion of crypt architecture, crypt abscesses, and inflammatory cells in the mucosa (lymphocytes, plasma cells, and granulocytes). Unlike the transmural inflammation seen in Crohn's disease, the inflammation of ulcerative colitis is limited to the mucosa. An important investigation in the assessment of colitis is biopsy. A very small piece of tissue (usually about 2mm) is removed from the bowel mucosa during endoscopy and examined under the microscope by a histopathologist. It can provide important information regarding the cause of the disease and the extent of bowel damage. Types There are many types of colitis. They are usually classified by the cause. Types of colitis include: Autoimmune Inflammatory bowel disease (IBD) – a group of chronic colitides. Ulcerative colitis (UC) – a chronic colitis that affects the large intestine. Crohn's disease (CD) – another type of IBD that often leads to colitis. Unknown Microscopic colitis – a colitis diagnosed by microscopic examination of colonic tissue; macroscopically (\"to the eye\") it appears normal. Lymphocytic colitis Collagenous colitis Treatment-caused Diversion colitis Chemical colitis Chemotherapy-induced colitis Radiation colitis Checkpoint inhibitor induced colitis Types There are four types of SCAD, based on endoscopic appearance. Pattern A is characterized by involvement of crescentic folds and is the most common type of SCAD (52%). Pattern B has an appearance similar to mild-to moderate ulcerative colitis (30.40%), whereas pattern C appears similar to Crohn's disease (10.90%). Pattern D is the least common, and appears similar to severe ulcerative colitis (6.50%). Diagnosis SCAD is diagnosed via colonoscopy, often incidentally during examination for unrelated concerns. Colonoscopy shows erythema of the colonic mucosa, which may be characterized by friability and exudate. The descending and sigmoid colon are typically involved. Biopsies of the affected area and the unaffected rectum confirm the diagnosis. Biopsies of SCAD show evidence of chronic inflammation. Rectal biopsies show normal mucosa. Microscopic colitis refers to two related medical conditions which cause diarrhea: collagenous colitis and lymphocytic colitis. Both conditions are characterized by the presence of chronic non-bloody watery diarrhea, normal appearances on colonoscopy and characteristic histopathology findings of inflammatory cells. Signs and symptoms The main symptom is persistent non-bloody watery diarrhea, which may be profuse. People may also experience abdominal pain, fecal incontinence, and unintentional weight loss. Microscopic colitis is the diagnosis in around 10% of cases investigated for chronic non-bloody diarrhea. Microscopic colitis has emerged as a major cause of chronic watery non-bloody diarrhoea, particularly in elderly females. The term is used as an umbrella term to categorize a subgroup of colitides with distinct clinicopathological phenotypes and no significant endoscopic abnormalities. Lymphocytic colitis is defined by an increased number of surface intraepithelial lymphocytes, and collagenous colitis by a thickened collagen band underneath the surface epithelium. There is increased inflammation in the lamina propria, but only little or no crypt architectural distortion. Incomplete and variant forms showing less characteristic features have been reported under different names. The differential diagnosis mainly includes resolving infectious colitis and changes related to the intake of drugs such as non-steroidal anti-inflammatory drugs. Substantial clinical and histological overlap between lymphocytic and collagenous colitis has been described, raising the suspicion that the conditions are two histological manifestations of the same entity, possibly representing different manifestations during the disease course or different stages of disease development. In this review, we provide a practical approach for pathologists, with a focus on diagnostic criteria and differential diagnosis, and discuss recent insights into the pathogenesis of disease and the relationship with classic chronic inflammatory bowel disease, i.e. Crohn's disease and ulcerative colitis.  The clinical presentation of ulcerative colitis depends on the extent of the disease process. Up to 15% of individuals may have severe disease upon initial onset of symptoms. A substantial proportion (up to 45%) of people with a history of UC without any ongoing symptoms (clinical remission) have objective evidence of ongoing inflammation. Ulcerative colitis is associated with a generalized inflammatory process that can affect many parts of the body. Sometimes, these associated extra-intestinal symptoms are the initial signs of the disease. Extent of involvement In contrast to Crohn's disease, which can affect areas of the gastrointestinal tract outside of the colon, ulcerative colitis is usually confined to the colon. Inflammation in ulcerative colitis is usually continuous, typically involving the rectum, with involvement extending proximally (to sigmoid colon, ascending colon, etc). In contrast, inflammation with Crohn's disease is often patchy, with so-called \"skip lesions.\" No disease specific markers are currently known in the blood, enabling the reliable separation of Crohn's disease and ulcerative colitis patients. The way doctors can tell the difference between Crohn's disease and UC is the location and nature of the inflammatory changes. Crohn's can affect any part of the gastrointestinal tract, from mouth to anus (skip lesions), although a majority of the cases start in the terminal ileum. Ulcerative colitis, in contrast, is restricted to the colon and the rectum. Microscopically, ulcerative colitis is restricted to the mucosa (epithelial lining of the gut), while Crohn's disease affects the full thickness of the bowel wall (\"transmural lesions\"). Lastly, Crohn's disease and ulcerative colitis present with extra-intestinal manifestations (such as liver problems, arthritis, skin manifestations and eye problems) in different proportions. Microscopic colitis is a clinicopathological entity which, in addition to typical symptoms such as watery diarrhea, is characterized by its specific histopathology. Since colonoscopy yields normal findings, microscopic colitis belongs in a histological domain. The term encompasses two forms: lymphocytic and collagenous colitis. Histologically, lymphocytic colitis shows an increase in intraepithelial lymphocytes of more than 20 lymphocytes per 100 surface colonocytes, while collagenous colitis is characterized by a thickened subepithelial collagen layer of more than 10 µm. Specific stains help in the quantification of both. Since microscopic colitis does not always affect the entire colon and the number of intraepithelial lymphocytes varies physiologically, obtaining stepwise biopsies of the colon (with information on location where possible) is recommended. A thickened collagen layer is relatively specific for collagenous colitis, whereas intraepithelial lymphocytosis is also found in other diseases. Therefore, to make a correct diagnosis, it is important to correlate histological findings with clinical symptoms, including the main symptom of watery diarrhea. Collagenous colitis is an inflammatory bowel disease affecting the colon specifically with peak incidence in the 5th decade of life, affecting women more than men. Its clinical presentation involves watery diarrhea in the absence of rectal bleeding. It is often classified under the umbrella entity microscopic colitis, that it shares with a related condition, lymphocytic colitis. Signs and symptoms Microscopic colitis causes chronic watery diarrhea with greater than 10 bowel movements per day. Some patients report nocturnal diarrhea, abdominal pain, urgency, fecal incontinence, fatigue, dehydration and weight loss. Patients report a significantly diminished quality of life. Causes The cause of collagenous colitis is unknown. Collagenous colitis is a relatively rare disorder presenting mainly in middle-aged women as watery diarrhea. Endoscopic and radiographic studies of the colon are usually normal, and diagnosis must be made by biopsy. The characteristic biopsy findings are a combination of increased mucosal inflammation (collagenous colitis) as well as subepithelial collagenous thickening. The mucosal inflammatory changes include increased lamina propria plasma cells, prominent intraepithelial lymphocytes, and in some cases, numerous eosinophils. The collagenous thickening has qualitative as well as quantitative differences from normal, and may be highlighted by Masson trichrome stains. Simply quantitating the thickness of a subepithelial collagen layer is neither adequate nor necessary for the diagnosis of collagenous colitis. Major problems in diagnosing collagenous colitis arise from focusing solely on the subepithelial region without attention to inflammatory changes. For example, tangential sectioning of normal colon results in an artifactually thickened basement membrane, and such cases have been wrongly interpreted as collagenous colitis. If biopsies lack the characteristic inflammatory pattern, a tangentially cut thick basement membrane should be ignored. The key to correct diagnosis of collagenous colitis is analyzing the summation of various inflammatory changes plus subepithelial collagenization, rather than focusing on any single feature in isolation. Collagenous colitis is an inflammatory mucosal disorder of the colon with distinctive histopathological features, including a thickened subepithelial collagen layer. The clinical course is usually benign, but serious complications, including death, may occur. In the present report, a 69-year-old woman with watery diarrhea and collagenous colitis developed bloody diarrhea that was refractory to treatment medications, including corticosteroids and azathioprine. Endoscopic and histopathological studies showed a focal neutrophilic inflammatory process that progressed to a diffuse and extensive form of colitis, eventually requiring total proctocolectomy. Careful histological review of the resected colon showed no evidence of persistent collagenous colitis. These findings suggest an important need for continued long-term follow-up of patients with collagenous colitis because superimposed and serious colonic complications may occur, including a severe and extensive pancolitis refractory to medications and necessitating total proctocolectomy. Various etiologies and diseases may be related to erosions and/or small ulcers without gross inflammatory changes in the surrounding mucosa found in the colon and terminal ileum during colonoscopy. However, studies on follow-up of these lesions are rare. Thus, we investigated the clinical significance of these lesions and their characteristics helpful for differential diagnosis. We reviewed the data of 183 patients with colonoscopically observed erosive or small ulcerative lesions (&lt;2 cm), and analyzed them according to the location, number, and size of lesions, histopathologic findings, chief complaints, laboratory findings, changes of symptoms, and changes in lesions during 4-12 week follow-up period. Histopathologic findings of these lesions included acute nonspecific inflammation, chronic nonspecific inflammation, Crohn's disease, tuberculous colitis, ischemic colitis, Behcet's disease, cytomegalovirus infection, eosinophilic colitis, ulcerative colitis or pseudomembranous colitis, but most of them were nonspecific (84%). In patients with nonspecific inflammation, histopathologic findings, symptoms, location and multiplicity of the lesions were not prognostic factors for the persistency of symptoms and lesions during follow-up period. Two patients with acute inflammation, who showed no improvement in symptoms and lesions, were later diagnosed as Crohn's disease. Erosive or small ulcerative lesions without macroscopic inflammatory changes in the surrounding mucosa during colonoscopy, are mainly nonspecific. However, careful follow-up is required when the symptoms and/or lesions are not improved. To investigate the prevalence of microscopic colitis among patients presenting with chronic watery diarrhea. Colonic biopsies from 400 patients presenting with chronic watery diarrhea and other symptoms pertaining to lower gastrointestinal tract were studied. After a detailed clinical history and thorough physical examination full length colonoscopy was done using flexible colonoscope. Colonic biopsies were taken from abnormal and normal areas. Three to five micron thick sections were cut and stained with hematoxylin and eosin and Masson's trichrome stain to highlight sub epithelial collagen. Fifteen out of 400 (3.7%) colonic biopsies from patients presenting with chronic diarrhea had evidence of microscopic colitis. Five out of fifteen biopsies (33%) were diagnosed as collagenous colitis, 10 biopsies (67%) had evidence of lymphocytic colitis; 14/400(3.5%) histologically normal biopsies were taken as controls to compare various demographic and risk factors. Ten out of 15 patients (67%) were clinically diagnosed as irritable bowel syndrome. In the remaining five an infective etiology was suspected. On colonoscopy12/15 (80%) had no abnormality and 3/15 (20%) had mild hyperemia. A possibility of microscopic colitis should be considered while examining colonoscopic biopsy of a patient with chronic watery diarrhea and normal colonoscopy to avoid the misdiagnosis that may affect the treatment of patients.\nHere is the question:\nPATHOLOGICAL ANATOMY: A 59-year-old woman presenting with chronic watery diarrhea of 4 months' evolution. In the endoscopy, the mucosa did not show relevant aspects. In particular, no ulcers or friable areas were observed. A biopsy of the transverse colon was performed. Histopathology revealed a thickened area below the superficial lining epithelium, which was more evident by Masson's trichrome technique and involved epithelial atrophy and denudation. There was also a clear increase in intraepithelial lymphocyte density. The diagnosis of the intestinal lesion is?\nHere are the potential choices:\n1. Chronic ulcerative colitis.\n2. Pseudomembranous colitis.\n3. Collagenous colitis.\n4. Fibrosing Crohn's disease.\nThe correct answer is: ",
        "gold_answer": "3 Collagenous colitis.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The literature review gives the present-day views of the definition, etiology, pathogenesis, diagnosis, and treatment of microscopic colitis (MC). In the present view, MC is an inflammatory bowel disease of unknown etiology, which is characterized by chronic watery diarrhea, no macroscopic signs of large bowel involvement in the presence of specific pathomorphological changes. There are two major forms of MC, which are similar in its clinical picture, yet, heterogeneous in histological criteria: collagenous colitis (CC) and lymphocytic colitis (LC). As of now, the prevalence of MC is about 100 cases per 100,000 population, which is similar with that in other inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. MC generally prevails in women aged over 50 years. The etiology and pathogenesis of MC have not fully investigated. Watery diarrhea is as a predominant pathognomonic symptom in all the patients with MC. The major histological criterion for the diagnosis of CC is subepithelial collagen lining thickening (more than 10 pm) and that for LC is higher intraepithelial lymphocyte counts (more than 20 intraepithelial lymphocytes/100 epitheliocytes). The topical glucocorticosteroid budesonide is currently the only agent, the efficacy of which has been proven in both inducing and maintaining remission in patients with MC in many clinical trials. Microscopic colitis (MC) is an encompassing term for two diseases; collagenous colitis and lymphocytic colitis. The colon appears normal by colonoscopy and a diagnosis is only obtained with a biopsy. The histopathology of collagenous colitis is mainly characterized by a thickening of the subepithelial basement membrane of the colonic mucosa with a band of collagen. Lymphocytic colitis is mainly characterized by an intraepithelial lymphocytosis without the collagen thickening. Even though the two diseases have a distinctive pathology their clinical symptoms are characterized by chronic watery diarrhea without bleeding. Microscopic colitis is thought to cause about 4-13% of all chronic diarrhea but their relative frequency is much higher among older people. The mean annual incidence for collagenous and lymphocytic colitis has been increasing. Steroids are the most effective treatment for microscopic colitis and budesonide is the most studied and effective therapy for MC. The aim of this paper is to give a review of two relatively new diseases which are among the most common cause of chronic diarrhea, especially among older people. Collagenous colitis and lymphocytic colitis are defined by a clinicopathologic syndrome with chronic watery diarrhea, microscopic lesions of colonic biopsies, and normal barium enema and colonoscopy. A histopathological study was performed on multiple colorectal biopsies to compare 12 cases of collagenous colitis (defined by a subepithelial collagen thicker than 10 microns) and 7 cases of lymphocytic colitis (defined by a number of intraepithelial lymphocytes more than 20 per 100 epithelial cells at least in one biopsied site). The study included a semiquantitative analysis of inflammatory infiltrate in the lamina propria, crypts distortion and epithelial detachment. The number of intraepithelial lymphocytes per 100 epithelial cells was determined in surface epithelium and crypts. The subepithelial collagen thickening was studied by computerised morphometry. The intraepithelial lymphocytes, villous atrophy and thickness of the subepithelial collagen were also determined in gastric and duodenal biopsies. In collagenous colitis, the subepithelial collagenous thickness ranged from 10 to 40 microns in the colon (median 20.99 microns). In 4 cases of collagenous colitis, no thickening of the collagen plate was seen in the rectum. We found constant epithelial detachment and mucosal distortion. In lymphocytic colitis, the thickness of the subepithelial collagen ranged from 6 to 10 microns in 4 cases and was less than 6 microns in 3 cases (median 6.24 microns). The median number of intraepithelial lymphocytes in surface epithelium was 22.35 (range 18.2 to 40) in lymphocytic colitis versus 12.22 (range 4.6 to 24.4) in collagenous colitis. In conclusion, we observed an overlap of both the collagenous plate thickness and the number of intraepithelial lymphocytes in collagenous colitis and lymphocytic colitis. This result favours a unified histogenesis for these two entities. Microscopic colitis (MC) is a chronic inflammatory process observed in colon biopsies of patients with chronic aqueous diarrhea. It is called microscopic because diagnosis is determined by histological studies since the microscopic characteristics of the colon endoscopy are normal. Two patterns exist: Lymphocytic Microscopic Colitis and Collagenous Microscopic Colitis. Etiology is unknown, and the proposed pathogenic mechanisms indicate an immunological phenomenon. Based on this, the authors of this study hypothesize that lymphocytic infiltration of the lamina propria could be related to cytotoxic lymphocytes CD8 as causative agents of colon tissue damage. Prove hypothesis of immunological pathogenesis of MC. APPARATUS AND METHODS: Thirty eight (38) patients with diagnosed MC were recruited for the last four years in the Pathology Laboratory at Ricardo Palma University. Twenty two (22) colon biopsies with the most severe histological lesions were selected. These biopsies were obtained from 17 patients: 5 patients had 2 biopsies in 2 colonoscopy sessions. Biopsies were fixed in neutral formaldehyde, processed through the paraffin inclusion method, and stained with hematoxiline-eosine and Masson trichromic to distinguish collagenous tissue. Immunohistochemistry was conducted in 4- or 5-micron-thick histological sections processed through the immunoperoxidase method. Nineteen (19) biopsies corresponded to Lymphocytic MC and 3 to Collagenous MC. Lymphocytic MC showed intraepithelial lymphocytosis, dystrophic epithelial damage in the areas of lymphocytic infiltration, lamina propria inflammation with lymphocytes and plasma cells, and normal basement membrane. Collagenous MC showed thickened basement membrane due to the presence of a collagenous band, mild to moderate intraepithelial lymphocytosis, vacuolization,and frequent detachment of protective epithelium. Twenty two (22) biopsies were positive in the immunohistochemical studies. Collagenous colitis and lymphocytic colitis are the two major conditions characterized by chronic watery diarrhoea, without endoscopic or radiological lesions, but with histological abnormalities and therefore considered as \"microscopic colitis\". The histology of colonic biopsies shows inflammation of the mucosa, and either thickening of the subepithelial collagen band or an increase of lymphocytes in the surface epithelium. Different variant forms have been reported under separate names. These are probably not specific entities. The incidence of microscopic colitis is slightly less than the incidence of chronic idiopathic inflammatory bowel diseases (IBD). Microscopic colitis and IBD are clearly different entities. The relation between both entities is weak but double. Biopsy samples from patients with IBD may mimic the features of lymphocytic or collagenous colitis, both in the initial onset and during follow-up. In the large majority of these cases, endoscopy shows or has shown mucosal lesions. In rare cases, however, a double diagnosis was made. Certain patients, usually of older age, presented first with a microscopic, usually collagenous colitis and developed subsequently genuine ulcerative colitis. A typical symptom of microscopic colitis (MC) is chronic watery diarrhea with normal endoscopic findings and characteristic inflammatory changes in histopathology. Treatment of the disease is mainly empiric. MC has two main subtypes: lymphocytic colitis and collagenous colitis. There are also untypical histopathological forms of MC: MC with giant cells, MC not otherwise specified (NOS) and cryptal lymphocytic coloproctitis. Some other histopathological changes in MC have been observed, especially Paneth cell hyperplasia or epithelial degeneration. Eosinophilic colitis, acute colitis, amyloidosis, ulcerative colitis and Crohn's disease should be taken into consideration in differential diagnosis. The most reliable biopsy material for histopathological examination are samples obtained from transverse colon. Some studies proved that treatment of MC makes it possible to reduce not only clinical, but also histopathological, manifestations. Diagnosis Colonoscopic appearances are normal or near normal. As the changes are often patchy, an examination limited to the rectum may miss cases of microscopic colitis, and so a full colonoscopy is necessary. Multiple colonic biopsies are taken in order to make the diagnosis. Histological features of colonic biopsies indicating microscopic colitis are: greater than 20 intraepithelial lymphocytes per 100 epithelial cells and, additionally, 10-20 μm of a thickened subepithelial collagen band in collagenous colitis. Inflammation of the lamina propria, with mainly mononuclear cells, may be observed in collagenous colitis. The simple clinical colitis activity index was created in 1998 and is used to assess the severity of symptoms. Endoscopic The best test for diagnosis of ulcerative colitis remains endoscopy, which is examination of the internal surface of the bowel using a flexible camera. Initially, a flexible sigmoidoscopy may be completed to establish the diagnosis. The physician may elect to limit the extent of the initial exam if severe colitis is encountered to minimize the risk of perforation of the colon. However, a complete colonoscopy with entry into the terminal ileum should be performed to rule out Crohn's disease, and assess extent and severity of disease. Endoscopic findings in ulcerative colitis include: erythema (redness of the mucosa), friability of the mucosa, superficial ulceration, and loss of the vascular appearance of the colon. When present, ulcerations may be confluent. Pseudopolyps may be observed. There are controversies about taking routine mucosal biopsy when the gross colonoscopic finding is normal. This study was conducted to determine the frequency of clinically important histological abnormalities, prospectively, in chronic diarrhea patients with grossly normal or nonspecific colonoscopic findings. One hundred and eighteen patients suffering from nonbloody diarrhea with average frequency of more than two times a day for more than 4 weeks were included. Multiple biopsies (cecum, ascending colon, mid-transverse colon, descending colon, sigmoid colon and rectum) were taken during colonoscopic examinations and each biopsy specimen was reviewed by one pathologist after H&amp;E and Masson-trichrome staining. Clinically significant abnormalities (2 collagenous colitis, 1 lymphocytic colitis, 1 eosinophilic enterocolitis, 1 ulcerative colitis and 4 melanosis coli) were observed in 9 patients (7.6%). Sixteen cases (13.6%) of borderline histological abnormalities were observed (8 cases of possible collagenous colitis and 8 cases showing some features of lymphocytic colitis). Ninety two cases (78.8%) showed nonspecific inflammation only. Clinically important histological lesions can exist in significant percentage in spite of normal or nonspecific colonoscopic findings, which can justify routine mucosal biopsy in the evaluation of chronic diarrhea patients. The clinical significance of borderline histological abnormalities needs to be determined by careful follow-up studies. Microscopic colitis (MC) is a clinical syndrome of severe watery diarrhea with few or no endoscopic abnormalities. The incidence of MC is reported similar to that of other inflammatory bowel diseases. The need for histological confirmation of MC frequently guides reimbursement health policies. With the advent of high-definition (HD) coloscopes, the incidence of reporting distinct endoscopic findings in MC has risen. This has the potential to improve timely diagnosis and cost-effective MC management and diminish the workload and costs of busy modern endoscopy units. Publications on distinct endoscopic findings in MC available until March 31st, 2017 were searched systematically (electronic and manual) in PubMed database. The following search terms/descriptors were used: collagenous colitis (CC) OR lymphocytic colitis (LC) AND endoscopy, colonoscopy, findings, macroscopic, erythema, mucosa, vasculature, scars, lacerations, fractures. An additional search for MC AND perforation was made. Eighty (n=80) articles, predominantly single case reports (n=49), were found. Overall, 1582 (1159F; 61.6±14.1 years) patients (pts) with MC and endoscopic findings were reported. The majority of articles (n=62) were on CC (pts 756; 77.5% females). We identified 16 papers comprising 779 pts (69.2% females) with LC and 7 articles describing 47 pts (72.3% females) diagnosed as MC. The youngest patient was 10 and the oldest a 97-year-old. Aside diarrhea, symptoms included abdominal pain, weight loss, bloating, flatulence, edema and others. In the study group we found 615 (38.8%) persons with macroscopic lesions in gut. Isolated linear ulcerations were identified in 7 pts (1.1%) while non-ulcerous lesions i.e. pseudomembranes, a variable degree of vasculature pruning &amp; dwindling, mucosal lacerations and abnormalities such as erythema/edema/nodularity, or surface textural alteration in 608 pts (98.1%). The location of endoscopic findings was not reported in 27 articles. The distinct endoscopic findings were described in the left (descending, sigmoid, rectum - 10/21/11 studies), right (cecum, ascending - 7/7 studies), transverse colon (n=12), as well as duodenum (n=4), and terminal ileum (n=2). In 17 (1.1%) pts colonic perforation occurred. Endoscopic findings are recognized with increased frequency in pts with MC. This could improve MC diagnosis by prompting a more extensive biopsy protocol in such cases and an earlier initiation of treatment. Procedure-related perforation has been reported in this group; therefore, cautious air insufflation is advisable when endoscopic findings are recognised. Pathology Microscopic colitis is characterized by an increase in inflammatory cells, particularly lymphocytes, in colonic biopsies with an otherwise normal appearance and architecture of the colon. Inflammatory cells are increased both in the surface epithelium (\"intraepithelial lymphocytes\") and in the lamina propria. The key feature is more than 20 intra-epithelial lymphocytes per 100 epithelial cells. These are the principal features of lymphocytic colitis. An additional distinguishing feature of collagenous colitis is a thickened subepithelial collagen layer, which may be up to 30 micrometres thick, that occurs in addition to the features found in lymphocytic colitis. The fact that the two types of microscopic colitis share many features including epidemiology, risk factors and, response to therapy has led to the suggestion that they are actually subtypes of the same disease. Lymphocytic colitis is a subtype of microscopic colitis, a condition characterized by chronic non-bloody watery diarrhea. Causes No definite cause has been determined. The peak incidence of lymphocytic colitis is in persons over age 50; the disease affects women and men equally. Some reports have implicated long-term usage of NSAIDs, proton pump inhibitors, and selective serotonin reuptake inhibitors, and other drugs. Associations with other autoimmune disorders suggests that overactive immune responses occur. Diagnosis The colonoscopy is normal but histology of the mucosal biopsy reveals an accumulation of lymphocytes in the colonic epithelium and connective tissue (lamina propria). Collagenous colitis shares this feature but additionally shows a distinctive thickening of the subepithelial collagen table. Ulcerative colitis is usually continuous from the rectum, with the rectum almost universally being involved. Perianal disease is rare. The degree of involvement endoscopically ranges from proctitis (rectal inflammation) to left sided colitis (extending to descending colon), to extensive colitis (extending proximal to descending colon). Histologic Biopsies of the mucosa are taken during endoscopy to confirm the diagnosis of UC and differentiate it from Crohn's disease, which is managed differently clinically. Histologic findings in ulcerative colitis includes: distortion of crypt architecture, crypt abscesses, and inflammatory cells in the mucosa (lymphocytes, plasma cells, and granulocytes). Unlike the transmural inflammation seen in Crohn's disease, the inflammation of ulcerative colitis is limited to the mucosa. An important investigation in the assessment of colitis is biopsy. A very small piece of tissue (usually about 2mm) is removed from the bowel mucosa during endoscopy and examined under the microscope by a histopathologist. It can provide important information regarding the cause of the disease and the extent of bowel damage. Types There are many types of colitis. They are usually classified by the cause. Types of colitis include: Autoimmune Inflammatory bowel disease (IBD) – a group of chronic colitides. Ulcerative colitis (UC) – a chronic colitis that affects the large intestine. Crohn's disease (CD) – another type of IBD that often leads to colitis. Unknown Microscopic colitis – a colitis diagnosed by microscopic examination of colonic tissue; macroscopically (\"to the eye\") it appears normal. Lymphocytic colitis Collagenous colitis Treatment-caused Diversion colitis Chemical colitis Chemotherapy-induced colitis Radiation colitis Checkpoint inhibitor induced colitis Types There are four types of SCAD, based on endoscopic appearance. Pattern A is characterized by involvement of crescentic folds and is the most common type of SCAD (52%). Pattern B has an appearance similar to mild-to moderate ulcerative colitis (30.40%), whereas pattern C appears similar to Crohn's disease (10.90%). Pattern D is the least common, and appears similar to severe ulcerative colitis (6.50%). Diagnosis SCAD is diagnosed via colonoscopy, often incidentally during examination for unrelated concerns. Colonoscopy shows erythema of the colonic mucosa, which may be characterized by friability and exudate. The descending and sigmoid colon are typically involved. Biopsies of the affected area and the unaffected rectum confirm the diagnosis. Biopsies of SCAD show evidence of chronic inflammation. Rectal biopsies show normal mucosa. Microscopic colitis refers to two related medical conditions which cause diarrhea: collagenous colitis and lymphocytic colitis. Both conditions are characterized by the presence of chronic non-bloody watery diarrhea, normal appearances on colonoscopy and characteristic histopathology findings of inflammatory cells. Signs and symptoms The main symptom is persistent non-bloody watery diarrhea, which may be profuse. People may also experience abdominal pain, fecal incontinence, and unintentional weight loss. Microscopic colitis is the diagnosis in around 10% of cases investigated for chronic non-bloody diarrhea. Microscopic colitis has emerged as a major cause of chronic watery non-bloody diarrhoea, particularly in elderly females. The term is used as an umbrella term to categorize a subgroup of colitides with distinct clinicopathological phenotypes and no significant endoscopic abnormalities. Lymphocytic colitis is defined by an increased number of surface intraepithelial lymphocytes, and collagenous colitis by a thickened collagen band underneath the surface epithelium. There is increased inflammation in the lamina propria, but only little or no crypt architectural distortion. Incomplete and variant forms showing less characteristic features have been reported under different names. The differential diagnosis mainly includes resolving infectious colitis and changes related to the intake of drugs such as non-steroidal anti-inflammatory drugs. Substantial clinical and histological overlap between lymphocytic and collagenous colitis has been described, raising the suspicion that the conditions are two histological manifestations of the same entity, possibly representing different manifestations during the disease course or different stages of disease development. In this review, we provide a practical approach for pathologists, with a focus on diagnostic criteria and differential diagnosis, and discuss recent insights into the pathogenesis of disease and the relationship with classic chronic inflammatory bowel disease, i.e. Crohn's disease and ulcerative colitis.  The clinical presentation of ulcerative colitis depends on the extent of the disease process. Up to 15% of individuals may have severe disease upon initial onset of symptoms. A substantial proportion (up to 45%) of people with a history of UC without any ongoing symptoms (clinical remission) have objective evidence of ongoing inflammation. Ulcerative colitis is associated with a generalized inflammatory process that can affect many parts of the body. Sometimes, these associated extra-intestinal symptoms are the initial signs of the disease. Extent of involvement In contrast to Crohn's disease, which can affect areas of the gastrointestinal tract outside of the colon, ulcerative colitis is usually confined to the colon. Inflammation in ulcerative colitis is usually continuous, typically involving the rectum, with involvement extending proximally (to sigmoid colon, ascending colon, etc). In contrast, inflammation with Crohn's disease is often patchy, with so-called \"skip lesions.\" No disease specific markers are currently known in the blood, enabling the reliable separation of Crohn's disease and ulcerative colitis patients. The way doctors can tell the difference between Crohn's disease and UC is the location and nature of the inflammatory changes. Crohn's can affect any part of the gastrointestinal tract, from mouth to anus (skip lesions), although a majority of the cases start in the terminal ileum. Ulcerative colitis, in contrast, is restricted to the colon and the rectum. Microscopically, ulcerative colitis is restricted to the mucosa (epithelial lining of the gut), while Crohn's disease affects the full thickness of the bowel wall (\"transmural lesions\"). Lastly, Crohn's disease and ulcerative colitis present with extra-intestinal manifestations (such as liver problems, arthritis, skin manifestations and eye problems) in different proportions. Microscopic colitis is a clinicopathological entity which, in addition to typical symptoms such as watery diarrhea, is characterized by its specific histopathology. Since colonoscopy yields normal findings, microscopic colitis belongs in a histological domain. The term encompasses two forms: lymphocytic and collagenous colitis. Histologically, lymphocytic colitis shows an increase in intraepithelial lymphocytes of more than 20 lymphocytes per 100 surface colonocytes, while collagenous colitis is characterized by a thickened subepithelial collagen layer of more than 10 µm. Specific stains help in the quantification of both. Since microscopic colitis does not always affect the entire colon and the number of intraepithelial lymphocytes varies physiologically, obtaining stepwise biopsies of the colon (with information on location where possible) is recommended. A thickened collagen layer is relatively specific for collagenous colitis, whereas intraepithelial lymphocytosis is also found in other diseases. Therefore, to make a correct diagnosis, it is important to correlate histological findings with clinical symptoms, including the main symptom of watery diarrhea. Collagenous colitis is an inflammatory bowel disease affecting the colon specifically with peak incidence in the 5th decade of life, affecting women more than men. Its clinical presentation involves watery diarrhea in the absence of rectal bleeding. It is often classified under the umbrella entity microscopic colitis, that it shares with a related condition, lymphocytic colitis. Signs and symptoms Microscopic colitis causes chronic watery diarrhea with greater than 10 bowel movements per day. Some patients report nocturnal diarrhea, abdominal pain, urgency, fecal incontinence, fatigue, dehydration and weight loss. Patients report a significantly diminished quality of life. Causes The cause of collagenous colitis is unknown. Collagenous colitis is a relatively rare disorder presenting mainly in middle-aged women as watery diarrhea. Endoscopic and radiographic studies of the colon are usually normal, and diagnosis must be made by biopsy. The characteristic biopsy findings are a combination of increased mucosal inflammation (collagenous colitis) as well as subepithelial collagenous thickening. The mucosal inflammatory changes include increased lamina propria plasma cells, prominent intraepithelial lymphocytes, and in some cases, numerous eosinophils. The collagenous thickening has qualitative as well as quantitative differences from normal, and may be highlighted by Masson trichrome stains. Simply quantitating the thickness of a subepithelial collagen layer is neither adequate nor necessary for the diagnosis of collagenous colitis. Major problems in diagnosing collagenous colitis arise from focusing solely on the subepithelial region without attention to inflammatory changes. For example, tangential sectioning of normal colon results in an artifactually thickened basement membrane, and such cases have been wrongly interpreted as collagenous colitis. If biopsies lack the characteristic inflammatory pattern, a tangentially cut thick basement membrane should be ignored. The key to correct diagnosis of collagenous colitis is analyzing the summation of various inflammatory changes plus subepithelial collagenization, rather than focusing on any single feature in isolation. Collagenous colitis is an inflammatory mucosal disorder of the colon with distinctive histopathological features, including a thickened subepithelial collagen layer. The clinical course is usually benign, but serious complications, including death, may occur. In the present report, a 69-year-old woman with watery diarrhea and collagenous colitis developed bloody diarrhea that was refractory to treatment medications, including corticosteroids and azathioprine. Endoscopic and histopathological studies showed a focal neutrophilic inflammatory process that progressed to a diffuse and extensive form of colitis, eventually requiring total proctocolectomy. Careful histological review of the resected colon showed no evidence of persistent collagenous colitis. These findings suggest an important need for continued long-term follow-up of patients with collagenous colitis because superimposed and serious colonic complications may occur, including a severe and extensive pancolitis refractory to medications and necessitating total proctocolectomy. Various etiologies and diseases may be related to erosions and/or small ulcers without gross inflammatory changes in the surrounding mucosa found in the colon and terminal ileum during colonoscopy. However, studies on follow-up of these lesions are rare. Thus, we investigated the clinical significance of these lesions and their characteristics helpful for differential diagnosis. We reviewed the data of 183 patients with colonoscopically observed erosive or small ulcerative lesions (&lt;2 cm), and analyzed them according to the location, number, and size of lesions, histopathologic findings, chief complaints, laboratory findings, changes of symptoms, and changes in lesions during 4-12 week follow-up period. Histopathologic findings of these lesions included acute nonspecific inflammation, chronic nonspecific inflammation, Crohn's disease, tuberculous colitis, ischemic colitis, Behcet's disease, cytomegalovirus infection, eosinophilic colitis, ulcerative colitis or pseudomembranous colitis, but most of them were nonspecific (84%). In patients with nonspecific inflammation, histopathologic findings, symptoms, location and multiplicity of the lesions were not prognostic factors for the persistency of symptoms and lesions during follow-up period. Two patients with acute inflammation, who showed no improvement in symptoms and lesions, were later diagnosed as Crohn's disease. Erosive or small ulcerative lesions without macroscopic inflammatory changes in the surrounding mucosa during colonoscopy, are mainly nonspecific. However, careful follow-up is required when the symptoms and/or lesions are not improved. To investigate the prevalence of microscopic colitis among patients presenting with chronic watery diarrhea. Colonic biopsies from 400 patients presenting with chronic watery diarrhea and other symptoms pertaining to lower gastrointestinal tract were studied. After a detailed clinical history and thorough physical examination full length colonoscopy was done using flexible colonoscope. Colonic biopsies were taken from abnormal and normal areas. Three to five micron thick sections were cut and stained with hematoxylin and eosin and Masson's trichrome stain to highlight sub epithelial collagen. Fifteen out of 400 (3.7%) colonic biopsies from patients presenting with chronic diarrhea had evidence of microscopic colitis. Five out of fifteen biopsies (33%) were diagnosed as collagenous colitis, 10 biopsies (67%) had evidence of lymphocytic colitis; 14/400(3.5%) histologically normal biopsies were taken as controls to compare various demographic and risk factors. Ten out of 15 patients (67%) were clinically diagnosed as irritable bowel syndrome. In the remaining five an infective etiology was suspected. On colonoscopy12/15 (80%) had no abnormality and 3/15 (20%) had mild hyperemia. A possibility of microscopic colitis should be considered while examining colonoscopic biopsy of a patient with chronic watery diarrhea and normal colonoscopy to avoid the misdiagnosis that may affect the treatment of patients.\nHere is the question:\nPATHOLOGICAL ANATOMY: A 59-year-old woman presenting with chronic watery diarrhea of 4 months' evolution. In the endoscopy, the mucosa did not show relevant aspects. In particular, no ulcers or friable areas were observed. A biopsy of the transverse colon was performed. Histopathology revealed a thickened area below the superficial lining epithelium, which was more evident by Masson's trichrome technique and involved epithelial atrophy and denudation. There was also a clear increase in intraepithelial lymphocyte density. The diagnosis of the intestinal lesion is?\nHere are the potential choices:\n1. Chronic ulcerative colitis.\n2. Pseudomembranous colitis.\n3. Collagenous colitis.\n4. Fibrosing Crohn's disease.\nThe correct answer is: 3. Collagenous colitis."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 74-year-old man was attacked by a wild boar while on his way home from his farm in the daytime in winter 2017 on the rural Izu peninsula. He did not provoke the boar; however, hunters were hunting animals in the mountains near the farm around the same time. The boar bit his left leg, and the man fell to the ground. The boar continued biting the man's left leg, and the man delivered a few kicks to the boar's face with his right leg. The boar then bit his right foot and ran away. The man was taken to a hospital, and a physical examination revealed 3 bite wounds on his left leg and right foot. The wounds were irrigated with sterilized saline and closed with sutures under local anesthesia. He received antibiotics and a tetanus toxoid booster. The next day, his wounds were found to be infected, and pus was drained from them. After these treatments, his wounds healed successfully. Animal bite wounds are frequently contaminated. Accordingly, in addition to early proper wound treatment, close observation of the wound is required for both the early detection of any signs of infection and early medical intervention, including appropriate drainage of pus and irrigation as necessary. We report two cases of severe tetanus infection. Case 1: A 73-year-old non-vaccinated man who fell in a local park developed a wound on the left little finger. The wound was debrided and a tetanus toxin shot given on day 4 following the injury. He developed trismus on day 6 requiring deep sedation and mechanical ventilation in the intensive care unit (ICU), with human anti-tetanus immune globulin (TIG) and antibiotics administered. Despite a very severe autonomic dysfunction, he recovered and was discharged mobile after 2 months of rehabilitation. Case 2: A 37-year-old woman fully vaccinated against tetanus in her childhood had apparently had booster vaccine for at least 20 years and was being treated for hyperthyroidism with thiamazole. She sustained two lacerations on the fingers of her right hand in her backyard. She noticed difficulty in opening her mouth on day 3 following the injury and was seen on day 7, for high fever and difficulty in speaking. She was diagnosed clinically as having tetanus and underwent wound debridement, and a shot of tetanus toxin, TIG, and antibiotics. On hospital admission day 2, she developed spasms and her blood pressure dropped drastically. She died the next day due to endotoxin shock caused by other bacteria. C. tetani is widely distributed in Japan, and these cases underscore the importance of maintaining adequate tetanus antibody levels through booster administration every 10 years in immune adults and appropriate post-exposure treatment with tetanus toxin and/or prophylactic TIG administration. Become almost non-existent in the developed countries, the hospital-borne tetanus always stays of current events in our country in spite of the forensic problem which it puts. The objectives of this study were to determine prevalence of this affection, to describe its clinical picture and to determine its lethality. It is about a retrospective study of a duration of 11 years realized in the service of the infectious diseases of Conakry. Among 8649 hospitalizations from 2001 till 2012 we brought together 239 cases of tetanus (2.7%) among which 60 hospital-borne tetanus (0.7%). Men represented 73% of these cases, with a sex-ratio M/F of 2.7. The age bracket of 20-40 years was the most affected with 32 cases (53.3%). A single patient had begun his vaccinal calendar which had remained incomplete. Both national hospitals of the CHU of Conakry and private hospitals were the biggest suppliers of this hospital-borne tetanus with respectively 22 and 27 cases (36.6 and 45%). Tetanus related to IM of quinine represented 26 cases (43.3%) whereas the hernial cure was found in 16 cases (26.6%). The average duration of invasion and incubation was respectively 1.5 days and 6 days for the dead (n = 45.7%) and 2 days and 10.5 days for the survivors. Three-quarters of 60 patients died. The fight against this type of tetanus passes inevitably by an improvement of the working conditions, a strict application of the rules of asepsis and the in-service training of the medical and paramedical staff. We present a case study of a 26-year-old morbidly obese man with a three-day history of right leg pain and swelling. The swelling was associated with low grade fever. He was alert and conscious upon presentation to the hospital. His physical examination showed gross swelling of the entire right lower limb with no systemic manifestations. There was no discharge and bullae from the swelling area of the leg. He had high blood sugar and was newly diagnosed with type 2 diabetes mellitus. He was diagnosed with necrotizing fasciitis. An intravenous imipenem-cilastatin 500 mg every 6 h together with clindamycin 900 mg every 8 h was started empirically. Extensive wound debridement was performed. The swab culture obtained intraoperatively grew <iPseudomonas aeruginosa.</i He required an above knee amputation due to worsening infection despite wound debridement. Post-operatively, he developed acute kidney injury with severe metabolic acidosis, which required daily hemodialysis. However, the patient deteriorated due to septic shock with multi-organ failure, resulting in his death. Currently, in our country (Republic of Serbia) tetanus is a rarely occurring disease, mainly affecting people older than 65 years of age. A small number of reported cases is mainly due to appropriate immunization. Therefore, each case of tetanus may be considered as failure of health care system to provide adequate immunization. A 71-year-old woman was injured in her garden. She sustained laceration in the left coccygeal region. The next day the wound was treated by a surgeon, but tetanus postexposure prophylaxis was not administrated. On the fifth day following the incident, the symptoms and signs of tetanus became apparent, and the patient died two days later. Postmortem examination revealed the wound that was not adequately treated, since there was a foreign body and a dressing inserted in the wound. Signs of acute (aerobic) infection were also present. Tetanus is a severe, potentially lethal disease that is absolutely preventable. Mistakes in immunization and surgical treatment of the wound can be considered as medical malpractice. The first reliable statistic data about perioperatory mortality were published in 1841 by the French Joseph-Francois Malgaigne (1806-1863): he referred to a mean mortality of 60% for amputations and this bad result was to be attributed mainly to hospital acquired diseases. The idea of \"hospital acquired disease\" although vague, included five infective nosologic entities, which at that time were diagnosed more frequently: erysipelas, tetan, pyemia, septicemia, and gangrene. Nonetheless, the suppuration with pus production was considered from most of the surgeons and doctors of that time as a necessary and unavoidable step in the process of wound healing. During the end of the eighteenth century, hospitals of the main European cities were transforming into aggregations of several wards, where the high concentration of patients created poor sanitary conditions and a consistent increase of perioperatory mortality. In 1865, Lister applied his first antiseptic dressing on the surface of an exposed fracture. These experimental attempts lead to an effective reduction of wound infections respect to the dressing with strings used previously. Lister's innovations in the field of wound treatment were based on two brand new concepts: germs causing rot were ubiquitarious and the wound infection was not a normal step in the process of wound healing. The concept of antisepsis was hardly accepted in the European surgical world: \"Of all countries, Italy is the most indifferent and uninterested in experimenting this method, which has been so favorably judged from the greatest surgical societies in Germany\". This quotation from the young surgeon Giuseppe Ruggi (1844-1925) from Bologna comes from his article where he presented his first experiences on aseptic medications started the previous year in the Surgical Department of Maggiore Hospital in Bologna. In his report, Ruggi described the adopted technique and suggested that the medication should be extended to all the surgical patients of the hospital:\"… this is needed to totally remove from the hospital all those elements of infection which grow in the wounds dressed with the old method\". The experimentation of this new dressing for the few treated cases was rigorous and concerned both the sterilization of surgical tools with the fenic acid (5%) and the shaving of the skin. Ruggi also observed that there was no correlation between the seriousness of the wound and its extension or way of healing: when \"simple\" cases that \"should heal without complication\" showed fever he often realized that \"it was often due to a medication performed without following the rules for an accurate disinfection and dressing\". Ruggi thought that the fever was connected to \"reabsorption of pyrogenic substances, which can be removed cleaning and disinfecting the wound\" in cases of wounds not accurately dressed and rarely medicated. Frequent postoperative medications of the wound were able to eliminate the fever within 2 h. Ruggi's attitude toward the fine reasoning lead him to introduce the concept of immunodeficiency related to physical deterioration: \"… patients treated for surgical disease may sometimes suffer from complications of medical conditions, which initially escape the most accurate investigations… The surgical operation could, in some cases, hold the balance of power\". The obtained results, published in 1879, appear extremely interesting. As he wrote in 1898, for the presentation of his case record of more than 1000 laparotomies, he had started \"… operating as a young surgeon without any tutor, helped only by his mind and what he could deduce from publications existing at the moment …\". From 1964 to 1980 a total of 18 patients with tetanus were treated at Tampere Central Hospital, 5 (28%) of whom died. No assurance regarding earlier immunization could be obtained in 15 cases. In 13 cases the site of infection was a small scratch on the finger, the legs or the face. The mean incubation period was 8 days. Ten patients suffered from severe tetanus and 8 from moderate tetanus. Eight patients, of whom 2 died, were treated in an ordinary ward. After the surgical intensive care unit was set up, 10 patients received treatment there. Three died. The mean duration of hospitalization was 27 days and the mean treatment period in the intensive care unit 24 days. Seven patients were asymptomatic when discharged and 6 had minor after-effects. Cardiovascular complications can be prevented by intensive care, but pulmonary embolism remains the commonest cause of death. Special attention should be paid to its prevention. Hemorrhagic shock and encephalopathy syndrome (HSES) is a type of acute encephalopathy mainly seen in infants. It is a syndrome encompassing an onset of high fever, disturbance of consciousness, convulsion, and shock that rapidly progresses to watery diarrhea and liver and renal dysfunctions. It is extremely rare in adults, and the number of reports is limited worldwide. We report the case of an adult patient with HSES, which occurred after influenza A infection. A 52-year-old man visited his family doctor 2 days after he noticed fever and was diagnosed with influenza A using an influenza rapid diagnosis kit; he underwent treatment on an outpatient basis. He was immediately hospitalized after developing fever, abdominal pain, malaise, and shock 16 hours after the commencement of the treatment. Abrupt acute brain swelling was noted 24 hours after hospitalization. The antibody titer to influenza A (H3N2) was 1:40. Computed tomography obtained 24 hours after treatment initiation confirmed acute cerebral edema and cerebral herniation. Electroencephalogram at that time showed a flat line. For the treatment of influenza A, laninamivir 150 mg was started immediately after the diagnosis by the family doctor, and 600 mg dose was given daily after hospitalization (or since 24 hours after the treatment initiation). For the management of shock, dobutamine 3 μg/kg/min and noradrenaline up to 0.2 μg/kg/min were used together with bolus infusion. The patient was declared brain dead on his 6th hospital day and he died on his 27th hospital day. Drastic courses such as that in our case with HSES can follow influenza infections even in adults. This report describes a 4-year prospective study of post-operative wound infections, utilizing a program of wound surveillance. Surgical wounds after 6030 operations of a general surgery service were surveyed by the authors and a specialist nurse, daily, and in the follow-up clinic for 30 days. The rates of infections showed a decline over the years of surveillance. On the first year there was a 6.37 per cent incidence of infections, and the fourth year, of 4.7 per cent. This represented an improvement in hospitalization days and expenses. Case Study  Mr. D., a 55-year-old male, presented to the medical oncology service with a diagnosis of stage III adenocarcinoma of the sigmoid colon. He presented 7 weeks post sigmoid colectomy with lymph node resection and was initiated on adjuvant chemotherapy with CAPOX (capecitabine [Xeloda] and oxaliplatin [Eloxatin]). Standard dosing was used: oxaliplatin at 130 mg/m(2) on day 1 and capecitabine at approximately 2,000 mg/m(2)/day (rounded to the nearest 500-mg tablet size) for 14 days on and 7 days off (1 cycle = 21 days). A capped body surface area of 2.4 m2 was used, due to the patient's body habitus. Adverse Effects  Mr. D. did not report any complications of therapy during cycle 1, days 1-7, other than grade 1 diarrhea, which was amenable to diphenoxylate/atropine when taken. The next week, he reported significant malaise and fatigue associated with persistent diarrhea occurring every 30 minutes for 5 days. Mr. D. was instructed to go to the emergency room for an immediate evaluation, but he refused. Mr. D. presented to the clinic in poor condition on day 14 of cycle 1. His diarrhea had increased to grade 3 and was not controlled with either loperamide or diphenoxylate/atropine, though he was not taking his medications as directed. He had been instructed to take two 2-mg loperamide tablets after the first loose stool, followed by 1 tablet of diphenoxylate/atropine 2 hours later. He could then alternate this with loperamide every 2 hours as needed, not to exceed 8 tablets of loperamide per day. Instead, he had taken 2 tablets of loperamide after the first loose stool, but either waited 6 hours to take 1 tablet of diphenoxylate/atropine or otherwise chose not to alternate the medications at all despite continued diarrhea, depending on the day. Mr. D.'s timing in taking his supportive medications was inconsistent, and his explanations of this timing were not exact. He also reported persistent grade 3 nausea with vomiting for 5 days, which did not improve with ondansetron and prochlorperazine, though he again did not take these consistently. He was advised to alternate ondansetron and prochlorperazine every 4 hours as needed, but only took one or the other medication approximately 3 times per day. According to Mr. D., his adverse effects initially began on day 9 of cycle 1. He had lost approximately 14 kg (31 lb) during cycle 1. Clinically, he was found to have grade 2 mucositis and grade 1 hand-foot syndrome. At the time of this visit, his absolute neutrophil count was 3,000/ìL, his hemoglobin was 14.4 g/dL, his hematocrit 42.2%, and his platelet count was 139,000/ìL. His kidney function was within the normal range. Mr. D. refused hospitalization despite the primary team's recommendation. He also refused to undergo stool sampling for Clostridium difficile. He was given IV fluids along with adjustments in supportive medications, including a prescription for 10% tincture of opium. He was instructed to use 0.6 mL every 6 hours in addition to alternating loperamide with diphenoxylate/atropine as noted previously. He was advised to rinse his mouth with a baking soda solution for relief of his grade 1 mucositis, and alternation of antiemetics every 4 hours was reiterated. He was to return prior to initiation of cycle 2 for further evaluation. Worsening Symptoms  The next day, Mr. D.'s wife called the clinic to report that her husband's diarrhea continued despite the use of tincture of opium and that it was associated with hematochezia. He was also experiencing a worsening of his mucositis, with an associated swelling of the tongue. He was instructed to present to the emergency center, which he did on day 16 of cycle 1. By then, he was found to be febrile at 39.5°C. He was tachycardic, with a heart rate of 126, and he was experiencing significant abdominal pain associated with the diarrhea. The mucositis was worsening, with new odynophagia. At this time, Mr. D.'s absolute neutrophil count had dropped dramatically to 160/ìL, his hemoglobin was 13.1 g/dL, his hematocrit was 39.2%, and his platelet count was 68,000/ìL. He was admitted to the inpatient service and started on empiric antibiotics. His blood cultures remained negative during hospitalization, but stool cultures were positive for C. difficile. His antimicrobial regimen was deescalated to oral vancomycin once his stool volume decreased. He was treated with an institutional compounded mouthwash of diphenhydramine, aluminum/magnesium hydroxide, and viscous lidocaine for the mucositis, which also slowly improved. He was given a dose of growth factor. Neutropenia eventually resolved, with an absolute neutrophil count of 4,820/ìL on the day of discharge. He was discharged 26 days after initiating cycle 1, at which time his myelosuppression and mucositis were also resolved. Throughout his course, he did not report any neurotoxicity. DPD Testing  Due to his severe symptoms of neutropenia, mucositis, and diarrhea, Mr. D. was tested for dihydropyrimidine dehydrogenase (DPD) deficiency. Testing confirmed a heterozygous IVS14+IG&gt;A mutation. For this reason, all further adjuvant therapy was withheld, and he was followed on clinical surveillance only.  The investigations included a group of 26 patients with acute generalized tetanus, cared for in the Clinic according to a unitary method. A number of 17 prognostic, clinical and laboratory criteria were analyzed from the viewpoint of the pathogenic and clinicoevolutive incidence and significance. According to the severity, lethal course of the disease the following sequence was established in order of gravity: serum sickness, kypokaliemia, hyperpyruvicemia greater than an incubation of less 6 days, invasion within less than 24 hours, hyperlactacidemia greater than age over 60 years, persistent hypertension and tachycardia, hyperazoltemia, hyperglycemia, frequent paroxysmal contractions (before sedation) greater than late admission to hospital, associated cardiopulmonary pathology, hyponatriemia insufficient dressing of the wound and rural environment. The importance of the biological indices is emphasized, both as elements of prognosis and as orientative criteria for the treatment of the case. Although guidelines to prevent surgical site infections (SSIs) were published more than a decade ago, prophylactic antibiotics are still used subjectively in clinical practice. In this study, we evaluated the safety of single-dose preoperative intravenous antibiotics without postoperative antibiotics in the field of clean wound surgery performed under local anesthesia. We also surveyed the present clinical conditions for prophylactic antibiotic use in the plastic surgery departments of training hospitals in Korea. A total of 360 consecutive patients who underwent clean wound surgery under local anesthesia in an outpatient clinic from March 2018 to October 2018 were reviewed. In the study group, a single surgeon administered first-generation cephalosporins intravenously within 1 hour of skin incision and did not prescribe additional antibiotics. In the control group, 2 other surgeons prescribed oral first-generation cephalosporins postoperatively for 2 to 3 days without preoperative antibiotics. A telephone survey about perioperative antibiotic regimens was conducted at the departments of plastic surgery in training hospitals. There were 128 patients in the study group and 232 patients in the control group. There were no significant differences between the 2 groups regarding SSIs and other surgical complications. A total of 41 training hospitals answered the survey and every hospital had protocols of prescribing postoperative oral antibiotics routinely at the time of discharge with a mean duration of 3.9 days. Only 11 hospitals (26.8%) prescribed parenteral antibiotics before surgery as well as postoperative oral antibiotics. Intravenous injection of single-dose first-generation cephalosporins 1 hour before surgery without postoperative antibiotics did not increase the incidence of SSIs compared with the usual practice of giving only postoperative antibiotics prescription for 2 to 3 days in cases of clean wound surgery performed under local anesthesia. Proper antibiotic prophylaxis should be performed by surgeons in training hospitals without hesitation. 150 tetanus cases registered on the region of Murcia have been retrospectively analyzed, they have been collected from the patients admitted at a Intensive Care Unit during a period of 18 years; the clinical together with the epidemiological features, as well as their variations, have been studied through out the years. The impact of a vaccination program in adults which was performed in our region during 1981 has been also evaluated in relationship with the incidence of disease and the economical cost of it. Incidence remained homogeneous until 1982, from that date on a sudden decrease on the number of cases was observed, related with the vaccination program [Period previous to the vaccination program: mean 10 cases/year, versus 5 cases/year since it was started (p &lt; 0.001)]. Regarding the epidemiological characteristics, it is remarkable the shift of the disease toward a more advanced age of onset together with a predominance on females beginning in 1978, but without reaching statically significance. More frequent route of infection is nowadays the intramuscular suppurative injection. Besides this fact the severity of the cases have been increasing (from 59% to 71%, p &lt; 0.005), which has determined that the global mortality of the disease remains almost the same (38%). Mortality has no relationship with age, but is related with being a female (p &lt; 0.05), with intramuscular injection as route of infection (p &lt; 0.025), with the clinical stage (p &lt; 0.001) and with a short incubation period (p &lt; 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) We report on a young man who presented at our emergency unit with pain and swelling of his left hand, after he had been bitten into his left middle finger by a sidewinder rattlesnake one hour ago. Local findings were a swollen left middle finger, a red-livid discoloration along his nail rim with paleness of the surrounding skin. Vital signs were stable, ECG showed sinus rhythm, laboratory parameters were normal, without signs of liver or kidney damage and without coagulopathy. Diagnosis was local tissue reaction due to a snake bite of a sidewinder rattlesnake without evidence of systemic toxic effect. Due to the absence of systemic toxic effects the patient received monitoring of his vital signs and we controlled local tissue reaction constantly and laboratory parameters every 6 hours, as recommended by the \"Giftnotrufzentrale\" (poison emergency advisory service). The patient left hospital on his own will against medical advice in the night after first laboratory control, which showed no signs of organ damage and we recommended reasessment the following morning. At that time the swelling had extended to the whole arm, furthermore large hematoma reaching up to the axilla had developed over night. Again we contacted the \"Giftnotrufzentrale\" and decided to begin the administration of an antivenom, after allergic testing. The administration was without complications, the swelling decreased constantly and since laboratory controll still showed no signs of systemic toxin effect, we could discharge the patient on day 3. Follow-up visit 6 months later showed complete and natural healing. Snake bites are altogether rare among our patients, nevertheless since possible toxin effects and its dynamics are unpredictable and can vary highly, they demand monitoring at close intervals of vitals signs, local swelling and laboratory parameters. As early as possible an advisory service, such as \"Giftnotrufzentrale\" should be contacted to acquire information on possible toxin effects and availability of antivenoms. Contact to other medical disciplines (e.g. dermatology, intensive care unit, surgery, neurology, dialysis…) should be sought, depending on the further course of toxin effects. Possible comorbidities as well as allergisation due to previous bites strongly influence the course of the disease and should be evaluated. We recommend to keep precise records on the ocurrence of systemic toxin effects, as well as on local findings (e.g. fotodocumentation, marking of erythema, measurement of swelling). Manipulation of the wound is usually ineffective and therefore not recommended, also in respect of self-endangerment. After stabilization of the patient a vaccination against tetanus, if necessary, should not be forgotten. This report describes a 4 year prospective study of postoperative wound infections, utilizing a program of wound surveillance. Surgical wounds after 6030 operations of a general surgery service were surveyed by the authors and a specialist nurse, daily and in the follow up clinic for 30 days. Results were reported to all the surgeons monthly. The rates of infections demonstrated a decline over the years of surveillance. In the first year there was a 6.37 percent incidence of infection and the fourth year 4.7 percent. This represents an improvement in hospitalization days and expenses. A case of skin injuries due to stings by crown-of-thorns starfish, Acanthaster planci, in a 53-year-old Okinawan woman is reported. She went to a beach to gather shellfish on 8 April 2001 and fell to the ground with her left palm on a crown-of-thorns starfish that happened to be close to her. She hurried to the emergency section of our hospital. An emergency doctor sterilized the wound and administered an antibiotic, an analgesic agent and an injection of a tetanus antitoxin. He tried to remove the remaining spines from the palm with great difficulty. Because swelling and subcutaneous indurations of the left palm had persisted thereafter, oral and topical administration of corticosteroid started on 13 April. Physical examination at the dermatology section revealed approximately 10 stab wounds of the left palm with pus, subcutaneous bleeding and many abrasions around them. X-rays of the left hand showed foreign bodies, 2-10 mm in size, located on the lesions. The patient was treated with a topical injection of 2 mg triamcinolone acetonide (Kenacort-A), diluted fivefold with 1% Xylocaine, once a week. Some of the foreign body granulomatous lesions improved but pain and subcutaneous indurations persisted in most of the lesions. Because the X-ray photographs showed many remaining spines, surgical excision to remove them was performed under local anesthesia 3 months after the injury. All the symptoms improved after the operation. Scanning electron microscopic examination of the spines revealed that their tips had fragile lattice-like structures. Tetanus prophylaxis in routine wound management is a major strategy for tetanus prevention in health care settings. Failed wound management interventions leave patient dangerously exposed to this disease. We report the case of a patient with tetanus occurred after medical treatment for head injury performed in a healthcare facility without appropriate tetanus prophylaxis. This study aims to remind clinicians of the importance of prophylaxis in previously unvaccinated wounded patients or with a doubtful immune status. A 52-year-old patient who had not previously been vaccinated against tetanus was admitted to Yalgado Ouédraogo University Hospital CHU/YO with cervical pain, dysphagia, difficulty walking and opening the mouth. The patient had a personal history of deep wound on his forehead sutured without previous anti-tetanus prophylaxis approximately three weeks before. Physical examination on admission showed loose lockjaw, abdominal spasm, dysphagia, a body temperature of 36,5 °C and a scar on his forehead measuring about 7 cm. The diagnosis of generalized tetanus (stage II) infection occurring after forehead wound was retained. Treatment outcome was favorable and the patient was dismissed on September 18, 2015. The prevention of tetanus associated with an appropriate treatment requires rigorous application of aseptic techniques, systematization of antitetanus serum therapy in the management of previously unvaccinated patients or with a doubtful immune status presenting with a deep wound. Case 1: A 39-year-old man with chronic lower extremity lymphedema was admitted to the hospital with acute fever, chills, and left lower extremity pain, swelling, and erythema for the third time in as many months. Examination revealed a temperature of 39 degrees C (102.2 degrees F), and erythmatous induration on the left leg (Figure). The patient was treated with IV clindamycin and cefazolin, with clinical improvement. He was discharged with azithromycin, 500 mg daily for 3 days, done twice monthly. Case 2: A 52-year-old morbidly obese man with stasis dermatitis presented with acute lower extremity pain, swelling, and associated fever. He had been taking prophylactic antibiotics for his recurrent cellulitis for more than a decade and had significantly decreased his number of reoccurrences while on this therapy. He was admitted to the hospital, treated with IV cefazolin, and had a rapid improvement over 48 hours. He was subsequently discharged with continued suppressive antibiotic therapy.\nHere is the question:\nEPIDEMIOLOGY AND PREVENTIVE MEDICINE: Luis is a 25-year-old young man who underwent splenectomy after a bicycle accident 1 year ago. He has a dog that bit him 24 hours ago and has caused a small wound on his right hand. He went to his health center (located 3 hours from the nearest hospital) for fever of 39ºC, pain in the wound and general malaise. On examination, BP 100/60 mm Hg, HR 110 beats per minute, slight swelling in the wound without pus. Which of the following actions is most indicated at this time?\nHere are the potential choices:\n1. Send to hospital for rabies and tetanus vaccination and keep under observation.\n2. Clean the wound and administer intramuscular nonspecific ganunaglobulin.\n3. Give 400 mg of oral moxifloxacin and send to the hospital.\n4. Give clindamycin 600 mg oral every 8 hours and observation.\nThe correct answer is: ",
        "gold_answer": "3 Give 400 mg of oral moxifloxacin and send to the hospital.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 74-year-old man was attacked by a wild boar while on his way home from his farm in the daytime in winter 2017 on the rural Izu peninsula. He did not provoke the boar; however, hunters were hunting animals in the mountains near the farm around the same time. The boar bit his left leg, and the man fell to the ground. The boar continued biting the man's left leg, and the man delivered a few kicks to the boar's face with his right leg. The boar then bit his right foot and ran away. The man was taken to a hospital, and a physical examination revealed 3 bite wounds on his left leg and right foot. The wounds were irrigated with sterilized saline and closed with sutures under local anesthesia. He received antibiotics and a tetanus toxoid booster. The next day, his wounds were found to be infected, and pus was drained from them. After these treatments, his wounds healed successfully. Animal bite wounds are frequently contaminated. Accordingly, in addition to early proper wound treatment, close observation of the wound is required for both the early detection of any signs of infection and early medical intervention, including appropriate drainage of pus and irrigation as necessary. We report two cases of severe tetanus infection. Case 1: A 73-year-old non-vaccinated man who fell in a local park developed a wound on the left little finger. The wound was debrided and a tetanus toxin shot given on day 4 following the injury. He developed trismus on day 6 requiring deep sedation and mechanical ventilation in the intensive care unit (ICU), with human anti-tetanus immune globulin (TIG) and antibiotics administered. Despite a very severe autonomic dysfunction, he recovered and was discharged mobile after 2 months of rehabilitation. Case 2: A 37-year-old woman fully vaccinated against tetanus in her childhood had apparently had booster vaccine for at least 20 years and was being treated for hyperthyroidism with thiamazole. She sustained two lacerations on the fingers of her right hand in her backyard. She noticed difficulty in opening her mouth on day 3 following the injury and was seen on day 7, for high fever and difficulty in speaking. She was diagnosed clinically as having tetanus and underwent wound debridement, and a shot of tetanus toxin, TIG, and antibiotics. On hospital admission day 2, she developed spasms and her blood pressure dropped drastically. She died the next day due to endotoxin shock caused by other bacteria. C. tetani is widely distributed in Japan, and these cases underscore the importance of maintaining adequate tetanus antibody levels through booster administration every 10 years in immune adults and appropriate post-exposure treatment with tetanus toxin and/or prophylactic TIG administration. Become almost non-existent in the developed countries, the hospital-borne tetanus always stays of current events in our country in spite of the forensic problem which it puts. The objectives of this study were to determine prevalence of this affection, to describe its clinical picture and to determine its lethality. It is about a retrospective study of a duration of 11 years realized in the service of the infectious diseases of Conakry. Among 8649 hospitalizations from 2001 till 2012 we brought together 239 cases of tetanus (2.7%) among which 60 hospital-borne tetanus (0.7%). Men represented 73% of these cases, with a sex-ratio M/F of 2.7. The age bracket of 20-40 years was the most affected with 32 cases (53.3%). A single patient had begun his vaccinal calendar which had remained incomplete. Both national hospitals of the CHU of Conakry and private hospitals were the biggest suppliers of this hospital-borne tetanus with respectively 22 and 27 cases (36.6 and 45%). Tetanus related to IM of quinine represented 26 cases (43.3%) whereas the hernial cure was found in 16 cases (26.6%). The average duration of invasion and incubation was respectively 1.5 days and 6 days for the dead (n = 45.7%) and 2 days and 10.5 days for the survivors. Three-quarters of 60 patients died. The fight against this type of tetanus passes inevitably by an improvement of the working conditions, a strict application of the rules of asepsis and the in-service training of the medical and paramedical staff. We present a case study of a 26-year-old morbidly obese man with a three-day history of right leg pain and swelling. The swelling was associated with low grade fever. He was alert and conscious upon presentation to the hospital. His physical examination showed gross swelling of the entire right lower limb with no systemic manifestations. There was no discharge and bullae from the swelling area of the leg. He had high blood sugar and was newly diagnosed with type 2 diabetes mellitus. He was diagnosed with necrotizing fasciitis. An intravenous imipenem-cilastatin 500 mg every 6 h together with clindamycin 900 mg every 8 h was started empirically. Extensive wound debridement was performed. The swab culture obtained intraoperatively grew <iPseudomonas aeruginosa.</i He required an above knee amputation due to worsening infection despite wound debridement. Post-operatively, he developed acute kidney injury with severe metabolic acidosis, which required daily hemodialysis. However, the patient deteriorated due to septic shock with multi-organ failure, resulting in his death. Currently, in our country (Republic of Serbia) tetanus is a rarely occurring disease, mainly affecting people older than 65 years of age. A small number of reported cases is mainly due to appropriate immunization. Therefore, each case of tetanus may be considered as failure of health care system to provide adequate immunization. A 71-year-old woman was injured in her garden. She sustained laceration in the left coccygeal region. The next day the wound was treated by a surgeon, but tetanus postexposure prophylaxis was not administrated. On the fifth day following the incident, the symptoms and signs of tetanus became apparent, and the patient died two days later. Postmortem examination revealed the wound that was not adequately treated, since there was a foreign body and a dressing inserted in the wound. Signs of acute (aerobic) infection were also present. Tetanus is a severe, potentially lethal disease that is absolutely preventable. Mistakes in immunization and surgical treatment of the wound can be considered as medical malpractice. The first reliable statistic data about perioperatory mortality were published in 1841 by the French Joseph-Francois Malgaigne (1806-1863): he referred to a mean mortality of 60% for amputations and this bad result was to be attributed mainly to hospital acquired diseases. The idea of \"hospital acquired disease\" although vague, included five infective nosologic entities, which at that time were diagnosed more frequently: erysipelas, tetan, pyemia, septicemia, and gangrene. Nonetheless, the suppuration with pus production was considered from most of the surgeons and doctors of that time as a necessary and unavoidable step in the process of wound healing. During the end of the eighteenth century, hospitals of the main European cities were transforming into aggregations of several wards, where the high concentration of patients created poor sanitary conditions and a consistent increase of perioperatory mortality. In 1865, Lister applied his first antiseptic dressing on the surface of an exposed fracture. These experimental attempts lead to an effective reduction of wound infections respect to the dressing with strings used previously. Lister's innovations in the field of wound treatment were based on two brand new concepts: germs causing rot were ubiquitarious and the wound infection was not a normal step in the process of wound healing. The concept of antisepsis was hardly accepted in the European surgical world: \"Of all countries, Italy is the most indifferent and uninterested in experimenting this method, which has been so favorably judged from the greatest surgical societies in Germany\". This quotation from the young surgeon Giuseppe Ruggi (1844-1925) from Bologna comes from his article where he presented his first experiences on aseptic medications started the previous year in the Surgical Department of Maggiore Hospital in Bologna. In his report, Ruggi described the adopted technique and suggested that the medication should be extended to all the surgical patients of the hospital:\"… this is needed to totally remove from the hospital all those elements of infection which grow in the wounds dressed with the old method\". The experimentation of this new dressing for the few treated cases was rigorous and concerned both the sterilization of surgical tools with the fenic acid (5%) and the shaving of the skin. Ruggi also observed that there was no correlation between the seriousness of the wound and its extension or way of healing: when \"simple\" cases that \"should heal without complication\" showed fever he often realized that \"it was often due to a medication performed without following the rules for an accurate disinfection and dressing\". Ruggi thought that the fever was connected to \"reabsorption of pyrogenic substances, which can be removed cleaning and disinfecting the wound\" in cases of wounds not accurately dressed and rarely medicated. Frequent postoperative medications of the wound were able to eliminate the fever within 2 h. Ruggi's attitude toward the fine reasoning lead him to introduce the concept of immunodeficiency related to physical deterioration: \"… patients treated for surgical disease may sometimes suffer from complications of medical conditions, which initially escape the most accurate investigations… The surgical operation could, in some cases, hold the balance of power\". The obtained results, published in 1879, appear extremely interesting. As he wrote in 1898, for the presentation of his case record of more than 1000 laparotomies, he had started \"… operating as a young surgeon without any tutor, helped only by his mind and what he could deduce from publications existing at the moment …\". From 1964 to 1980 a total of 18 patients with tetanus were treated at Tampere Central Hospital, 5 (28%) of whom died. No assurance regarding earlier immunization could be obtained in 15 cases. In 13 cases the site of infection was a small scratch on the finger, the legs or the face. The mean incubation period was 8 days. Ten patients suffered from severe tetanus and 8 from moderate tetanus. Eight patients, of whom 2 died, were treated in an ordinary ward. After the surgical intensive care unit was set up, 10 patients received treatment there. Three died. The mean duration of hospitalization was 27 days and the mean treatment period in the intensive care unit 24 days. Seven patients were asymptomatic when discharged and 6 had minor after-effects. Cardiovascular complications can be prevented by intensive care, but pulmonary embolism remains the commonest cause of death. Special attention should be paid to its prevention. Hemorrhagic shock and encephalopathy syndrome (HSES) is a type of acute encephalopathy mainly seen in infants. It is a syndrome encompassing an onset of high fever, disturbance of consciousness, convulsion, and shock that rapidly progresses to watery diarrhea and liver and renal dysfunctions. It is extremely rare in adults, and the number of reports is limited worldwide. We report the case of an adult patient with HSES, which occurred after influenza A infection. A 52-year-old man visited his family doctor 2 days after he noticed fever and was diagnosed with influenza A using an influenza rapid diagnosis kit; he underwent treatment on an outpatient basis. He was immediately hospitalized after developing fever, abdominal pain, malaise, and shock 16 hours after the commencement of the treatment. Abrupt acute brain swelling was noted 24 hours after hospitalization. The antibody titer to influenza A (H3N2) was 1:40. Computed tomography obtained 24 hours after treatment initiation confirmed acute cerebral edema and cerebral herniation. Electroencephalogram at that time showed a flat line. For the treatment of influenza A, laninamivir 150 mg was started immediately after the diagnosis by the family doctor, and 600 mg dose was given daily after hospitalization (or since 24 hours after the treatment initiation). For the management of shock, dobutamine 3 μg/kg/min and noradrenaline up to 0.2 μg/kg/min were used together with bolus infusion. The patient was declared brain dead on his 6th hospital day and he died on his 27th hospital day. Drastic courses such as that in our case with HSES can follow influenza infections even in adults. This report describes a 4-year prospective study of post-operative wound infections, utilizing a program of wound surveillance. Surgical wounds after 6030 operations of a general surgery service were surveyed by the authors and a specialist nurse, daily, and in the follow-up clinic for 30 days. The rates of infections showed a decline over the years of surveillance. On the first year there was a 6.37 per cent incidence of infections, and the fourth year, of 4.7 per cent. This represented an improvement in hospitalization days and expenses. Case Study  Mr. D., a 55-year-old male, presented to the medical oncology service with a diagnosis of stage III adenocarcinoma of the sigmoid colon. He presented 7 weeks post sigmoid colectomy with lymph node resection and was initiated on adjuvant chemotherapy with CAPOX (capecitabine [Xeloda] and oxaliplatin [Eloxatin]). Standard dosing was used: oxaliplatin at 130 mg/m(2) on day 1 and capecitabine at approximately 2,000 mg/m(2)/day (rounded to the nearest 500-mg tablet size) for 14 days on and 7 days off (1 cycle = 21 days). A capped body surface area of 2.4 m2 was used, due to the patient's body habitus. Adverse Effects  Mr. D. did not report any complications of therapy during cycle 1, days 1-7, other than grade 1 diarrhea, which was amenable to diphenoxylate/atropine when taken. The next week, he reported significant malaise and fatigue associated with persistent diarrhea occurring every 30 minutes for 5 days. Mr. D. was instructed to go to the emergency room for an immediate evaluation, but he refused. Mr. D. presented to the clinic in poor condition on day 14 of cycle 1. His diarrhea had increased to grade 3 and was not controlled with either loperamide or diphenoxylate/atropine, though he was not taking his medications as directed. He had been instructed to take two 2-mg loperamide tablets after the first loose stool, followed by 1 tablet of diphenoxylate/atropine 2 hours later. He could then alternate this with loperamide every 2 hours as needed, not to exceed 8 tablets of loperamide per day. Instead, he had taken 2 tablets of loperamide after the first loose stool, but either waited 6 hours to take 1 tablet of diphenoxylate/atropine or otherwise chose not to alternate the medications at all despite continued diarrhea, depending on the day. Mr. D.'s timing in taking his supportive medications was inconsistent, and his explanations of this timing were not exact. He also reported persistent grade 3 nausea with vomiting for 5 days, which did not improve with ondansetron and prochlorperazine, though he again did not take these consistently. He was advised to alternate ondansetron and prochlorperazine every 4 hours as needed, but only took one or the other medication approximately 3 times per day. According to Mr. D., his adverse effects initially began on day 9 of cycle 1. He had lost approximately 14 kg (31 lb) during cycle 1. Clinically, he was found to have grade 2 mucositis and grade 1 hand-foot syndrome. At the time of this visit, his absolute neutrophil count was 3,000/ìL, his hemoglobin was 14.4 g/dL, his hematocrit 42.2%, and his platelet count was 139,000/ìL. His kidney function was within the normal range. Mr. D. refused hospitalization despite the primary team's recommendation. He also refused to undergo stool sampling for Clostridium difficile. He was given IV fluids along with adjustments in supportive medications, including a prescription for 10% tincture of opium. He was instructed to use 0.6 mL every 6 hours in addition to alternating loperamide with diphenoxylate/atropine as noted previously. He was advised to rinse his mouth with a baking soda solution for relief of his grade 1 mucositis, and alternation of antiemetics every 4 hours was reiterated. He was to return prior to initiation of cycle 2 for further evaluation. Worsening Symptoms  The next day, Mr. D.'s wife called the clinic to report that her husband's diarrhea continued despite the use of tincture of opium and that it was associated with hematochezia. He was also experiencing a worsening of his mucositis, with an associated swelling of the tongue. He was instructed to present to the emergency center, which he did on day 16 of cycle 1. By then, he was found to be febrile at 39.5°C. He was tachycardic, with a heart rate of 126, and he was experiencing significant abdominal pain associated with the diarrhea. The mucositis was worsening, with new odynophagia. At this time, Mr. D.'s absolute neutrophil count had dropped dramatically to 160/ìL, his hemoglobin was 13.1 g/dL, his hematocrit was 39.2%, and his platelet count was 68,000/ìL. He was admitted to the inpatient service and started on empiric antibiotics. His blood cultures remained negative during hospitalization, but stool cultures were positive for C. difficile. His antimicrobial regimen was deescalated to oral vancomycin once his stool volume decreased. He was treated with an institutional compounded mouthwash of diphenhydramine, aluminum/magnesium hydroxide, and viscous lidocaine for the mucositis, which also slowly improved. He was given a dose of growth factor. Neutropenia eventually resolved, with an absolute neutrophil count of 4,820/ìL on the day of discharge. He was discharged 26 days after initiating cycle 1, at which time his myelosuppression and mucositis were also resolved. Throughout his course, he did not report any neurotoxicity. DPD Testing  Due to his severe symptoms of neutropenia, mucositis, and diarrhea, Mr. D. was tested for dihydropyrimidine dehydrogenase (DPD) deficiency. Testing confirmed a heterozygous IVS14+IG&gt;A mutation. For this reason, all further adjuvant therapy was withheld, and he was followed on clinical surveillance only.  The investigations included a group of 26 patients with acute generalized tetanus, cared for in the Clinic according to a unitary method. A number of 17 prognostic, clinical and laboratory criteria were analyzed from the viewpoint of the pathogenic and clinicoevolutive incidence and significance. According to the severity, lethal course of the disease the following sequence was established in order of gravity: serum sickness, kypokaliemia, hyperpyruvicemia greater than an incubation of less 6 days, invasion within less than 24 hours, hyperlactacidemia greater than age over 60 years, persistent hypertension and tachycardia, hyperazoltemia, hyperglycemia, frequent paroxysmal contractions (before sedation) greater than late admission to hospital, associated cardiopulmonary pathology, hyponatriemia insufficient dressing of the wound and rural environment. The importance of the biological indices is emphasized, both as elements of prognosis and as orientative criteria for the treatment of the case. Although guidelines to prevent surgical site infections (SSIs) were published more than a decade ago, prophylactic antibiotics are still used subjectively in clinical practice. In this study, we evaluated the safety of single-dose preoperative intravenous antibiotics without postoperative antibiotics in the field of clean wound surgery performed under local anesthesia. We also surveyed the present clinical conditions for prophylactic antibiotic use in the plastic surgery departments of training hospitals in Korea. A total of 360 consecutive patients who underwent clean wound surgery under local anesthesia in an outpatient clinic from March 2018 to October 2018 were reviewed. In the study group, a single surgeon administered first-generation cephalosporins intravenously within 1 hour of skin incision and did not prescribe additional antibiotics. In the control group, 2 other surgeons prescribed oral first-generation cephalosporins postoperatively for 2 to 3 days without preoperative antibiotics. A telephone survey about perioperative antibiotic regimens was conducted at the departments of plastic surgery in training hospitals. There were 128 patients in the study group and 232 patients in the control group. There were no significant differences between the 2 groups regarding SSIs and other surgical complications. A total of 41 training hospitals answered the survey and every hospital had protocols of prescribing postoperative oral antibiotics routinely at the time of discharge with a mean duration of 3.9 days. Only 11 hospitals (26.8%) prescribed parenteral antibiotics before surgery as well as postoperative oral antibiotics. Intravenous injection of single-dose first-generation cephalosporins 1 hour before surgery without postoperative antibiotics did not increase the incidence of SSIs compared with the usual practice of giving only postoperative antibiotics prescription for 2 to 3 days in cases of clean wound surgery performed under local anesthesia. Proper antibiotic prophylaxis should be performed by surgeons in training hospitals without hesitation. 150 tetanus cases registered on the region of Murcia have been retrospectively analyzed, they have been collected from the patients admitted at a Intensive Care Unit during a period of 18 years; the clinical together with the epidemiological features, as well as their variations, have been studied through out the years. The impact of a vaccination program in adults which was performed in our region during 1981 has been also evaluated in relationship with the incidence of disease and the economical cost of it. Incidence remained homogeneous until 1982, from that date on a sudden decrease on the number of cases was observed, related with the vaccination program [Period previous to the vaccination program: mean 10 cases/year, versus 5 cases/year since it was started (p &lt; 0.001)]. Regarding the epidemiological characteristics, it is remarkable the shift of the disease toward a more advanced age of onset together with a predominance on females beginning in 1978, but without reaching statically significance. More frequent route of infection is nowadays the intramuscular suppurative injection. Besides this fact the severity of the cases have been increasing (from 59% to 71%, p &lt; 0.005), which has determined that the global mortality of the disease remains almost the same (38%). Mortality has no relationship with age, but is related with being a female (p &lt; 0.05), with intramuscular injection as route of infection (p &lt; 0.025), with the clinical stage (p &lt; 0.001) and with a short incubation period (p &lt; 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) We report on a young man who presented at our emergency unit with pain and swelling of his left hand, after he had been bitten into his left middle finger by a sidewinder rattlesnake one hour ago. Local findings were a swollen left middle finger, a red-livid discoloration along his nail rim with paleness of the surrounding skin. Vital signs were stable, ECG showed sinus rhythm, laboratory parameters were normal, without signs of liver or kidney damage and without coagulopathy. Diagnosis was local tissue reaction due to a snake bite of a sidewinder rattlesnake without evidence of systemic toxic effect. Due to the absence of systemic toxic effects the patient received monitoring of his vital signs and we controlled local tissue reaction constantly and laboratory parameters every 6 hours, as recommended by the \"Giftnotrufzentrale\" (poison emergency advisory service). The patient left hospital on his own will against medical advice in the night after first laboratory control, which showed no signs of organ damage and we recommended reasessment the following morning. At that time the swelling had extended to the whole arm, furthermore large hematoma reaching up to the axilla had developed over night. Again we contacted the \"Giftnotrufzentrale\" and decided to begin the administration of an antivenom, after allergic testing. The administration was without complications, the swelling decreased constantly and since laboratory controll still showed no signs of systemic toxin effect, we could discharge the patient on day 3. Follow-up visit 6 months later showed complete and natural healing. Snake bites are altogether rare among our patients, nevertheless since possible toxin effects and its dynamics are unpredictable and can vary highly, they demand monitoring at close intervals of vitals signs, local swelling and laboratory parameters. As early as possible an advisory service, such as \"Giftnotrufzentrale\" should be contacted to acquire information on possible toxin effects and availability of antivenoms. Contact to other medical disciplines (e.g. dermatology, intensive care unit, surgery, neurology, dialysis…) should be sought, depending on the further course of toxin effects. Possible comorbidities as well as allergisation due to previous bites strongly influence the course of the disease and should be evaluated. We recommend to keep precise records on the ocurrence of systemic toxin effects, as well as on local findings (e.g. fotodocumentation, marking of erythema, measurement of swelling). Manipulation of the wound is usually ineffective and therefore not recommended, also in respect of self-endangerment. After stabilization of the patient a vaccination against tetanus, if necessary, should not be forgotten. This report describes a 4 year prospective study of postoperative wound infections, utilizing a program of wound surveillance. Surgical wounds after 6030 operations of a general surgery service were surveyed by the authors and a specialist nurse, daily and in the follow up clinic for 30 days. Results were reported to all the surgeons monthly. The rates of infections demonstrated a decline over the years of surveillance. In the first year there was a 6.37 percent incidence of infection and the fourth year 4.7 percent. This represents an improvement in hospitalization days and expenses. A case of skin injuries due to stings by crown-of-thorns starfish, Acanthaster planci, in a 53-year-old Okinawan woman is reported. She went to a beach to gather shellfish on 8 April 2001 and fell to the ground with her left palm on a crown-of-thorns starfish that happened to be close to her. She hurried to the emergency section of our hospital. An emergency doctor sterilized the wound and administered an antibiotic, an analgesic agent and an injection of a tetanus antitoxin. He tried to remove the remaining spines from the palm with great difficulty. Because swelling and subcutaneous indurations of the left palm had persisted thereafter, oral and topical administration of corticosteroid started on 13 April. Physical examination at the dermatology section revealed approximately 10 stab wounds of the left palm with pus, subcutaneous bleeding and many abrasions around them. X-rays of the left hand showed foreign bodies, 2-10 mm in size, located on the lesions. The patient was treated with a topical injection of 2 mg triamcinolone acetonide (Kenacort-A), diluted fivefold with 1% Xylocaine, once a week. Some of the foreign body granulomatous lesions improved but pain and subcutaneous indurations persisted in most of the lesions. Because the X-ray photographs showed many remaining spines, surgical excision to remove them was performed under local anesthesia 3 months after the injury. All the symptoms improved after the operation. Scanning electron microscopic examination of the spines revealed that their tips had fragile lattice-like structures. Tetanus prophylaxis in routine wound management is a major strategy for tetanus prevention in health care settings. Failed wound management interventions leave patient dangerously exposed to this disease. We report the case of a patient with tetanus occurred after medical treatment for head injury performed in a healthcare facility without appropriate tetanus prophylaxis. This study aims to remind clinicians of the importance of prophylaxis in previously unvaccinated wounded patients or with a doubtful immune status. A 52-year-old patient who had not previously been vaccinated against tetanus was admitted to Yalgado Ouédraogo University Hospital CHU/YO with cervical pain, dysphagia, difficulty walking and opening the mouth. The patient had a personal history of deep wound on his forehead sutured without previous anti-tetanus prophylaxis approximately three weeks before. Physical examination on admission showed loose lockjaw, abdominal spasm, dysphagia, a body temperature of 36,5 °C and a scar on his forehead measuring about 7 cm. The diagnosis of generalized tetanus (stage II) infection occurring after forehead wound was retained. Treatment outcome was favorable and the patient was dismissed on September 18, 2015. The prevention of tetanus associated with an appropriate treatment requires rigorous application of aseptic techniques, systematization of antitetanus serum therapy in the management of previously unvaccinated patients or with a doubtful immune status presenting with a deep wound. Case 1: A 39-year-old man with chronic lower extremity lymphedema was admitted to the hospital with acute fever, chills, and left lower extremity pain, swelling, and erythema for the third time in as many months. Examination revealed a temperature of 39 degrees C (102.2 degrees F), and erythmatous induration on the left leg (Figure). The patient was treated with IV clindamycin and cefazolin, with clinical improvement. He was discharged with azithromycin, 500 mg daily for 3 days, done twice monthly. Case 2: A 52-year-old morbidly obese man with stasis dermatitis presented with acute lower extremity pain, swelling, and associated fever. He had been taking prophylactic antibiotics for his recurrent cellulitis for more than a decade and had significantly decreased his number of reoccurrences while on this therapy. He was admitted to the hospital, treated with IV cefazolin, and had a rapid improvement over 48 hours. He was subsequently discharged with continued suppressive antibiotic therapy.\nHere is the question:\nEPIDEMIOLOGY AND PREVENTIVE MEDICINE: Luis is a 25-year-old young man who underwent splenectomy after a bicycle accident 1 year ago. He has a dog that bit him 24 hours ago and has caused a small wound on his right hand. He went to his health center (located 3 hours from the nearest hospital) for fever of 39ºC, pain in the wound and general malaise. On examination, BP 100/60 mm Hg, HR 110 beats per minute, slight swelling in the wound without pus. Which of the following actions is most indicated at this time?\nHere are the potential choices:\n1. Send to hospital for rabies and tetanus vaccination and keep under observation.\n2. Clean the wound and administer intramuscular nonspecific ganunaglobulin.\n3. Give 400 mg of oral moxifloxacin and send to the hospital.\n4. Give clindamycin 600 mg oral every 8 hours and observation.\nThe correct answer is: 2. Clean the wound and administer intramuscular nonspecific ganunaglobulin."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n 2.1. History and clinical-gynecological investigation including a Pap smear are the first step in the clarification. The history should make sure if there is in fact bleeding from the genital and not from the urological or the intestinal region. Drug intake should be recorded, and risk factors for the development of endometrial carcinoma should be considered. This will not affect further investigation. The clinical-gynecological investigation should prove the source of postmenopausal bleeding according to the anatomical site--uterine, infra-, or suprauterine. The causes of infrauterine bleeding may easily be diagnosed by means of inspection of the external genitalia and further by using a speculum. The causes of uterine bleeding are of major importance. Cytology and colposcopy, supported by bimanual investigation, exclude cervical carcinoma as a cause of bleeding. Atypical endometrial cells on the cytological smear arouse suspicion of endometrial carcinoma. 2.2. Transvaginal sonography (TVS) is the next step if the above-mentioned investigations are negative. Both adnexa should always be investigated and the findings sonographically documented, so that solid cystic masses in the adnexal area can be better identified as suprauterine causes of postmenopausal bleeding. Then the uterus should be investigated. Further procedures are decided from the results of measurement of the longitudinal section of the endometrium at the level of maximum endometrial thickness. If the endometrial thickness is _&lt;4 mm, an observant attitude can be assumed. After 3 months the patient should be controlled against using TVS. If bleeding recurs or the endometrial thickness is &gt;4 mm on TVS, the procedure given in subparagraph 2.3 should be followed. In case the endometrial thickness is &gt;4mm or not measurable, a histomorphological investigation according to subparagraph 2.3 should be performed. In such cases, saline infusion sonohysterography(SIS) is useful as a simple method to supplement TVS. It can aid in the decision making as to which further, more invasive measures should be taken (endometrial biopsy/hysteroscopic resection). Computerized tomography or magnetic resonance imaging are, as a rule, not indicated in patients with postmenopausal bleeding. 2.3. A definite diagnosis is possible only on the basis of a histological investigation. If TVS or SS show evidence of a polypoid state, removal under hysteroscopic control is the diagnostic method of choice. In cases of symmetrical or asymmetrical thickening of the endometrium on SIS, a less invasive biopsy may be sufficient. If the biopsy specimen does not yield representative diagnostic material, one should proceed as described above. A fractionated curettage should as a rule not be performed solely, but in combination with hysteroscopy. The most frequent symptom suggesting endometrial pathology is uterine bleeding. Each postmenopausal uterine bleeding requires fraction explorative curettage and histopathologic examination of the material obtained from the cervical canal and uterine cavity. The aim of this study was to estimate the efficacy of ultrasonography as a non-invasive method in detection of endometrial pathology in postmenopausal women, and to find out whether its more frequent use could safely decrease the number of curettages in detection of these conditions. A prospective investigation has been performed in postmenopausal women not menstruating for more than a year, and who reported to the Department of Obstetrics and Gynaecology in Novi Sad for uterine bleeding during 1996 and 1997. Each woman underwent ultrasonographic examination by vaginal probe of 5 MHz and fraction curettage, whereas the samples from cervical canal (if obtained) and from uterine cavity were sent to histopathologic examination to the Institute of Pathology in Novi Sad. Standard statistical methods have been used for the analysis of the results. Validity of the applied ultrasonographic method in detecting endometrial pathology has been estimated by calculation of its sensitivity and specificity. A satisfactory visualisation of the endometrium has been obtained in all 35 examined cases. The thinnest endometrium was 1 mm wide and the thickest one was--25 mm. The fraction curettage has been used to obtain material from the cervix in 2 cases and from the uterine cavity in 35 cases. In our patients with uterine bleeding, who were in the postmenopause for 13 years on average, endometrial atrophy was recorded in 17.14%, endometrial polyp in 11.43%, endometrial hyperplasia in 22.86%, endometrial adenocarcinoma in 42.86% and uterine sarcoma in 5.71%. There were 2 false negative ultrasonographic findings (2 cases of endometrial hyperplasia) and sonographic thickness less than standard versus 2 false positive cases (endometrium thicker than the limit value, 7 and 14 mm, with no real pathology) which showed that the sensitivity of the investigated method was 93.10% and the specificity was 66.66%, if the limit value for the thickness of endometrium was 3 mm. Ultrasonographic thickness of endometrium means maximum double thickness in longitudinal plane, i.e. the distance of the opposite bordering surfaces of endometrium and myometrium. The procedure of measurements of endometrial thickness is simple in most cases. Most authors agree that there is a positive correlation between the thickness of endometrium and its pathological conditions. The most often used limit values are 3 and 4 mm. Higher limit values of endometrial thickness increase the sensitivity of the method even to 100%, but negatively affect its specificity making this method inadequate as a screening method for endometrial carcinoma. Many authors insist on introducing other criteria for evaluation of the endometrium i.e. for taking its thickness as the only criterion. Ultrasonography does not provide a completely safe differentiation between benign hyperplasia and endometrial carcinoma. The transvaginal sonography is an efficient and acceptable, noninvasive method for early detection of endometrial pathology in postmenopausal women. The thickened endometrium during menopause is the most significant ultrasonographic criterion implicating its pathology. The vaginosonographically measured thickness of 3 mm and less, gives a relatively safe prediction of endometrial atrophy, whereas the thickness above 3 mm requires explorative curettage and histopathologic examination of the endometrium, no matter if the woman has or has not uterine bleeding. (ABSTRACT TRUNCATED) The study comprises 96042 cytologic cases within a period of 10 years. After screening women were admitted for biopsies. The histologic findings are reported. By 690 \"right positive smears\" 71 squamous cell cervical cancers stage Ib or more 87 microcarcinomata-1, 377 carcinomata-in-situ of the cervix, 100 dysplasias, 47 adenocarcinomata and 8 different malign tumors were found. 61 cases having histologic diagnosis outside are just mentioned. 629 cases which had been diagnosed in our hospital are described extensively. The first biopsy was nearly always taken by selective scraping of the ecto- and endocervix. Technical improvements of this method are explained. The efficiency of cytodiagnosis is especially pointed out by separating cases which could have been recognized or suspected by means of inspection or colposcopy only. 140 out of 282 carcinomata-in-situ and 7 invasive, mainly endocervical cancers (Ib-III), could only be diagnosed by a smear. In 17 woemn who turned out to have invasive cancer (Ib -III) a positive smear was the only reason for admission. Careful inspection of the cervix in the hospital, however, was sufficent to reveal the correct diagnosis. In our material the cervical smear could be of little help in cancer diagnosis of the upper genital tract such as adenocarcinoma of the corpus uteri, sarcoma and ovarian cancer. 39 of the 45 women with endometrial cancer cells in the specimen had bleeding anomalies, especially postmenopausal. The number of \"false negative smears\" mainly yields from histologic examination of 2415 uteri after hysterectomy and 4497 specimen after curettage of cervix and corpus uteri. In the first group 1 microcarcinoma-2 and 5 carcinomata-in-situ, in the second group which obviously is less representative 4 carcinomata-in-situ were found unexpectedly. It is also searched for cases which had a negative smear first and a positive or suspect smear later. This happened in 41 patients. The underlying lesion were 5 advanced cancers, 2 microcarcinomata-3 and 34 carcinomata-in-situ. Up to 30 months elapsed between the last negative cytologic finding and histologic diagnosis. 121 out of 811 suspect or positive smears were \"false positive\". Cytologic grouping III, IV and V inconsistently matched with the corresponding histologic results. The type and extension of squamous cell atypias are anticipated with little certainty. The great number of suspect specimen (group III) both in microcarcinoma-4 (6 in 78) and carcinoma-in-situ (33 in 344) was striking. Therefore we consider a histologic diagnosis to be necessary in this group as well as in group IV and V. The method of fractioned cervical scraping makes the decision of hospital admission easier. Low risk for the patient does not imply any loss in diagnostic security. Colposcopy: If the results of a cervical cancer screening test, such as Pap smear or HPV test, are abnormal this more thorough examination of the cervix and vaginal tissues may be needed. Loop electrical excision procedure (LEEP): a procedure to quickly remove abnormal vaginal tissue within the cervix. A local anesthetic and a solution to enhance the points of removal visually is administered during the process. There is a chance of experiencing watery, pinkish discharge, brownish discharge, and mild cramping. Endometrial biopsy: a procedure that collects a tissue sample from the endometrium lining of the uterus. The sample is tested and checked under a microscope for abnormals cells or indicators of cancer. IUD insertion: an intrauterine device that is T-shaped and is placed in the uterus through the cervix. It is a reversible contraceptive that can be done in a doctor's office. Diagnosis The NICE guidelines states that: \"Many women presenting to primary care with symptoms of HMB can be offered treatment without the need for further examination or investigation. However, investigation via a diagnostic technique might be warranted for women for whom history or examination suggests a structural or endometrial pathology or for whom the initial treatment has failed.\" Diagnosis is largely achieved by obtaining a complete medical history followed by physical exam and vaginal ultrasonography. If need be, laboratory tests or hysteroscopy may be used. The following are a list of diagnostic procedures that medical professionals may use to identify the cause of the abnormal uterine bleeding. Pelvic and rectal examination to ensure that bleeding is not from lower reproductive tract (i.e. vagina, cervix) or rectum Pap smear to rule out cervical neoplasia Pelvic ultrasound scan is the first line diagnostic tool for identifying structural abnormalities. Transvaginal ultrasound to examine the endometrial thickness in women with postmenopausal bleeding is increasingly being used to aid in the diagnosis of endometrial cancer in the United States. In the United Kingdom, both an endometrial biopsy and a transvaginal ultrasound used in conjunction are the standard of care for diagnosing endometrial cancer. The homogeneity of the tissue visible on transvaginal ultrasound can help to indicate whether the thickness is cancerous. Ultrasound findings alone are not conclusive in cases of endometrial cancer, so another screening method (for example endometrial biopsy) must be used in conjunction. Other imaging studies are of limited use. CT scans are used for preoperative imaging of tumors that appear advanced on physical exam or have a high-risk subtype (at high risk of metastasis). They can also be used to investigate extrapelvic disease. An MRI can be of some use in determining if the cancer has spread to the cervix or if it is an endocervical Procedure Generally, an endometrial biopsy follows this process: The patient is asked to lie on the table with her feet in the stirrups for a pelvic examination. She may or may not be given localized anesthesia. A speculum will be inserted into the vagina to spread the walls of the vagina apart to expose the cervix. The cervix will then be cleansed with an antiseptic solution. A tenaculum, a type of forceps, will hold the cervix steady for the biopsy. The biopsy curette will be inserted into the uterine fundus and with a scraping and rotating motion some tissue will be removed. The removed tissue will be placed in formalin or equivalent for preservation. The tissue will be sent to a laboratory, where it will be processed and tested. It will then be read microscopically by a pathologist who will provide a histologic diagnosis. 1. Diagnostic value of ultrasonic endometrium thickness measurement and estimation of ultrasonic endometrium qualitative features in detecting of pathological changes at women in perimenopausal period. 2. Estimation of comparative estrogens and testosterone level in diagnostic of endometrial changes at women in postmenopausal period. 3. Qualification usefulness of analysis of macroscopic hysteroscopy uterine cavity image in detecting of pathological changes at women in perimenopausal period. 4. Comparative analysis of fractional curettage and hysteroscopy as a method of receiving material from uterus to histological estimation at women in perimenopausal period. Material to investigations consist of 242 patients in age 40-86 years, which were divided into groups in dependence from obtained diagnosis on the ground histological estimation sampling received from uterus (BZ--\"without changes\", M--submucosus myomas, P--endometrial polyps, H--endometrial hyperplasia, CA--endometrial carcinoma). In all of women transvaginal ultrasonic estimation of endometrium (TVS) and fractional curettage were executed. In 160 from them also hysteroscopy with endometrial biopsy was performed. In 53 women in postmenopausal period not using of hormonal replacement therapy one marked concentration estron (E1), estradiol (E2) and testosterone (T) in serum of blood. TVS were performed using a transducer with an emission frequency of 7.0 MHz (B &amp; K Medical 3535). Serum concentration of testosterone and estradiol were executed with EIA assay, however concentration of estron with RIA assays. To endoscopic investigations diagnostic and operative hysteroscops and resectoscope were used. Average thickness of endometrium in group CA, H and P (properly 8.96 and 6.09 and 5.02 mm) showed essential differences in comparison with group BZ (3.38 mm, Tab. 1). In group CA and H greatest cumulation of abnormal features of TVS image (endometrial thickness &gt; 2.5 mm, hyperechoic, heterogeneous and containing cystic spaces endometrium, deformation of middle echo, indistinctness of endo-myometrial border, presence of focal changes in structure of endometrium and presence of fluid in uterine cavity &gt; 1 cm3) was ascertained (Tab. 2, 3, 4). Hysteroscopic macroscopic image showed conformity with histological estimation in groups BZ, M, P, H and CA properly in 78.35, 93.75, 88.33, 22.22 and 88.33% (Tab. 7). On base of histological estimation 159 (65.7% of chances) of pathological changes (P-68, CA-37, M-32, H-22 chances) were detected (Tab. 8). Among them were 41 of asymptomatic chances (P-24, M-7, H-6, CA-4 chances). In hysteroscopy, all but one chance of pathological changes were detected, however curettage skipped most of focal changes. 1. Ultrasonic measurement of endometrial thickness is sensitive index in detecting cancer and pathological endometrial hyperplasia, instead possesses smaller value in detecting of endometrial polyps and endometrial myomas. 2. Connection of measurement of endometrial thickness with estimation of qualitative features of endometrial and uterine cavity TVS image improves results of detecting all of types intrauterine pathology. 3. Dependence between estrogens level and with thickness of endometrium was confirmed. Practical value of hormonal estimations in diagnostics of endometrial pathological changes is however not large. 4. Analysis of hysteroscopic picture is characterised high agreement with histological investigation with reference to endometrial cancer, endometrial polyps and submucosus myomas. 5. Hysteroskopy with direct biopsy possesses superiority over curettage in detecting all of types of intrauterine pathology, in particular focal changes. 6. Hysteroscopy should determine method of choice at women with recurrent bleedings from uterus, which with curettage pathological changes did not detect. Examination Routine screening of asymptomatic people is not indicated since the disease is highly curable in its early, symptomatic stages. Instead, women, particularly menopausal women, should be aware of the symptoms and risk factors of endometrial cancer. A cervical screening test, such as a Pap smear, is not a useful diagnostic tool for endometrial cancer because the smear will be normal 50% of the time. A Pap smear can detect disease that has spread to the cervix. Results from a pelvic examination are frequently normal, especially in the early stages of disease. Changes in the size, shape or consistency of the uterus or its surrounding, supporting structures may exist when the disease is more advanced. Cervical stenosis, the narrowing of the cervical opening, is a sign of endometrial cancer when pus or blood is found collected in the uterus (pyometra or hematometra). The pelvic exam during pregnancy is similar to the exam for non-pregnant women. One difference is that more attention is give to the uterus and cervix. The growth of the uterus is measured each visit, although this does not require a pelvic exam. As the due date approaches, the assessment of the cervix will indicate whether labor has begun or is progressing. Much time is spent determining the health of the fetus. A normal finding during the exam on the pregnant patient is that the cervix has a bluish tinge in early pregnancy. If a bluish tinge is observed in non-pregnant women, this is a sign of hypoxia. See also Well-woman examination Pap test Trauma-Informed Care References Female genital procedures The spread of cervical squamous cell carcinoma to the inner surface of the uterus with replacement of the endometrium is rare. Continuity of the lesion must be demonstrated to confirm superficial spread and rule out concomitant endometrial cancer. We present the case of a 66-year-old white woman with superficial spreading squamous cell carcinoma of the cervix that involved the endometrium. Her relevant past history included conization of the cervix to treat cervical intraepithelial neoplasia III with positive margins. She subsequently had three negative cervical vaginal cytology results, each with a positive high-risk human papillomavirus test. Transvaginal ultrasound showed occupation of the entire uterine cavity by dense material consistent with pyometra in addition to myometrial thinning due to tension and cervical dilation. The patient presented with greenish vaginal discharge of 3 months' duration. The cervix was not visible during speculum examination. Access for endometrial sampling was not possible, raising suspicion of post-conization cervical stenosis. The patient was treated with laparoscopic hysterectomy with double adnexectomy. Histologic examination showed superficial squamous cell carcinoma invading the cervix to a depth of 2.8 mm; superficial spreading squamous cell carcinoma in situ was also observed in the lower uterine segment and endometrium. The patient was free of symptoms 12 months after surgery. Squamous cell carcinoma of the cervix with superficial spread to the endometrium is not included in the 2020 (fifth edition) World Health Organization Classification of Female Genital Tract Tumors or the 2018 International Federation of Gynecology and Obstetrics cervical cancer staging system. More clinical cases are needed to identify other prognostic factors and inform clinical practice guidelines on the management of this disease. The aim of the authors is to show the data for the reception diagnosis, age, histological results and the conduct after the performed diagnostic hysteroscopies in Gynecological clinic of UMBAL-Pleven. For the fulfillment of this aim was made a prospective study for 7 years' period: from 01/01/1997 to 31/01/2003. The objects of observation were 74 women of age from 16 to 65 years, with performed hysteroscopies for gynecologic complaints. There were performed 74 diagnostic hysteroscopies for the studied period. The hysteroscopic findings were 20 cases with endometrial polyposis, 14--submucosal myoamatic nodes, deforming the uterine cavity, 4--cervical polyp, 19--increased endometrium, 9--Asherman syndrome, 1--bicomous uterus, 1--a suspected section for endometrial carcinoma and 6 cases without pathologic findings. There were performed 59 trial abrasions and the removed materials were sent for histological examination The performed comparative analysis between the hysteroscopic presentation and histological findings showed a coincidence of the diagnosis. It was made the conclusion, that the hysteroscopy is an easy, accessible and inexpensive diagnostic method, which must take its place as one of the basic contemporary diagnostic methods in gynecology. To introduce a special case of endometrial cavity fluid (ECF), highlighting the application of hysteroscopy and laparoscopic surgical techniques in the treatment of cervical sinus tract. Narrated video featuring the diagnosis and surgical management of a case of recurrent ECF. Informed consent was obtained from the patient, and approval was granted by the ethics committee of the First Affiliated Hospital of the Wenzhou Medical University. Academic tertiary hospital. A 36-year-old woman, gravida 0, had menstrual spotting for 13 years after abdominal myomectomy of a 104 × 86 × 111-mm myoma on the posterior uterine wall near the cervix. She failed to conceive after her marriage for 10 years, and 5 operations, including hysteroscopy and laparoscopy, were performed to increase pregnancy opportunities. She also underwent in vitro fertilization and embryo transfer procedures many times, but failed. Transvaginal sonography preoperatively suggested that ECF sometimes appeared and sometimes disappeared. The local echo of the posterior wall of the cervix was enhanced. A 40-mm cystic dark area was found beside the right ovary, which seemed to connect with the cervical hyperechoic part. Additionally, a solid mass of the right adnexa with abundant blood supply was detected. First, hysteroscopy was performed to explore the ECF. A deep and narrow cervical sinus with a steady stream of accumulated blood overflowed in the lower part of the cervix, and a normal uterine cavity was found. Laparoscopic adhesiolysis and enucleation of the cystic structure that connected to the sinus tract then were performed. Hysteroscopy was repeated to determine the thinnest cervical region by the light transmission test. A horizontal incision was made on the thinnest layer. Scar tissues were removed. The incision was sutured in full layer intermittently and continuously under laparoscopy. The postoperative thickness of the muscular layer in the sinus was confirmed by light transmission test of hysteroscopy. The patient was discharged on the third day after operation, uneventfully. Histopathologic examination showed that the cystic structure and scar tissue contained smooth muscle tissue and were covered by both mucinous columnar epithelium of the cervical canal and endometrial glandular epithelium. Restoration of normal anatomy, removal of uterine effusion, and symptomatic relief. At the 6-month follow-up, the patient's menstrual cycles returned to normal without the recurrence of menstrual spotting. The ultrasound scan also showed a symmetrical uterus without ECF. Patients with ECF who underwent assisted reproductive surgeries were related to the poor prognosis. However, the treatment should be different according to the causes, appearance time, and accumulation amount, including expectant treatment, postponement of embryo transfer, transvaginal aspiration, laparoscopic salpingectomy, or proximal tubal occlusion. For patients with recurrent ECF and/or special appearance on ultrasound, endoscopic examination is necessary. In addition, patients with large myomas at difficult locations required a uniform strategy to reduce the intraoperative and postoperative complications, especially for the nulligravida women. The aim of the study was to compare the accuracy of hydrosonography with that of transvaginal ultrasonography in detection of intracavitary pathologies in patients with history of abnormal uterine bleeding. Prospective, randomized, and unblinded study. A total of 197 women (n = 130 premenopausal and n = 67 postmenopausal) aged between 23 and 71 years (mean age 45.7 +/- 8.9) presenting with a history of abnormal uterine bleeding were included into the study. Hydrosonography was carried out by experienced gynecologists, on the same setting in an outpatient clinic immediately after the performance of transvaginal sonography. The finally obtained surgical-pathologic findings were compared with the results obtained from transvaginal sonography and hydrosonography. Sensitivity, specificity, positive, and negative predictive values were calculated for each procedure. The surgical-pathologic examination confirmed normal physiologic endometrium in 50 (48%) of 104 women who were said to have normal endometrium on transvaginal sonography. Seventy (75%) of 93 women diagnosed of intracavitary pathologies on transvaginal sonography were confirmed by surgical-pathologic findings. The sensitivity, specificity, positive predictive value, and negative predictive value of transvaginal sonography in the detection of intracavitary pathology were 56, 68, 75, and 48%, respectively. Surgical-pathologic results revealed intracavitary pathologies in 23 (30%) of 76 women who were said to have normal endometrium on hydrosonography. Among 121 women diagnosed of intracavitary pathologies on hydrosonography, 101 (81%) women were confirmed after histological evaluation of the surgical specimens. The sensitivity, specificity, positive predictive value, and negative predictive value of hydrosonography in the detection of intracavitary pathology were 81, 73, 83, and 70%, respectively. Sensitivity and negative predictive value were significantly higher with hydrosonography. There were five cases of endometrial malignancy in which one of the case of malignancy was on polyp and two cases of endometrial hyperplasia with atypia which were not stated on sonographic results. Hydrosonography is more accurate than transvaginal ultrasography in the detection of intracavitary pathologies in women with abnormal uterine bleeding. To report the combined hysteroscopic and laparoscopic treatment of a complete septate uterus with unilateral cervical aplasia (class U2bC3V0/ESHRE/ESGE classification) and isolated mullerian remnants. Step-by-step presentation of the surgical treatment (Canadian Task Force classification 4). Complete septate uterus with unilateral cervical aplasia (formally Robert's uterus) is characterized by the presence of a uterine septum completely dividing the endometrial cavity into an obstructed hemicavity and a contralateral nonobstructing hemicavity connected normally to the existing cervix. It has always been described as isolated without any associated anomaly. A 30-year-old woman was referred to our department for dysmenorrhea and primary infertility. Hysterosalpingography showed the presence of a right (RT) hemiuterus with a patent fallopian tube; further evaluation with 2- and 3-dimensional ultrasound and magnetic resonance imaging showed an externally normal-appearing uterus, a right normal hemicavity connected normally with the existed cervix and, a left hemicavity fully divided from the right one by a complete septum and not connected with the cervix. Interestingly, a peculiar complex mass with cystic areas, attached posterolaterally from the left side to the uterine wall at the level of the isthmus and the upper cervix, was also diagnosed. The study protocol was approved by our local institutional review board. During outpatient hysteroscopy, a right uterine hemicavity with a single ostium was identified without any communication with the left hemicavity. The patient was then scheduled for combined laparoscopic and hysteroscopic treatment. During laparoscopy, a normal uterine body with multiple myomas and a pseudocystic lesion attached posteriorly and left laterally to the uterus at the level of the isthmus and the upper cervix were shown; no communication between the cystic part of that lesion and the isthmus or the cervicovaginal canal was observed. During hysteroscopy, a longitudinal incision of the septum with a 5F bipolar electrode was performed; the left hemicavity was opened, and the corresponding tubal ostium was identified. The pseudocystic lesion was then excised after opening and sent for pathological analysis; the defect was closed with interrupted intracorporeal knots. A single normal endometrial cavity with both tubal ostia was obtained, thus restoring obstruction by unification of the uterine cavity. A histologic report of the removed pseudocystic lesion was compatible with the diagnosis of mullerian remnants. A follow-up hysteroscopy 3 months after showed a normal uterine cavity without postsurgical adhesions. The use of 3-dimensional ultrasound and magnetic resonance imaging in combination with the new ESHRE/ESGE classification system gives the opportunity to obtain a precise representation of the female genital anatomy even in the presence of complex anomalies. Although a septate uterus with unilateral cervical aplasia has been already described, the presence of mullerian remnants is a rare entity associated with cyclic pelvic pain, thus needing adequate recognition and treatment. The combined hysteroscopic and laparoscopic approach offers a unique opportunity for the treatment of complex anomalies.\nHere is the question:\nGYNECOLOGY AND OBSTETRICS: A 67-year-old patient with a history of menopause at 55 years of age, 3 pregnancies with 3 euthyroid deliveries, type 2 diabetes of 6 years of evolution, treatment with nifedipone for hypertension. She consulted for intermittent scanty metrorrhagia of 2 months of evolution. The gynecological examination showed external genitalia without lesions, an atrophic cervix, a normal uterus and appendages on palpation and a normal cytological study of the cervix. The transvaginal ultrasound study shows a 7 mm hyperechogenic endometrium. Which of the following tests is the most appropriate and most sensitive to establish a diagnosis?\nHere are the potential choices:\n1. Conization of the cervix.\n2. Endometrial cytology.\n3. Hysteroscopy and endometrial biopsy.\n4. Magnetic resonance imaging of the pelvis.\n5. Examination under anesthesia of the genital tract and biopsy of the cervix and endometrium.\nThe correct answer is: ",
        "gold_answer": "3 Hysteroscopy and endometrial biopsy.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n 2.1. History and clinical-gynecological investigation including a Pap smear are the first step in the clarification. The history should make sure if there is in fact bleeding from the genital and not from the urological or the intestinal region. Drug intake should be recorded, and risk factors for the development of endometrial carcinoma should be considered. This will not affect further investigation. The clinical-gynecological investigation should prove the source of postmenopausal bleeding according to the anatomical site--uterine, infra-, or suprauterine. The causes of infrauterine bleeding may easily be diagnosed by means of inspection of the external genitalia and further by using a speculum. The causes of uterine bleeding are of major importance. Cytology and colposcopy, supported by bimanual investigation, exclude cervical carcinoma as a cause of bleeding. Atypical endometrial cells on the cytological smear arouse suspicion of endometrial carcinoma. 2.2. Transvaginal sonography (TVS) is the next step if the above-mentioned investigations are negative. Both adnexa should always be investigated and the findings sonographically documented, so that solid cystic masses in the adnexal area can be better identified as suprauterine causes of postmenopausal bleeding. Then the uterus should be investigated. Further procedures are decided from the results of measurement of the longitudinal section of the endometrium at the level of maximum endometrial thickness. If the endometrial thickness is _&lt;4 mm, an observant attitude can be assumed. After 3 months the patient should be controlled against using TVS. If bleeding recurs or the endometrial thickness is &gt;4 mm on TVS, the procedure given in subparagraph 2.3 should be followed. In case the endometrial thickness is &gt;4mm or not measurable, a histomorphological investigation according to subparagraph 2.3 should be performed. In such cases, saline infusion sonohysterography(SIS) is useful as a simple method to supplement TVS. It can aid in the decision making as to which further, more invasive measures should be taken (endometrial biopsy/hysteroscopic resection). Computerized tomography or magnetic resonance imaging are, as a rule, not indicated in patients with postmenopausal bleeding. 2.3. A definite diagnosis is possible only on the basis of a histological investigation. If TVS or SS show evidence of a polypoid state, removal under hysteroscopic control is the diagnostic method of choice. In cases of symmetrical or asymmetrical thickening of the endometrium on SIS, a less invasive biopsy may be sufficient. If the biopsy specimen does not yield representative diagnostic material, one should proceed as described above. A fractionated curettage should as a rule not be performed solely, but in combination with hysteroscopy. The most frequent symptom suggesting endometrial pathology is uterine bleeding. Each postmenopausal uterine bleeding requires fraction explorative curettage and histopathologic examination of the material obtained from the cervical canal and uterine cavity. The aim of this study was to estimate the efficacy of ultrasonography as a non-invasive method in detection of endometrial pathology in postmenopausal women, and to find out whether its more frequent use could safely decrease the number of curettages in detection of these conditions. A prospective investigation has been performed in postmenopausal women not menstruating for more than a year, and who reported to the Department of Obstetrics and Gynaecology in Novi Sad for uterine bleeding during 1996 and 1997. Each woman underwent ultrasonographic examination by vaginal probe of 5 MHz and fraction curettage, whereas the samples from cervical canal (if obtained) and from uterine cavity were sent to histopathologic examination to the Institute of Pathology in Novi Sad. Standard statistical methods have been used for the analysis of the results. Validity of the applied ultrasonographic method in detecting endometrial pathology has been estimated by calculation of its sensitivity and specificity. A satisfactory visualisation of the endometrium has been obtained in all 35 examined cases. The thinnest endometrium was 1 mm wide and the thickest one was--25 mm. The fraction curettage has been used to obtain material from the cervix in 2 cases and from the uterine cavity in 35 cases. In our patients with uterine bleeding, who were in the postmenopause for 13 years on average, endometrial atrophy was recorded in 17.14%, endometrial polyp in 11.43%, endometrial hyperplasia in 22.86%, endometrial adenocarcinoma in 42.86% and uterine sarcoma in 5.71%. There were 2 false negative ultrasonographic findings (2 cases of endometrial hyperplasia) and sonographic thickness less than standard versus 2 false positive cases (endometrium thicker than the limit value, 7 and 14 mm, with no real pathology) which showed that the sensitivity of the investigated method was 93.10% and the specificity was 66.66%, if the limit value for the thickness of endometrium was 3 mm. Ultrasonographic thickness of endometrium means maximum double thickness in longitudinal plane, i.e. the distance of the opposite bordering surfaces of endometrium and myometrium. The procedure of measurements of endometrial thickness is simple in most cases. Most authors agree that there is a positive correlation between the thickness of endometrium and its pathological conditions. The most often used limit values are 3 and 4 mm. Higher limit values of endometrial thickness increase the sensitivity of the method even to 100%, but negatively affect its specificity making this method inadequate as a screening method for endometrial carcinoma. Many authors insist on introducing other criteria for evaluation of the endometrium i.e. for taking its thickness as the only criterion. Ultrasonography does not provide a completely safe differentiation between benign hyperplasia and endometrial carcinoma. The transvaginal sonography is an efficient and acceptable, noninvasive method for early detection of endometrial pathology in postmenopausal women. The thickened endometrium during menopause is the most significant ultrasonographic criterion implicating its pathology. The vaginosonographically measured thickness of 3 mm and less, gives a relatively safe prediction of endometrial atrophy, whereas the thickness above 3 mm requires explorative curettage and histopathologic examination of the endometrium, no matter if the woman has or has not uterine bleeding. (ABSTRACT TRUNCATED) The study comprises 96042 cytologic cases within a period of 10 years. After screening women were admitted for biopsies. The histologic findings are reported. By 690 \"right positive smears\" 71 squamous cell cervical cancers stage Ib or more 87 microcarcinomata-1, 377 carcinomata-in-situ of the cervix, 100 dysplasias, 47 adenocarcinomata and 8 different malign tumors were found. 61 cases having histologic diagnosis outside are just mentioned. 629 cases which had been diagnosed in our hospital are described extensively. The first biopsy was nearly always taken by selective scraping of the ecto- and endocervix. Technical improvements of this method are explained. The efficiency of cytodiagnosis is especially pointed out by separating cases which could have been recognized or suspected by means of inspection or colposcopy only. 140 out of 282 carcinomata-in-situ and 7 invasive, mainly endocervical cancers (Ib-III), could only be diagnosed by a smear. In 17 woemn who turned out to have invasive cancer (Ib -III) a positive smear was the only reason for admission. Careful inspection of the cervix in the hospital, however, was sufficent to reveal the correct diagnosis. In our material the cervical smear could be of little help in cancer diagnosis of the upper genital tract such as adenocarcinoma of the corpus uteri, sarcoma and ovarian cancer. 39 of the 45 women with endometrial cancer cells in the specimen had bleeding anomalies, especially postmenopausal. The number of \"false negative smears\" mainly yields from histologic examination of 2415 uteri after hysterectomy and 4497 specimen after curettage of cervix and corpus uteri. In the first group 1 microcarcinoma-2 and 5 carcinomata-in-situ, in the second group which obviously is less representative 4 carcinomata-in-situ were found unexpectedly. It is also searched for cases which had a negative smear first and a positive or suspect smear later. This happened in 41 patients. The underlying lesion were 5 advanced cancers, 2 microcarcinomata-3 and 34 carcinomata-in-situ. Up to 30 months elapsed between the last negative cytologic finding and histologic diagnosis. 121 out of 811 suspect or positive smears were \"false positive\". Cytologic grouping III, IV and V inconsistently matched with the corresponding histologic results. The type and extension of squamous cell atypias are anticipated with little certainty. The great number of suspect specimen (group III) both in microcarcinoma-4 (6 in 78) and carcinoma-in-situ (33 in 344) was striking. Therefore we consider a histologic diagnosis to be necessary in this group as well as in group IV and V. The method of fractioned cervical scraping makes the decision of hospital admission easier. Low risk for the patient does not imply any loss in diagnostic security. Colposcopy: If the results of a cervical cancer screening test, such as Pap smear or HPV test, are abnormal this more thorough examination of the cervix and vaginal tissues may be needed. Loop electrical excision procedure (LEEP): a procedure to quickly remove abnormal vaginal tissue within the cervix. A local anesthetic and a solution to enhance the points of removal visually is administered during the process. There is a chance of experiencing watery, pinkish discharge, brownish discharge, and mild cramping. Endometrial biopsy: a procedure that collects a tissue sample from the endometrium lining of the uterus. The sample is tested and checked under a microscope for abnormals cells or indicators of cancer. IUD insertion: an intrauterine device that is T-shaped and is placed in the uterus through the cervix. It is a reversible contraceptive that can be done in a doctor's office. Diagnosis The NICE guidelines states that: \"Many women presenting to primary care with symptoms of HMB can be offered treatment without the need for further examination or investigation. However, investigation via a diagnostic technique might be warranted for women for whom history or examination suggests a structural or endometrial pathology or for whom the initial treatment has failed.\" Diagnosis is largely achieved by obtaining a complete medical history followed by physical exam and vaginal ultrasonography. If need be, laboratory tests or hysteroscopy may be used. The following are a list of diagnostic procedures that medical professionals may use to identify the cause of the abnormal uterine bleeding. Pelvic and rectal examination to ensure that bleeding is not from lower reproductive tract (i.e. vagina, cervix) or rectum Pap smear to rule out cervical neoplasia Pelvic ultrasound scan is the first line diagnostic tool for identifying structural abnormalities. Transvaginal ultrasound to examine the endometrial thickness in women with postmenopausal bleeding is increasingly being used to aid in the diagnosis of endometrial cancer in the United States. In the United Kingdom, both an endometrial biopsy and a transvaginal ultrasound used in conjunction are the standard of care for diagnosing endometrial cancer. The homogeneity of the tissue visible on transvaginal ultrasound can help to indicate whether the thickness is cancerous. Ultrasound findings alone are not conclusive in cases of endometrial cancer, so another screening method (for example endometrial biopsy) must be used in conjunction. Other imaging studies are of limited use. CT scans are used for preoperative imaging of tumors that appear advanced on physical exam or have a high-risk subtype (at high risk of metastasis). They can also be used to investigate extrapelvic disease. An MRI can be of some use in determining if the cancer has spread to the cervix or if it is an endocervical Procedure Generally, an endometrial biopsy follows this process: The patient is asked to lie on the table with her feet in the stirrups for a pelvic examination. She may or may not be given localized anesthesia. A speculum will be inserted into the vagina to spread the walls of the vagina apart to expose the cervix. The cervix will then be cleansed with an antiseptic solution. A tenaculum, a type of forceps, will hold the cervix steady for the biopsy. The biopsy curette will be inserted into the uterine fundus and with a scraping and rotating motion some tissue will be removed. The removed tissue will be placed in formalin or equivalent for preservation. The tissue will be sent to a laboratory, where it will be processed and tested. It will then be read microscopically by a pathologist who will provide a histologic diagnosis. 1. Diagnostic value of ultrasonic endometrium thickness measurement and estimation of ultrasonic endometrium qualitative features in detecting of pathological changes at women in perimenopausal period. 2. Estimation of comparative estrogens and testosterone level in diagnostic of endometrial changes at women in postmenopausal period. 3. Qualification usefulness of analysis of macroscopic hysteroscopy uterine cavity image in detecting of pathological changes at women in perimenopausal period. 4. Comparative analysis of fractional curettage and hysteroscopy as a method of receiving material from uterus to histological estimation at women in perimenopausal period. Material to investigations consist of 242 patients in age 40-86 years, which were divided into groups in dependence from obtained diagnosis on the ground histological estimation sampling received from uterus (BZ--\"without changes\", M--submucosus myomas, P--endometrial polyps, H--endometrial hyperplasia, CA--endometrial carcinoma). In all of women transvaginal ultrasonic estimation of endometrium (TVS) and fractional curettage were executed. In 160 from them also hysteroscopy with endometrial biopsy was performed. In 53 women in postmenopausal period not using of hormonal replacement therapy one marked concentration estron (E1), estradiol (E2) and testosterone (T) in serum of blood. TVS were performed using a transducer with an emission frequency of 7.0 MHz (B &amp; K Medical 3535). Serum concentration of testosterone and estradiol were executed with EIA assay, however concentration of estron with RIA assays. To endoscopic investigations diagnostic and operative hysteroscops and resectoscope were used. Average thickness of endometrium in group CA, H and P (properly 8.96 and 6.09 and 5.02 mm) showed essential differences in comparison with group BZ (3.38 mm, Tab. 1). In group CA and H greatest cumulation of abnormal features of TVS image (endometrial thickness &gt; 2.5 mm, hyperechoic, heterogeneous and containing cystic spaces endometrium, deformation of middle echo, indistinctness of endo-myometrial border, presence of focal changes in structure of endometrium and presence of fluid in uterine cavity &gt; 1 cm3) was ascertained (Tab. 2, 3, 4). Hysteroscopic macroscopic image showed conformity with histological estimation in groups BZ, M, P, H and CA properly in 78.35, 93.75, 88.33, 22.22 and 88.33% (Tab. 7). On base of histological estimation 159 (65.7% of chances) of pathological changes (P-68, CA-37, M-32, H-22 chances) were detected (Tab. 8). Among them were 41 of asymptomatic chances (P-24, M-7, H-6, CA-4 chances). In hysteroscopy, all but one chance of pathological changes were detected, however curettage skipped most of focal changes. 1. Ultrasonic measurement of endometrial thickness is sensitive index in detecting cancer and pathological endometrial hyperplasia, instead possesses smaller value in detecting of endometrial polyps and endometrial myomas. 2. Connection of measurement of endometrial thickness with estimation of qualitative features of endometrial and uterine cavity TVS image improves results of detecting all of types intrauterine pathology. 3. Dependence between estrogens level and with thickness of endometrium was confirmed. Practical value of hormonal estimations in diagnostics of endometrial pathological changes is however not large. 4. Analysis of hysteroscopic picture is characterised high agreement with histological investigation with reference to endometrial cancer, endometrial polyps and submucosus myomas. 5. Hysteroskopy with direct biopsy possesses superiority over curettage in detecting all of types of intrauterine pathology, in particular focal changes. 6. Hysteroscopy should determine method of choice at women with recurrent bleedings from uterus, which with curettage pathological changes did not detect. Examination Routine screening of asymptomatic people is not indicated since the disease is highly curable in its early, symptomatic stages. Instead, women, particularly menopausal women, should be aware of the symptoms and risk factors of endometrial cancer. A cervical screening test, such as a Pap smear, is not a useful diagnostic tool for endometrial cancer because the smear will be normal 50% of the time. A Pap smear can detect disease that has spread to the cervix. Results from a pelvic examination are frequently normal, especially in the early stages of disease. Changes in the size, shape or consistency of the uterus or its surrounding, supporting structures may exist when the disease is more advanced. Cervical stenosis, the narrowing of the cervical opening, is a sign of endometrial cancer when pus or blood is found collected in the uterus (pyometra or hematometra). The pelvic exam during pregnancy is similar to the exam for non-pregnant women. One difference is that more attention is give to the uterus and cervix. The growth of the uterus is measured each visit, although this does not require a pelvic exam. As the due date approaches, the assessment of the cervix will indicate whether labor has begun or is progressing. Much time is spent determining the health of the fetus. A normal finding during the exam on the pregnant patient is that the cervix has a bluish tinge in early pregnancy. If a bluish tinge is observed in non-pregnant women, this is a sign of hypoxia. See also Well-woman examination Pap test Trauma-Informed Care References Female genital procedures The spread of cervical squamous cell carcinoma to the inner surface of the uterus with replacement of the endometrium is rare. Continuity of the lesion must be demonstrated to confirm superficial spread and rule out concomitant endometrial cancer. We present the case of a 66-year-old white woman with superficial spreading squamous cell carcinoma of the cervix that involved the endometrium. Her relevant past history included conization of the cervix to treat cervical intraepithelial neoplasia III with positive margins. She subsequently had three negative cervical vaginal cytology results, each with a positive high-risk human papillomavirus test. Transvaginal ultrasound showed occupation of the entire uterine cavity by dense material consistent with pyometra in addition to myometrial thinning due to tension and cervical dilation. The patient presented with greenish vaginal discharge of 3 months' duration. The cervix was not visible during speculum examination. Access for endometrial sampling was not possible, raising suspicion of post-conization cervical stenosis. The patient was treated with laparoscopic hysterectomy with double adnexectomy. Histologic examination showed superficial squamous cell carcinoma invading the cervix to a depth of 2.8 mm; superficial spreading squamous cell carcinoma in situ was also observed in the lower uterine segment and endometrium. The patient was free of symptoms 12 months after surgery. Squamous cell carcinoma of the cervix with superficial spread to the endometrium is not included in the 2020 (fifth edition) World Health Organization Classification of Female Genital Tract Tumors or the 2018 International Federation of Gynecology and Obstetrics cervical cancer staging system. More clinical cases are needed to identify other prognostic factors and inform clinical practice guidelines on the management of this disease. The aim of the authors is to show the data for the reception diagnosis, age, histological results and the conduct after the performed diagnostic hysteroscopies in Gynecological clinic of UMBAL-Pleven. For the fulfillment of this aim was made a prospective study for 7 years' period: from 01/01/1997 to 31/01/2003. The objects of observation were 74 women of age from 16 to 65 years, with performed hysteroscopies for gynecologic complaints. There were performed 74 diagnostic hysteroscopies for the studied period. The hysteroscopic findings were 20 cases with endometrial polyposis, 14--submucosal myoamatic nodes, deforming the uterine cavity, 4--cervical polyp, 19--increased endometrium, 9--Asherman syndrome, 1--bicomous uterus, 1--a suspected section for endometrial carcinoma and 6 cases without pathologic findings. There were performed 59 trial abrasions and the removed materials were sent for histological examination The performed comparative analysis between the hysteroscopic presentation and histological findings showed a coincidence of the diagnosis. It was made the conclusion, that the hysteroscopy is an easy, accessible and inexpensive diagnostic method, which must take its place as one of the basic contemporary diagnostic methods in gynecology. To introduce a special case of endometrial cavity fluid (ECF), highlighting the application of hysteroscopy and laparoscopic surgical techniques in the treatment of cervical sinus tract. Narrated video featuring the diagnosis and surgical management of a case of recurrent ECF. Informed consent was obtained from the patient, and approval was granted by the ethics committee of the First Affiliated Hospital of the Wenzhou Medical University. Academic tertiary hospital. A 36-year-old woman, gravida 0, had menstrual spotting for 13 years after abdominal myomectomy of a 104 × 86 × 111-mm myoma on the posterior uterine wall near the cervix. She failed to conceive after her marriage for 10 years, and 5 operations, including hysteroscopy and laparoscopy, were performed to increase pregnancy opportunities. She also underwent in vitro fertilization and embryo transfer procedures many times, but failed. Transvaginal sonography preoperatively suggested that ECF sometimes appeared and sometimes disappeared. The local echo of the posterior wall of the cervix was enhanced. A 40-mm cystic dark area was found beside the right ovary, which seemed to connect with the cervical hyperechoic part. Additionally, a solid mass of the right adnexa with abundant blood supply was detected. First, hysteroscopy was performed to explore the ECF. A deep and narrow cervical sinus with a steady stream of accumulated blood overflowed in the lower part of the cervix, and a normal uterine cavity was found. Laparoscopic adhesiolysis and enucleation of the cystic structure that connected to the sinus tract then were performed. Hysteroscopy was repeated to determine the thinnest cervical region by the light transmission test. A horizontal incision was made on the thinnest layer. Scar tissues were removed. The incision was sutured in full layer intermittently and continuously under laparoscopy. The postoperative thickness of the muscular layer in the sinus was confirmed by light transmission test of hysteroscopy. The patient was discharged on the third day after operation, uneventfully. Histopathologic examination showed that the cystic structure and scar tissue contained smooth muscle tissue and were covered by both mucinous columnar epithelium of the cervical canal and endometrial glandular epithelium. Restoration of normal anatomy, removal of uterine effusion, and symptomatic relief. At the 6-month follow-up, the patient's menstrual cycles returned to normal without the recurrence of menstrual spotting. The ultrasound scan also showed a symmetrical uterus without ECF. Patients with ECF who underwent assisted reproductive surgeries were related to the poor prognosis. However, the treatment should be different according to the causes, appearance time, and accumulation amount, including expectant treatment, postponement of embryo transfer, transvaginal aspiration, laparoscopic salpingectomy, or proximal tubal occlusion. For patients with recurrent ECF and/or special appearance on ultrasound, endoscopic examination is necessary. In addition, patients with large myomas at difficult locations required a uniform strategy to reduce the intraoperative and postoperative complications, especially for the nulligravida women. The aim of the study was to compare the accuracy of hydrosonography with that of transvaginal ultrasonography in detection of intracavitary pathologies in patients with history of abnormal uterine bleeding. Prospective, randomized, and unblinded study. A total of 197 women (n = 130 premenopausal and n = 67 postmenopausal) aged between 23 and 71 years (mean age 45.7 +/- 8.9) presenting with a history of abnormal uterine bleeding were included into the study. Hydrosonography was carried out by experienced gynecologists, on the same setting in an outpatient clinic immediately after the performance of transvaginal sonography. The finally obtained surgical-pathologic findings were compared with the results obtained from transvaginal sonography and hydrosonography. Sensitivity, specificity, positive, and negative predictive values were calculated for each procedure. The surgical-pathologic examination confirmed normal physiologic endometrium in 50 (48%) of 104 women who were said to have normal endometrium on transvaginal sonography. Seventy (75%) of 93 women diagnosed of intracavitary pathologies on transvaginal sonography were confirmed by surgical-pathologic findings. The sensitivity, specificity, positive predictive value, and negative predictive value of transvaginal sonography in the detection of intracavitary pathology were 56, 68, 75, and 48%, respectively. Surgical-pathologic results revealed intracavitary pathologies in 23 (30%) of 76 women who were said to have normal endometrium on hydrosonography. Among 121 women diagnosed of intracavitary pathologies on hydrosonography, 101 (81%) women were confirmed after histological evaluation of the surgical specimens. The sensitivity, specificity, positive predictive value, and negative predictive value of hydrosonography in the detection of intracavitary pathology were 81, 73, 83, and 70%, respectively. Sensitivity and negative predictive value were significantly higher with hydrosonography. There were five cases of endometrial malignancy in which one of the case of malignancy was on polyp and two cases of endometrial hyperplasia with atypia which were not stated on sonographic results. Hydrosonography is more accurate than transvaginal ultrasography in the detection of intracavitary pathologies in women with abnormal uterine bleeding. To report the combined hysteroscopic and laparoscopic treatment of a complete septate uterus with unilateral cervical aplasia (class U2bC3V0/ESHRE/ESGE classification) and isolated mullerian remnants. Step-by-step presentation of the surgical treatment (Canadian Task Force classification 4). Complete septate uterus with unilateral cervical aplasia (formally Robert's uterus) is characterized by the presence of a uterine septum completely dividing the endometrial cavity into an obstructed hemicavity and a contralateral nonobstructing hemicavity connected normally to the existing cervix. It has always been described as isolated without any associated anomaly. A 30-year-old woman was referred to our department for dysmenorrhea and primary infertility. Hysterosalpingography showed the presence of a right (RT) hemiuterus with a patent fallopian tube; further evaluation with 2- and 3-dimensional ultrasound and magnetic resonance imaging showed an externally normal-appearing uterus, a right normal hemicavity connected normally with the existed cervix and, a left hemicavity fully divided from the right one by a complete septum and not connected with the cervix. Interestingly, a peculiar complex mass with cystic areas, attached posterolaterally from the left side to the uterine wall at the level of the isthmus and the upper cervix, was also diagnosed. The study protocol was approved by our local institutional review board. During outpatient hysteroscopy, a right uterine hemicavity with a single ostium was identified without any communication with the left hemicavity. The patient was then scheduled for combined laparoscopic and hysteroscopic treatment. During laparoscopy, a normal uterine body with multiple myomas and a pseudocystic lesion attached posteriorly and left laterally to the uterus at the level of the isthmus and the upper cervix were shown; no communication between the cystic part of that lesion and the isthmus or the cervicovaginal canal was observed. During hysteroscopy, a longitudinal incision of the septum with a 5F bipolar electrode was performed; the left hemicavity was opened, and the corresponding tubal ostium was identified. The pseudocystic lesion was then excised after opening and sent for pathological analysis; the defect was closed with interrupted intracorporeal knots. A single normal endometrial cavity with both tubal ostia was obtained, thus restoring obstruction by unification of the uterine cavity. A histologic report of the removed pseudocystic lesion was compatible with the diagnosis of mullerian remnants. A follow-up hysteroscopy 3 months after showed a normal uterine cavity without postsurgical adhesions. The use of 3-dimensional ultrasound and magnetic resonance imaging in combination with the new ESHRE/ESGE classification system gives the opportunity to obtain a precise representation of the female genital anatomy even in the presence of complex anomalies. Although a septate uterus with unilateral cervical aplasia has been already described, the presence of mullerian remnants is a rare entity associated with cyclic pelvic pain, thus needing adequate recognition and treatment. The combined hysteroscopic and laparoscopic approach offers a unique opportunity for the treatment of complex anomalies.\nHere is the question:\nGYNECOLOGY AND OBSTETRICS: A 67-year-old patient with a history of menopause at 55 years of age, 3 pregnancies with 3 euthyroid deliveries, type 2 diabetes of 6 years of evolution, treatment with nifedipone for hypertension. She consulted for intermittent scanty metrorrhagia of 2 months of evolution. The gynecological examination showed external genitalia without lesions, an atrophic cervix, a normal uterus and appendages on palpation and a normal cytological study of the cervix. The transvaginal ultrasound study shows a 7 mm hyperechogenic endometrium. Which of the following tests is the most appropriate and most sensitive to establish a diagnosis?\nHere are the potential choices:\n1. Conization of the cervix.\n2. Endometrial cytology.\n3. Hysteroscopy and endometrial biopsy.\n4. Magnetic resonance imaging of the pelvis.\n5. Examination under anesthesia of the genital tract and biopsy of the cervix and endometrium.\nThe correct answer is: 3. Hysteroscopy and endometrial biopsy."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Herpetic encephalitis (HE) is the commonest cause of acute sporadic encephalitis in the United States and Europe. In 20% of cases, the clinical course is atypical and this may lead to delay in diagnosis and treatment. A 24 year old patient presented with aseptic meningitis, which had been present for the previous 10 days and which then became complicated by fever and aphasia. The cerebrospinal fluid (CSF) showed marked pleocytosis and increased protein. Cerebrospinal puncture was found to be positive for DNA of the herpes simplex virus. Magnetic resonance (MR) imaging showed a temporal lesion with intense uptake of contrast. Treatment was started with acyclovir and the patient improved over the days following this. At present the diagnosis of herpetic encephalitis is based on polymerase chain reaction (PCR) studies of the CSF and MR imaging. The correlation between patients with HE with cerebrospinal puncture showing positive for herpes and alterations on MR is 89%. In view of the 20% of atypical forms, a high degree of clinical suspicion is necessary to try to obtain early diagnosis and treatment. Neoplastic meningitis (NM) is diagnosed by the presence of malignant cells in the cerebrospinal fluid (CSF). We report 3 patients with NM, who were misdiagnosed with infectious meningitis in emergency department (ED). Case 1. A 68-year-old man visited our ED with a 3-month history of headache. With MRI and CSF study, he was diagnosed with tuberculous meningitis. After 20 days, repeated CSF cytology showed malignant cells. His diagnosis was lung cancer with NM. Case 2. A 57-year-old man visited regional hospital ED with a 3-week history of headache and diplopia. Brain MRI was not contributory. With CSF examination, his diagnosis was aseptic meningitis. With worsening headache, he was referred to our ED. Repeated CSF showed malignant cells. His diagnosis was stomach cancer with NM. Case 3. A 75-year-old man visited a regional hospital with headache lasting for 4 months. His diagnosis was sinusitis. Persistent symptom brought him back, and he developed recurrent generalized seizures. Brain MRI showed diffuse leptomeningeal enhancement suggesting meningitis, and he was transferred to our ED. CSF exam showed malignant cells. His diagnosis was NM with unknown primary focus. When evaluating the patients with headache in ED, NM should be kept in mind as a differential diagnosis of meningitis.  A brain abscess typically presents as an expanding intracranial mass lesion rather than as an infectious process. Although the evolution of signs and symptoms is extremely variable, ranging from hours to weeks or even months, most patients present to the hospital 11–12 days following onset of symptoms. The classic clinical triad of headache, fever, and a focal neurologic deficit is present in <50% of cases. The most common symptom in patients with a brain abscess is headache, occurring in >75% of patients. The headache is often characterized as a constant, dull, aching sensation, either hemicranial or generalized, and it becomes progressively more severe and refractory to therapy. Fever is present in only 50% of patients at the time of diagnosis, and its absence should not exclude the diagnosis. The new onset of focal or generalized seizure activity is a presenting sign in 15–35% of patients. Focal neurologic deficits including hemiparesis, aphasia, or visual field defects are part of Since treatment of herpes simplex virus encephalitis (HSVE) is most effective when started early, a sensitive and specific method for early diagnosis would be of great benefit. MRI and CT are commonly used for this purpose. In this study, we presented two patients who had serologically confirmed HSVE and had normal CT and MRI, but were diagnosed as having HSVE by means of SPECT in the early stage. Case 1 was a 56-year-old man who suddenly developed alexia. On admission, physical and neurological examination were unremarkable except for alexia, agraphia, acalculia, and left-right disorientation. Brain CT, MRI, and cerebral angiography were all normal. However, SPECT showed hyperaccumulation of 99m Tc-HM-PAO in the right temporal-occipital area. On the 5th hospital day, he became comatose. CSF study revealed marked pleocytosis. Even then, MRI including Gd-enhanced study was normal while SPECT continued to show hyperaccumulation. Detection of herpes simplex virus DNA in CSF by polymerase chain reaction was negative. Anti-HSV antibody titer in CSF and serum confirmed intrathecal production of the antibody on the 14th hospital day. Abnormal accumulation of tracer in SPECT returned to normal on the 31st day when he was alert but still had a mild Gerstman syndrome. Case 2 was a 61-year-old man with disturbance of consciousness, mental dysfunction, and generalized convulsion. He was diagnosed as having HSVE by means of CSF pleocytosis, detection of HSV DNA in CSF by polymerase chain reaction, and presence of anti-HSV antibody in the CSF. CT and MRI again revealed no abnormality while SPECT clearly showed hyperaccumulation in the left temporal lobe in an early stage. Hyperaccumulation of lipophilic tracer on SPECT study, especially in the temporal lobes, has been reported in the early stage of HSVE by previous investigators. Unlike MRI or enhanced CT, the increased tracer accumulation in SPECT does not reflect disruption of the blood-brain-barrier or inflammatory edema, but reflects hyperperfusion or some other HSVE related abnormality which is currently unknown. From these observations, we suggest that local hyperperfusion occurs before local inflammation, and that SPECT is the most useful scanning method for early diagnosis of HSVE when this disease is clinically suspected. Changes in diagnosis and management of intracranial infections have been studied on a continuous series of 102 cases 1968 through 1980. Use of CT scan has not increased the number of patients diagnosed in acute phase (before the fifteenth day) but has increased the rate of case observed before the second day (37 p. cent with and 27 p. cent without the CT scan). However the neurological status and specially the state of consciousness has not changed. Four specific data of abscess diagnosis have been defined on 56 cases suspected to have an intracranial infection; 16 out of these cases have proven by surgery not to be infectious lesion. Evolution under treatment is best followed by CT. Final aspect on CT are not different after puncture or after excision. Average delay of disappearance of edema is 20 days and of abscess is 44 days. Importance of bacteriological study in the choice of antibiotics is underlined by comparison of bacteriological and clinical results. Since the introduction of a laboratory of bacteriology in the hospital in 1976, we observed a decrease of sterile cultures (11.5 p. cent and 56 p. cent before 1976), an increase of the number of germs identified in each case and specially anaerobic germs (40 p. cent after and 10 p. cent before 1976) and a decrease in mortality and sequelae (respectively 8,3 p. cent and 19.4 p. cent before 1976 and 11,5 p. cent and 33 p. cent before 1976). Use of CT scan and progress in bacteriological study have led us to simplify our surgical attitude in case of intracranial abscess: puncture as soon as the diagnosis is done on CT; antibiotics according to the bacteriological study and survey by CT in neurosurgical unit. Introduction. Paraneoplastic limbic encephalitis (PLE) is a rare disorder that typically follows a chronic or subacute course of personality changes, memory loss, seizures, and hallucinations. Early diagnosis is difficult and characteristic symptoms can be mimicked by a variety of conditions. We present a case of PLE, initially presenting as acute herpetic encephalitis. Case Presentation. A 56-year-old male was admitted for evaluation of acute onset headache, fever, and confusion. On neurological examination he was confused with MMSE score of 15/30. CSF analysis revealed marked lymphocytic pleocytosis. A possible diagnosis of acute herpetic encephalitis was rendered and patient was treated with acyclovir. CSF PCR was negative. Cranial MRI revealed bilateral hyperintense lesions in medial temporal lobes with contrast enhancement. Despite treatment with acyclovir patient was deteriorated; thus, a paraneoplastic syndrome was suspected. Chest CT showed a right paratracheal lymph node mass, while a biopsy revealed neuroendocrine lung cancer. Auto antibodies to Hu were also detected. The patient was treated with steroids and chemotherapy. Six months later, he had complete tumour remission and marked neurological improvement. Discussion. PLE can rarely invade acutely, being indistinguishable from herpetic encephalitis. Inclusion of PLE in the differential diagnosis of acute encephalitis is of great clinical significance.  Lumbar puncture is the best way to prove bacterial meningitis. It should be performed without any delay if the diagnosis is suspected. Herniation is a rare complication of LP. CT is normal in most cases of purulent meningitis, including those complicated by a subsequent herniation; normal CT results does not mean that performing a LP is safe. Three main clinical features can help determine which patient is at risk of herniation and should have a CT before LP. This risk has to be determined rapidly in the emergency ward while assessing anamnestic data, localization signs or symptoms, and level of consciousness. Cranial imaging (mainly MRI) is useful in the course of bacterial meningitis. Patients who do not respond well to treatment or with atypical presentation, persistence of fever, or new neurological signs should undergo brain imaging; MRI and CT may identify subdural effusions, brain abscesses, empyemas, hydrocephaly, or brain parenchymal changes (cerebritis, infarction, hemorrhage). CT and MRI are useful to screen for an ENT cause of bacterial meningitis, and mandatory in case of pneumococcal meningitis. Numerous MRI sequences are useful to identify bacterial meningitis complications: SE T1 without and with gadolinium injection, SE T2, FLAIR, gradient-echo T2, diffusion weighted imaging, MR angiography. 10 days before admission a 45-year old female experienced general weakness, and T 38 degrees C. During that period she had no cardio-respiratory nor neurological complaints, and the temperature varied between 37.5 degrees C and 38 degrees C. Her medical history was unremarkable, without immunodeficiency. The day before admission she presented with left arm paresis and during the next day it progressed to paralysis. She had no headache. On admission the following diagnostic procedures were performed: the cranial CT scan showed two lesions (possibly meta lesions). Chest X-ray was normal. WBC=15x10(9)/L, ESR=90/120. On the second day following admission brain MRI showed multiple abscesses in both hemispheres, mostly in the gray/white junction. High doses of IV metronidasol, cephtriaxon and cipfloxacin were administered without obtaining specimens for micro-biological diagnosis. In next two days she developed coma, respiratory insufficiency and septic temperature. Brain surgery was not performed due to severe involvement of the brain with multiple abscesses. Repeated chest X-ray revealed bilateral pneumonia. A lethal outcome occurred on the third day, regardless of all efforts. Autopsy showed multiple brain abscesses as well as on the lungs and liver. A beta-hemolytic streptococcal infection was established. Prevention includes treatment of the infection source. The classic triad of headache, fever and focal deficit occur in less than 50% of patients. Even in such cases brain abscess must be reconsidered CT appearance of brain abscess is similar to that of neoplastic and other infectious and non infectious diseases--especially in the stage of early cerebritis. If the CT findings are not clear, MRI should be performed. We report a case of a brain abscess which initially presented with subcortical hematoma and ultimately resulted in fatal brain stem infarction due to its rupture into the subarachnoid space. A 50-year-old male was admitted to a nearby hospital with complaints of headache, fever, and sensory aphasia. He had ventricular septal defect found 15 years previously, sinusitis, and liver cirrhosis. Computerized tomographic (CT) scan revealed a left temporal subcortical hematoma. Gadolinium-DTPA enhanced magnetic resonance imaging (MRI) showed faint ring-like enhancement at the margin of the lesion. The left internal carotid angiogram demonstrated the vascular blush and early venous filling of the vein of Labbé. Administration of antibiotics and predonine resulted in resolution of fever within five days. MRI obtained 17 days after the onset showed typical ring-like enhancement. The mass was just adjacent to the lateral ventricle. The patient was transferred to our hospital for further examination and treatment 21 days after the onset. Fever had recurred 2 days before admission to our hospital. One day after admission, the patient began to vomit. About 15 hours following this symptom, he suddenly became comatose and tetraplegic. CT scan demonstrated a rupture of the abscess. Emergent drainage from the lateral ventricle and the abscess cavity was undertaken. Follow-up CT scan revealed multiple infarctions involving the upper brain stem and the bilateral thalamus. He died on the 29th day after the onset. The mechanisms of hemorrhage with a brain abscess and cerebral infarction after rupture of brain abscess are discussed. Hemorrhage with brain abscess is extremely rare. However, brain abscess should be considered as a possible etiology of an atypical hematoma. To avoid fatal rupture of the brain abscess, immediate treatment is essential. Once the rupture of the brain abscess occurs, its contents might cause vasospasm severe enough to cause cerebral infarction. We often face situations when the exact etiological diagnosis of meningitis is difficult. The reason behind this is that many pathogens have similar clinical, radiological, and laboratory pictures. The low yield of the pathogen in cerebrospinal fluid (CSF), non-availability of detail tests in all corners of the world, delay in availability of reliable results (like cultures), and difficulty in performing confirmatory tests like brain biopsy (in inconclusive cases) make the job of a clinician challenging. We report here a case where a late diagnosis of a disease owing to inconclusive results leads to dissemination. The complications following the introduction of the treatment based on presumption lead to further difficulty. We remained inclined to our diagnosis based on clinical judgement, acknowledged and managed the inflammatory changes secondary to the infection, and finally won the long battle. So, sometimes we need to make decisions based on clinical grounds. We need to depend on the fact that uncommon presentations of common diseases are commoner than a common presentation of uncommon diseases. The SARS-CoV-2 virus, which causes COVID-19, could give rise to damage the nervous system. Many studies have been conducted on this topic, but few have focused specifically on encephalitis. The effect of SARS-CoV-2 on the clinical expression of other neurotropic viruses, such as Herpesviridae, is unknown. We describe the cases of two young men (39 and 18 years old) in whom SARS-CoV-2 had been detected -reverse transcription polymerase chain reaction (RT-PCR)-, and with a clinical diagnosis and cerebrospinal fluid (CSF) analysis consistent with encephalitis. The first patient had a positive PCR for varicella zoster virus in CSF, while the second had a positive PCR for herpes simplex virus types 1 and 2. The first patient, who was recently diagnosed with human immunodeficiency virus, presented with fever, headache, vomiting, cough, inappropriate behaviour and epileptic seizures; the second was seen to have fever, headache, myalgia and exanthema. Both offered the same laboratory findings (lymphopenia and high interleukin 6). CSF showed pleocytosis with a predominance of monomorphonuclear cells, hyperproteinorrachia and normal glycorrhachia. A cranial CT scan showed only mild diffuse cerebral oedema in the first case. Both cases were treated with corticosteroids, antibiotics and acyclovir. The second progressed favourably, while the first did not. Little is known about co-infection of SARS-CoV-2 with neurotropic viruses, such as Herpesviridae, and we have only limited evidence of direct neurological involvement of SARS-CoV-2, due to the technical difficulty of detecting it in the nervous system, thus making it important to take co-infection into account in order to be able to establish an early diagnosis and treatment to improve prognosis. The initial assessment of patients with infectious diseases is challenging because of the extremely broad differential diagnosis as well as different host pathogen interactions influenced by a different immune status. The formal initial assessment, including the present and past medical history, thorough physical examination, clinical first impressions as well as routine laboratory analyses, is the basis of every preliminary diagnosis. Specific chief complaints have to be recognized in order to narrow down the differential diagnosis. In cases of life-threatening illnesses, such as septicemia, endocarditis, bacterial meningitis and severe pneumonia, the first diagnostic and therapeutic steps should be performed in a rapid sequence: bacterial blood samples, sputum and/or liquor samples are required and the initial antibiotic therapy has to be chosen empirically as the relevant bacterial spectrum related to the suspected illness must be covered. In less urgent cases it is recommended that a multi-step diagnostic approach be carried out which takes the differential diagnosis into account and prioritizes the probabilities. In the latter situation antibiotic treatment should be delayed to diagnose the infection correctly. Importantly, atypical courses must necessitate careful and critical reassessment of the diagnosis.  Meningoencephalitis produce by Koch bacillus is a disease including various symptoms, with often atypical onset and evolution, and with an etiological diagnosis being rarely established. It therefore remains a disease with severe prognosis, despite adequate treatment. a 47 years old male from Neamt County, with chronic otitis in his recent medical history, comes to the emergency room for fever, severe headache, confusion, equilibrium disorders, influenced health status, and meningeal irritation signs. Given his otitis and antibiotic therapy received in recent medical history, the patient was initially diagnosed and treated for beheaded bacterial meningitis (348 elements/mm3, 89% lymphocytes, 5% granulocytes, proteinorrhachia 1.54 g/l). Clinical and paraclinical evolution was poor with persistent fever and headache, impaired mental state, and the spinal puncture showed increased pleocytosis (725 elements/mm3), lymphocytosis (78%), increased proteinorrhachia (2.12 g/l), and low levels of glycorrhachia and chlorurorrhachia. Tuberculosis meningoencephalytis was suspected (confirmed after 3 weeks through cultures on Lowenstein-Jensen medium: positive for Mycobacterium tuberculosis), and a tuberculostatic treatment associating four drugs and intravenous Ciprofloxacin was started. Although the treatment included substances against cerebral edema and neurotrophic agent, his evolution showed persistent headache syndrome. We noticed very slow decrease in CSF pleocytosis (after a month) of treatment the patient still had 240 elements/mm3, 85% lymphocytesand 15% granulocytes. Moreover, due to hepatic toxicity a reduction of the tuberculostatic doses was needed. The beginning of the tuberculosis infection symptoms is often surprising, with clinical signs regarding secondary determinations (meningoencephalitis) association with another infection (otitis--wrong diagnosis). as well as persistent yet slowly favorably evolving symptoms, both clinically and paraclinically (CSF parameters). The etiological agent is extremely rarely isolated, due to a very slow growth of the Koch bacillus on special culture mediums and also because such diagnosis is not often considered before starting the treatment. The authors report their experience with CT scanning ina series of 4 cases of subdural empyema, over a period of 10 months; all the patients were male, aged 16 to 25 years. A review of the literature shows that this disease, in spite of the large variety and efficacy of the available antibiotics, is marked by a significant mortality and morbidity rate if the diagnosis is delayed. Study of the cases reported here, as well as those in the literature, attests that CT scanning of the brain is nowadays the method of choice for early diagnosis of these lesions, and for timing of appropriate intervention according to variations in the development stage of the suppuration. From the study of this series of cases, it is clear that in the future, CT scanning of the brain will certainly allow the hope of a greater survival rate and an appreciable decrease in morbidity in cases of subdural empyema. The infection may take the form of a brainstem encephalitis, or “rhombencephalitis,” specifically with several days of headache, fever, nausea, and vomiting followed by asymmetrical cranial-nerve palsies, signs of cerebellar dysfunction, hemiparesis, quadriparesis, or sensory loss. Respiratory failure has been reported. Of 62 cases of Listeria brainstem encephalitis reported 25 years ago by Armstrong and Fung 8 percent were in immunosuppressed patients, however, in the current era 20 percent or fewer of affected patients are immunocompetent. In the elderly, no additional cause of immune disorder appears to be necessary. Meningeal signs were present in the only half the patients in the above mentioned series, and the spinal fluid often showed misleadingly mild abnormalities. CSF cultures yielded Listeria in only 40 percent of cases (blood cultures were even more often normal). Consistent with our experience, the early CT scan was often normal; MRI, however, has revealed abnormal Diagnosis The CSF findings are much the same as in aseptic meningitis (lymphocytic pleocytosis, mild protein elevation, normal glucose values). Occasionally, early sampling of CSF may show few or no cells and subsequent tests may be more typical of an inflammatory disorder. Recovery of virus from blood or CSF is usually not possible and PCR testing is routinely only applied during local epidemics and for the detection of herpes viruses. Recently, it has been possible to use next generation sequencing to identify obscure causes of encephalitis. However, antiviral immunoglobulin (Ig) M antibody is present in the serum and CSF within the first days of symptomatic disease and can be detected and quantified by means of ELISA, making it preferable to other testing serologic for specific diagnosis. Some patients have not developed antibodies by the time of admission to the hospital and the test may have to be repeated in several days. The MRI may be normal or show signal changes and edema in Male, 23 FINAL DIAGNOSIS: Neurocysticerosis Symptoms: Diplopia • fever • headache • insomnia • neck stiffness • vomiting Albendazole Clinical Procedure: - Specialty: Neurology. Challenging differential diagnosis. Neurocysticercosis is a brain infection caused by the larval stage of the tapeworm Taenia (T.) solium. It is the most important parasitic disease of the human central nervous system and represents the most common cause of acquired epilepsy in developing countries. Here, we report the case of a 23-year-old Chinese man who presented to the emergency department with a 7-day history of helmet headache radiating to the nuchal region and associated with vomiting, confusion, and fever. Cerebrospinal fluid (CSF) was clear, with increased pressure, lymphocytic pleocytosis, decreased glucose, and increased protein levels. Bacterial antigen detection test on CSF was negative, as were CSF bacterial and fungal cultures. Despite broad-spectrum antibiotic and antiviral therapy, the patient still complained of insomnia, diplopia, headache, neck stiffness, and pain in the sacral region. A second LP was performed and CSF had the same characteristics as the first LP. A brain and spinal cord MRI revealed widespread arachnoiditis and small septated cysts with CSF-like signal in the cisterna magna, within the fourth ventricle, and at the level of L3-L4. Cysticercus-specific immunoglobin G antibodies were detected by ELISA in the CSF. The patient received albendazole (15 mg/kg/day) and dexamethasone (5 mg/day) for 4 weeks, with progressive resolution of neurological symptoms. This case shows that, even if rare, neurocysticercosis may be responsible for meningeal symptoms and should be included in the differential diagnosis, especially in patients from endemic countries. Ninety consecutive cases of brain abscess admitted to this center between 1964 and 1978 have been reviewed. The overall mortality has fallen in three consecutive 5-year periods from 42 to 21 to 9.7%. A number of factors seem to be responsible for this. Early surgical intervention was associated with the reduction in mortality between the first and second 5-year periods. Recognition of the significance and extent of cerebral edema, confirmed since computed tomographic (CT) scans have been available, led to a greater use of steroids during the last 5-year period, but the number of patients thus treated was too small to permit an assessment of any effect on mortality. There is no evidence to suggest a change in the natural history of the disease, and surgical management has not altered significantly. Experience with CT scanning in this center in the diagnosis of brain abscess is limited. It is therefore not possible no assess whether any improvement in mortality may have arisen from the early and accurate diagnosis obtainable with this technique. Improvement in culture technique has been of major importance, leading to a better understanding of the bacteriology of brain abscesses. This has allowed a more rational antibiotic program to be instituted, in particular the use of agents active against obligate anaerobes. Traumatic pseudoaneurysms of the middle meningeal artery, which are associated with high mortality, are difficult to detect early by CT. We provide serial CT scans to show the steps of their formation and suggest characteristics that could be useful in the detection. A 25-year-old man was initially in deep coma had an anisocoric pupil after a traffic accident. Brain CT showed basal skull fracture and traumatic subarachnoid hemorrhage with severe brain swelling. Emergent decompressive craniectomy was performed, and 2 days later, an EDH appeared at the left temporal fossa. Careful examination of the image revealed a hypodense nodule inside the acute hematoma. He underwent craniotomy to remove the hematoma. Serial CT of the residual hematoma showed the gradual development of an organized hematoma around the hypodense nodule. The nodule had low density, which was strongly enhanced on CT after injection of contrast medium. The nodule was highly suspected to be a vascular lesion. A middle meningeal artery pseudoaneurysm was discovered through a 3-dimensional computed tomographic angiography. He underwent another craniotomy to remove the pseudoaneurysm. The diagnostic approach was CT, 3-dimensional CT, and craniotomies. Four CT findings may be useful for early diagnosis: (1) basal skull fracture in the temporal region; (2) hypodense nodule within an acute hematoma; (3) hypodense nodule within an organized and encapsulated hematoma; and (4) strong and homogenous enhancement of the hypodense nodule within an organized and encapsulated hematoma. Three-dimensional computed tomographic angiography is an effective and noninvasive tool to confirm this diagnosis. Clinical patterns of tuberculous meningitis have been analyzed for 32 admissions to the bacterial meningitis department of the 2nd Moscow Infection Hospital in 1983-1991. Early diagnosis of tuberculous meningitis caused great difficulties because of rare cases of tuberculous history, atypical symptoms (an acute onset, in particular), an obscure meningeal syndrome, rare neurological symptoms, atypical liquor characteristics (frequent neutrophil pleocytosis, a small protein rise, normal glucose). Secondary bacterial meningitides presented most serious difficulties for differential diagnosis. So did cerebral abscesses and viral meningitis. Antituberculous therapy should be started at first sings of tuberculous nature of meningitis as the disease outcomes are determined to a large extent by early administration of proper treatment. Dengue, a mosquito-borne disease caused by a flavivirus, is recognized in over 120 countries with 3.6 billion people living in areas at risk. Neurological manifestations are infrequently reported as clinical consequences of dengue infection. Though severe dengue may be associated with meningoencephalitis, meningitis is a rare initial presentation of otherwise uncomplicated dengue fever. We report two adult patients who presented with fever, headache, and nuchal rigidity without the typical symptoms of dengue infection. Cerebrospinal fluid (CSF) analysis showed lymphocytic pleocytosis in one and slight neutrophilic pleocytosis in the other with a normal glucose value and negative bacterial cultures. Dengue was suspected because thrombocytopenia was symptomatic in one patient and documented during the hospital course, and was confirmed by demonstration of IgM antibody in the cerebrospinal fluid samples specific for dengue in both cases. Our report demonstrates that meningitis with or without encephalitis can be the first manifestation of dengue infection. In endemic areas, dengue infection should be considered as a probable etiological agent of meningitis. Regular monitoring of platelet count can be an invaluable diagnostic screening tool. In appropriate clinical settings detection of anti-dengue IgM both in serum and in CSF may lead to correct diagnosis.\nHere is the question:\nNEUROLOGY: A 52-year-old man comes to the Emergency Department with headache and fever (37.8°C) of 2 days' evolution. In the last few hours, he also had difficulty in nomination and comprehension. The examination did not show nuchal rigidity, the most striking finding being the presence of a mixed aphasia. The cranial CT shows a faint hypodensity in the left temporal lobe without mass effect and without contrast uptake. Which of the following statements is correct?\nHere are the potential choices:\n1. Bacterial meningitis is the first diagnostic impression and treatment with 3rd generation cephalosporin should be initiated as soon as possible.\n2. Most likely this patient's CSF shows a lymphocyte-predominant pleocytosis with normal glycorrhachia.\n3. We would suspect limbic encephalitis.\n4. This is an early stage brain abscess.\nThe correct answer is: ",
        "gold_answer": "2 Most likely this patient's CSF shows a lymphocyte-predominant pleocytosis with normal glycorrhachia.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Herpetic encephalitis (HE) is the commonest cause of acute sporadic encephalitis in the United States and Europe. In 20% of cases, the clinical course is atypical and this may lead to delay in diagnosis and treatment. A 24 year old patient presented with aseptic meningitis, which had been present for the previous 10 days and which then became complicated by fever and aphasia. The cerebrospinal fluid (CSF) showed marked pleocytosis and increased protein. Cerebrospinal puncture was found to be positive for DNA of the herpes simplex virus. Magnetic resonance (MR) imaging showed a temporal lesion with intense uptake of contrast. Treatment was started with acyclovir and the patient improved over the days following this. At present the diagnosis of herpetic encephalitis is based on polymerase chain reaction (PCR) studies of the CSF and MR imaging. The correlation between patients with HE with cerebrospinal puncture showing positive for herpes and alterations on MR is 89%. In view of the 20% of atypical forms, a high degree of clinical suspicion is necessary to try to obtain early diagnosis and treatment. Neoplastic meningitis (NM) is diagnosed by the presence of malignant cells in the cerebrospinal fluid (CSF). We report 3 patients with NM, who were misdiagnosed with infectious meningitis in emergency department (ED). Case 1. A 68-year-old man visited our ED with a 3-month history of headache. With MRI and CSF study, he was diagnosed with tuberculous meningitis. After 20 days, repeated CSF cytology showed malignant cells. His diagnosis was lung cancer with NM. Case 2. A 57-year-old man visited regional hospital ED with a 3-week history of headache and diplopia. Brain MRI was not contributory. With CSF examination, his diagnosis was aseptic meningitis. With worsening headache, he was referred to our ED. Repeated CSF showed malignant cells. His diagnosis was stomach cancer with NM. Case 3. A 75-year-old man visited a regional hospital with headache lasting for 4 months. His diagnosis was sinusitis. Persistent symptom brought him back, and he developed recurrent generalized seizures. Brain MRI showed diffuse leptomeningeal enhancement suggesting meningitis, and he was transferred to our ED. CSF exam showed malignant cells. His diagnosis was NM with unknown primary focus. When evaluating the patients with headache in ED, NM should be kept in mind as a differential diagnosis of meningitis.  A brain abscess typically presents as an expanding intracranial mass lesion rather than as an infectious process. Although the evolution of signs and symptoms is extremely variable, ranging from hours to weeks or even months, most patients present to the hospital 11–12 days following onset of symptoms. The classic clinical triad of headache, fever, and a focal neurologic deficit is present in <50% of cases. The most common symptom in patients with a brain abscess is headache, occurring in >75% of patients. The headache is often characterized as a constant, dull, aching sensation, either hemicranial or generalized, and it becomes progressively more severe and refractory to therapy. Fever is present in only 50% of patients at the time of diagnosis, and its absence should not exclude the diagnosis. The new onset of focal or generalized seizure activity is a presenting sign in 15–35% of patients. Focal neurologic deficits including hemiparesis, aphasia, or visual field defects are part of Since treatment of herpes simplex virus encephalitis (HSVE) is most effective when started early, a sensitive and specific method for early diagnosis would be of great benefit. MRI and CT are commonly used for this purpose. In this study, we presented two patients who had serologically confirmed HSVE and had normal CT and MRI, but were diagnosed as having HSVE by means of SPECT in the early stage. Case 1 was a 56-year-old man who suddenly developed alexia. On admission, physical and neurological examination were unremarkable except for alexia, agraphia, acalculia, and left-right disorientation. Brain CT, MRI, and cerebral angiography were all normal. However, SPECT showed hyperaccumulation of 99m Tc-HM-PAO in the right temporal-occipital area. On the 5th hospital day, he became comatose. CSF study revealed marked pleocytosis. Even then, MRI including Gd-enhanced study was normal while SPECT continued to show hyperaccumulation. Detection of herpes simplex virus DNA in CSF by polymerase chain reaction was negative. Anti-HSV antibody titer in CSF and serum confirmed intrathecal production of the antibody on the 14th hospital day. Abnormal accumulation of tracer in SPECT returned to normal on the 31st day when he was alert but still had a mild Gerstman syndrome. Case 2 was a 61-year-old man with disturbance of consciousness, mental dysfunction, and generalized convulsion. He was diagnosed as having HSVE by means of CSF pleocytosis, detection of HSV DNA in CSF by polymerase chain reaction, and presence of anti-HSV antibody in the CSF. CT and MRI again revealed no abnormality while SPECT clearly showed hyperaccumulation in the left temporal lobe in an early stage. Hyperaccumulation of lipophilic tracer on SPECT study, especially in the temporal lobes, has been reported in the early stage of HSVE by previous investigators. Unlike MRI or enhanced CT, the increased tracer accumulation in SPECT does not reflect disruption of the blood-brain-barrier or inflammatory edema, but reflects hyperperfusion or some other HSVE related abnormality which is currently unknown. From these observations, we suggest that local hyperperfusion occurs before local inflammation, and that SPECT is the most useful scanning method for early diagnosis of HSVE when this disease is clinically suspected. Changes in diagnosis and management of intracranial infections have been studied on a continuous series of 102 cases 1968 through 1980. Use of CT scan has not increased the number of patients diagnosed in acute phase (before the fifteenth day) but has increased the rate of case observed before the second day (37 p. cent with and 27 p. cent without the CT scan). However the neurological status and specially the state of consciousness has not changed. Four specific data of abscess diagnosis have been defined on 56 cases suspected to have an intracranial infection; 16 out of these cases have proven by surgery not to be infectious lesion. Evolution under treatment is best followed by CT. Final aspect on CT are not different after puncture or after excision. Average delay of disappearance of edema is 20 days and of abscess is 44 days. Importance of bacteriological study in the choice of antibiotics is underlined by comparison of bacteriological and clinical results. Since the introduction of a laboratory of bacteriology in the hospital in 1976, we observed a decrease of sterile cultures (11.5 p. cent and 56 p. cent before 1976), an increase of the number of germs identified in each case and specially anaerobic germs (40 p. cent after and 10 p. cent before 1976) and a decrease in mortality and sequelae (respectively 8,3 p. cent and 19.4 p. cent before 1976 and 11,5 p. cent and 33 p. cent before 1976). Use of CT scan and progress in bacteriological study have led us to simplify our surgical attitude in case of intracranial abscess: puncture as soon as the diagnosis is done on CT; antibiotics according to the bacteriological study and survey by CT in neurosurgical unit. Introduction. Paraneoplastic limbic encephalitis (PLE) is a rare disorder that typically follows a chronic or subacute course of personality changes, memory loss, seizures, and hallucinations. Early diagnosis is difficult and characteristic symptoms can be mimicked by a variety of conditions. We present a case of PLE, initially presenting as acute herpetic encephalitis. Case Presentation. A 56-year-old male was admitted for evaluation of acute onset headache, fever, and confusion. On neurological examination he was confused with MMSE score of 15/30. CSF analysis revealed marked lymphocytic pleocytosis. A possible diagnosis of acute herpetic encephalitis was rendered and patient was treated with acyclovir. CSF PCR was negative. Cranial MRI revealed bilateral hyperintense lesions in medial temporal lobes with contrast enhancement. Despite treatment with acyclovir patient was deteriorated; thus, a paraneoplastic syndrome was suspected. Chest CT showed a right paratracheal lymph node mass, while a biopsy revealed neuroendocrine lung cancer. Auto antibodies to Hu were also detected. The patient was treated with steroids and chemotherapy. Six months later, he had complete tumour remission and marked neurological improvement. Discussion. PLE can rarely invade acutely, being indistinguishable from herpetic encephalitis. Inclusion of PLE in the differential diagnosis of acute encephalitis is of great clinical significance.  Lumbar puncture is the best way to prove bacterial meningitis. It should be performed without any delay if the diagnosis is suspected. Herniation is a rare complication of LP. CT is normal in most cases of purulent meningitis, including those complicated by a subsequent herniation; normal CT results does not mean that performing a LP is safe. Three main clinical features can help determine which patient is at risk of herniation and should have a CT before LP. This risk has to be determined rapidly in the emergency ward while assessing anamnestic data, localization signs or symptoms, and level of consciousness. Cranial imaging (mainly MRI) is useful in the course of bacterial meningitis. Patients who do not respond well to treatment or with atypical presentation, persistence of fever, or new neurological signs should undergo brain imaging; MRI and CT may identify subdural effusions, brain abscesses, empyemas, hydrocephaly, or brain parenchymal changes (cerebritis, infarction, hemorrhage). CT and MRI are useful to screen for an ENT cause of bacterial meningitis, and mandatory in case of pneumococcal meningitis. Numerous MRI sequences are useful to identify bacterial meningitis complications: SE T1 without and with gadolinium injection, SE T2, FLAIR, gradient-echo T2, diffusion weighted imaging, MR angiography. 10 days before admission a 45-year old female experienced general weakness, and T 38 degrees C. During that period she had no cardio-respiratory nor neurological complaints, and the temperature varied between 37.5 degrees C and 38 degrees C. Her medical history was unremarkable, without immunodeficiency. The day before admission she presented with left arm paresis and during the next day it progressed to paralysis. She had no headache. On admission the following diagnostic procedures were performed: the cranial CT scan showed two lesions (possibly meta lesions). Chest X-ray was normal. WBC=15x10(9)/L, ESR=90/120. On the second day following admission brain MRI showed multiple abscesses in both hemispheres, mostly in the gray/white junction. High doses of IV metronidasol, cephtriaxon and cipfloxacin were administered without obtaining specimens for micro-biological diagnosis. In next two days she developed coma, respiratory insufficiency and septic temperature. Brain surgery was not performed due to severe involvement of the brain with multiple abscesses. Repeated chest X-ray revealed bilateral pneumonia. A lethal outcome occurred on the third day, regardless of all efforts. Autopsy showed multiple brain abscesses as well as on the lungs and liver. A beta-hemolytic streptococcal infection was established. Prevention includes treatment of the infection source. The classic triad of headache, fever and focal deficit occur in less than 50% of patients. Even in such cases brain abscess must be reconsidered CT appearance of brain abscess is similar to that of neoplastic and other infectious and non infectious diseases--especially in the stage of early cerebritis. If the CT findings are not clear, MRI should be performed. We report a case of a brain abscess which initially presented with subcortical hematoma and ultimately resulted in fatal brain stem infarction due to its rupture into the subarachnoid space. A 50-year-old male was admitted to a nearby hospital with complaints of headache, fever, and sensory aphasia. He had ventricular septal defect found 15 years previously, sinusitis, and liver cirrhosis. Computerized tomographic (CT) scan revealed a left temporal subcortical hematoma. Gadolinium-DTPA enhanced magnetic resonance imaging (MRI) showed faint ring-like enhancement at the margin of the lesion. The left internal carotid angiogram demonstrated the vascular blush and early venous filling of the vein of Labbé. Administration of antibiotics and predonine resulted in resolution of fever within five days. MRI obtained 17 days after the onset showed typical ring-like enhancement. The mass was just adjacent to the lateral ventricle. The patient was transferred to our hospital for further examination and treatment 21 days after the onset. Fever had recurred 2 days before admission to our hospital. One day after admission, the patient began to vomit. About 15 hours following this symptom, he suddenly became comatose and tetraplegic. CT scan demonstrated a rupture of the abscess. Emergent drainage from the lateral ventricle and the abscess cavity was undertaken. Follow-up CT scan revealed multiple infarctions involving the upper brain stem and the bilateral thalamus. He died on the 29th day after the onset. The mechanisms of hemorrhage with a brain abscess and cerebral infarction after rupture of brain abscess are discussed. Hemorrhage with brain abscess is extremely rare. However, brain abscess should be considered as a possible etiology of an atypical hematoma. To avoid fatal rupture of the brain abscess, immediate treatment is essential. Once the rupture of the brain abscess occurs, its contents might cause vasospasm severe enough to cause cerebral infarction. We often face situations when the exact etiological diagnosis of meningitis is difficult. The reason behind this is that many pathogens have similar clinical, radiological, and laboratory pictures. The low yield of the pathogen in cerebrospinal fluid (CSF), non-availability of detail tests in all corners of the world, delay in availability of reliable results (like cultures), and difficulty in performing confirmatory tests like brain biopsy (in inconclusive cases) make the job of a clinician challenging. We report here a case where a late diagnosis of a disease owing to inconclusive results leads to dissemination. The complications following the introduction of the treatment based on presumption lead to further difficulty. We remained inclined to our diagnosis based on clinical judgement, acknowledged and managed the inflammatory changes secondary to the infection, and finally won the long battle. So, sometimes we need to make decisions based on clinical grounds. We need to depend on the fact that uncommon presentations of common diseases are commoner than a common presentation of uncommon diseases. The SARS-CoV-2 virus, which causes COVID-19, could give rise to damage the nervous system. Many studies have been conducted on this topic, but few have focused specifically on encephalitis. The effect of SARS-CoV-2 on the clinical expression of other neurotropic viruses, such as Herpesviridae, is unknown. We describe the cases of two young men (39 and 18 years old) in whom SARS-CoV-2 had been detected -reverse transcription polymerase chain reaction (RT-PCR)-, and with a clinical diagnosis and cerebrospinal fluid (CSF) analysis consistent with encephalitis. The first patient had a positive PCR for varicella zoster virus in CSF, while the second had a positive PCR for herpes simplex virus types 1 and 2. The first patient, who was recently diagnosed with human immunodeficiency virus, presented with fever, headache, vomiting, cough, inappropriate behaviour and epileptic seizures; the second was seen to have fever, headache, myalgia and exanthema. Both offered the same laboratory findings (lymphopenia and high interleukin 6). CSF showed pleocytosis with a predominance of monomorphonuclear cells, hyperproteinorrachia and normal glycorrhachia. A cranial CT scan showed only mild diffuse cerebral oedema in the first case. Both cases were treated with corticosteroids, antibiotics and acyclovir. The second progressed favourably, while the first did not. Little is known about co-infection of SARS-CoV-2 with neurotropic viruses, such as Herpesviridae, and we have only limited evidence of direct neurological involvement of SARS-CoV-2, due to the technical difficulty of detecting it in the nervous system, thus making it important to take co-infection into account in order to be able to establish an early diagnosis and treatment to improve prognosis. The initial assessment of patients with infectious diseases is challenging because of the extremely broad differential diagnosis as well as different host pathogen interactions influenced by a different immune status. The formal initial assessment, including the present and past medical history, thorough physical examination, clinical first impressions as well as routine laboratory analyses, is the basis of every preliminary diagnosis. Specific chief complaints have to be recognized in order to narrow down the differential diagnosis. In cases of life-threatening illnesses, such as septicemia, endocarditis, bacterial meningitis and severe pneumonia, the first diagnostic and therapeutic steps should be performed in a rapid sequence: bacterial blood samples, sputum and/or liquor samples are required and the initial antibiotic therapy has to be chosen empirically as the relevant bacterial spectrum related to the suspected illness must be covered. In less urgent cases it is recommended that a multi-step diagnostic approach be carried out which takes the differential diagnosis into account and prioritizes the probabilities. In the latter situation antibiotic treatment should be delayed to diagnose the infection correctly. Importantly, atypical courses must necessitate careful and critical reassessment of the diagnosis.  Meningoencephalitis produce by Koch bacillus is a disease including various symptoms, with often atypical onset and evolution, and with an etiological diagnosis being rarely established. It therefore remains a disease with severe prognosis, despite adequate treatment. a 47 years old male from Neamt County, with chronic otitis in his recent medical history, comes to the emergency room for fever, severe headache, confusion, equilibrium disorders, influenced health status, and meningeal irritation signs. Given his otitis and antibiotic therapy received in recent medical history, the patient was initially diagnosed and treated for beheaded bacterial meningitis (348 elements/mm3, 89% lymphocytes, 5% granulocytes, proteinorrhachia 1.54 g/l). Clinical and paraclinical evolution was poor with persistent fever and headache, impaired mental state, and the spinal puncture showed increased pleocytosis (725 elements/mm3), lymphocytosis (78%), increased proteinorrhachia (2.12 g/l), and low levels of glycorrhachia and chlorurorrhachia. Tuberculosis meningoencephalytis was suspected (confirmed after 3 weeks through cultures on Lowenstein-Jensen medium: positive for Mycobacterium tuberculosis), and a tuberculostatic treatment associating four drugs and intravenous Ciprofloxacin was started. Although the treatment included substances against cerebral edema and neurotrophic agent, his evolution showed persistent headache syndrome. We noticed very slow decrease in CSF pleocytosis (after a month) of treatment the patient still had 240 elements/mm3, 85% lymphocytesand 15% granulocytes. Moreover, due to hepatic toxicity a reduction of the tuberculostatic doses was needed. The beginning of the tuberculosis infection symptoms is often surprising, with clinical signs regarding secondary determinations (meningoencephalitis) association with another infection (otitis--wrong diagnosis). as well as persistent yet slowly favorably evolving symptoms, both clinically and paraclinically (CSF parameters). The etiological agent is extremely rarely isolated, due to a very slow growth of the Koch bacillus on special culture mediums and also because such diagnosis is not often considered before starting the treatment. The authors report their experience with CT scanning ina series of 4 cases of subdural empyema, over a period of 10 months; all the patients were male, aged 16 to 25 years. A review of the literature shows that this disease, in spite of the large variety and efficacy of the available antibiotics, is marked by a significant mortality and morbidity rate if the diagnosis is delayed. Study of the cases reported here, as well as those in the literature, attests that CT scanning of the brain is nowadays the method of choice for early diagnosis of these lesions, and for timing of appropriate intervention according to variations in the development stage of the suppuration. From the study of this series of cases, it is clear that in the future, CT scanning of the brain will certainly allow the hope of a greater survival rate and an appreciable decrease in morbidity in cases of subdural empyema. The infection may take the form of a brainstem encephalitis, or “rhombencephalitis,” specifically with several days of headache, fever, nausea, and vomiting followed by asymmetrical cranial-nerve palsies, signs of cerebellar dysfunction, hemiparesis, quadriparesis, or sensory loss. Respiratory failure has been reported. Of 62 cases of Listeria brainstem encephalitis reported 25 years ago by Armstrong and Fung 8 percent were in immunosuppressed patients, however, in the current era 20 percent or fewer of affected patients are immunocompetent. In the elderly, no additional cause of immune disorder appears to be necessary. Meningeal signs were present in the only half the patients in the above mentioned series, and the spinal fluid often showed misleadingly mild abnormalities. CSF cultures yielded Listeria in only 40 percent of cases (blood cultures were even more often normal). Consistent with our experience, the early CT scan was often normal; MRI, however, has revealed abnormal Diagnosis The CSF findings are much the same as in aseptic meningitis (lymphocytic pleocytosis, mild protein elevation, normal glucose values). Occasionally, early sampling of CSF may show few or no cells and subsequent tests may be more typical of an inflammatory disorder. Recovery of virus from blood or CSF is usually not possible and PCR testing is routinely only applied during local epidemics and for the detection of herpes viruses. Recently, it has been possible to use next generation sequencing to identify obscure causes of encephalitis. However, antiviral immunoglobulin (Ig) M antibody is present in the serum and CSF within the first days of symptomatic disease and can be detected and quantified by means of ELISA, making it preferable to other testing serologic for specific diagnosis. Some patients have not developed antibodies by the time of admission to the hospital and the test may have to be repeated in several days. The MRI may be normal or show signal changes and edema in Male, 23 FINAL DIAGNOSIS: Neurocysticerosis Symptoms: Diplopia • fever • headache • insomnia • neck stiffness • vomiting Albendazole Clinical Procedure: - Specialty: Neurology. Challenging differential diagnosis. Neurocysticercosis is a brain infection caused by the larval stage of the tapeworm Taenia (T.) solium. It is the most important parasitic disease of the human central nervous system and represents the most common cause of acquired epilepsy in developing countries. Here, we report the case of a 23-year-old Chinese man who presented to the emergency department with a 7-day history of helmet headache radiating to the nuchal region and associated with vomiting, confusion, and fever. Cerebrospinal fluid (CSF) was clear, with increased pressure, lymphocytic pleocytosis, decreased glucose, and increased protein levels. Bacterial antigen detection test on CSF was negative, as were CSF bacterial and fungal cultures. Despite broad-spectrum antibiotic and antiviral therapy, the patient still complained of insomnia, diplopia, headache, neck stiffness, and pain in the sacral region. A second LP was performed and CSF had the same characteristics as the first LP. A brain and spinal cord MRI revealed widespread arachnoiditis and small septated cysts with CSF-like signal in the cisterna magna, within the fourth ventricle, and at the level of L3-L4. Cysticercus-specific immunoglobin G antibodies were detected by ELISA in the CSF. The patient received albendazole (15 mg/kg/day) and dexamethasone (5 mg/day) for 4 weeks, with progressive resolution of neurological symptoms. This case shows that, even if rare, neurocysticercosis may be responsible for meningeal symptoms and should be included in the differential diagnosis, especially in patients from endemic countries. Ninety consecutive cases of brain abscess admitted to this center between 1964 and 1978 have been reviewed. The overall mortality has fallen in three consecutive 5-year periods from 42 to 21 to 9.7%. A number of factors seem to be responsible for this. Early surgical intervention was associated with the reduction in mortality between the first and second 5-year periods. Recognition of the significance and extent of cerebral edema, confirmed since computed tomographic (CT) scans have been available, led to a greater use of steroids during the last 5-year period, but the number of patients thus treated was too small to permit an assessment of any effect on mortality. There is no evidence to suggest a change in the natural history of the disease, and surgical management has not altered significantly. Experience with CT scanning in this center in the diagnosis of brain abscess is limited. It is therefore not possible no assess whether any improvement in mortality may have arisen from the early and accurate diagnosis obtainable with this technique. Improvement in culture technique has been of major importance, leading to a better understanding of the bacteriology of brain abscesses. This has allowed a more rational antibiotic program to be instituted, in particular the use of agents active against obligate anaerobes. Traumatic pseudoaneurysms of the middle meningeal artery, which are associated with high mortality, are difficult to detect early by CT. We provide serial CT scans to show the steps of their formation and suggest characteristics that could be useful in the detection. A 25-year-old man was initially in deep coma had an anisocoric pupil after a traffic accident. Brain CT showed basal skull fracture and traumatic subarachnoid hemorrhage with severe brain swelling. Emergent decompressive craniectomy was performed, and 2 days later, an EDH appeared at the left temporal fossa. Careful examination of the image revealed a hypodense nodule inside the acute hematoma. He underwent craniotomy to remove the hematoma. Serial CT of the residual hematoma showed the gradual development of an organized hematoma around the hypodense nodule. The nodule had low density, which was strongly enhanced on CT after injection of contrast medium. The nodule was highly suspected to be a vascular lesion. A middle meningeal artery pseudoaneurysm was discovered through a 3-dimensional computed tomographic angiography. He underwent another craniotomy to remove the pseudoaneurysm. The diagnostic approach was CT, 3-dimensional CT, and craniotomies. Four CT findings may be useful for early diagnosis: (1) basal skull fracture in the temporal region; (2) hypodense nodule within an acute hematoma; (3) hypodense nodule within an organized and encapsulated hematoma; and (4) strong and homogenous enhancement of the hypodense nodule within an organized and encapsulated hematoma. Three-dimensional computed tomographic angiography is an effective and noninvasive tool to confirm this diagnosis. Clinical patterns of tuberculous meningitis have been analyzed for 32 admissions to the bacterial meningitis department of the 2nd Moscow Infection Hospital in 1983-1991. Early diagnosis of tuberculous meningitis caused great difficulties because of rare cases of tuberculous history, atypical symptoms (an acute onset, in particular), an obscure meningeal syndrome, rare neurological symptoms, atypical liquor characteristics (frequent neutrophil pleocytosis, a small protein rise, normal glucose). Secondary bacterial meningitides presented most serious difficulties for differential diagnosis. So did cerebral abscesses and viral meningitis. Antituberculous therapy should be started at first sings of tuberculous nature of meningitis as the disease outcomes are determined to a large extent by early administration of proper treatment. Dengue, a mosquito-borne disease caused by a flavivirus, is recognized in over 120 countries with 3.6 billion people living in areas at risk. Neurological manifestations are infrequently reported as clinical consequences of dengue infection. Though severe dengue may be associated with meningoencephalitis, meningitis is a rare initial presentation of otherwise uncomplicated dengue fever. We report two adult patients who presented with fever, headache, and nuchal rigidity without the typical symptoms of dengue infection. Cerebrospinal fluid (CSF) analysis showed lymphocytic pleocytosis in one and slight neutrophilic pleocytosis in the other with a normal glucose value and negative bacterial cultures. Dengue was suspected because thrombocytopenia was symptomatic in one patient and documented during the hospital course, and was confirmed by demonstration of IgM antibody in the cerebrospinal fluid samples specific for dengue in both cases. Our report demonstrates that meningitis with or without encephalitis can be the first manifestation of dengue infection. In endemic areas, dengue infection should be considered as a probable etiological agent of meningitis. Regular monitoring of platelet count can be an invaluable diagnostic screening tool. In appropriate clinical settings detection of anti-dengue IgM both in serum and in CSF may lead to correct diagnosis.\nHere is the question:\nNEUROLOGY: A 52-year-old man comes to the Emergency Department with headache and fever (37.8°C) of 2 days' evolution. In the last few hours, he also had difficulty in nomination and comprehension. The examination did not show nuchal rigidity, the most striking finding being the presence of a mixed aphasia. The cranial CT shows a faint hypodensity in the left temporal lobe without mass effect and without contrast uptake. Which of the following statements is correct?\nHere are the potential choices:\n1. Bacterial meningitis is the first diagnostic impression and treatment with 3rd generation cephalosporin should be initiated as soon as possible.\n2. Most likely this patient's CSF shows a lymphocyte-predominant pleocytosis with normal glycorrhachia.\n3. We would suspect limbic encephalitis.\n4. This is an early stage brain abscess.\nThe correct answer is: 3. We would suspect limbic encephalitis."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The risk of venous thromboembolism (VTE) increases up to 5-10-fold during pregnancy and VTE represents the first cause of maternal mortality. The annual incidence of VTE is 0.97 per 1000 women during pregnancy and 7.19 per 1000 in the puerperium. The risk is higher in carriers of inherited thrombophilia. Prophylaxis of VTE during pregnancy in thrombophilic women, is still controversial, whereas there is agreement on the used of LMWH or oral anticoagulants during puerperium. LMWH is suggested during pregnancy in antithrombin deficient women, compound heterozygotes for prothrombin G20210A and factor V Leiden, and homozygotes for these conditions, with no prior VTE. In heterozygotes for F V Leiden or prothrombin G20210A with no prior VTE surveillance is preferred during pregnancy and LMWH or OA during puerperium. For patients with APLAs and no prior VTE or fetal loss, one of the following approaches is suggested: prophylactic LMWH and/or low-dose aspirin, mini dose heparin, surveillance (7 degrees ACCP). Patients with APLAs and a history of thrombosis should receive therapeutic-dose LMWH or UH plus low-dose aspirin during pregnancy and long term OA postpartum. In women with prior VTE and inherited thrombophilia, prophylactic or intermediate-dose LMWH is recommended during pregnancy plus post-partum OA. Intermediate-dose LMWH during pregnancy is suggested in antithrombin-deficient women, compound heterozygotes for prothrombin G20210A and factor V Leiden, and homozygotes for these conditions. For the management of acute thrombotic events in pregnancy therapeutic doses of low molecular weight heparins (LMWH) may be used, unless the shorter half-life of intravenous unfractionated heparin (UH) and predictable reversibility by protamine are important. Treatment should be continued up until delivery and into the puerperium. Pregnant women who have had an acute thrombotic event should be delivered by a specialist team. In the case of recent thrombosis, delivery should be planned and the time during which anticoagulation therapy is ceased around the time of delivery should be minimised. Therapeutic doses of LMWH contraindicate the use of regional anaesthesia, and a switch to intravenous UH before delivery may allow greater flexibility in this regard. Prophylactic doses of LMWH can be used to reduce the risk of recurrent thromboembolic events in pregnancy. The regimen used will depend on the previous history, the family history and the presence of risk factors, including the genetic and acquired causes of thrombophilia. Women with mechanical heart valves are at high risk during pregnancy and require therapeutic anticoagulation throughout pregnancy under the direction of experienced specialists. Low-dose aspirin can reduce the risk of recurrent pre-eclampsia by about 15%, but the role of UH and LMWH in the prevention of recurrent miscarriage or obstetric complications associated with uteroplacental insufficiency is still uncertain. Pregnancy and the puerperium put women at increased risk of venous thromboembolism (VTE) due to both baseline maternal risk factors and the development of pregnancy-related prothrombotic anatomic and physiologic changes. Pregnant women are at an approximately 5-fold increased risk of VTE compared with nonpregnant women, and the risk of VTE increases further (to ≥ 20-fold) in puerperium; risk remains increased until approximately 12 weeks postpartum. Pregnancy-related VTE accounts for about 10% of maternal deaths in the developed world. Clinicians should promptly evaluate any signs or symptoms suspicious for VTE, generally starting with ultrasound of the lower extremities. For treatment of women with established VTE, low molecular weight heparins (LMWHs) are preferred due to a favorable safety and efficacy profile. Unfractionated heparin (UFH) and potentially fondaparinux are alternatives. Warfarin should be avoided in the antepartum period due to teratogenicity, and the non-vitamin K oral anticoagulants are currently not recommended due to the lack of data. Low molecular weight heparin, UFH, and warfarin are all acceptable in the postpartum period and for breast-feeding women, but the non-vitamin K oral anticoagulants should be avoided. Prophylaxis (generally with LMWH or in some cases UFH) is recommended for women at highest risk of pregnancy-related VTE, such as those with inherited thrombophilias and a strong family or personal history of VTE. Prophylaxis with LMWH and aspirin is recommended for women with antiphospholipid syndrome. Clinicians should engage in multidisciplinary discussion, particularly around the time of delivery, to manage the details of anticoagulation in their pregnant patients.  Venous thromboembolism (VTE) occurs infrequently but is a leading cause of illness and death during pregnancy and the puerperium. In the general population the incidence of pregnancy-associated VTE is approximately 1 in 1500 deliveries. The risk of VTE is five times higher in a pregnant than in a nonpregnant woman. Postpartum the VTE risk is even higher. Women with congenital abnormalities or persistent presence of antiphospholipid antibodies have an increased risk of VTE during pregnancy and the puerperium. Women with previous VTE have an approximately 3.5-fold increased risk of recurrent VTE during pregnancy. Heparin does not cross the placenta and is therefore the anticoagulant of choice. In case of acute thrombosis during pregnancy, treatment is performed in the same manner as for nonpregnant patients. There is an ongoing debate whether pregnant women with previous venous thrombosis should routinely receive prophylactic anticoagulation. Patients who have hereditary antithrombin deficiency, antiphospholipid antibodies, a combined abnormality, or a history of a severe thrombotic event (pulmonary embolism or extended deep vein thrombosis) should be advised to use prophylactic heparin during pregnancy, starting during the first trimester. Postpartum prophylaxis should be given to all women with an increased risk for VTE. A large body of evidence has been presented that hypercoagulability may cause recurrent abortions, stillbirth, and preeclampsia. There is no doubt that the antiphospholipid syndrome is strongly associated with fetal loss. The combination of heparin and aspirin significantly decreases the fetal loss rate during pregnancy and thus this is the treatment of choice in this patient group. Several studies indicate that women with recurrent miscarriage may benefit from heparin administration during pregnancy, however, data from controlled trials have not yet been published. In women with artificial heart valves, maternal and fetal complications are frequent despite anticoagulation, but oral anticoagulants can reduce the risk for maternal complications. Whether or not pregnant women with a previous episode of venous thromboembolism (VTE) should receive antithrombotic prophylaxis is a matter of debate. In order to estimate the rate of recurrent deep venous thrombosis (DVT) or pulmonary embolism (PE) during pregnancy and puerperium we retrospectively investigated a cohort of 1104 women with previous VTE; after a single DVT or isolated PE, 88 of them became pregnant at least once without receiving antithrombotic prophylaxis. Overall, 155 pregnancies and 120 puerperium periods without prophylaxis were recorded. There were nine recurrences during pregnancy and 10 during puerperium, with a rate of 5.8% [95% confidence interval (CI) 3.0-10.6] and 8.3% (95%CI 4.5-14.6) respectively. In pregnancy, the rate of recurrence was 7.5% (95%CI 4.0-13.7) if the first VTE was unprovoked, related to pregnancy or to oral contraceptive use, whereas no recurrence occurred if the first VTE was related to other transient risk factors. In puerperium, the rate of recurrence was 15.5% (95%CI 7.7-28.7) in women with a pregnancy-related first VTE, with a risk 3.9-times higher than in the remaining women. Inherited thrombophilia was not associated with a statistically significant increase in risk of recurrence in pregnancy or in puerperium, yet the rate of recurrence in puerperium was 14.2% (95%CI 5.7-31.4) in overall carriers of factor V Leiden and 30% (95%CI 10.7-60.3) in carriers with a pregnancy-related first VTE, with a risk 6.8 times higher than in women without thrombophilia and with a non pregnancy-related first VTE.  The incidence of venous thromboembolism is significantly increased during pregnancy, recurrent venous thromboembolism being a serious complication because it is potentially life-threatening. According to recent ACCP guidelines, women with \"high-risk\" thrombophilias (e.g., homozygosity for factor V Leiden) who had a single prior episode of VTE treated with oral anticoagulants, should receive LMWH or UFH during pregnancy and puerperium, followed by resumption of long-term anticoagulants postpartum.We present the case of a young woman with a history of severe deep vein thrombosis of the inferior vena cava, occurring during oral contraceptive use. Subsequent investigation revealed homozygosity for Leiden mutation. She was treated with enoxaparin throughout gestation and 6 weeks postpartum and no complications appeared. The aim of this paper is to present the latest developments in therapy and prophylaxis of deep vein thrombosis and other pregnancy complications in women with inherited or acquired thrombophilia and in women with mechanical heart valves. The data presented in the paper have been extracted from the Current Contents database. It is well known that the hypercoagulable state in pregnant women, caused either by the physiological changes of pregnancy or by inherited thrombophilia, increases the risk of venous thromboembolism (VTE), pulmonary embolism (PE), preeclampsia, recurrent early and late fetal loss, intrauterine growth retardation (IUGR), placental abruption, and other less probable complications of pregnancy and its outcome. In women with mechanical heart valves, the risk of systemic embolism is also seen to increase during pregnancy. According to data analyzed, positive antiphospholipid antibodies (APLA) as well as anticardiolipin antibody and lupus anticoagulant (nonspecific inhibitor) positivity, homozygosity and heterozygosity for factor V Leiden mutation and heterozygosity for the prothrombin G20210A variant, MTHFR C677T variant homozygosity and hyperhomocysteinemia are in strong association with pregnancy complications and severe pregnancy outcome. The strongest association for late fetal loss was seen in women with protein S deficiency. In order to reduce such risks, anticoagulation therapy is administered throughout pregnancy. The antithrombotic agents available for the prevention and treatment of VTE during pregnancy and pregnancy complications include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and aspirin. Vitamin K antagonists are contraindicated in pregnancy. Low-dose aspirin may have a role in the prevention of some pregnancy complications, although its safety in early pregnancy is uncertain. LMWH and UFH are quite safe and efficacious when properly selected, dosed and monitored. The efficacy and safety of LMWH have been demonstrated in the prevention and treatment of VTE in pregnancy. LMWH in association with aspirin administered throughout pregnancy have been shown to be associated with a lower risk of complications in women with APLA syndrome. Women at a high risk of preeclampsia are recommended to use low-dose aspirin throughout pregnancy. When there is a history of preeclampsia, the administration of anticoagulation therapy is not recommended as a prophylaxis in subsequent pregnancies, as the risk appears to be already decreased as compared with previous pregnancy. LMWH has probable advantages over UFH for the incidence of side effects. In pregnant women with mechanical heart valves, anticoagulant therapy during pregnancy should include assessment of additional risk factors for thromboembolism including valve type, position, and history of thromboembolism, and decision should also be strongly influenced by the patient's preferences. If the risk of thromboembolism in patients with mechanical heart valves is considered very high, and efficacy or safety of prophylaxis with UFH or LMWH is not satisfactory (older-generation prosthesis in the mitral position or history of thromboembolism), administration of vitamin K antagonists throughout pregnancy is recommended with replacement by UFH or LMWH close to delivery. It should be considered that limited effectiveness of UFH or LMWH in patients with mechanical heart valves might be due to inadequate dosing. The necessity of anticoagulation therapy in women with inherited or acquired thrombophilia is biologically plausible; nevertheless, optimum management in such cases remains unknown. Venous thromboembolism occurs infrequently but is a leading cause of illness and death during pregnancy and the puerperium and remains a diagnostic and therapeutic challenge. In the general population the incidence of pregnancy associated VTE has been estimated to vary from 1 in 1000 to 1 in 2000 deliveries. The risk of VTE is five times higher in a pregnant woman than in a nonpregnant woman of similar age. Postpartum VTE is more common than antepartum VTE. Women with congenital abnormalities or persistent presence of antiphospholipid antibodies have an increased risk of VTE during pregnancy and the puerperium. In individuals with well defined hereditary thrombosis risk factors, such as the factor V:R506Q mutation, the factor II:G20210A variation, antithrombin-deficiency or protein C-deficiency, a relative risk of pregnancy associated VTE between 3.4 and 15.2 has been found. Women with previous VTE have an approximately 3.5 fold increased risk of recurrent VTE during pregnancy compared to non-pregnant periods. Our ability to diagnose deep-vein thrombosis clinically is generally poor and is further hampered during pregnancy since dyspnea, tachypnea, swelling and discomfort in the legs are common. Objective diagnosis is essential for treatment decisions. Exposure to radiation of less than 50,000 microGy (5 rad) has not been associated with a significant risk of fetal injury. Therefore, besides sonography, routine diagnostic procedures should be performed, if clinically necessary. Heparin does not cross the placenta and is therefore the anticoagulant treatment of choice during pregnancy. In case of acute new onset of thrombosis during pregnancy, treatment is performed like in non-pregnant patients with acute deep vein thrombosis or pulmonary embolism. There is ongoing debate, whether or not pregnant women with previous venous thrombosis should routinely receive prophylactic anticoagulation. In patients who have hereditary antithrombin deficiency, antiphospholipid antibodies, a combined abnormality or a history of a severe thrombotic event (pulmonary embolism, extended deep vein thrombosis) should be advised to use prophylactic heparin during pregnancy, starting during the first trimester. Post partum prophylaxis should be given in all women with an increased risk for VTE. This article discusses the management of venous thromboembolism (VTE) and thrombophilia, as well as the use of antithrombotic agents, during pregnancy and is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that benefits do, or do not, outweigh risks, burden, and costs. Grade 2 recommendations are weaker and imply that the magnitude of the benefits and risks, burden, and costs are less certain. Support for recommendations may come from high-quality, moderate-quality or low-quality studies; labeled, respectively, A, B, and C. Among the key recommendations in this chapter are the following: for pregnant women, in general, we recommend that vitamin K antagonists should be substituted with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1A], except perhaps in women with mechanical heart valves. For pregnant patients, we suggest LMWH over UFH for the prevention and treatment of VTE (Grade 2C). For pregnant women with acute VTE, we recommend that subcutaneous LMWH or UFH should be continued throughout pregnancy (Grade 1B) and suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a total minimum duration of therapy of 6 months) [Grade 2C]. For pregnant patients with a single prior episode of VTE associated with a transient risk factor that is no longer present and no thrombophilia, we recommend clinical surveillance antepartum and anticoagulant prophylaxis postpartum (Grade 1C). For other pregnant women with a history of a single prior episode of VTE who are not receiving long-term anticoagulant therapy, we recommend one of the following, rather than routine care or full-dose anticoagulation: antepartum prophylactic LMWH/UFH or intermediate-dose LMWH/UFH or clinical surveillance throughout pregnancy plus postpartum anticoagulants (Grade 1C). For such patients with a higher risk thrombophilia, in addition to postpartum prophylaxis, we suggest antepartum prophylactic or intermediate-dose LMWH or prophylactic or intermediate-dose UFH, rather than clinical surveillance (Grade 2C). We suggest that pregnant women with multiple episodes of VTE who are not receiving long-term anticoagulants receive antepartum prophylactic, intermediate-dose, or adjusted-dose LMWH or intermediate or adjusted-dose UFH, followed by postpartum anticoagulants (Grade 2C). For those pregnant women with prior VTE who are receiving long-term anticoagulants, we recommend LMWH or UFH throughout pregnancy (either adjusted-dose LMWH or UFH, 75% of adjusted-dose LMWH, or intermediate-dose LMWH) followed by resumption of long-term anticoagulants postpartum (Grade 1C). We suggest both antepartum and postpartum prophylaxis for pregnant women with no prior history of VTE but antithrombin deficiency (Grade 2C). For all other pregnant women with thrombophilia but no prior VTE, we suggest antepartum clinical surveillance or prophylactic LMWH or UFH, plus postpartum anticoagulants, rather than routine care (Grade 2C). For women with recurrent early pregnancy loss or unexplained late pregnancy loss, we recommend screening for antiphospholipid antibodies (APLAs) [Grade 1A]. For women with these pregnancy complications who test positive for APLAs and have no history of venous or arterial thrombosis, we recommend antepartum administration of prophylactic or intermediate-dose UFH or prophylactic LMWH combined with aspirin (Grade 1B). We recommend that the decision about anticoagulant management during pregnancy for pregnant women with mechanical heart valves include an assessment of additional risk factors for thromboembolism including valve type, position, and history of thromboembolism (Grade 1C). While patient values and preferences are important for all decisions regarding antithrombotic therapy in pregnancy, this is particularly so for women with mechanical heart valves. For these women, we recommend either adjusted-dose bid LMWH throughout pregnancy (Grade 1C), adjusted-dose UFH throughout pregnancy (Grade 1C), or one of these two regimens until the thirteenth week with warfarin substitution until close to delivery before restarting LMWH or UFH) [Grade 1C]. However, if a pregnant woman with a mechanical heart valve is judged to be at very high risk of thromboembolism and there are concerns about the efficacy and safety of LMWH or UFH as dosed above, we suggest vitamin K antagonists throughout pregnancy with replacement by UFH or LMWH close to delivery, after a thorough discussion of the potential risks and benefits of this approach (Grade 2C). Venous thromboembolism (VTE) remains the leading cause of maternal death. Today, various risk factors and conditions are known to increase the risk for VTE associated with pregnancy. Having identified the individual risk of a pregnant women, appropriate preventive measures can be taken. If VTE occurs during pregnancy, an appropriate immediate diagnostic work-up is essential in order to avoid further complications. For deep vein thrombosis (DVT) the diagnostic tool of choice is color-coded duplex-sonography, for pulmonary embolism (PE) perfusion/ventilation lung scan can be used. Integrating a detailed individual and family history, the presence of thrombophilia or other risk factors, a risk stratification can be undertaken. These risk categories are defined in the present paper and the appropriate treatment measures are described. As oral anticoagulants cross the placenta and may cause embryopathy in any trimester, oral anticoagulants should be avoided throughout pregnancy. Therefore, heparin is the anti-coagulant of choice for pregnant women, with low molecular weight heparins (LMWH) having distinctive pharmacological advantages over unfractionated heparins. Besides a potential for bleeding, the main side effects of heparin include heparin-induced thrombocytopenia which prompts for platelet monitoring, especially in the first weeks of heparin treatment, and, secondly, heparin-induced osteoporosis, which is a potential sequel of long-term heparin administration. Even though there are abundant reports in the literature on the use of LMWH in pregnant women, that show that they are safe and effective, LMWH are not specifically licensed for the use in pregnancy. Venous thromboembolism (VTE) occurs infrequently but is a leading cause of illness and death during pregnancy and the puerperium. In the general population the incidence of pregnancy associated VTE is approximately 1 in 1500 deliveries The risk of VTE is five times higher in a pregnant than in a non-pregnant woman. Postpartum the VTE-risk is even higher. Women with congenital abnormalities or persistent presence of antiphospholipid antibodies have an increased risk of VTE during pregnancy and the puerperium. In individuals with well defined hereditary thrombosis risk factors, such as the factor V:R506Q mutation, the factor II:G20210A variation, antithrombin-deficiency or protein C-deficiency, a relative risk of pregnancy associated VTE between 3.4 and 15.2 has been found. Women with previous VTE have an approximately 3.5 fold increased risk of recurrent VTE during pregnancy compared to non-pregnant periods. Our ability to diagnose pregnancy-associated VTE clinically is generally poor, since dyspnea, tachypnea, swelling and discomfort in the legs are common. Objective diagnosis is essential for treatment decisions. Exposure to radiation of less than 50,000 microGy (5 rad) has not been associated with a significant risk of fetal injury Therefore, besides sonography, routine diagnostic procedures should be performed, if clinically necessary. Heparin does not cross the placenta and is therefore the anticoagulant of choice. In case of acute thrombosis during pregnancy, treatment is performed like in nonpregnant patients. There is ongoing debate, whether or not pregnant women with previous venous thrombosis should routinely receive prophylactic anticoagulation. In patients who have hereditary antithrombin deficiency, antiphospholipid antibodies, a combined abnormality or a history of a severe thrombotic event (pulmonary embolism, extended deep vein thrombosis) should be advised to use prophylactic heparin during pregnancy, starting during the first trimester. Post partum prophylaxis should be given in all women with an increased risk for VTE. Venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality in pregnancy and the puerperium. To reduce the incidence of VTE, it is helpful to understand the haemostatic changes during pregnancy and to recognise thrombophilic states. According to the individual risk profile a prophylactic or therapeutic anticoagulation needs to be considered. A narrative, non-systematic overview of articles published in English, German or French over the past three decades with an emphasis on manuscripts from 2003 to 2008. Heparins are the main agents used for anticoagulation during pregnancy. Low-molecular-weight heparins have more advantages than unfractionated heparin and should be preferred. Vitamin-K antagonists are not recommended in this condition as first-line treatment because of the risk for embryopathy and fetal bleeding, but they can be given under certain conditions. Subgroups of patients, such as women with prosthetic heart valves, require special attention. Adverse pregnancy outcomes due to hereditary thrombophilia are new indications for use of anticoagulants during pregnancy. National and international guidelines on prevention and treatment of thromboembolism are helpful in applying the proper regimen in pregnant women. Venous thromboembolism (VTE) is a potentially life-threatening medical condition during pregnancy and the puerperium. During pregnancy, the risk of VTE is increased four to tenfold compared to non-pregnant women of comparable age. The risk is even higher in the puerperium. Physician awareness followed by adequate treatment may reduce the number of events. The most important risk factors are previous VTE or thrombophilia, although other acquired risk factors may result in similar impacts. Treatment is based on personalized risk assessment at the first patient visit during pregnancy, followed by repeated assessment of complications or at admission and final assessment at delivery. Hydration and mobilization are advised for all women. Pharmacological prevention by low-molecular-weight heparin (LMWH) is advised based on risk stratification. International guidelines differ by indications and range of management options. The purpose of this review is to summarize our knowledge on risk factors for VTE during pregnancy and puerperium and guide management options. The assessment of the frequency of venous thromboembolism (VTE) in women with F V Leiden in association with pregnancy and puerperium and according these results and available data to formulate the principles of thromboprophylaxis. Retrospective case control study. The assessment of frequency of VTE in the group of 224 women with F V Leiden in heterozygous form in association with 460 pregnancies and in the group of 40 women with F V Leiden in homozygous form in association with 70 pregnancies. This frequency of VTE in those groups was compared with the frequency of VTE in the control group of 201 women without F V Leiden in association with 422 pregnancies. F V Leiden evaluation was done in the period of 1996-2003. In the group of women with F V Leiden in heterozygous form VTE occurred 44-fold during pregnancy and puerperium. In 17 cases VTE was manifested in pregnancy (once in Ist trimester, twice in IInd trimester, 14 times in IIIrd trimester), in 27 women VTE occurred in puerperium and always within the first 10 days after delivery. Proximal venous thrombosis was diagnosed in 34 cases, in 5 cases being complicated by pulmonary embolism. In 10 women thrombosis was distal. The frequency of VTE is 9.6%. In the group of women with homozyous form VTE occurred in 14 cases (20%). In 5 cases VTE occurred during pregnancy, in 9 cases after delivery and in all cases within first 2 weeks after delivery. The frequency of VTE in the control group is 0.24%. The results were statistically assessed by Fishers exact test in programme NCSS 2004. Frequency of VTE in both cohorts of women with F V Leiden reached statistical significance in comparison with the control group. Pregnancy and puerperium are significant risk factors for VTE in the group of women with F V Leiden in heterozygous form and mainly in homozygous form. Fatal pulmonary embolism remains the most common cause of mortality among pregnant women in many Western countries. The physiological changes of pregnancy produce a hypercoagulable state that increases the risk of venous thromboembolism (VTE). Women with inherited or acquired thrombophilias are at particularly high risk of VTE during pregnancy, and thromboprophylaxis may be advisable in some cases. Thrombophilia is also associated with complications of pregnancy, including fetal loss, pre-eclampsia, intra-uterine growth restriction, and placental abruption. The antithrombotic agents available for the prevention and treatment of VTE during pregnancy, and pregnancy complications, include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and aspirin. Vitamin K antagonists are contra-indicated in pregnancy. Low-dose aspirin may have a role in the prevention of some pregnancy complications, although its safety in early and late pregnancy is uncertain. The efficacy and safety of LMWHs have been demonstrated for the prevention and treatment of VTE in pregnancy. These agents are increasingly being used in place of UFH, which is associated with a higher incidence of side effects compared with LMWH, in addition to the need for regular laboratory monitoring. Evidence is also emerging to support the use of LMWH in the prevention of recurrent fetal loss, although further trials are needed to explore the role of LMWHs in this indication and in the prevention of other complications of pregnancy.\nHere is the question:\nHEMATOLOGY: A 25-year-old woman who wishes to become pregnant and wants to know what treatment she should take during the eventual pregnancy, as she is a heterozygous factor V Leiden carrier. She has never had any thrombotic phenomena. The determination of this factor was performed as a family study after an episode of pulmonary embolism in a sibling. What treatment should be advised?\nHere are the potential choices:\n1. Since pregnancy is a prothrombotic state, there would be a high risk of venous thromboembolism, so pregnancy should be discouraged.\n2. Treatment with low molecular weight heparin at prophylactic doses should be carried out in the immediate puerperium, with optional follow-up during pregnancy.\n3. Factor V Leiden in heterozygosis is a low-risk thrombophilia and there is no need for any treatment in pregnancy and puerperium.\n4. Low-dose aspirin should be advised during pregnancy and puerperium.\n5. Treatment with antivitamin K drugs (acenocoumarol) during pregnancy.\nThe correct answer is: ",
        "gold_answer": "3 Factor V Leiden in heterozygosis is a low-risk thrombophilia and there is no need for any treatment in pregnancy and puerperium.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The risk of venous thromboembolism (VTE) increases up to 5-10-fold during pregnancy and VTE represents the first cause of maternal mortality. The annual incidence of VTE is 0.97 per 1000 women during pregnancy and 7.19 per 1000 in the puerperium. The risk is higher in carriers of inherited thrombophilia. Prophylaxis of VTE during pregnancy in thrombophilic women, is still controversial, whereas there is agreement on the used of LMWH or oral anticoagulants during puerperium. LMWH is suggested during pregnancy in antithrombin deficient women, compound heterozygotes for prothrombin G20210A and factor V Leiden, and homozygotes for these conditions, with no prior VTE. In heterozygotes for F V Leiden or prothrombin G20210A with no prior VTE surveillance is preferred during pregnancy and LMWH or OA during puerperium. For patients with APLAs and no prior VTE or fetal loss, one of the following approaches is suggested: prophylactic LMWH and/or low-dose aspirin, mini dose heparin, surveillance (7 degrees ACCP). Patients with APLAs and a history of thrombosis should receive therapeutic-dose LMWH or UH plus low-dose aspirin during pregnancy and long term OA postpartum. In women with prior VTE and inherited thrombophilia, prophylactic or intermediate-dose LMWH is recommended during pregnancy plus post-partum OA. Intermediate-dose LMWH during pregnancy is suggested in antithrombin-deficient women, compound heterozygotes for prothrombin G20210A and factor V Leiden, and homozygotes for these conditions. For the management of acute thrombotic events in pregnancy therapeutic doses of low molecular weight heparins (LMWH) may be used, unless the shorter half-life of intravenous unfractionated heparin (UH) and predictable reversibility by protamine are important. Treatment should be continued up until delivery and into the puerperium. Pregnant women who have had an acute thrombotic event should be delivered by a specialist team. In the case of recent thrombosis, delivery should be planned and the time during which anticoagulation therapy is ceased around the time of delivery should be minimised. Therapeutic doses of LMWH contraindicate the use of regional anaesthesia, and a switch to intravenous UH before delivery may allow greater flexibility in this regard. Prophylactic doses of LMWH can be used to reduce the risk of recurrent thromboembolic events in pregnancy. The regimen used will depend on the previous history, the family history and the presence of risk factors, including the genetic and acquired causes of thrombophilia. Women with mechanical heart valves are at high risk during pregnancy and require therapeutic anticoagulation throughout pregnancy under the direction of experienced specialists. Low-dose aspirin can reduce the risk of recurrent pre-eclampsia by about 15%, but the role of UH and LMWH in the prevention of recurrent miscarriage or obstetric complications associated with uteroplacental insufficiency is still uncertain. Pregnancy and the puerperium put women at increased risk of venous thromboembolism (VTE) due to both baseline maternal risk factors and the development of pregnancy-related prothrombotic anatomic and physiologic changes. Pregnant women are at an approximately 5-fold increased risk of VTE compared with nonpregnant women, and the risk of VTE increases further (to ≥ 20-fold) in puerperium; risk remains increased until approximately 12 weeks postpartum. Pregnancy-related VTE accounts for about 10% of maternal deaths in the developed world. Clinicians should promptly evaluate any signs or symptoms suspicious for VTE, generally starting with ultrasound of the lower extremities. For treatment of women with established VTE, low molecular weight heparins (LMWHs) are preferred due to a favorable safety and efficacy profile. Unfractionated heparin (UFH) and potentially fondaparinux are alternatives. Warfarin should be avoided in the antepartum period due to teratogenicity, and the non-vitamin K oral anticoagulants are currently not recommended due to the lack of data. Low molecular weight heparin, UFH, and warfarin are all acceptable in the postpartum period and for breast-feeding women, but the non-vitamin K oral anticoagulants should be avoided. Prophylaxis (generally with LMWH or in some cases UFH) is recommended for women at highest risk of pregnancy-related VTE, such as those with inherited thrombophilias and a strong family or personal history of VTE. Prophylaxis with LMWH and aspirin is recommended for women with antiphospholipid syndrome. Clinicians should engage in multidisciplinary discussion, particularly around the time of delivery, to manage the details of anticoagulation in their pregnant patients.  Venous thromboembolism (VTE) occurs infrequently but is a leading cause of illness and death during pregnancy and the puerperium. In the general population the incidence of pregnancy-associated VTE is approximately 1 in 1500 deliveries. The risk of VTE is five times higher in a pregnant than in a nonpregnant woman. Postpartum the VTE risk is even higher. Women with congenital abnormalities or persistent presence of antiphospholipid antibodies have an increased risk of VTE during pregnancy and the puerperium. Women with previous VTE have an approximately 3.5-fold increased risk of recurrent VTE during pregnancy. Heparin does not cross the placenta and is therefore the anticoagulant of choice. In case of acute thrombosis during pregnancy, treatment is performed in the same manner as for nonpregnant patients. There is an ongoing debate whether pregnant women with previous venous thrombosis should routinely receive prophylactic anticoagulation. Patients who have hereditary antithrombin deficiency, antiphospholipid antibodies, a combined abnormality, or a history of a severe thrombotic event (pulmonary embolism or extended deep vein thrombosis) should be advised to use prophylactic heparin during pregnancy, starting during the first trimester. Postpartum prophylaxis should be given to all women with an increased risk for VTE. A large body of evidence has been presented that hypercoagulability may cause recurrent abortions, stillbirth, and preeclampsia. There is no doubt that the antiphospholipid syndrome is strongly associated with fetal loss. The combination of heparin and aspirin significantly decreases the fetal loss rate during pregnancy and thus this is the treatment of choice in this patient group. Several studies indicate that women with recurrent miscarriage may benefit from heparin administration during pregnancy, however, data from controlled trials have not yet been published. In women with artificial heart valves, maternal and fetal complications are frequent despite anticoagulation, but oral anticoagulants can reduce the risk for maternal complications. Whether or not pregnant women with a previous episode of venous thromboembolism (VTE) should receive antithrombotic prophylaxis is a matter of debate. In order to estimate the rate of recurrent deep venous thrombosis (DVT) or pulmonary embolism (PE) during pregnancy and puerperium we retrospectively investigated a cohort of 1104 women with previous VTE; after a single DVT or isolated PE, 88 of them became pregnant at least once without receiving antithrombotic prophylaxis. Overall, 155 pregnancies and 120 puerperium periods without prophylaxis were recorded. There were nine recurrences during pregnancy and 10 during puerperium, with a rate of 5.8% [95% confidence interval (CI) 3.0-10.6] and 8.3% (95%CI 4.5-14.6) respectively. In pregnancy, the rate of recurrence was 7.5% (95%CI 4.0-13.7) if the first VTE was unprovoked, related to pregnancy or to oral contraceptive use, whereas no recurrence occurred if the first VTE was related to other transient risk factors. In puerperium, the rate of recurrence was 15.5% (95%CI 7.7-28.7) in women with a pregnancy-related first VTE, with a risk 3.9-times higher than in the remaining women. Inherited thrombophilia was not associated with a statistically significant increase in risk of recurrence in pregnancy or in puerperium, yet the rate of recurrence in puerperium was 14.2% (95%CI 5.7-31.4) in overall carriers of factor V Leiden and 30% (95%CI 10.7-60.3) in carriers with a pregnancy-related first VTE, with a risk 6.8 times higher than in women without thrombophilia and with a non pregnancy-related first VTE.  The incidence of venous thromboembolism is significantly increased during pregnancy, recurrent venous thromboembolism being a serious complication because it is potentially life-threatening. According to recent ACCP guidelines, women with \"high-risk\" thrombophilias (e.g., homozygosity for factor V Leiden) who had a single prior episode of VTE treated with oral anticoagulants, should receive LMWH or UFH during pregnancy and puerperium, followed by resumption of long-term anticoagulants postpartum.We present the case of a young woman with a history of severe deep vein thrombosis of the inferior vena cava, occurring during oral contraceptive use. Subsequent investigation revealed homozygosity for Leiden mutation. She was treated with enoxaparin throughout gestation and 6 weeks postpartum and no complications appeared. The aim of this paper is to present the latest developments in therapy and prophylaxis of deep vein thrombosis and other pregnancy complications in women with inherited or acquired thrombophilia and in women with mechanical heart valves. The data presented in the paper have been extracted from the Current Contents database. It is well known that the hypercoagulable state in pregnant women, caused either by the physiological changes of pregnancy or by inherited thrombophilia, increases the risk of venous thromboembolism (VTE), pulmonary embolism (PE), preeclampsia, recurrent early and late fetal loss, intrauterine growth retardation (IUGR), placental abruption, and other less probable complications of pregnancy and its outcome. In women with mechanical heart valves, the risk of systemic embolism is also seen to increase during pregnancy. According to data analyzed, positive antiphospholipid antibodies (APLA) as well as anticardiolipin antibody and lupus anticoagulant (nonspecific inhibitor) positivity, homozygosity and heterozygosity for factor V Leiden mutation and heterozygosity for the prothrombin G20210A variant, MTHFR C677T variant homozygosity and hyperhomocysteinemia are in strong association with pregnancy complications and severe pregnancy outcome. The strongest association for late fetal loss was seen in women with protein S deficiency. In order to reduce such risks, anticoagulation therapy is administered throughout pregnancy. The antithrombotic agents available for the prevention and treatment of VTE during pregnancy and pregnancy complications include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and aspirin. Vitamin K antagonists are contraindicated in pregnancy. Low-dose aspirin may have a role in the prevention of some pregnancy complications, although its safety in early pregnancy is uncertain. LMWH and UFH are quite safe and efficacious when properly selected, dosed and monitored. The efficacy and safety of LMWH have been demonstrated in the prevention and treatment of VTE in pregnancy. LMWH in association with aspirin administered throughout pregnancy have been shown to be associated with a lower risk of complications in women with APLA syndrome. Women at a high risk of preeclampsia are recommended to use low-dose aspirin throughout pregnancy. When there is a history of preeclampsia, the administration of anticoagulation therapy is not recommended as a prophylaxis in subsequent pregnancies, as the risk appears to be already decreased as compared with previous pregnancy. LMWH has probable advantages over UFH for the incidence of side effects. In pregnant women with mechanical heart valves, anticoagulant therapy during pregnancy should include assessment of additional risk factors for thromboembolism including valve type, position, and history of thromboembolism, and decision should also be strongly influenced by the patient's preferences. If the risk of thromboembolism in patients with mechanical heart valves is considered very high, and efficacy or safety of prophylaxis with UFH or LMWH is not satisfactory (older-generation prosthesis in the mitral position or history of thromboembolism), administration of vitamin K antagonists throughout pregnancy is recommended with replacement by UFH or LMWH close to delivery. It should be considered that limited effectiveness of UFH or LMWH in patients with mechanical heart valves might be due to inadequate dosing. The necessity of anticoagulation therapy in women with inherited or acquired thrombophilia is biologically plausible; nevertheless, optimum management in such cases remains unknown. Venous thromboembolism occurs infrequently but is a leading cause of illness and death during pregnancy and the puerperium and remains a diagnostic and therapeutic challenge. In the general population the incidence of pregnancy associated VTE has been estimated to vary from 1 in 1000 to 1 in 2000 deliveries. The risk of VTE is five times higher in a pregnant woman than in a nonpregnant woman of similar age. Postpartum VTE is more common than antepartum VTE. Women with congenital abnormalities or persistent presence of antiphospholipid antibodies have an increased risk of VTE during pregnancy and the puerperium. In individuals with well defined hereditary thrombosis risk factors, such as the factor V:R506Q mutation, the factor II:G20210A variation, antithrombin-deficiency or protein C-deficiency, a relative risk of pregnancy associated VTE between 3.4 and 15.2 has been found. Women with previous VTE have an approximately 3.5 fold increased risk of recurrent VTE during pregnancy compared to non-pregnant periods. Our ability to diagnose deep-vein thrombosis clinically is generally poor and is further hampered during pregnancy since dyspnea, tachypnea, swelling and discomfort in the legs are common. Objective diagnosis is essential for treatment decisions. Exposure to radiation of less than 50,000 microGy (5 rad) has not been associated with a significant risk of fetal injury. Therefore, besides sonography, routine diagnostic procedures should be performed, if clinically necessary. Heparin does not cross the placenta and is therefore the anticoagulant treatment of choice during pregnancy. In case of acute new onset of thrombosis during pregnancy, treatment is performed like in non-pregnant patients with acute deep vein thrombosis or pulmonary embolism. There is ongoing debate, whether or not pregnant women with previous venous thrombosis should routinely receive prophylactic anticoagulation. In patients who have hereditary antithrombin deficiency, antiphospholipid antibodies, a combined abnormality or a history of a severe thrombotic event (pulmonary embolism, extended deep vein thrombosis) should be advised to use prophylactic heparin during pregnancy, starting during the first trimester. Post partum prophylaxis should be given in all women with an increased risk for VTE. This article discusses the management of venous thromboembolism (VTE) and thrombophilia, as well as the use of antithrombotic agents, during pregnancy and is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that benefits do, or do not, outweigh risks, burden, and costs. Grade 2 recommendations are weaker and imply that the magnitude of the benefits and risks, burden, and costs are less certain. Support for recommendations may come from high-quality, moderate-quality or low-quality studies; labeled, respectively, A, B, and C. Among the key recommendations in this chapter are the following: for pregnant women, in general, we recommend that vitamin K antagonists should be substituted with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1A], except perhaps in women with mechanical heart valves. For pregnant patients, we suggest LMWH over UFH for the prevention and treatment of VTE (Grade 2C). For pregnant women with acute VTE, we recommend that subcutaneous LMWH or UFH should be continued throughout pregnancy (Grade 1B) and suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a total minimum duration of therapy of 6 months) [Grade 2C]. For pregnant patients with a single prior episode of VTE associated with a transient risk factor that is no longer present and no thrombophilia, we recommend clinical surveillance antepartum and anticoagulant prophylaxis postpartum (Grade 1C). For other pregnant women with a history of a single prior episode of VTE who are not receiving long-term anticoagulant therapy, we recommend one of the following, rather than routine care or full-dose anticoagulation: antepartum prophylactic LMWH/UFH or intermediate-dose LMWH/UFH or clinical surveillance throughout pregnancy plus postpartum anticoagulants (Grade 1C). For such patients with a higher risk thrombophilia, in addition to postpartum prophylaxis, we suggest antepartum prophylactic or intermediate-dose LMWH or prophylactic or intermediate-dose UFH, rather than clinical surveillance (Grade 2C). We suggest that pregnant women with multiple episodes of VTE who are not receiving long-term anticoagulants receive antepartum prophylactic, intermediate-dose, or adjusted-dose LMWH or intermediate or adjusted-dose UFH, followed by postpartum anticoagulants (Grade 2C). For those pregnant women with prior VTE who are receiving long-term anticoagulants, we recommend LMWH or UFH throughout pregnancy (either adjusted-dose LMWH or UFH, 75% of adjusted-dose LMWH, or intermediate-dose LMWH) followed by resumption of long-term anticoagulants postpartum (Grade 1C). We suggest both antepartum and postpartum prophylaxis for pregnant women with no prior history of VTE but antithrombin deficiency (Grade 2C). For all other pregnant women with thrombophilia but no prior VTE, we suggest antepartum clinical surveillance or prophylactic LMWH or UFH, plus postpartum anticoagulants, rather than routine care (Grade 2C). For women with recurrent early pregnancy loss or unexplained late pregnancy loss, we recommend screening for antiphospholipid antibodies (APLAs) [Grade 1A]. For women with these pregnancy complications who test positive for APLAs and have no history of venous or arterial thrombosis, we recommend antepartum administration of prophylactic or intermediate-dose UFH or prophylactic LMWH combined with aspirin (Grade 1B). We recommend that the decision about anticoagulant management during pregnancy for pregnant women with mechanical heart valves include an assessment of additional risk factors for thromboembolism including valve type, position, and history of thromboembolism (Grade 1C). While patient values and preferences are important for all decisions regarding antithrombotic therapy in pregnancy, this is particularly so for women with mechanical heart valves. For these women, we recommend either adjusted-dose bid LMWH throughout pregnancy (Grade 1C), adjusted-dose UFH throughout pregnancy (Grade 1C), or one of these two regimens until the thirteenth week with warfarin substitution until close to delivery before restarting LMWH or UFH) [Grade 1C]. However, if a pregnant woman with a mechanical heart valve is judged to be at very high risk of thromboembolism and there are concerns about the efficacy and safety of LMWH or UFH as dosed above, we suggest vitamin K antagonists throughout pregnancy with replacement by UFH or LMWH close to delivery, after a thorough discussion of the potential risks and benefits of this approach (Grade 2C). Venous thromboembolism (VTE) remains the leading cause of maternal death. Today, various risk factors and conditions are known to increase the risk for VTE associated with pregnancy. Having identified the individual risk of a pregnant women, appropriate preventive measures can be taken. If VTE occurs during pregnancy, an appropriate immediate diagnostic work-up is essential in order to avoid further complications. For deep vein thrombosis (DVT) the diagnostic tool of choice is color-coded duplex-sonography, for pulmonary embolism (PE) perfusion/ventilation lung scan can be used. Integrating a detailed individual and family history, the presence of thrombophilia or other risk factors, a risk stratification can be undertaken. These risk categories are defined in the present paper and the appropriate treatment measures are described. As oral anticoagulants cross the placenta and may cause embryopathy in any trimester, oral anticoagulants should be avoided throughout pregnancy. Therefore, heparin is the anti-coagulant of choice for pregnant women, with low molecular weight heparins (LMWH) having distinctive pharmacological advantages over unfractionated heparins. Besides a potential for bleeding, the main side effects of heparin include heparin-induced thrombocytopenia which prompts for platelet monitoring, especially in the first weeks of heparin treatment, and, secondly, heparin-induced osteoporosis, which is a potential sequel of long-term heparin administration. Even though there are abundant reports in the literature on the use of LMWH in pregnant women, that show that they are safe and effective, LMWH are not specifically licensed for the use in pregnancy. Venous thromboembolism (VTE) occurs infrequently but is a leading cause of illness and death during pregnancy and the puerperium. In the general population the incidence of pregnancy associated VTE is approximately 1 in 1500 deliveries The risk of VTE is five times higher in a pregnant than in a non-pregnant woman. Postpartum the VTE-risk is even higher. Women with congenital abnormalities or persistent presence of antiphospholipid antibodies have an increased risk of VTE during pregnancy and the puerperium. In individuals with well defined hereditary thrombosis risk factors, such as the factor V:R506Q mutation, the factor II:G20210A variation, antithrombin-deficiency or protein C-deficiency, a relative risk of pregnancy associated VTE between 3.4 and 15.2 has been found. Women with previous VTE have an approximately 3.5 fold increased risk of recurrent VTE during pregnancy compared to non-pregnant periods. Our ability to diagnose pregnancy-associated VTE clinically is generally poor, since dyspnea, tachypnea, swelling and discomfort in the legs are common. Objective diagnosis is essential for treatment decisions. Exposure to radiation of less than 50,000 microGy (5 rad) has not been associated with a significant risk of fetal injury Therefore, besides sonography, routine diagnostic procedures should be performed, if clinically necessary. Heparin does not cross the placenta and is therefore the anticoagulant of choice. In case of acute thrombosis during pregnancy, treatment is performed like in nonpregnant patients. There is ongoing debate, whether or not pregnant women with previous venous thrombosis should routinely receive prophylactic anticoagulation. In patients who have hereditary antithrombin deficiency, antiphospholipid antibodies, a combined abnormality or a history of a severe thrombotic event (pulmonary embolism, extended deep vein thrombosis) should be advised to use prophylactic heparin during pregnancy, starting during the first trimester. Post partum prophylaxis should be given in all women with an increased risk for VTE. Venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality in pregnancy and the puerperium. To reduce the incidence of VTE, it is helpful to understand the haemostatic changes during pregnancy and to recognise thrombophilic states. According to the individual risk profile a prophylactic or therapeutic anticoagulation needs to be considered. A narrative, non-systematic overview of articles published in English, German or French over the past three decades with an emphasis on manuscripts from 2003 to 2008. Heparins are the main agents used for anticoagulation during pregnancy. Low-molecular-weight heparins have more advantages than unfractionated heparin and should be preferred. Vitamin-K antagonists are not recommended in this condition as first-line treatment because of the risk for embryopathy and fetal bleeding, but they can be given under certain conditions. Subgroups of patients, such as women with prosthetic heart valves, require special attention. Adverse pregnancy outcomes due to hereditary thrombophilia are new indications for use of anticoagulants during pregnancy. National and international guidelines on prevention and treatment of thromboembolism are helpful in applying the proper regimen in pregnant women. Venous thromboembolism (VTE) is a potentially life-threatening medical condition during pregnancy and the puerperium. During pregnancy, the risk of VTE is increased four to tenfold compared to non-pregnant women of comparable age. The risk is even higher in the puerperium. Physician awareness followed by adequate treatment may reduce the number of events. The most important risk factors are previous VTE or thrombophilia, although other acquired risk factors may result in similar impacts. Treatment is based on personalized risk assessment at the first patient visit during pregnancy, followed by repeated assessment of complications or at admission and final assessment at delivery. Hydration and mobilization are advised for all women. Pharmacological prevention by low-molecular-weight heparin (LMWH) is advised based on risk stratification. International guidelines differ by indications and range of management options. The purpose of this review is to summarize our knowledge on risk factors for VTE during pregnancy and puerperium and guide management options. The assessment of the frequency of venous thromboembolism (VTE) in women with F V Leiden in association with pregnancy and puerperium and according these results and available data to formulate the principles of thromboprophylaxis. Retrospective case control study. The assessment of frequency of VTE in the group of 224 women with F V Leiden in heterozygous form in association with 460 pregnancies and in the group of 40 women with F V Leiden in homozygous form in association with 70 pregnancies. This frequency of VTE in those groups was compared with the frequency of VTE in the control group of 201 women without F V Leiden in association with 422 pregnancies. F V Leiden evaluation was done in the period of 1996-2003. In the group of women with F V Leiden in heterozygous form VTE occurred 44-fold during pregnancy and puerperium. In 17 cases VTE was manifested in pregnancy (once in Ist trimester, twice in IInd trimester, 14 times in IIIrd trimester), in 27 women VTE occurred in puerperium and always within the first 10 days after delivery. Proximal venous thrombosis was diagnosed in 34 cases, in 5 cases being complicated by pulmonary embolism. In 10 women thrombosis was distal. The frequency of VTE is 9.6%. In the group of women with homozyous form VTE occurred in 14 cases (20%). In 5 cases VTE occurred during pregnancy, in 9 cases after delivery and in all cases within first 2 weeks after delivery. The frequency of VTE in the control group is 0.24%. The results were statistically assessed by Fishers exact test in programme NCSS 2004. Frequency of VTE in both cohorts of women with F V Leiden reached statistical significance in comparison with the control group. Pregnancy and puerperium are significant risk factors for VTE in the group of women with F V Leiden in heterozygous form and mainly in homozygous form. Fatal pulmonary embolism remains the most common cause of mortality among pregnant women in many Western countries. The physiological changes of pregnancy produce a hypercoagulable state that increases the risk of venous thromboembolism (VTE). Women with inherited or acquired thrombophilias are at particularly high risk of VTE during pregnancy, and thromboprophylaxis may be advisable in some cases. Thrombophilia is also associated with complications of pregnancy, including fetal loss, pre-eclampsia, intra-uterine growth restriction, and placental abruption. The antithrombotic agents available for the prevention and treatment of VTE during pregnancy, and pregnancy complications, include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and aspirin. Vitamin K antagonists are contra-indicated in pregnancy. Low-dose aspirin may have a role in the prevention of some pregnancy complications, although its safety in early and late pregnancy is uncertain. The efficacy and safety of LMWHs have been demonstrated for the prevention and treatment of VTE in pregnancy. These agents are increasingly being used in place of UFH, which is associated with a higher incidence of side effects compared with LMWH, in addition to the need for regular laboratory monitoring. Evidence is also emerging to support the use of LMWH in the prevention of recurrent fetal loss, although further trials are needed to explore the role of LMWHs in this indication and in the prevention of other complications of pregnancy.\nHere is the question:\nHEMATOLOGY: A 25-year-old woman who wishes to become pregnant and wants to know what treatment she should take during the eventual pregnancy, as she is a heterozygous factor V Leiden carrier. She has never had any thrombotic phenomena. The determination of this factor was performed as a family study after an episode of pulmonary embolism in a sibling. What treatment should be advised?\nHere are the potential choices:\n1. Since pregnancy is a prothrombotic state, there would be a high risk of venous thromboembolism, so pregnancy should be discouraged.\n2. Treatment with low molecular weight heparin at prophylactic doses should be carried out in the immediate puerperium, with optional follow-up during pregnancy.\n3. Factor V Leiden in heterozygosis is a low-risk thrombophilia and there is no need for any treatment in pregnancy and puerperium.\n4. Low-dose aspirin should be advised during pregnancy and puerperium.\n5. Treatment with antivitamin K drugs (acenocoumarol) during pregnancy.\nThe correct answer is: 3. Factor V Leiden in heterozygosis is a low-risk thrombophilia and there is no need for any treatment in pregnancy and puerperium."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Lumbar stenosis is a common disorder, usually characterized clinically by neurogenic claudication with or without lumbar/sacral radiculopathy corresponding to the level of stenosis. We present a case of lumbar stenosis manifesting as a multilevel radiculopathy inferior to the nerve roots at the level of the stenosis. A 55-year-old gentleman presented with bilateral lower extremity pain with neurogenic claudication in an L5/S1 distribution (posterior thigh, calf, into the foot) concomitant with dorsiflexion and plantarflexion weakness. Imaging revealed grade I spondylolisthesis of L3 on L4 with severe spinal canal stenosis at L3-L4, mild left L4-L5 disc herniation, no stenosis at L5-S1, and no instability. EMG revealed active and chronic L5 and S1 radiculopathy. The patient underwent bilateral L3-L4 hemilaminotomy with left L4-L5 microdiscectomy for treatment of his L3-L4 stenosis. Postoperatively, he exhibited significant improvement in dorsiflexion and plantarflexion. The L5-S1 level was not involved in the operative decompression. Patients with radiculopathy and normal imaging at the level corresponding to the radiculopathy should not be ruled out for operative intervention should they have imaging evidence of lumbar stenosis superior to the expected affected level.  Gout in the spine and adnexa is rare in clinical practice and can also be easily misdiagnosed, we reported a patient with nerve root compression due to lumbar gout stones in the lumbar spinal canal. A 51-year-old male was admitted to the hospital with lumbar pain with numbness in the left lower limb for more than 6 months. The physical examination showed that tenderness and percussion pain were present at L4-S1 spinous process. Straight leg raise test: 50° on the left side were positive. Laboratory tests showed that the sUA was 669 μmol/L, MRI of the lumbar spine showed that cystic T1WI low signal and T2WI mixed high signal shadows were seen in the spinal canal at the level of L4-L5. Combining with lab examinations, imaging examinations, and histopathological results, the patient was diagnosed with lumbar spinal canal tophi. After active improvement of all examinations, the patient underwent surgical treatment with decompression and internal fixation of the L4-L5 segment. After surgery, the patient's symptoms improved and muscle strength returned to normal. Among the 95 previously reported patients with lumbar gout, the ratio of men to women was 2.96:1, and the peak age group of incidence was 56 to 65 years. The onset of the disease was mainly in a single segment of the lumbar spine, with 34.41% of all cases occurring at the L4-L5 level. 61.05% of the patients had a history of gout attacks or hyperuricemia, and the most frequently involved site was the foot and ankle, followed by the wrist. Sixty-seven patients underwent surgical treatment, and 22 chose conservative treatment, with overall satisfactory results. The incidence of lumbar gout is low and relatively rare in the clinic and pathological biopsy is still the gold standard. Vertebral plate incision and decompression are often selected for surgical treatment, and whether to perform fusion should be comprehensively considered for the destruction of vertebral bone by gout and the reasonable selection of the extent of surgical resection. Whether choosing surgical treatment or conservative therapy, the control of uric acid levels should be emphasized. Limbus vertebral fracture is an uncommon injury described in adolescents. It refers to the separation of a bony fragment from the unfused ring apophysis of lumbar vertebral end plate. It usually presents with back pain with/without radiculopathy masquerading an acute disc prolapse. However, the presentation as acute cauda equina syndrome has seldom been reported. A 15-year-old male presented to the casualty with a history of acute-onset low back pain and bilateral lower limb radicular pain with weakness, after lifting of a heavy Indian musical instrument (Dholak). This was associated with urinary retention and numbness in perineal region. Examination revealed L5 and S1 weakness with absent ankle jerks bilaterally. Bulbocavernosus reflex was absent. Emergency magnetic resonance imaging imaging was done, which revealed a limbus fracture of cephalad part of L4 vertebral body with displaced fragment into the spinal canal causing compression of the cauda equina. Emergency surgery was done in the form of L3-L4 midline interlaminar microscopic decompression. The patient had complete neurological recovery including the bladder control within 1 month of surgery. The patient had no functional deficits during follow-up at 3 and6 months. Dynamic radiographs taken at the end of 6 months did not show any sign of instability. When an adolescent patient with no previous history of backpain presents with acute cauda equina syndrome, a possibility of limbus fracture should also be considered. Early diagnosis and surgical decompression in such cases can bring about complete neurological recovery and excellent clinical outcome. Lumbar spondylolisthesis is reported to present with a familiar pattern, with the dysplastic type of spondylolysis being minor but more hereditary than the isthmic type. Siblings presenting during adolescence with neurological symptoms owing to high-grade dysplastic-type spondylolisthesis are rare. The older brother suffered from left leg pain and numbness and dysesthesia of the right posterior thigh and calf and could not walk without a crutch at the age of 15 years. He had canal stenosis with disc bulging and dysplastic bilateral facet joint at L5/S1. The L5 vertebral body was slipped anterior downward to S1, with a round-shaped S1 cranial endplate. We diagnosed dysplastic-type spondylolisthesis and performed posterior lumbar interbody fusion at L5/S with mild reduction and sublaminar wiring at L4/5. The younger brother had no neurological symptoms at age 14 years but suffered from bilateral lower leg numbness at age 18 years. He had canal stenosis with disc bulging at L4/5 and L5/S1 and dysplastic bilateral facet joint at L5/S1 with right pars defect. The L5 vertebral body was vertically displaced anterior to the S1 vertebral body, with an S1 round-shaped cranial endplate. We diagnosed dysplastic-type spondylolisthesis, and posterior lumbar interbody fusion at L4/5 and L5/S with reduction was performed. Their neurological symptoms of the lower legs disappeared, and interbody bone fusion was obtained. The surgical technique for high-grade dysplastic spondylolisthesis remains controversial in terms of in situ fusion versus reduction. We recommend that surgery be performed promptly at the end of bone maturation because neurological symptoms often appear at the end of bone maturation. Because high-grade slips are rare but siblings may be present, the sibling should also be screened when dysplastic spondylolisthesis is detected. Over 95% of lumbar disc herniations affect either the L4/L5 or L5/S1 disc spaces, or both. Patients commonly experience sharp, stabbing low back pain that radiates from the lower lumbar region down to the foot. [6] [7] [8] Nonsurgical management usually suffices in cases of lower extremity radiculopathy [9] [10] [11] and acute lumbar disc herniation. [8] The most common indication for surgical intervention is persistent, intractable pain despite at least 6 weeks of optimal conservative treatment. [12] Society and culture United States Under rules promulgated by Titles II and XVI of the United States Social Security Act, spinal stenosis is recognized as a disabling condition under Listing 1.04 C. The listing states: \"Lumbar spinal stenosis resulting in neurogenic claudication, established by findings on appropriate medically acceptable imaging, manifested by chronic nonradicular pain and weakness, and resulting in inability to ambulate effectively, as defined in 1.00B2b.\" The regulation is written specifically for lumbar stenosis. References External links Geriatrics Spinal cord disorders Bones of the vertebral column Among people with lower-extremity pain in combination with back pain, lumbar stenosis as the cause is two times more likely in those older than 70 years of age while in those younger than 60 years it is less than half as likely. The character of the pain is also useful for diagnosis. When the discomfort does not occur while seated, the likelihood of lumbar spinal stenosis increases considerably, around 7.4 times. Other features increasing the likelihood of lumbar stenosis are improvement in symptoms on bending forward (6.4 times), pain that occurs in both buttocks or legs (6.3 times), and the presence of neurogenic claudication (3.7 times). On the other hand, the absence of neurogenic claudication makes lumbar stenosis much less likely as the explanation for the pain. Causes Lumbar disc herniations occur in the back, most often between the fourth and fifth lumbar vertebral bodies or between the fifth and the sacrum. Here, symptoms can be felt in the lower back, buttocks, thigh, anal/genital region (via the perineal nerve), and may radiate into the foot and/or toe. The sciatic nerve is the most commonly affected nerve, causing symptoms of sciatica. The femoral nerve can also be affected and cause the patient to experience a numb, tingling feeling throughout one or both legs and even feet or a burning feeling in the hips and legs. A herniation in the lumbar region often compresses the nerve root exiting at the level below the disc. Thus, a herniation of the L4–5 disc compresses the L5 nerve root, only if the herniation is posterolateral. Cervical disc herniation Most individuals have five lumbar vertebrae, while some have four or six. Lumbar disorders that normally affect L5 will affect L4 or L6 in these latter individuals. Segmental movements The range of segmental movements in a single segment is difficult to measure clinically, not only because of variations between individuals, but also because it is age and sex dependent. Furthermore, flexion and extension in the lumbal spine is the product of a combination of rotation and translation in the sagittal plane between each vertebra. Ranges of segmental movements in the lumbar spine (White and Punjabi, 1990) are (in degrees): Congenital anomalies Congenital vertebral anomalies can cause compression of the spinal cord by deforming the vertebral canal or causing instability. The straight leg–raising (SLR) maneuver is a simple bedside test for nerve root disease. With the patient supine, passive flexion of the extended leg at the hip stretches the L5 and S1 nerve roots and 113 CHAPTER 22 Back and Neck Pain 4th Lumbar vertebral body 5th Lumbar vertebral body 4th Lumbar pedicle L4 root Protruded L4-L5 disk L5 Root S1 Root S2 Root Protruded L5-S1 disk FIguRE 22-3 Compression of L5 and S1 roots by herniated disks. (From AH Ropper, MA Samuels: Adams and Victor’s Principles of Neurology, 9th ed. New York, McGraw-Hill, 2009; with permission.) the sciatic nerve. Passive dorsiflexion of the foot during the maneuver adds to the stretch. In healthy individuals, flexion to at least 80° is normally possible without causing pain, although a tight, stretching sensation in the hamstring muscles is common. The SLR test is positive if the maneuver reproduces the patient’s usual back or limb pain. Eliciting the SLR sign in both the supine and sitting positions can help The straight leg raise (SLR) test consists of a supine patient having his/her fully extended leg passively stretched from 0 to about 80 degrees. The onset of radiating back pain in either leg supports a diagnosis of a stenotic canal. A herniation compressing the L5 nerve root will present as a weakness of ankle dorsiflexion and an extension of the great toe. This deficit also may diminish the Achilles tendon reflex. L4 radiculopathy may present with weakness in the quadriceps and a decreased patellar tendon reflex. Documentation is paramount, as these initial findings likely will be used as a baseline for all future evaluations. Compression, injury, or irritation of the lumbar spinal nerve roots can occur from multiple potential sources. Most commonly, this occurs as a consequence of the degenerative cascade or an acute disc herniation. Lumbar radiculopathy (aka sciatica) describes the constellation of symptoms resulting from lumbar nerve compression. Individuals present with variable degrees of radiating pain, paresthesia (numbness/tingling), and weakness in the lower extremities. Lumbar stenosis is a condition in which the narrowing of the spinal canal occurs. This narrowing is usually secondary to degenerative spondylosis and spondylolisthesis. Classically individuals present with low back and/or lower extremity pain/paresthesias, which worsen with lumbar extension, prolonged standing, and ambulation. The pathophysiology appears to be due to mechanical compression of the lumbosacral spinal nerve roots resulting in ischemia. [16] [17] PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 22-1 Vertebral anatomy. (From A Gauthier Cornuelle, DH Gronefeld: Radiographic Anatomy Positioning. New York, McGraw-Hill, 1998; with permission.) Radicular pain is typically sharp and radiates from the low back to a leg within the territory of a nerve root (see “Lumbar Disk Disease,” below). Coughing, sneezing, or voluntary contraction of abdominal muscles (lifting heavy objects or straining at stool) may elicit the radiating pain. The pain may increase in postures that stretch the nerves and nerve roots. Sitting with the leg outstretched places traction on the sciatic nerve and L5 and S1 roots because the nerve passes posterior to the hip. The femoral nerve (L2, L3, and L4 roots) passes anterior to the hip and is not stretched by sitting. FIguRE 22-2 Spinal column. (From A Gauthier Cornuelle, DH Gronefeld: Radiographic Anatomy Positioning. New York, McGraw-Hill, 1998; with permission.) Stenosis in the lumbar spine can lead to neurogenic claudication, myeloradiculopathy symptoms, sensory disturbances, motor weakness, and pathologic reflexes. Patients will present with complaints of cramping pain in the leg, calf, and or buttocks. They might report an increase in pain with walking or standing for prolonged periods and relief when sitting or leaning forward while using a shopping cart. [9] Disk herniation is most common at the L4-5 and L5-S1 levels. A herniated disk at L5-S1 can lead to plantarflexion weakness, decrease sensation in the lateral foot, and cause pain in the posterior leg. A disk herniation at L4-5 can lead to a foot drop and numbness in the large toe web and dorsal aspect of the foot. Lastly, an L3-4 disk herniation can lead to knee extension weakness, numbness in the medial foot, and pain in the anterior thigh. L5 nerve root exits at the L5-S1 foramina. When compressed by a herniated disc, it causes back pain that radiates into the buttock, lateral thigh, lateral calf, the dorsum of the foot, and the great toe. Sensory loss is present on the web space between the big toe and second toe, the dorsum of the foot, and lateral calf. There is a weakness in hip abduction, knee flexion, foot dorsiflexion, big toe dorsiflexion, foot inversion, and eversion. Patients present with decreased semitendinosus/semimembranosus reflex. Weakness in foot dorsiflexion makes it challenging to walk on the heels. Chronic L5 radiculopathy may cause atrophy of the extensor digitorum brevis and the tibialis anterior of the anterior leg. Gout in the spine is very rare. The clinical symptoms of the spinal gout are various and lack of specificity. The authors report a case of spinal gout causing lumbar stenosis. We never find such wide-invasive spinal gouty lesion in the published studies. A 68-year-old male had low back pain radiating to bilateral lower limbs, accompanying with intermittent claudication that lasted for 3 months and aggravated 5 days ago. Spinal gout, lumbar stenosis. The patient underwent L2-L4 laminectomy, L2/3 L3/4 an d L4/5 discectomy and transforaminal lumbar interbody fusion with pedicle screw fixation. Dual-energy computed tomography detected extensive tophaceous deposits in L1/2 L2/3 L3/4 and L4/5 lumbar discs as well as the posterior column, especially L2-L3 and L4-L5 facet joints. During the surgery, we found a mass of chalky white material at the posterior column of L3 to L5 vertebral bodies, which also involved the intervertebral discs. Pathological examination confirmed the diagnosis of spinal gout. Although spinal gout is thought to be rare, the diagnosis should be considered if the patient had severe back pain and a history of gout. Dual-energy computed tomography is highly recommended for these patients. to provide crucial collateral flow in maintaining lower limb viabil-ity. It must be emphasized, however, that patients should be subjected to angiography only if their symptoms warrant surgi-cal intervention.Differential DiagnosisDegenerative hip or spine disease, lumbar disk herniation, spinal stenosis, diabetic neuropathy, and other neuromuscular problems can produce symptoms that may be mistaken for vas-cular claudication. Such cases can be distinguished from true claudication by the fact that the discomfort from neuromuscular problems is often relieved by sitting or lying down, as opposed to cessation of ambulation. In addition, complaints that are Table 23-13Clinical outcome of renal artery stent placement in the treatment of renovascular hypertension and renal insufficiencyAUTHORYEARPATIENT NO.TECHNICAL SUCCESS (%)FOLLOW-UP (MONTHS)RENAL INSUFFICIENCY (%)RENOVASCULAR HYPERTENSION (%)COMPLICATION (%)RESTENOSIS Symptoms for spinal stenosis apparently result from an incongruity between the capacity and contents of the spinal nerve passages. These symptoms are most frequently seen in men in their fifth or sixth decade of life. Spinal extension generally exacerbates the claudication-type symptoms (lower-extremity pain and paresthesia), whereas spinal flexion diminishes these symptoms. Differential diagnosis is needed to rule out vascular claudication due to atherosclerosis. Decisions regarding surgery should be made based not only on diagnostic imaging but also on a thorough history and clinical examination. Herniation of Lumbar Intervertebral Discs (Table 10-1) This condition is a major cause of severe and chronic or recurrent low back and leg pain. It occurs mainly during the third and fourth decades of life when the nucleus pulposus is still gelatinous. The disc between the fifth lumbar or first sacral vertebrae (L5-S1) is most often involved, and, with decreasing frequency, that between the fourth and fifth (L4-L5), third and fourth (L3-L4), second and third (L2-L3), and—quite infrequently—the first and second (L1-L2) lumbar vertebrae. Disc disease is relatively rare but well described in the thoracic portion of the spine. It is frequent in the cervical spine, especially at the fifth and sixth and the sixth and seventh cervical vertebrae (see further on). Lumbar disc arthroplasty is now a common treatment for lumbar degenerative disc disease. Whereas the immediate and delayed complications in patients with artificial lumbar discs are well reported, the durability of artificial disc hardware after severe spine trauma is unknown. The authors describe the management of a rare case of a traumatic lumbar burst fracture in a patient who had undergone disc arthroplasty. This 31-year-old male contractor had undergone placement of an L4-5 Charité artificial disc (DePuy Spine) and L5-S1 anterior lumbar fusion 10 months before he fell from a roof and sustained a traumatic L-3 burst fracture with significant canal compromise and cauda equina injury. Despite the considerable compressive load on his spine, the artificial disc (L4-5) remained intact without any radiological signs of hardware failure, and the vertebrae above (L-4) and below (L-5) the artificial disc had no signs of injury. For the L-3 burst fracture the patient underwent an open decompressive laminectomy at L2-3 and posterior fusion with instrumentation from L-2 to L-4. At 24 months postinjury, he had returned to full work activities as a contractor with minimal back pain and mild right lower-extremity sensory changes and weakness left over from the trauma. The total disc arthroplasty at L4-5 is functional and has preserved motion, and there is a solid fusion at L2-4 and L5-S1. This case demonstrates that a lumbar artificial disc can tolerate a significant load from trauma and remain functional without hardware failure even after a traumatic burst fracture at the adjacent lumbar vertebral body and shows the successful treatment of this fracture, with posterior fusion preserving the motion of an artificial disc. In contrast with patients with herniations of the nucleus pulposus, those with spinal stenosis experience onset of symptoms at a slightly older age; more males are affected than females. The symptoms tend to be somewhat more chronic, and therefore, the patients will have symptoms of back pain for a longer period of time before developing radiating root pains and will not come to surgical treatment until relatively late. Bilateral root symptomatology is more common although examination shows multiple nerve root involvement only slightly more frequently as well as involvement of the L1 to L4 nerve roots. The spinal movements tend to be somewhat better and straight leg raising tests are usually symmetrical and somewhat less restricted in those patients than in the acute disk syndrome. Postfusion and post-chemonucleolysis spinal stenosis will, of course, have the symptomatology of the initial problem, but their recurrent problems would tend to parallel those of spinal stenosis rather than disk herniation. Lumbar spinal stenosis is classified as a narrowing of the spinal canal in the lumbar region of the vertebrae. This may lead to compression of the nerve root of the spinal cord and result in pain of the lower back and lower extremities. Other symptoms include impaired walking and a slightly stooped posture due to loss of disc height and bulging of the disc. Lumbar spinal stenosis is very prevalent with 9.3% of the general population producing symptoms and the number is continuing to rise in patients older than 60. It's generally an indication for spinal surgery in patients older than 65 years of age. However, there is a myth and fear among most patients that only surgery is the cure for such conditions and spine surgery is very risky. There are many non-surgical treatments available to prevent, halt and even reverse many spine diseases. Also, some surgery patients can be operated on in a daycare procedure or with minimum length of stay in hospital, with statistically good outcomes. Uncertainty still exists regarding the treatment of the patients presenting with gunshot wounds to the spine. Neurological insults, cerebrospinal fluid fistula, infection, lead or copper toxicity, migration of bullets, and spinal instability are included among the common challenging issues. An 18-year-old woman was admitted with low back pain following a gunshot injury five days ago. She was neurologically intact. Radiological examinations showed that a bullet was settled in L4-5 disc space. The bullet was removed with a unilateral L4-5 partial hemilaminectomy and discectomy from the left side. The second case was of a 29-year-old man admitted with radiating leg pain on the right side following a gunshot injury from his left side of lower back four months ago. He had only positive straight leg raising test. Radiological studies showed two bullets, one was in the psoas muscle on the left side and the other was in spinal canal that had caused a burst fracture of the L5 vertebra. Following L5 laminectomy and bilateral L5-S1 facetectomy, the bullet was removed from the spinal canal and L5-S1 transpedicular posterior stabilization was performed. The postoperative period of both patients was unremarkable. Bullet settling into the lumbar spinal canal without causing neurological deficit may require surgical intervention. Removal of bullets provided not only pain relief in both the cases but also prevented future complications such as migration of the bullets, plumbism, and neuropathic pain and instability. Lumbar disc degeneration is defined as the wear and tear of lumbar intervertebral disc, and it is mainly occurring at L3-L4 and L4-S1 vertebrae. Lumbar disc degeneration may lead to disc bulging, osteophytes, loss of disc space, and compression and irritation of the adjacent nerve root. Clinical presentations associated with lumbar disc degeneration and lumbosacral nerve lesion are discogenic pain, radical pain, muscular weakness, and cutaneous. Discogenic pain is usually felt in the lumbar region, or sometimes, it may feel in the buttocks, down to the upper thighs, and it is typically presented with sudden forced flexion and/or rotational moment. Radical pain, muscular weakness, and sensory defects associated with lumbosacral nerve lesions are distributed on lower extremities, the buttock, lower abdomen, and groin region. A lumbosacral plexus lesion presents different symptoms in the territories of the lumbar and sacral nerves. Patients with lumbar plexus lesion clinically present with weakness of hip flexion, knee extension, thigh adduction, and sensory loss in the lower abdomen, inguinal region, and over the entire medial, lateral, and anterior surfaces of the thigh and the medial lower leg, while sacral plexus lesion presents clinical symptoms at nerve fibers destined for the sciatic nerve, common peroneal nerve, and pudendal nerve. Weakness of ankle inversion, plantar flexion, and foot drop are the main clinical manifestations of the sacral plexus lesion area. Numbness and decreased sensation are also present along the anterolateral calf and dorsum of the foot. On examination, foot eversion is usually stronger than foot dorsiflexion. The patients may also present with pain and difficulty of bowel movements, sexual dysfunction assessments, and loss of cutaneous sensation in the areas of the anal canal, anus, labia major, labia minor, clitoris, penis, and scrotum. A 56-year-old alcoholic male incurred L5 vertebral body and bilateral L4 pars fractures with progressive L4 on L5 anterolisthesis following low-energy falls while intoxicated. Recently, he had a L3-S1 laminectomy for lumbar spinal stenosis with claudication. Preoperative imaging and radiographs were negative for pars defects and instability, so an isolated decompressive surgery was performed. Following low-energy falls, his outpatient work-up revealed fractures through the bilateral L4 pedicles and posterior third of L5 vertebral body, with recurrence of axial back pain and bilateral lower extremity radiculopathy. He underwent revision decompression from L4-S1 and posterior instrumented fusion with transforaminal lumbar interbody fusion performed at each revised level. His axial back pain and radiculopathy improved postoperatively. Instability of a lumbar spine fracture pattern can be due to the remote or prior iatrogenic disruption of the posterior ligamentous complex. Our patient benefitted from surgery and his low back pain was resolved. Some patients with LSS may be asymptomatic and have a normal neurologic examination. Other individuals with asymptomatic LSS may have neurologic deficits due to superimposed lumbar radiculopathy. The Valsalva maneuver often does not exacerbate LSS-related radicular pain as it does in IV disk prolapse. Only 10% of patients present with a positive straight leg raise test. [24] Pedal pulses should also be checked during the physical exam to rule out vascular claudication. A patient who can perform a five-repetition sit-to-stand (5R-STS) test in 10.4 seconds may be considered to have no functional impairment. [25] Oblique lumbar interbody fusion (OLIF) is an effective and safe surgical technique widely used for treating spondylolisthesis; however, its use is controversial because of several associated complications, including endplate injury. We report a rare vertebral body fracture following OLIF in a patient with poor bone quality. A 72-year-old male patient visited our clinic for 2 years with lower back pain, leg radiating pain, and intermittent neurogenic claudication. Lumbar magnetic resonance imaging revealed L4-5 stenosis. We performed OLIF with percutaneous pedicle screw fixation and L4 subtotal decompressive laminectomy. We resected the anterior longitudinal ligament partially for anterior column release and inserted a huge cage to maximize segmental lordosis. No complications during and after the operation were observed. Further, the radiating pain and back pain improved, and the patient was discharged. Two weeks after the operation, the patient visited the outpatient department complaining of sudden recurred pain, which occurred while going to the bathroom. Radiography and computed tomography revealed a split fracture of the L5 body and an anterior cage displacement. In revision of OLIF, we removed the dislocated cage and filled the bone cement between the anterior longitudinal ligament and empty disc space. Further, we performed posterior lumbar interbody fusion L4-5, and the screw was extended to S1. After the second surgery, back pain and radiating pain in the left leg improved, and he was discharged without complications. In this case, owing to insufficient intervertebral space during L4-5 OLIF, a huge cage was used to achieve sufficient segmental lordosis after anterior column release, but a vertebral body coronal fracture occurred. In patients with poor bone quality and less flexibility, a huge cage and over-distraction could cause a vertebral fracture; hence, selecting an appropriate cage or considering a posterior approach is recommended. Nerve root injury (radiculopathy) is a common cause of neck, arm, low back, buttock, and leg pain (see Figs. 31-2 and 31-3). The nerve roots exit at a level above their respective vertebral bodies in the cervical region (e.g., the C7 nerve root exits at the C6-C7 level) and below their respective vertebral bodies in the thoracic and lumbar regions (e.g., the T1 nerve root exits at the T1-T2 level). The cervical nerve roots follow a short intraspinal course before exiting. By contrast, because the spinal cord ends at the vertebral L1 or L2 level, the lumbar nerve roots follow a long intraspinal course and can be injured anywhere from the upper lumbar spine to their exit at the intervertebral foramen. For example, disk herniation at the L4-L5 level can produce not only L5 root compression, but also compression of the traversing S1 nerve root (Fig. 22-3). The lumbar nerve roots are mobile in the spinal canal, but eventually pass through the narrow lateral recess of the spinal canal and\nHere is the question:\nORTHOPEDIC SURGERY AND TRAUMATOLOGY: The most likely diagnosis of a 74-year-old patient who since two months ago begins with lumbar pain radiating to lower limbs, neurogenic claudication and limitation to extension the trunk is:\nHere are the potential choices:\n1. L4-L5 disc herniation.\n2. Lumbar vertebral fracture.\n3. L5-S1 vertebral instability.\n4. Lumbar canal stenosis.\nThe correct answer is: ",
        "gold_answer": "4 Lumbar canal stenosis.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Lumbar stenosis is a common disorder, usually characterized clinically by neurogenic claudication with or without lumbar/sacral radiculopathy corresponding to the level of stenosis. We present a case of lumbar stenosis manifesting as a multilevel radiculopathy inferior to the nerve roots at the level of the stenosis. A 55-year-old gentleman presented with bilateral lower extremity pain with neurogenic claudication in an L5/S1 distribution (posterior thigh, calf, into the foot) concomitant with dorsiflexion and plantarflexion weakness. Imaging revealed grade I spondylolisthesis of L3 on L4 with severe spinal canal stenosis at L3-L4, mild left L4-L5 disc herniation, no stenosis at L5-S1, and no instability. EMG revealed active and chronic L5 and S1 radiculopathy. The patient underwent bilateral L3-L4 hemilaminotomy with left L4-L5 microdiscectomy for treatment of his L3-L4 stenosis. Postoperatively, he exhibited significant improvement in dorsiflexion and plantarflexion. The L5-S1 level was not involved in the operative decompression. Patients with radiculopathy and normal imaging at the level corresponding to the radiculopathy should not be ruled out for operative intervention should they have imaging evidence of lumbar stenosis superior to the expected affected level.  Gout in the spine and adnexa is rare in clinical practice and can also be easily misdiagnosed, we reported a patient with nerve root compression due to lumbar gout stones in the lumbar spinal canal. A 51-year-old male was admitted to the hospital with lumbar pain with numbness in the left lower limb for more than 6 months. The physical examination showed that tenderness and percussion pain were present at L4-S1 spinous process. Straight leg raise test: 50° on the left side were positive. Laboratory tests showed that the sUA was 669 μmol/L, MRI of the lumbar spine showed that cystic T1WI low signal and T2WI mixed high signal shadows were seen in the spinal canal at the level of L4-L5. Combining with lab examinations, imaging examinations, and histopathological results, the patient was diagnosed with lumbar spinal canal tophi. After active improvement of all examinations, the patient underwent surgical treatment with decompression and internal fixation of the L4-L5 segment. After surgery, the patient's symptoms improved and muscle strength returned to normal. Among the 95 previously reported patients with lumbar gout, the ratio of men to women was 2.96:1, and the peak age group of incidence was 56 to 65 years. The onset of the disease was mainly in a single segment of the lumbar spine, with 34.41% of all cases occurring at the L4-L5 level. 61.05% of the patients had a history of gout attacks or hyperuricemia, and the most frequently involved site was the foot and ankle, followed by the wrist. Sixty-seven patients underwent surgical treatment, and 22 chose conservative treatment, with overall satisfactory results. The incidence of lumbar gout is low and relatively rare in the clinic and pathological biopsy is still the gold standard. Vertebral plate incision and decompression are often selected for surgical treatment, and whether to perform fusion should be comprehensively considered for the destruction of vertebral bone by gout and the reasonable selection of the extent of surgical resection. Whether choosing surgical treatment or conservative therapy, the control of uric acid levels should be emphasized. Limbus vertebral fracture is an uncommon injury described in adolescents. It refers to the separation of a bony fragment from the unfused ring apophysis of lumbar vertebral end plate. It usually presents with back pain with/without radiculopathy masquerading an acute disc prolapse. However, the presentation as acute cauda equina syndrome has seldom been reported. A 15-year-old male presented to the casualty with a history of acute-onset low back pain and bilateral lower limb radicular pain with weakness, after lifting of a heavy Indian musical instrument (Dholak). This was associated with urinary retention and numbness in perineal region. Examination revealed L5 and S1 weakness with absent ankle jerks bilaterally. Bulbocavernosus reflex was absent. Emergency magnetic resonance imaging imaging was done, which revealed a limbus fracture of cephalad part of L4 vertebral body with displaced fragment into the spinal canal causing compression of the cauda equina. Emergency surgery was done in the form of L3-L4 midline interlaminar microscopic decompression. The patient had complete neurological recovery including the bladder control within 1 month of surgery. The patient had no functional deficits during follow-up at 3 and6 months. Dynamic radiographs taken at the end of 6 months did not show any sign of instability. When an adolescent patient with no previous history of backpain presents with acute cauda equina syndrome, a possibility of limbus fracture should also be considered. Early diagnosis and surgical decompression in such cases can bring about complete neurological recovery and excellent clinical outcome. Lumbar spondylolisthesis is reported to present with a familiar pattern, with the dysplastic type of spondylolysis being minor but more hereditary than the isthmic type. Siblings presenting during adolescence with neurological symptoms owing to high-grade dysplastic-type spondylolisthesis are rare. The older brother suffered from left leg pain and numbness and dysesthesia of the right posterior thigh and calf and could not walk without a crutch at the age of 15 years. He had canal stenosis with disc bulging and dysplastic bilateral facet joint at L5/S1. The L5 vertebral body was slipped anterior downward to S1, with a round-shaped S1 cranial endplate. We diagnosed dysplastic-type spondylolisthesis and performed posterior lumbar interbody fusion at L5/S with mild reduction and sublaminar wiring at L4/5. The younger brother had no neurological symptoms at age 14 years but suffered from bilateral lower leg numbness at age 18 years. He had canal stenosis with disc bulging at L4/5 and L5/S1 and dysplastic bilateral facet joint at L5/S1 with right pars defect. The L5 vertebral body was vertically displaced anterior to the S1 vertebral body, with an S1 round-shaped cranial endplate. We diagnosed dysplastic-type spondylolisthesis, and posterior lumbar interbody fusion at L4/5 and L5/S with reduction was performed. Their neurological symptoms of the lower legs disappeared, and interbody bone fusion was obtained. The surgical technique for high-grade dysplastic spondylolisthesis remains controversial in terms of in situ fusion versus reduction. We recommend that surgery be performed promptly at the end of bone maturation because neurological symptoms often appear at the end of bone maturation. Because high-grade slips are rare but siblings may be present, the sibling should also be screened when dysplastic spondylolisthesis is detected. Over 95% of lumbar disc herniations affect either the L4/L5 or L5/S1 disc spaces, or both. Patients commonly experience sharp, stabbing low back pain that radiates from the lower lumbar region down to the foot. [6] [7] [8] Nonsurgical management usually suffices in cases of lower extremity radiculopathy [9] [10] [11] and acute lumbar disc herniation. [8] The most common indication for surgical intervention is persistent, intractable pain despite at least 6 weeks of optimal conservative treatment. [12] Society and culture United States Under rules promulgated by Titles II and XVI of the United States Social Security Act, spinal stenosis is recognized as a disabling condition under Listing 1.04 C. The listing states: \"Lumbar spinal stenosis resulting in neurogenic claudication, established by findings on appropriate medically acceptable imaging, manifested by chronic nonradicular pain and weakness, and resulting in inability to ambulate effectively, as defined in 1.00B2b.\" The regulation is written specifically for lumbar stenosis. References External links Geriatrics Spinal cord disorders Bones of the vertebral column Among people with lower-extremity pain in combination with back pain, lumbar stenosis as the cause is two times more likely in those older than 70 years of age while in those younger than 60 years it is less than half as likely. The character of the pain is also useful for diagnosis. When the discomfort does not occur while seated, the likelihood of lumbar spinal stenosis increases considerably, around 7.4 times. Other features increasing the likelihood of lumbar stenosis are improvement in symptoms on bending forward (6.4 times), pain that occurs in both buttocks or legs (6.3 times), and the presence of neurogenic claudication (3.7 times). On the other hand, the absence of neurogenic claudication makes lumbar stenosis much less likely as the explanation for the pain. Causes Lumbar disc herniations occur in the back, most often between the fourth and fifth lumbar vertebral bodies or between the fifth and the sacrum. Here, symptoms can be felt in the lower back, buttocks, thigh, anal/genital region (via the perineal nerve), and may radiate into the foot and/or toe. The sciatic nerve is the most commonly affected nerve, causing symptoms of sciatica. The femoral nerve can also be affected and cause the patient to experience a numb, tingling feeling throughout one or both legs and even feet or a burning feeling in the hips and legs. A herniation in the lumbar region often compresses the nerve root exiting at the level below the disc. Thus, a herniation of the L4–5 disc compresses the L5 nerve root, only if the herniation is posterolateral. Cervical disc herniation Most individuals have five lumbar vertebrae, while some have four or six. Lumbar disorders that normally affect L5 will affect L4 or L6 in these latter individuals. Segmental movements The range of segmental movements in a single segment is difficult to measure clinically, not only because of variations between individuals, but also because it is age and sex dependent. Furthermore, flexion and extension in the lumbal spine is the product of a combination of rotation and translation in the sagittal plane between each vertebra. Ranges of segmental movements in the lumbar spine (White and Punjabi, 1990) are (in degrees): Congenital anomalies Congenital vertebral anomalies can cause compression of the spinal cord by deforming the vertebral canal or causing instability. The straight leg–raising (SLR) maneuver is a simple bedside test for nerve root disease. With the patient supine, passive flexion of the extended leg at the hip stretches the L5 and S1 nerve roots and 113 CHAPTER 22 Back and Neck Pain 4th Lumbar vertebral body 5th Lumbar vertebral body 4th Lumbar pedicle L4 root Protruded L4-L5 disk L5 Root S1 Root S2 Root Protruded L5-S1 disk FIguRE 22-3 Compression of L5 and S1 roots by herniated disks. (From AH Ropper, MA Samuels: Adams and Victor’s Principles of Neurology, 9th ed. New York, McGraw-Hill, 2009; with permission.) the sciatic nerve. Passive dorsiflexion of the foot during the maneuver adds to the stretch. In healthy individuals, flexion to at least 80° is normally possible without causing pain, although a tight, stretching sensation in the hamstring muscles is common. The SLR test is positive if the maneuver reproduces the patient’s usual back or limb pain. Eliciting the SLR sign in both the supine and sitting positions can help The straight leg raise (SLR) test consists of a supine patient having his/her fully extended leg passively stretched from 0 to about 80 degrees. The onset of radiating back pain in either leg supports a diagnosis of a stenotic canal. A herniation compressing the L5 nerve root will present as a weakness of ankle dorsiflexion and an extension of the great toe. This deficit also may diminish the Achilles tendon reflex. L4 radiculopathy may present with weakness in the quadriceps and a decreased patellar tendon reflex. Documentation is paramount, as these initial findings likely will be used as a baseline for all future evaluations. Compression, injury, or irritation of the lumbar spinal nerve roots can occur from multiple potential sources. Most commonly, this occurs as a consequence of the degenerative cascade or an acute disc herniation. Lumbar radiculopathy (aka sciatica) describes the constellation of symptoms resulting from lumbar nerve compression. Individuals present with variable degrees of radiating pain, paresthesia (numbness/tingling), and weakness in the lower extremities. Lumbar stenosis is a condition in which the narrowing of the spinal canal occurs. This narrowing is usually secondary to degenerative spondylosis and spondylolisthesis. Classically individuals present with low back and/or lower extremity pain/paresthesias, which worsen with lumbar extension, prolonged standing, and ambulation. The pathophysiology appears to be due to mechanical compression of the lumbosacral spinal nerve roots resulting in ischemia. [16] [17] PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 22-1 Vertebral anatomy. (From A Gauthier Cornuelle, DH Gronefeld: Radiographic Anatomy Positioning. New York, McGraw-Hill, 1998; with permission.) Radicular pain is typically sharp and radiates from the low back to a leg within the territory of a nerve root (see “Lumbar Disk Disease,” below). Coughing, sneezing, or voluntary contraction of abdominal muscles (lifting heavy objects or straining at stool) may elicit the radiating pain. The pain may increase in postures that stretch the nerves and nerve roots. Sitting with the leg outstretched places traction on the sciatic nerve and L5 and S1 roots because the nerve passes posterior to the hip. The femoral nerve (L2, L3, and L4 roots) passes anterior to the hip and is not stretched by sitting. FIguRE 22-2 Spinal column. (From A Gauthier Cornuelle, DH Gronefeld: Radiographic Anatomy Positioning. New York, McGraw-Hill, 1998; with permission.) Stenosis in the lumbar spine can lead to neurogenic claudication, myeloradiculopathy symptoms, sensory disturbances, motor weakness, and pathologic reflexes. Patients will present with complaints of cramping pain in the leg, calf, and or buttocks. They might report an increase in pain with walking or standing for prolonged periods and relief when sitting or leaning forward while using a shopping cart. [9] Disk herniation is most common at the L4-5 and L5-S1 levels. A herniated disk at L5-S1 can lead to plantarflexion weakness, decrease sensation in the lateral foot, and cause pain in the posterior leg. A disk herniation at L4-5 can lead to a foot drop and numbness in the large toe web and dorsal aspect of the foot. Lastly, an L3-4 disk herniation can lead to knee extension weakness, numbness in the medial foot, and pain in the anterior thigh. L5 nerve root exits at the L5-S1 foramina. When compressed by a herniated disc, it causes back pain that radiates into the buttock, lateral thigh, lateral calf, the dorsum of the foot, and the great toe. Sensory loss is present on the web space between the big toe and second toe, the dorsum of the foot, and lateral calf. There is a weakness in hip abduction, knee flexion, foot dorsiflexion, big toe dorsiflexion, foot inversion, and eversion. Patients present with decreased semitendinosus/semimembranosus reflex. Weakness in foot dorsiflexion makes it challenging to walk on the heels. Chronic L5 radiculopathy may cause atrophy of the extensor digitorum brevis and the tibialis anterior of the anterior leg. Gout in the spine is very rare. The clinical symptoms of the spinal gout are various and lack of specificity. The authors report a case of spinal gout causing lumbar stenosis. We never find such wide-invasive spinal gouty lesion in the published studies. A 68-year-old male had low back pain radiating to bilateral lower limbs, accompanying with intermittent claudication that lasted for 3 months and aggravated 5 days ago. Spinal gout, lumbar stenosis. The patient underwent L2-L4 laminectomy, L2/3 L3/4 an d L4/5 discectomy and transforaminal lumbar interbody fusion with pedicle screw fixation. Dual-energy computed tomography detected extensive tophaceous deposits in L1/2 L2/3 L3/4 and L4/5 lumbar discs as well as the posterior column, especially L2-L3 and L4-L5 facet joints. During the surgery, we found a mass of chalky white material at the posterior column of L3 to L5 vertebral bodies, which also involved the intervertebral discs. Pathological examination confirmed the diagnosis of spinal gout. Although spinal gout is thought to be rare, the diagnosis should be considered if the patient had severe back pain and a history of gout. Dual-energy computed tomography is highly recommended for these patients. to provide crucial collateral flow in maintaining lower limb viabil-ity. It must be emphasized, however, that patients should be subjected to angiography only if their symptoms warrant surgi-cal intervention.Differential DiagnosisDegenerative hip or spine disease, lumbar disk herniation, spinal stenosis, diabetic neuropathy, and other neuromuscular problems can produce symptoms that may be mistaken for vas-cular claudication. Such cases can be distinguished from true claudication by the fact that the discomfort from neuromuscular problems is often relieved by sitting or lying down, as opposed to cessation of ambulation. In addition, complaints that are Table 23-13Clinical outcome of renal artery stent placement in the treatment of renovascular hypertension and renal insufficiencyAUTHORYEARPATIENT NO.TECHNICAL SUCCESS (%)FOLLOW-UP (MONTHS)RENAL INSUFFICIENCY (%)RENOVASCULAR HYPERTENSION (%)COMPLICATION (%)RESTENOSIS Symptoms for spinal stenosis apparently result from an incongruity between the capacity and contents of the spinal nerve passages. These symptoms are most frequently seen in men in their fifth or sixth decade of life. Spinal extension generally exacerbates the claudication-type symptoms (lower-extremity pain and paresthesia), whereas spinal flexion diminishes these symptoms. Differential diagnosis is needed to rule out vascular claudication due to atherosclerosis. Decisions regarding surgery should be made based not only on diagnostic imaging but also on a thorough history and clinical examination. Herniation of Lumbar Intervertebral Discs (Table 10-1) This condition is a major cause of severe and chronic or recurrent low back and leg pain. It occurs mainly during the third and fourth decades of life when the nucleus pulposus is still gelatinous. The disc between the fifth lumbar or first sacral vertebrae (L5-S1) is most often involved, and, with decreasing frequency, that between the fourth and fifth (L4-L5), third and fourth (L3-L4), second and third (L2-L3), and—quite infrequently—the first and second (L1-L2) lumbar vertebrae. Disc disease is relatively rare but well described in the thoracic portion of the spine. It is frequent in the cervical spine, especially at the fifth and sixth and the sixth and seventh cervical vertebrae (see further on). Lumbar disc arthroplasty is now a common treatment for lumbar degenerative disc disease. Whereas the immediate and delayed complications in patients with artificial lumbar discs are well reported, the durability of artificial disc hardware after severe spine trauma is unknown. The authors describe the management of a rare case of a traumatic lumbar burst fracture in a patient who had undergone disc arthroplasty. This 31-year-old male contractor had undergone placement of an L4-5 Charité artificial disc (DePuy Spine) and L5-S1 anterior lumbar fusion 10 months before he fell from a roof and sustained a traumatic L-3 burst fracture with significant canal compromise and cauda equina injury. Despite the considerable compressive load on his spine, the artificial disc (L4-5) remained intact without any radiological signs of hardware failure, and the vertebrae above (L-4) and below (L-5) the artificial disc had no signs of injury. For the L-3 burst fracture the patient underwent an open decompressive laminectomy at L2-3 and posterior fusion with instrumentation from L-2 to L-4. At 24 months postinjury, he had returned to full work activities as a contractor with minimal back pain and mild right lower-extremity sensory changes and weakness left over from the trauma. The total disc arthroplasty at L4-5 is functional and has preserved motion, and there is a solid fusion at L2-4 and L5-S1. This case demonstrates that a lumbar artificial disc can tolerate a significant load from trauma and remain functional without hardware failure even after a traumatic burst fracture at the adjacent lumbar vertebral body and shows the successful treatment of this fracture, with posterior fusion preserving the motion of an artificial disc. In contrast with patients with herniations of the nucleus pulposus, those with spinal stenosis experience onset of symptoms at a slightly older age; more males are affected than females. The symptoms tend to be somewhat more chronic, and therefore, the patients will have symptoms of back pain for a longer period of time before developing radiating root pains and will not come to surgical treatment until relatively late. Bilateral root symptomatology is more common although examination shows multiple nerve root involvement only slightly more frequently as well as involvement of the L1 to L4 nerve roots. The spinal movements tend to be somewhat better and straight leg raising tests are usually symmetrical and somewhat less restricted in those patients than in the acute disk syndrome. Postfusion and post-chemonucleolysis spinal stenosis will, of course, have the symptomatology of the initial problem, but their recurrent problems would tend to parallel those of spinal stenosis rather than disk herniation. Lumbar spinal stenosis is classified as a narrowing of the spinal canal in the lumbar region of the vertebrae. This may lead to compression of the nerve root of the spinal cord and result in pain of the lower back and lower extremities. Other symptoms include impaired walking and a slightly stooped posture due to loss of disc height and bulging of the disc. Lumbar spinal stenosis is very prevalent with 9.3% of the general population producing symptoms and the number is continuing to rise in patients older than 60. It's generally an indication for spinal surgery in patients older than 65 years of age. However, there is a myth and fear among most patients that only surgery is the cure for such conditions and spine surgery is very risky. There are many non-surgical treatments available to prevent, halt and even reverse many spine diseases. Also, some surgery patients can be operated on in a daycare procedure or with minimum length of stay in hospital, with statistically good outcomes. Uncertainty still exists regarding the treatment of the patients presenting with gunshot wounds to the spine. Neurological insults, cerebrospinal fluid fistula, infection, lead or copper toxicity, migration of bullets, and spinal instability are included among the common challenging issues. An 18-year-old woman was admitted with low back pain following a gunshot injury five days ago. She was neurologically intact. Radiological examinations showed that a bullet was settled in L4-5 disc space. The bullet was removed with a unilateral L4-5 partial hemilaminectomy and discectomy from the left side. The second case was of a 29-year-old man admitted with radiating leg pain on the right side following a gunshot injury from his left side of lower back four months ago. He had only positive straight leg raising test. Radiological studies showed two bullets, one was in the psoas muscle on the left side and the other was in spinal canal that had caused a burst fracture of the L5 vertebra. Following L5 laminectomy and bilateral L5-S1 facetectomy, the bullet was removed from the spinal canal and L5-S1 transpedicular posterior stabilization was performed. The postoperative period of both patients was unremarkable. Bullet settling into the lumbar spinal canal without causing neurological deficit may require surgical intervention. Removal of bullets provided not only pain relief in both the cases but also prevented future complications such as migration of the bullets, plumbism, and neuropathic pain and instability. Lumbar disc degeneration is defined as the wear and tear of lumbar intervertebral disc, and it is mainly occurring at L3-L4 and L4-S1 vertebrae. Lumbar disc degeneration may lead to disc bulging, osteophytes, loss of disc space, and compression and irritation of the adjacent nerve root. Clinical presentations associated with lumbar disc degeneration and lumbosacral nerve lesion are discogenic pain, radical pain, muscular weakness, and cutaneous. Discogenic pain is usually felt in the lumbar region, or sometimes, it may feel in the buttocks, down to the upper thighs, and it is typically presented with sudden forced flexion and/or rotational moment. Radical pain, muscular weakness, and sensory defects associated with lumbosacral nerve lesions are distributed on lower extremities, the buttock, lower abdomen, and groin region. A lumbosacral plexus lesion presents different symptoms in the territories of the lumbar and sacral nerves. Patients with lumbar plexus lesion clinically present with weakness of hip flexion, knee extension, thigh adduction, and sensory loss in the lower abdomen, inguinal region, and over the entire medial, lateral, and anterior surfaces of the thigh and the medial lower leg, while sacral plexus lesion presents clinical symptoms at nerve fibers destined for the sciatic nerve, common peroneal nerve, and pudendal nerve. Weakness of ankle inversion, plantar flexion, and foot drop are the main clinical manifestations of the sacral plexus lesion area. Numbness and decreased sensation are also present along the anterolateral calf and dorsum of the foot. On examination, foot eversion is usually stronger than foot dorsiflexion. The patients may also present with pain and difficulty of bowel movements, sexual dysfunction assessments, and loss of cutaneous sensation in the areas of the anal canal, anus, labia major, labia minor, clitoris, penis, and scrotum. A 56-year-old alcoholic male incurred L5 vertebral body and bilateral L4 pars fractures with progressive L4 on L5 anterolisthesis following low-energy falls while intoxicated. Recently, he had a L3-S1 laminectomy for lumbar spinal stenosis with claudication. Preoperative imaging and radiographs were negative for pars defects and instability, so an isolated decompressive surgery was performed. Following low-energy falls, his outpatient work-up revealed fractures through the bilateral L4 pedicles and posterior third of L5 vertebral body, with recurrence of axial back pain and bilateral lower extremity radiculopathy. He underwent revision decompression from L4-S1 and posterior instrumented fusion with transforaminal lumbar interbody fusion performed at each revised level. His axial back pain and radiculopathy improved postoperatively. Instability of a lumbar spine fracture pattern can be due to the remote or prior iatrogenic disruption of the posterior ligamentous complex. Our patient benefitted from surgery and his low back pain was resolved. Some patients with LSS may be asymptomatic and have a normal neurologic examination. Other individuals with asymptomatic LSS may have neurologic deficits due to superimposed lumbar radiculopathy. The Valsalva maneuver often does not exacerbate LSS-related radicular pain as it does in IV disk prolapse. Only 10% of patients present with a positive straight leg raise test. [24] Pedal pulses should also be checked during the physical exam to rule out vascular claudication. A patient who can perform a five-repetition sit-to-stand (5R-STS) test in 10.4 seconds may be considered to have no functional impairment. [25] Oblique lumbar interbody fusion (OLIF) is an effective and safe surgical technique widely used for treating spondylolisthesis; however, its use is controversial because of several associated complications, including endplate injury. We report a rare vertebral body fracture following OLIF in a patient with poor bone quality. A 72-year-old male patient visited our clinic for 2 years with lower back pain, leg radiating pain, and intermittent neurogenic claudication. Lumbar magnetic resonance imaging revealed L4-5 stenosis. We performed OLIF with percutaneous pedicle screw fixation and L4 subtotal decompressive laminectomy. We resected the anterior longitudinal ligament partially for anterior column release and inserted a huge cage to maximize segmental lordosis. No complications during and after the operation were observed. Further, the radiating pain and back pain improved, and the patient was discharged. Two weeks after the operation, the patient visited the outpatient department complaining of sudden recurred pain, which occurred while going to the bathroom. Radiography and computed tomography revealed a split fracture of the L5 body and an anterior cage displacement. In revision of OLIF, we removed the dislocated cage and filled the bone cement between the anterior longitudinal ligament and empty disc space. Further, we performed posterior lumbar interbody fusion L4-5, and the screw was extended to S1. After the second surgery, back pain and radiating pain in the left leg improved, and he was discharged without complications. In this case, owing to insufficient intervertebral space during L4-5 OLIF, a huge cage was used to achieve sufficient segmental lordosis after anterior column release, but a vertebral body coronal fracture occurred. In patients with poor bone quality and less flexibility, a huge cage and over-distraction could cause a vertebral fracture; hence, selecting an appropriate cage or considering a posterior approach is recommended. Nerve root injury (radiculopathy) is a common cause of neck, arm, low back, buttock, and leg pain (see Figs. 31-2 and 31-3). The nerve roots exit at a level above their respective vertebral bodies in the cervical region (e.g., the C7 nerve root exits at the C6-C7 level) and below their respective vertebral bodies in the thoracic and lumbar regions (e.g., the T1 nerve root exits at the T1-T2 level). The cervical nerve roots follow a short intraspinal course before exiting. By contrast, because the spinal cord ends at the vertebral L1 or L2 level, the lumbar nerve roots follow a long intraspinal course and can be injured anywhere from the upper lumbar spine to their exit at the intervertebral foramen. For example, disk herniation at the L4-L5 level can produce not only L5 root compression, but also compression of the traversing S1 nerve root (Fig. 22-3). The lumbar nerve roots are mobile in the spinal canal, but eventually pass through the narrow lateral recess of the spinal canal and\nHere is the question:\nORTHOPEDIC SURGERY AND TRAUMATOLOGY: The most likely diagnosis of a 74-year-old patient who since two months ago begins with lumbar pain radiating to lower limbs, neurogenic claudication and limitation to extension the trunk is:\nHere are the potential choices:\n1. L4-L5 disc herniation.\n2. Lumbar vertebral fracture.\n3. L5-S1 vertebral instability.\n4. Lumbar canal stenosis.\nThe correct answer is: 4. Lumbar canal stenosis."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n  Pituitary apoplexy is an uncommon but life-threatening condition that is often overlooked and underdiagnosed. We report a 45-year-old man who presented to our emergency department with a sudden onset headache, acute confusion, signs of meningeal irritation and ophthalmoplegia. An initial diagnosis of acute meningoencephalitis was made, which was amended to pituitary apoplexy following thorough investigation within the emergency department.A 45-year-old man was brought to our emergency department by ambulance with a history of sudden onset of frontal headache and acute confusion. His wife provided the history. There was no significant past medical history of diabetes, hypertension, recent travel abroad, exposure to sick contacts, involvement in outdoor pursuits such as hiking/cave diving, or trauma. He worked in a bank and had been well until 24 h prior to the onset of sudden headache, which was gradually worsening in nature and associated with increasing confusion. The patient's wife reported that he had neither experienced any fevers, night sweats, or coryzal symptoms nor received any recent vaccinations. He was not on any regular medications. He was a non-smoker and occasionally consumed alcohol. There was no significant family history. On examination in the ED, his temperature was 37.6°C, his pulse was 110/min, and he was normotensive and normoglycaemic. A macular blanching rash was noted over the patient's trunk. The patient was disoriented to time and place. Neurological examination revealed reduced GCS (11/15-E3, M6, V2), marked neck stiffness, a positive Kernig's sign and a right sixth nerve palsy.A provisional diagnosis of acute meningoencephalitis was made and the patient was started on a course of intravenous antibiotics with benzyl penicillin 1.2 g, cefotaxime 2 g and acyclovir 750 mg. Baseline blood investigations revealed hyponatraemia (122 mmol/l), a white-cell count of 11 × 109/l and a C-reactive protein &gt; 250. Due to the sudden onset of the symptoms and lack of prodrome, an urgent CT head scan was performed to rule out a cerebrovascular event. The scan demonstrated an enlarged pituitary gland (3 cm in diameter) with impingement of the optic chiasm. The centre of the enlarged pituitary gland was noted to be hypodense in comparison to its periphery, which was consistent with a diagnosis of pituitary apoplexy. A subsequent MRI confirmed the diagnosis (Figure 1) of an enlarged sella containing abnormal soft tissue with increased signal intensity suggestive of haemorrhage (Figure 1A).Post-MRI a lumbar puncture was performed revealing glucose 3.4 mmol/l, protein 1.0 g/l, red cells of 53/mm3 and white cells of 174/mm3 with predominant neutrophilia. No organisms were seen, and CSF cultures and HSV DNA tests were found to be negative. Endocrinological investigations demonstrated low concentrations of thyroid hormones [TSH: 0.14 mIu/l (0.35-5.5 mlU/l), FT3: 1.1 nmol/l (1.2-3.0 nmol/l), FT4: 9.6 pmol/l (8-22 pmol/l)], gonadal hormones (LH: &lt; 1 u/l) and prolactin: 16 u/l (&lt;450 u/l). Serum FSH was 2.9 u/l (0.8-11.5 u/L) and cortisol 575 nmol/l (450-700 nmol/l). The patient was treated for hypopituitarism based on clinical and radiological findings with intravenous fluids, hydrocortisone (100 mg) and thyroxine (50 μg) as loading doses in the ED.Within 24 h of commencement of therapy the patient's GCS rose to 15, and within 48 h there was marked improvement in the right sixth cranial nerve palsy. Formal visual field assessment demonstrated temporal visual field loss in the left eye. The patient was discharged to his usual residence a week later and follow-up was organised with both the endocrinologists and ophthalmologists. Follow-up MRI demonstrated that there was no significant change in either size or signal characteristics of the pituitary fossa mass (Figure 1B). When bacterial meningitis is suspected, blood cultures should be immediately obtained and empirical antimicrobial and adjunctive dexamethasone therapy initiated without delay (Table 164-1). The diagnosis of bacterial meningitis is made by examination of the CSF (Table 164-2). The need to obtain neuroimaging studies (CT or MRI) prior to LP requires clinical judgment. In an immunocompetent patient with no known history of recent head trauma, a normal level of consciousness, and no evidence of papilledema or focal neurologic deficits, it is considered safe to perform LP without prior neuroimaging studies. If LP is delayed in order to obtain neuroimaging studies, empirical antibiotic therapy should be initiated after blood cultures are obtained. Antibiotic therapy initiated a few hours prior to LP will not significantly alter the CSF WBC count or glucose concentration, nor is it likely to prevent visualization of organisms by Gram’s stain or detection of bacterial nucleic acid by Angiography After a subarachnoid hemorrhage is confirmed, its origin needs to be determined. If the bleeding is likely to have originated from an aneurysm (as determined by the CT scan appearance), the choice is between cerebral angiography (injecting radiocontrast through a catheter to the brain arteries) and CT angiography (visualizing blood vessels with radiocontrast on a CT scan) to identify aneurysms. Catheter angiography also offers the possibility of coiling an aneurysm (see below). In emergency department patients complaining of acute-onset headache without significant risk factors for SAH, evidence suggests that CT scanning of the head followed by CT angiography can reliably exclude SAH without the need for a lumbar puncture. The risk of missing an aneurysmal bleed as the cause of SAH with this approach is less than 1%. Lumbar puncture Non-adenomatosus lesions of the pituitary represent a small part of the intrasellar processes and they have heterogeneous presentation. Making a precise diagnosis is of great importance, as it may lead to more efficient management. A 65-year-old man was admitted to the hospital because of headache and right cranial nerve III palsy. Basic laboratory work-up was normal whereas endocrinological assessment revealed hypopituitarism without diabetes insipidus. Plain radiography showed an enlarged sella and frontal and paranasal sinusitis. Computed tomography (CT) and magnetic resonance imaging (MRI) of the sella revealed an intrasellar lesion with extension to the sphenoid and cavernous sinuses as well as the suprasellar region, exerting pressure on the optic chiasm. On T1-weighted images the mass had a low-intensity signal with a smooth enhancing rim with bright signal. Given the presence of multiple sinusitis and imaging characteristics a pre-operative diagnosis of pituitary abscess was made. The patient was operated via transphenoidal route and purulent material was drained out. Cultures of the material were positive for Staphylococcus aureus. Antibiotics as well as cortisol replacement therapy were given. Three months later hypopituitarism persisted but there was significant improvement in the neurological findings. We report a case of an unusual presentation of a pituitary abscess. High index of suspicion, the presence of associated conditions such as pituitary tumors, meningitis or sinusitis, as well as diabetes insipidus and specific imaging features are the main diagnostic clues. Pre-operative diagnosis, which will lead to prompt antibiotic therapy and transphenoidal drainage, can decrease high mortality and morbidity associated with this disease. Computed tomography (CT) findings of chronic subdural hematomas are usually diagnostic, unless hematomas are isodense and bilateral. The authors report two cases of bilateral chronic subdural hematomas, in which CT scans on admission were both misdiagnosed as delayed subarachnoid hemorrhage (SAH). The first case was a 43-year-old woman who suffered from a sudden onset of headache and nausea. She had no past history of head injury. CT scans on admission did not clearly reveal the Sylvian fissures and the mesencephalic cistern, without any mass effects. A lumbar puncture demonstrated xanthochromic cerebrospinal fluid (CSF), which was considered to be responsible for her headache. Cerebral angiography performed on day 4 failed to demonstrate any cerebral vascular disorders. Follow-up CT scans on day 7 demonstrated a high density lesion in the left subdural space. Magnetic resonance images (MRIs) confirmed a diagnosis of bilateral chronic subdural hematomas. Removal of the hematomas cleared all signs and symptoms smoothly. The second case was a 44-year-old man who was referred from another hospital because of xanthochromic CSF found by lumbar puncture. He began to suffer headache and be subject to vomiting 6 weeks earlier and these symptoms were still present on the day of admission. CT scans did not clearly show the cerebral cisterns without mass effects. Because the second lumbar puncture showed xanthochromic CSF again, SAH from aneurysm was suspected. However, emergency cerebral angiography failed to demonstrate cerebral aneurysms. MRI performed two days later demonstrated bilateral chronic subdural hematomas. Following surgery, the patient improved immediately and was discharged from hospital without any complications. In both cases, a retrospective study of the angiograms revealed the evidence of bilateral avascular areas over the convexities in the venous phase. The reason why these subdural hematomas were missed at the time of angiography was due to too much attention being paid to the arterial phase in an effort aimed only at identifying cerebral aneurysms. There are no reports of chronic subdural hematoma which demonstrated sudden onset of headache associated with xanthochromic CSF. The introduction of new diagnostic and therapeutic techniques has changed the clinical attitude and consequences of brain abscesses (BA). To analyse clinical-radiological features, therapy, prognostic factors and evolution of BA in our institution. Retrospective study of all clinical records of patients diagnosed with BA from 1982 to 1992. Twenty-six patients with a mean age of 46.2 years were selected. The incidence was 2.6 patients/10,000 admission/year. Among 17 patients (65%) some extraprenchymatous infectious focus was found, which was located at the otorhynolaryngeal area in twelve patients. Mean duration of symptoms was 12.9 days, headache being the most common of them (69%). With CT 18 patients had a single mass, eight patients multiple masses, and 21 patients a ring enhancement when the contrast material was introduced. The causative organism was recovered from 15 patients. The organism recovered more frequently were Streptococcus spp, Enterobacteriaceae and Staphylococcus aureus. Twenty patients (77%) underwent surgical therapy, which consisted in ablation (12) or drainage (8). All patients received antibiotics for a mean of 37 days: the most frequent antibiotic combination used was penicillin+chloramphenicol. Six patients died (23%) and 7 remained with sequelae. Although statistically non-significant, the acute presentation was associated with a higher mortality rate, and the use of dexamethasone was associated with a lower mortality rate (p = 0.053 and 0.062, respectively). BA is associated with a high mortality rate and a high sequelae rate despite appropriate diagnostic and therapeutic measures. ORL infection is the most frequent predisposing factor. The use of dexamethasone is not associated with a higher mortality rate. One recommended diagnostic approach is as follows. If any urgent red flags are present such as visual loss, new seizures, new weakness, new confusion, further workup with imaging and possibly a lumbar puncture should be done (see red flags section for more details). If the headache is sudden onset (thunderclap headache), a computed tomography test to look for a brain bleed (subarachnoid hemorrhage) should be done. If the CT scan does not show a bleed, a lumbar puncture should be done to look for blood in the CSF, as the CT scan can be falsely negative and subarachnoid hemorrhages can be fatal. If there are signs of infection such as fever, rash, or stiff neck, a lumbar puncture to look for meningitis should be considered. If there is jaw claudication and scalp tenderness in an older person, a temporal artery biopsy to look for temporal arteritis should be performed and immediate treatment should be started. Neuroimaging The aim of the study is to assess outcome of surgical treatment of anterior cranial base meningiomas with special emphasis on the evaluation of visual skills after surgery. A series of 52 consecutive patients operated on for anterior cranial base meningioma in the last ten years is reported. 18 patients had decreased visual acuity on admission, 6 experienced blindness in one eye, and 4 were totally blind; defects of visual fields were found in 17 patients. Primary optic atrophy and secondary optic atrophy were noted in fundcoscopy in 20 and 2 patients, respectively. Papilloedema was found in 3 patients. Meningiomas were resected radically (Simpson I surgery) in 13 patients and in 34 patients Simpson II surgery with coagulation of the dural attachment was made; meningiomas were partially removed in 5 patients (Simpson IV surgery). In one patient dense hemiparesis occurred after the surgery, and 3 others presented adynamic syndrome, one of whom made a good recovery in follow-up examination. Two patients died: the first one due to a large brain oedema and the second one due to myocardial infarction after uncomplicated postoperative course. The postoperative course in the other 46 patients was uneventful with good outcome. Visual acuity improved in 15 cases and did not change in 10 patients; visual acuity further decreased in 3 patients. Visual recovery is significantly related to preoperative visual acuity values of no less than 0.3 D and to the presence of normal optic discs on fundoscopic examination additionally tumour size less than 3.5 cm favourably affects visual prognosis in meningiomas of tuberculum sellae. A 75-year-old lady presented with sudden severe headache and vomiting. Examination was normal, and CT and lumbar puncture not convincing for subarachnoid haemorrhage. Shortly thereafter, she developed painless diplopia. Examination confirmed right third cranial nerve palsy plus homonymous left inferior quadrantanopia. Urgent cerebral MRI with angiography was requested to assess for a possible posterior communicating artery aneurysm, but revealed an unsuspected pituitary mass. Pituitary adenoma with pituitary apoplexy was diagnosed. Pituitary apopolexy is a syndrome comprising sudden headache, meningism, visual and/or oculomotor deficits, with an intrasellar mass. It is commonly due to haemorrhage or infarction within a pituitary adenoma. Treatment includes prompt steroid administration, and potentially surgical decompression. While subarachnoid haemorrhage is an important, well-recognised cause of sudden severe headache, other aetiologies, including pituitary apoplexy, should be considered and sought.  Although reports of single cases of painful ophthalmoplegia (PO) are common, studies considering larger case series are lacking. Here, we aimed to determine the relative frequencies of ocular neuropathies, the causes, the usefulness of diagnostic procedures and the role of steroid treatment in PO. Between January 2006 and September 2012, 149 patients' charts who presented with diplopia in our emergency department were studied retrospectively. 34 of them met the inclusion criteria that included recent (≤3 days) symptom onset and a minimum of diagnostic work. 32% of single or combined ocular motor nerve palsies were of diabetic microvascular etiology and most of them were IIIrd or VIth nerve neuropathies. The most useful, in terms of sensitivity and specificity of diagnostic test in the acute setting was ESR, whereas MR-angiography and focused cavernous sinus imaging led to diagnosis in the post-acute phase. Pain response to steroids was non-specific, in contrast to palsy improvement after steroid administration which was indicative of Tolosa-Hunt syndrome or temporal arteritis. Although acute and subacute PO might be intuitively associated with Tolosa-Hunt syndrome or sinister pathology such as aneurysmal hemorrhage, our data show that these causes are far less common than diabetic microvascular palsies. Brain CT, MR-imaging of brainstem, cerebellum or hemispheres, CSF analysis and pain response to steroids are nonspecific and hence less helpful in order to arrive at a diagnosis. Instead, improved ocular motility after steroid treatment, as well as MR-angiography and cavernous sinus imaging appear more useful for this purpose. Investigations include blood tests (electrolytes, liver and kidney function, inflammatory markers and a complete blood count) and usually X-ray examination of the chest. The most important test in identifying or ruling out meningitis is analysis of the cerebrospinal fluid (fluid that envelops the brain and the spinal cord) through lumbar puncture (LP). However, if the patient is at risk for a cerebral mass lesion or elevated intracranial pressure (recent head injury, a known immune system problem, localizing neurological signs, or evidence on examination of a raised ICP), a lumbar puncture may be contraindicated because of the possibility of fatal brain herniation. In such cases, a CT or MRI scan is generally performed prior to the lumbar puncture to exclude this possibility. Otherwise, the CT or MRI should be performed after the LP, with MRI preferred over CT due to its superiority in demonstrating areas of cerebral edema, ischemia, and meningeal inflammation. This is a review of 1,000 consecutive cases of severe head injury admitted to our Neurosurgical Department between January 1973 and August 1976, before the advent of CT scanning. All patients were comatose following head injury (GCS less than or equal to 8) and were treated homogeneously by the same neurosurgical team by a protocol that included immediate resuscitation on arrival, diagnosis of intracranial lesions by angiography, early surgery when needed, mechanical ventilation, steroids, and mannitol. Extracranial lesions, even if preponderant, were treated by various specialists in the Neurosurgical Department, which for all practical purposes operated as an Emergency Department. Admission criteria were very broad with no preadmission selection. The overall mortality for this series was 45%. A little less than half the patients made good recoveries or remained moderately disabled (47%); 6% were severely disabled, and 2% survived in a persistent vegetative state. More than two-thirds of the patients were brought to our Neurosurgical Department after a short stay at a general hospital; 72% were admitted within 6 hours of injury; 71% were traffic accident victims; and 34% had significant associated extracranial injuries. Carotid angiography was performed in 78% of the patients and indicated the presence of an intracranial haematoma requiring surgery in 36% of the whole series. Mortality was significantly higher in operated than in unoperated patients (56% versus 39%); those treated surgically, however, were older, in worse clinical condition, and showed a higher incidence of acute subdural haematomas associated with brain contusion. Carotid angiography proved very effective in revealing the presence of an expansive lesion but failed to reflect the severity of brain damage, since the group with \"negative\" angiograms showed a high mortality (52%). Patients with a lucid interval had a higher percentage of surgical lesions than those with immediate coma (58% versus 26%); but fully 42% of them did not require surgery, and 25% had negative angiograms. From the prognostic point of view the clinical data elicited after initial resuscitation were highly predictive of the outcome: some individual neurological signs, such as mydriasis, posturing and eye movements, were not inferior to the GCS score in that respect. Age also proved a strong predictor, since elderly patients are more likely to have severe subdural and parenchymal lesions and their clinical severity is accordingly greater.(ABSTRACT TRUNCATED AT 400 WORDS) Subarachnoid bleed If an aneurysm ruptures, blood leaks into the space around the brain. This is called a subarachnoid hemorrhage. Onset is usually sudden without prodrome, classically presenting as a \"thunderclap headache\" worse than previous headaches. Symptoms of a subarachnoid hemorrhage differ depending on the site and size of the aneurysm. Symptoms of a ruptured aneurysm can include: a sudden severe headache that can last from several hours to days nausea and vomiting drowsiness, confusion and/or loss of consciousness visual abnormalities meningism dizziness Almost all aneurysms rupture at their apex. This leads to hemorrhage in the subarachnoid space and sometimes in brain parenchyma. Minor leakage from aneurysm may precede rupture, causing warning headaches. About 60% of patients die immediately after rupture. Larger aneurysms have a greater tendency to rupture, though most ruptured aneurysms are less than 10 mm in diameter. Lumbar puncture is the best way to prove bacterial meningitis. It should be performed without any delay if the diagnosis is suspected. Herniation is a rare complication of LP. CT is normal in most cases of purulent meningitis, including those complicated by a subsequent herniation; normal CT results does not mean that performing a LP is safe. Three main clinical features can help determine which patient is at risk of herniation and should have a CT before LP. This risk has to be determined rapidly in the emergency ward while assessing anamnestic data, localization signs or symptoms, and level of consciousness. Cranial imaging (mainly MRI) is useful in the course of bacterial meningitis. Patients who do not respond well to treatment or with atypical presentation, persistence of fever, or new neurological signs should undergo brain imaging; MRI and CT may identify subdural effusions, brain abscesses, empyemas, hydrocephaly, or brain parenchymal changes (cerebritis, infarction, hemorrhage). CT and MRI are useful to screen for an ENT cause of bacterial meningitis, and mandatory in case of pneumococcal meningitis. Numerous MRI sequences are useful to identify bacterial meningitis complications: SE T1 without and with gadolinium injection, SE T2, FLAIR, gradient-echo T2, diffusion weighted imaging, MR angiography. Diagnosis Diagnosis of a ruptured cerebral aneurysm is commonly made by finding signs of subarachnoid hemorrhage on a computed tomography (CT) scan. If the CT scan is negative but a ruptured aneurysm is still suspected based on clinical findings, a lumbar puncture can be performed to detect blood in the cerebrospinal fluid. Computed tomography angiography (CTA) is an alternative to traditional angiography and can be performed without the need for arterial catheterization. This test combines a regular CT scan with a contrast dye injected into a vein. Once the dye is injected into a vein, it travels to the cerebral arteries, and images are created using a CT scan. These images show exactly how blood flows into the brain arteries. Visual complications represent common deficits following surgical or endovascular repair of paraclinoid aneurysms. Different etiologies should be investigated to prevent devastating consequences. Herein we present a point-of-care evaluation to investigate sudden visual loss after coiling of paraclinoid aneurysms. A 20-year-old male was admitted for a sudden headache. Head computed tomography showed a subarachnoid hemorrhage and subsequent angiography revealed a 9-mm left supraclinoid aneurysm of the internal carotid artery treated with endovascular coil embolization. Thirty minutes after intensive care unit admission, the patient reported a left amaurosis. To exclude secondary etiologies, an immediate evaluation with point-of-care devices (color-doppler and B-mode ultrasound and automated pupillometry) was performed. Sonographic evaluations were negative for ischemic/thrombotic events and neurologic pupil index within physiological ranges provide evidence of third cranial nerve responsiveness. The symptomatology resolved progressively over 120 minutes with low-dose steroid therapy, 30° head-of-bed elevation, and blood pressure management. Visual deficits can occur after endovascular procedure and should be investigated. Suspected visual loss is a neurological emergency that deserves a prompt evaluation. Ultrasound and automated pupillometry have proved to be an effective, rapid, reliable, and non-invasive combination for a clinical decision-making strategy in the management of post-procedural acute visual deficits. Two cases of cerebral aneurysm combined with polycystic kidneys (PCKs) were presented. Case 1, a 24-year-old hypertensive male, was referred to our clinic owing to sudden onset of severe headache at August 20, 1982. Neurological findings on admission were stuporous, right vitreous hemorrhage (so-called Terson's syndrome), and hypertension. CT scans showed subarachnoid hemorrhage, and right MCA bifurcation aneurysm with marked vasospasms by cerebral angiography was revealed. Intentional delayed operation with V-P shunt was performed. He discharged with mild left upper limb paresis, and visual impairment on the right. Bilateral PCKs were confirmed by postoperative DIP and CT scan. Case 2, a 51-year-old female, who suddenly complained of severe headache, was referred to our department 3 days after subarachnoid hemorrhage. One year previously, she had been pointed out PCKs. Neurological findings on admission at February 29, 1980, were drowsy, left third cranial nerve palsy, and hypertension. Cerebral angiography showed multiple aneurysms (bilateral IC-PC &amp; A-com). Neck clipping (1-IC-PC &amp; A-com) and coating (r-IC-PC) were performed at the next day of admission, and V-P shunt operation was followed about 8 weeks after first operation. About 2 weeks after discharge, she suddenly became loss of consciousness and expired. Autopsy revealed intracerebral hemorrhage in left basal ganglia and thalamus. Both kidneys were PCKs of Potter type 3 and cysts of the liver were also noted. In young hypertensive patients with cerebral aneurysms, it should be in mind whether PCKs may be combined or not, and cerebral angiography in PCKs were reasonable to find out harbored cerebral aneurysm.(ABSTRACT TRUNCATED AT 250 WORDS) Pituitary abscesses are rare. The case reported here concerns a 28-year old African. Gradual development of diplopia over 6 months was the first clinical manifestation. Three months later this development had reached a more severe and infectious context, with complete right ophthalmoplegia, meningitis and coma (GCS = 9). CT scan showed an image in favour of a pituitary abscess with suprasellar extension, associated with thrombophlebitis of the cavernous sinus. An antibiotic therapy consisting of cefotaxime and metronidazole administered for 1 month, and netilmicin for 15 days succeeded in controlling the infectious syndrome. This resulted in cure of visual disorders, reduction in size of the CT scan image and reconstruction of the pituitary sella which had been destroyed. The diagnosis of pituitary abscess should be made when confronted with an infectious syndrome (unexplained fever, repeated meningitis). CT does not recognize the nature of the hypophyseal mass it shows: necrosis of a pituitary adenoma, giant aneurysm or craniopharyngioma may mimic local infection. Surgery confirms the diagnosis and is regarded as the best treatment. The patient's life is threatened when meningitis is present, and the functional prognosis is poor when recovery from visual disorders is compromised due to late diagnosis. In this paper a comparative analysis of the clinical course of the disease and therapeutic data in our patient is presented and compared with other reported cases. A case of acute spontaneous subdural hematoma associated with three aneurysms is reported. On March 12, 1984, a 47-year-old woman experienced the sudden onset of severe headache over the bilateral frontal region and vomiting. Three hours later, she was transferred to our hospital by ambulance car because of continuous headache and vomiting. She had no history of head trauma. She had been medicated hypertension for five years. On admission she suffered from headache and nausea. But there was no clinical sign in physical and neurological examinations. The meningeal irritation was not present, but lumbar puncture showed slightly pinky CSF with normal pressure. A plain computed tomographic scan showed a thin high density mass in the left temporal extra-axial region and the slight deviation of the midline structures to the right. Left carotid arteriogram showed an avascular region over the left cerebral convexity, an aneurysm of the left A2-A3 junction and a questionable aneurysm of the bifurcation of left middle cerebral artery. Right carotid arteriogram showed an aneurysm of the bifurcation of right middle cerebral artery. We diagnosed this case as an acute subdural hematoma by CT scan and arteriogram. We were perplexed preoperatively whether this bleeding was spontaneous or secondary to the rupture of aneurysm, and we could not deny the possibility of a ruptured aneurysm. On March 15, 1984, three days after onset, operation was performed. At operation, a small subdural hematoma was removed, and the underlying cortex was normal.(ABSTRACT TRUNCATED AT 250 WORDS)\nHere is the question:\nNEUROLOGY AND NEUROSURGERY: A 51-year-old woman comes to the emergency department with a sudden decrease in visual acuity, severe headache, nausea and vomiting. Hypotensive and afebrile. She presented right ophthalmoparesis due to involvement of the third cranial nerve. A cranial CT scan shows a mass in the hyperdense selar region with erosion of the anterior clinoid processes. What is the best approach to follow?\nHere are the potential choices:\n1. Suspect chemical meningitis derived from a ruptured epidermoid tumor and start immediate treatment with corticosteroids.\n2. It would indicate the performance of a cerebral angiography to rule out an aneurysm, since it is most likely that we are facing a case of subarachnoid hemorrhage and the mass that is evident in the CT is a thrombosed parasellar aneurysm.\n3. Admission to ICU and treatment of the shock suffered by the patient and once stabilized perform brain MRI for scheduled surgery.\n4. Urgent biochemistry and hemogram, initiation of high-dose corticosteroid therapy and urgent transsphenoidal surgery.\n5. Lumbar puncture to rule out bacterial meningitis after starting empirical antibiotherapy. Once the patient was stabilized, study of the selar mass.\nThe correct answer is: ",
        "gold_answer": "5 Lumbar puncture to rule out bacterial meningitis after starting empirical antibiotherapy. Once the patient was stabilized, study of the selar mass.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n  Pituitary apoplexy is an uncommon but life-threatening condition that is often overlooked and underdiagnosed. We report a 45-year-old man who presented to our emergency department with a sudden onset headache, acute confusion, signs of meningeal irritation and ophthalmoplegia. An initial diagnosis of acute meningoencephalitis was made, which was amended to pituitary apoplexy following thorough investigation within the emergency department.A 45-year-old man was brought to our emergency department by ambulance with a history of sudden onset of frontal headache and acute confusion. His wife provided the history. There was no significant past medical history of diabetes, hypertension, recent travel abroad, exposure to sick contacts, involvement in outdoor pursuits such as hiking/cave diving, or trauma. He worked in a bank and had been well until 24 h prior to the onset of sudden headache, which was gradually worsening in nature and associated with increasing confusion. The patient's wife reported that he had neither experienced any fevers, night sweats, or coryzal symptoms nor received any recent vaccinations. He was not on any regular medications. He was a non-smoker and occasionally consumed alcohol. There was no significant family history. On examination in the ED, his temperature was 37.6°C, his pulse was 110/min, and he was normotensive and normoglycaemic. A macular blanching rash was noted over the patient's trunk. The patient was disoriented to time and place. Neurological examination revealed reduced GCS (11/15-E3, M6, V2), marked neck stiffness, a positive Kernig's sign and a right sixth nerve palsy.A provisional diagnosis of acute meningoencephalitis was made and the patient was started on a course of intravenous antibiotics with benzyl penicillin 1.2 g, cefotaxime 2 g and acyclovir 750 mg. Baseline blood investigations revealed hyponatraemia (122 mmol/l), a white-cell count of 11 × 109/l and a C-reactive protein &gt; 250. Due to the sudden onset of the symptoms and lack of prodrome, an urgent CT head scan was performed to rule out a cerebrovascular event. The scan demonstrated an enlarged pituitary gland (3 cm in diameter) with impingement of the optic chiasm. The centre of the enlarged pituitary gland was noted to be hypodense in comparison to its periphery, which was consistent with a diagnosis of pituitary apoplexy. A subsequent MRI confirmed the diagnosis (Figure 1) of an enlarged sella containing abnormal soft tissue with increased signal intensity suggestive of haemorrhage (Figure 1A).Post-MRI a lumbar puncture was performed revealing glucose 3.4 mmol/l, protein 1.0 g/l, red cells of 53/mm3 and white cells of 174/mm3 with predominant neutrophilia. No organisms were seen, and CSF cultures and HSV DNA tests were found to be negative. Endocrinological investigations demonstrated low concentrations of thyroid hormones [TSH: 0.14 mIu/l (0.35-5.5 mlU/l), FT3: 1.1 nmol/l (1.2-3.0 nmol/l), FT4: 9.6 pmol/l (8-22 pmol/l)], gonadal hormones (LH: &lt; 1 u/l) and prolactin: 16 u/l (&lt;450 u/l). Serum FSH was 2.9 u/l (0.8-11.5 u/L) and cortisol 575 nmol/l (450-700 nmol/l). The patient was treated for hypopituitarism based on clinical and radiological findings with intravenous fluids, hydrocortisone (100 mg) and thyroxine (50 μg) as loading doses in the ED.Within 24 h of commencement of therapy the patient's GCS rose to 15, and within 48 h there was marked improvement in the right sixth cranial nerve palsy. Formal visual field assessment demonstrated temporal visual field loss in the left eye. The patient was discharged to his usual residence a week later and follow-up was organised with both the endocrinologists and ophthalmologists. Follow-up MRI demonstrated that there was no significant change in either size or signal characteristics of the pituitary fossa mass (Figure 1B). When bacterial meningitis is suspected, blood cultures should be immediately obtained and empirical antimicrobial and adjunctive dexamethasone therapy initiated without delay (Table 164-1). The diagnosis of bacterial meningitis is made by examination of the CSF (Table 164-2). The need to obtain neuroimaging studies (CT or MRI) prior to LP requires clinical judgment. In an immunocompetent patient with no known history of recent head trauma, a normal level of consciousness, and no evidence of papilledema or focal neurologic deficits, it is considered safe to perform LP without prior neuroimaging studies. If LP is delayed in order to obtain neuroimaging studies, empirical antibiotic therapy should be initiated after blood cultures are obtained. Antibiotic therapy initiated a few hours prior to LP will not significantly alter the CSF WBC count or glucose concentration, nor is it likely to prevent visualization of organisms by Gram’s stain or detection of bacterial nucleic acid by Angiography After a subarachnoid hemorrhage is confirmed, its origin needs to be determined. If the bleeding is likely to have originated from an aneurysm (as determined by the CT scan appearance), the choice is between cerebral angiography (injecting radiocontrast through a catheter to the brain arteries) and CT angiography (visualizing blood vessels with radiocontrast on a CT scan) to identify aneurysms. Catheter angiography also offers the possibility of coiling an aneurysm (see below). In emergency department patients complaining of acute-onset headache without significant risk factors for SAH, evidence suggests that CT scanning of the head followed by CT angiography can reliably exclude SAH without the need for a lumbar puncture. The risk of missing an aneurysmal bleed as the cause of SAH with this approach is less than 1%. Lumbar puncture Non-adenomatosus lesions of the pituitary represent a small part of the intrasellar processes and they have heterogeneous presentation. Making a precise diagnosis is of great importance, as it may lead to more efficient management. A 65-year-old man was admitted to the hospital because of headache and right cranial nerve III palsy. Basic laboratory work-up was normal whereas endocrinological assessment revealed hypopituitarism without diabetes insipidus. Plain radiography showed an enlarged sella and frontal and paranasal sinusitis. Computed tomography (CT) and magnetic resonance imaging (MRI) of the sella revealed an intrasellar lesion with extension to the sphenoid and cavernous sinuses as well as the suprasellar region, exerting pressure on the optic chiasm. On T1-weighted images the mass had a low-intensity signal with a smooth enhancing rim with bright signal. Given the presence of multiple sinusitis and imaging characteristics a pre-operative diagnosis of pituitary abscess was made. The patient was operated via transphenoidal route and purulent material was drained out. Cultures of the material were positive for Staphylococcus aureus. Antibiotics as well as cortisol replacement therapy were given. Three months later hypopituitarism persisted but there was significant improvement in the neurological findings. We report a case of an unusual presentation of a pituitary abscess. High index of suspicion, the presence of associated conditions such as pituitary tumors, meningitis or sinusitis, as well as diabetes insipidus and specific imaging features are the main diagnostic clues. Pre-operative diagnosis, which will lead to prompt antibiotic therapy and transphenoidal drainage, can decrease high mortality and morbidity associated with this disease. Computed tomography (CT) findings of chronic subdural hematomas are usually diagnostic, unless hematomas are isodense and bilateral. The authors report two cases of bilateral chronic subdural hematomas, in which CT scans on admission were both misdiagnosed as delayed subarachnoid hemorrhage (SAH). The first case was a 43-year-old woman who suffered from a sudden onset of headache and nausea. She had no past history of head injury. CT scans on admission did not clearly reveal the Sylvian fissures and the mesencephalic cistern, without any mass effects. A lumbar puncture demonstrated xanthochromic cerebrospinal fluid (CSF), which was considered to be responsible for her headache. Cerebral angiography performed on day 4 failed to demonstrate any cerebral vascular disorders. Follow-up CT scans on day 7 demonstrated a high density lesion in the left subdural space. Magnetic resonance images (MRIs) confirmed a diagnosis of bilateral chronic subdural hematomas. Removal of the hematomas cleared all signs and symptoms smoothly. The second case was a 44-year-old man who was referred from another hospital because of xanthochromic CSF found by lumbar puncture. He began to suffer headache and be subject to vomiting 6 weeks earlier and these symptoms were still present on the day of admission. CT scans did not clearly show the cerebral cisterns without mass effects. Because the second lumbar puncture showed xanthochromic CSF again, SAH from aneurysm was suspected. However, emergency cerebral angiography failed to demonstrate cerebral aneurysms. MRI performed two days later demonstrated bilateral chronic subdural hematomas. Following surgery, the patient improved immediately and was discharged from hospital without any complications. In both cases, a retrospective study of the angiograms revealed the evidence of bilateral avascular areas over the convexities in the venous phase. The reason why these subdural hematomas were missed at the time of angiography was due to too much attention being paid to the arterial phase in an effort aimed only at identifying cerebral aneurysms. There are no reports of chronic subdural hematoma which demonstrated sudden onset of headache associated with xanthochromic CSF. The introduction of new diagnostic and therapeutic techniques has changed the clinical attitude and consequences of brain abscesses (BA). To analyse clinical-radiological features, therapy, prognostic factors and evolution of BA in our institution. Retrospective study of all clinical records of patients diagnosed with BA from 1982 to 1992. Twenty-six patients with a mean age of 46.2 years were selected. The incidence was 2.6 patients/10,000 admission/year. Among 17 patients (65%) some extraprenchymatous infectious focus was found, which was located at the otorhynolaryngeal area in twelve patients. Mean duration of symptoms was 12.9 days, headache being the most common of them (69%). With CT 18 patients had a single mass, eight patients multiple masses, and 21 patients a ring enhancement when the contrast material was introduced. The causative organism was recovered from 15 patients. The organism recovered more frequently were Streptococcus spp, Enterobacteriaceae and Staphylococcus aureus. Twenty patients (77%) underwent surgical therapy, which consisted in ablation (12) or drainage (8). All patients received antibiotics for a mean of 37 days: the most frequent antibiotic combination used was penicillin+chloramphenicol. Six patients died (23%) and 7 remained with sequelae. Although statistically non-significant, the acute presentation was associated with a higher mortality rate, and the use of dexamethasone was associated with a lower mortality rate (p = 0.053 and 0.062, respectively). BA is associated with a high mortality rate and a high sequelae rate despite appropriate diagnostic and therapeutic measures. ORL infection is the most frequent predisposing factor. The use of dexamethasone is not associated with a higher mortality rate. One recommended diagnostic approach is as follows. If any urgent red flags are present such as visual loss, new seizures, new weakness, new confusion, further workup with imaging and possibly a lumbar puncture should be done (see red flags section for more details). If the headache is sudden onset (thunderclap headache), a computed tomography test to look for a brain bleed (subarachnoid hemorrhage) should be done. If the CT scan does not show a bleed, a lumbar puncture should be done to look for blood in the CSF, as the CT scan can be falsely negative and subarachnoid hemorrhages can be fatal. If there are signs of infection such as fever, rash, or stiff neck, a lumbar puncture to look for meningitis should be considered. If there is jaw claudication and scalp tenderness in an older person, a temporal artery biopsy to look for temporal arteritis should be performed and immediate treatment should be started. Neuroimaging The aim of the study is to assess outcome of surgical treatment of anterior cranial base meningiomas with special emphasis on the evaluation of visual skills after surgery. A series of 52 consecutive patients operated on for anterior cranial base meningioma in the last ten years is reported. 18 patients had decreased visual acuity on admission, 6 experienced blindness in one eye, and 4 were totally blind; defects of visual fields were found in 17 patients. Primary optic atrophy and secondary optic atrophy were noted in fundcoscopy in 20 and 2 patients, respectively. Papilloedema was found in 3 patients. Meningiomas were resected radically (Simpson I surgery) in 13 patients and in 34 patients Simpson II surgery with coagulation of the dural attachment was made; meningiomas were partially removed in 5 patients (Simpson IV surgery). In one patient dense hemiparesis occurred after the surgery, and 3 others presented adynamic syndrome, one of whom made a good recovery in follow-up examination. Two patients died: the first one due to a large brain oedema and the second one due to myocardial infarction after uncomplicated postoperative course. The postoperative course in the other 46 patients was uneventful with good outcome. Visual acuity improved in 15 cases and did not change in 10 patients; visual acuity further decreased in 3 patients. Visual recovery is significantly related to preoperative visual acuity values of no less than 0.3 D and to the presence of normal optic discs on fundoscopic examination additionally tumour size less than 3.5 cm favourably affects visual prognosis in meningiomas of tuberculum sellae. A 75-year-old lady presented with sudden severe headache and vomiting. Examination was normal, and CT and lumbar puncture not convincing for subarachnoid haemorrhage. Shortly thereafter, she developed painless diplopia. Examination confirmed right third cranial nerve palsy plus homonymous left inferior quadrantanopia. Urgent cerebral MRI with angiography was requested to assess for a possible posterior communicating artery aneurysm, but revealed an unsuspected pituitary mass. Pituitary adenoma with pituitary apoplexy was diagnosed. Pituitary apopolexy is a syndrome comprising sudden headache, meningism, visual and/or oculomotor deficits, with an intrasellar mass. It is commonly due to haemorrhage or infarction within a pituitary adenoma. Treatment includes prompt steroid administration, and potentially surgical decompression. While subarachnoid haemorrhage is an important, well-recognised cause of sudden severe headache, other aetiologies, including pituitary apoplexy, should be considered and sought.  Although reports of single cases of painful ophthalmoplegia (PO) are common, studies considering larger case series are lacking. Here, we aimed to determine the relative frequencies of ocular neuropathies, the causes, the usefulness of diagnostic procedures and the role of steroid treatment in PO. Between January 2006 and September 2012, 149 patients' charts who presented with diplopia in our emergency department were studied retrospectively. 34 of them met the inclusion criteria that included recent (≤3 days) symptom onset and a minimum of diagnostic work. 32% of single or combined ocular motor nerve palsies were of diabetic microvascular etiology and most of them were IIIrd or VIth nerve neuropathies. The most useful, in terms of sensitivity and specificity of diagnostic test in the acute setting was ESR, whereas MR-angiography and focused cavernous sinus imaging led to diagnosis in the post-acute phase. Pain response to steroids was non-specific, in contrast to palsy improvement after steroid administration which was indicative of Tolosa-Hunt syndrome or temporal arteritis. Although acute and subacute PO might be intuitively associated with Tolosa-Hunt syndrome or sinister pathology such as aneurysmal hemorrhage, our data show that these causes are far less common than diabetic microvascular palsies. Brain CT, MR-imaging of brainstem, cerebellum or hemispheres, CSF analysis and pain response to steroids are nonspecific and hence less helpful in order to arrive at a diagnosis. Instead, improved ocular motility after steroid treatment, as well as MR-angiography and cavernous sinus imaging appear more useful for this purpose. Investigations include blood tests (electrolytes, liver and kidney function, inflammatory markers and a complete blood count) and usually X-ray examination of the chest. The most important test in identifying or ruling out meningitis is analysis of the cerebrospinal fluid (fluid that envelops the brain and the spinal cord) through lumbar puncture (LP). However, if the patient is at risk for a cerebral mass lesion or elevated intracranial pressure (recent head injury, a known immune system problem, localizing neurological signs, or evidence on examination of a raised ICP), a lumbar puncture may be contraindicated because of the possibility of fatal brain herniation. In such cases, a CT or MRI scan is generally performed prior to the lumbar puncture to exclude this possibility. Otherwise, the CT or MRI should be performed after the LP, with MRI preferred over CT due to its superiority in demonstrating areas of cerebral edema, ischemia, and meningeal inflammation. This is a review of 1,000 consecutive cases of severe head injury admitted to our Neurosurgical Department between January 1973 and August 1976, before the advent of CT scanning. All patients were comatose following head injury (GCS less than or equal to 8) and were treated homogeneously by the same neurosurgical team by a protocol that included immediate resuscitation on arrival, diagnosis of intracranial lesions by angiography, early surgery when needed, mechanical ventilation, steroids, and mannitol. Extracranial lesions, even if preponderant, were treated by various specialists in the Neurosurgical Department, which for all practical purposes operated as an Emergency Department. Admission criteria were very broad with no preadmission selection. The overall mortality for this series was 45%. A little less than half the patients made good recoveries or remained moderately disabled (47%); 6% were severely disabled, and 2% survived in a persistent vegetative state. More than two-thirds of the patients were brought to our Neurosurgical Department after a short stay at a general hospital; 72% were admitted within 6 hours of injury; 71% were traffic accident victims; and 34% had significant associated extracranial injuries. Carotid angiography was performed in 78% of the patients and indicated the presence of an intracranial haematoma requiring surgery in 36% of the whole series. Mortality was significantly higher in operated than in unoperated patients (56% versus 39%); those treated surgically, however, were older, in worse clinical condition, and showed a higher incidence of acute subdural haematomas associated with brain contusion. Carotid angiography proved very effective in revealing the presence of an expansive lesion but failed to reflect the severity of brain damage, since the group with \"negative\" angiograms showed a high mortality (52%). Patients with a lucid interval had a higher percentage of surgical lesions than those with immediate coma (58% versus 26%); but fully 42% of them did not require surgery, and 25% had negative angiograms. From the prognostic point of view the clinical data elicited after initial resuscitation were highly predictive of the outcome: some individual neurological signs, such as mydriasis, posturing and eye movements, were not inferior to the GCS score in that respect. Age also proved a strong predictor, since elderly patients are more likely to have severe subdural and parenchymal lesions and their clinical severity is accordingly greater.(ABSTRACT TRUNCATED AT 400 WORDS) Subarachnoid bleed If an aneurysm ruptures, blood leaks into the space around the brain. This is called a subarachnoid hemorrhage. Onset is usually sudden without prodrome, classically presenting as a \"thunderclap headache\" worse than previous headaches. Symptoms of a subarachnoid hemorrhage differ depending on the site and size of the aneurysm. Symptoms of a ruptured aneurysm can include: a sudden severe headache that can last from several hours to days nausea and vomiting drowsiness, confusion and/or loss of consciousness visual abnormalities meningism dizziness Almost all aneurysms rupture at their apex. This leads to hemorrhage in the subarachnoid space and sometimes in brain parenchyma. Minor leakage from aneurysm may precede rupture, causing warning headaches. About 60% of patients die immediately after rupture. Larger aneurysms have a greater tendency to rupture, though most ruptured aneurysms are less than 10 mm in diameter. Lumbar puncture is the best way to prove bacterial meningitis. It should be performed without any delay if the diagnosis is suspected. Herniation is a rare complication of LP. CT is normal in most cases of purulent meningitis, including those complicated by a subsequent herniation; normal CT results does not mean that performing a LP is safe. Three main clinical features can help determine which patient is at risk of herniation and should have a CT before LP. This risk has to be determined rapidly in the emergency ward while assessing anamnestic data, localization signs or symptoms, and level of consciousness. Cranial imaging (mainly MRI) is useful in the course of bacterial meningitis. Patients who do not respond well to treatment or with atypical presentation, persistence of fever, or new neurological signs should undergo brain imaging; MRI and CT may identify subdural effusions, brain abscesses, empyemas, hydrocephaly, or brain parenchymal changes (cerebritis, infarction, hemorrhage). CT and MRI are useful to screen for an ENT cause of bacterial meningitis, and mandatory in case of pneumococcal meningitis. Numerous MRI sequences are useful to identify bacterial meningitis complications: SE T1 without and with gadolinium injection, SE T2, FLAIR, gradient-echo T2, diffusion weighted imaging, MR angiography. Diagnosis Diagnosis of a ruptured cerebral aneurysm is commonly made by finding signs of subarachnoid hemorrhage on a computed tomography (CT) scan. If the CT scan is negative but a ruptured aneurysm is still suspected based on clinical findings, a lumbar puncture can be performed to detect blood in the cerebrospinal fluid. Computed tomography angiography (CTA) is an alternative to traditional angiography and can be performed without the need for arterial catheterization. This test combines a regular CT scan with a contrast dye injected into a vein. Once the dye is injected into a vein, it travels to the cerebral arteries, and images are created using a CT scan. These images show exactly how blood flows into the brain arteries. Visual complications represent common deficits following surgical or endovascular repair of paraclinoid aneurysms. Different etiologies should be investigated to prevent devastating consequences. Herein we present a point-of-care evaluation to investigate sudden visual loss after coiling of paraclinoid aneurysms. A 20-year-old male was admitted for a sudden headache. Head computed tomography showed a subarachnoid hemorrhage and subsequent angiography revealed a 9-mm left supraclinoid aneurysm of the internal carotid artery treated with endovascular coil embolization. Thirty minutes after intensive care unit admission, the patient reported a left amaurosis. To exclude secondary etiologies, an immediate evaluation with point-of-care devices (color-doppler and B-mode ultrasound and automated pupillometry) was performed. Sonographic evaluations were negative for ischemic/thrombotic events and neurologic pupil index within physiological ranges provide evidence of third cranial nerve responsiveness. The symptomatology resolved progressively over 120 minutes with low-dose steroid therapy, 30° head-of-bed elevation, and blood pressure management. Visual deficits can occur after endovascular procedure and should be investigated. Suspected visual loss is a neurological emergency that deserves a prompt evaluation. Ultrasound and automated pupillometry have proved to be an effective, rapid, reliable, and non-invasive combination for a clinical decision-making strategy in the management of post-procedural acute visual deficits. Two cases of cerebral aneurysm combined with polycystic kidneys (PCKs) were presented. Case 1, a 24-year-old hypertensive male, was referred to our clinic owing to sudden onset of severe headache at August 20, 1982. Neurological findings on admission were stuporous, right vitreous hemorrhage (so-called Terson's syndrome), and hypertension. CT scans showed subarachnoid hemorrhage, and right MCA bifurcation aneurysm with marked vasospasms by cerebral angiography was revealed. Intentional delayed operation with V-P shunt was performed. He discharged with mild left upper limb paresis, and visual impairment on the right. Bilateral PCKs were confirmed by postoperative DIP and CT scan. Case 2, a 51-year-old female, who suddenly complained of severe headache, was referred to our department 3 days after subarachnoid hemorrhage. One year previously, she had been pointed out PCKs. Neurological findings on admission at February 29, 1980, were drowsy, left third cranial nerve palsy, and hypertension. Cerebral angiography showed multiple aneurysms (bilateral IC-PC &amp; A-com). Neck clipping (1-IC-PC &amp; A-com) and coating (r-IC-PC) were performed at the next day of admission, and V-P shunt operation was followed about 8 weeks after first operation. About 2 weeks after discharge, she suddenly became loss of consciousness and expired. Autopsy revealed intracerebral hemorrhage in left basal ganglia and thalamus. Both kidneys were PCKs of Potter type 3 and cysts of the liver were also noted. In young hypertensive patients with cerebral aneurysms, it should be in mind whether PCKs may be combined or not, and cerebral angiography in PCKs were reasonable to find out harbored cerebral aneurysm.(ABSTRACT TRUNCATED AT 250 WORDS) Pituitary abscesses are rare. The case reported here concerns a 28-year old African. Gradual development of diplopia over 6 months was the first clinical manifestation. Three months later this development had reached a more severe and infectious context, with complete right ophthalmoplegia, meningitis and coma (GCS = 9). CT scan showed an image in favour of a pituitary abscess with suprasellar extension, associated with thrombophlebitis of the cavernous sinus. An antibiotic therapy consisting of cefotaxime and metronidazole administered for 1 month, and netilmicin for 15 days succeeded in controlling the infectious syndrome. This resulted in cure of visual disorders, reduction in size of the CT scan image and reconstruction of the pituitary sella which had been destroyed. The diagnosis of pituitary abscess should be made when confronted with an infectious syndrome (unexplained fever, repeated meningitis). CT does not recognize the nature of the hypophyseal mass it shows: necrosis of a pituitary adenoma, giant aneurysm or craniopharyngioma may mimic local infection. Surgery confirms the diagnosis and is regarded as the best treatment. The patient's life is threatened when meningitis is present, and the functional prognosis is poor when recovery from visual disorders is compromised due to late diagnosis. In this paper a comparative analysis of the clinical course of the disease and therapeutic data in our patient is presented and compared with other reported cases. A case of acute spontaneous subdural hematoma associated with three aneurysms is reported. On March 12, 1984, a 47-year-old woman experienced the sudden onset of severe headache over the bilateral frontal region and vomiting. Three hours later, she was transferred to our hospital by ambulance car because of continuous headache and vomiting. She had no history of head trauma. She had been medicated hypertension for five years. On admission she suffered from headache and nausea. But there was no clinical sign in physical and neurological examinations. The meningeal irritation was not present, but lumbar puncture showed slightly pinky CSF with normal pressure. A plain computed tomographic scan showed a thin high density mass in the left temporal extra-axial region and the slight deviation of the midline structures to the right. Left carotid arteriogram showed an avascular region over the left cerebral convexity, an aneurysm of the left A2-A3 junction and a questionable aneurysm of the bifurcation of left middle cerebral artery. Right carotid arteriogram showed an aneurysm of the bifurcation of right middle cerebral artery. We diagnosed this case as an acute subdural hematoma by CT scan and arteriogram. We were perplexed preoperatively whether this bleeding was spontaneous or secondary to the rupture of aneurysm, and we could not deny the possibility of a ruptured aneurysm. On March 15, 1984, three days after onset, operation was performed. At operation, a small subdural hematoma was removed, and the underlying cortex was normal.(ABSTRACT TRUNCATED AT 250 WORDS)\nHere is the question:\nNEUROLOGY AND NEUROSURGERY: A 51-year-old woman comes to the emergency department with a sudden decrease in visual acuity, severe headache, nausea and vomiting. Hypotensive and afebrile. She presented right ophthalmoparesis due to involvement of the third cranial nerve. A cranial CT scan shows a mass in the hyperdense selar region with erosion of the anterior clinoid processes. What is the best approach to follow?\nHere are the potential choices:\n1. Suspect chemical meningitis derived from a ruptured epidermoid tumor and start immediate treatment with corticosteroids.\n2. It would indicate the performance of a cerebral angiography to rule out an aneurysm, since it is most likely that we are facing a case of subarachnoid hemorrhage and the mass that is evident in the CT is a thrombosed parasellar aneurysm.\n3. Admission to ICU and treatment of the shock suffered by the patient and once stabilized perform brain MRI for scheduled surgery.\n4. Urgent biochemistry and hemogram, initiation of high-dose corticosteroid therapy and urgent transsphenoidal surgery.\n5. Lumbar puncture to rule out bacterial meningitis after starting empirical antibiotherapy. Once the patient was stabilized, study of the selar mass.\nThe correct answer is: 4. Urgent biochemistry and hemogram, initiation of high-dose corticosteroid therapy and urgent transsphenoidal surgery."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Recent clinical advances in the field of gestational trophoblastic diseases are described. WHO modified its risk factor scoring system. This change was proposed to combine both the basic FIGO anatomic staging with the modified WHO risk factor scoring system. Patients who score as low-risk are treated with single agent chemotherapy, such as methotrexate (MTX), and patients refractory to MTX are treated with a combination chemotherapy, EMA/CO. Patients who score as high-risk are treated with EMA/CO, and patients refractory to the first line chemotherapy may be successfully treated with EP/EMA. Recent epidemiological data showed that women with complete hydatidiform moles could anticipate normal reproduction in the future. Studies found that pregnancies after treatment of molar pregnancy resulted in 69% full-term, live births; 8% premature deliveries; 1% ectopic pregnancies, and 0.5% stillbirths. First-trimester spontaneous abortions occurred in 17% of pregnancies, and major and minor malformations were detected in 0.4% of infants. Patients with hydatidiform mole were at increased risk of developing molar pregnancy in subsequent conceptions. After having one molar pregnancy, the risk of having molar disease in a future gestation was about 1%. The risk of persistent gestational trophoblastic tumors was increased by long-term oral contraceptive use before conception. In a large, multicenter, case-control study, the risk was shown to be increased in women who had ever used oral contraceptives, but was highest for women taking oral contraceptives during the cycle in which they became pregnant. Partial hydatidiform moles were never previously proven to transform into choriocarcinoma; however, a recent study with molecular techniques clearly showed that partial moles could transform into choriocarcinoma. All patients with suspected partial moles should be reviewed centrally and require hCG follow-up. In the past, it was seen as important not to get pregnant straight away after a GTD. Specialists recommended a waiting period of 6 months after the hCG levels become normal. Recently, this standpoint has been questioned. New medical data suggest that a significantly shorter waiting period after the hCG levels become normal is reasonable for approximately 97% of the patients with hydatidiform mole. Risk of a repeat GTD The risk of a repeat GTD is approximately 1 in 100, compared with approximately 1 in 1000 risk in the general population. Especially women whose hCG levels remain significantly elevated are at risk of developing a repeat GTD. Persistent trophoblastic disease The term «persistent trophoblastic disease» (PTD) is used when after treatment of a molar pregnancy, some molar tissue is left behind and again starts growing into a tumour. Although PTD can spread within the body like a malignant cancer, the overall cure rate is nearly 100%. Placental site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic disease. Little is known about its pathogenesis and natural history. This report describes two cases that arose in patients with documented complete hydatidiform moles and summarizes the antecedent prenatal histories of PSTTs based on a detailed Medline literature analysis. A 28-year-old, G(2)P(2) female had a live, 12-week gestation fetus and a coexisting molar pregnancy. Her hCG levels dropped promptly from 1.5 million to 23,273 IU/ml after termination, but rose shortly thereafter together with the onset of recurrent vaginal bleeding. Curettage revealed persistent mole. Persistently elevated hCG led to hysterectomy disclosing a fundal PSTT. The second case was that of a 48-year-old, G(2) woman who presented with symptoms of preeclampsia, hyperthyroidism, and elevated hCG. Curettage yielded a complete hydatidiform mole. Although the hCG level decreased for a short period, it soon increased despite treatment with methotrexate. A second curettage revealed a PSTT. A Medline literature analysis of PSTT, which consists almost entirely of individual cases and several small series, disclosed that PSTT is preceded in 61% of cases by normal term pregnancy, 12% molar pregnancy, 9% spontaneous abortion, 8% therapeutic abortion, and 3% with ectopic pregnancy, stillbirths or preterm delivery. No information is known in 7%. This report describes two additional cases of PSTT preceded by complete molar pregnancy. PSTT is a well recognized, but uncommon form of gestational trophoblastic disease. Although little is known about its pathogenesis, it is preceded not uncommonly by an abnormal pregnancy, including a molar pregnancy. Clinical data of molar pregnancies found in women undergoing elective abortion (group 1, n = 39) were compared to those of molar pregnancies in women who experienced spontaneous abortions (group 2, n = 157) and women in whom molar pregnancy was discovered before symptoms of spontaneous abortion were evident (group 3, n = 209). Group 1 women were younger and experienced uterine evacuation at an earlier stage of amenorrhea than groups 2 and 3. Group 3 had larger uteri at evacuation and longer intervals of positive tests for the beta-subunit of human chorionic gonadotropin during the postmolar phase as compared with groups 1 and 2. On the basis of available provincial data for the number of elective abortions, the estimated incidence of molar pregnancies in this population was 1:2,699. The presence of malignant gestational trophoblastic neoplasia was documented in a single patient in group 1. The incidence of malignant gestational trophoblastic neoplasia in this group was not significantly different from that in groups 2 and 3. Routine pathologic examination of the products of conception in women undergoing elective abortion coupled with routine assays of the beta-subunit of human chorionic gonadotropin when molar pregnancy is found can identify both noninvasive and invasive trophoblastic disease in these women. Complete hydatidiform molar pregnancies occur in approximately 1 of 1,000 conceptions. After uterine evacuation of the trophoblastic tissue, women are followed up with serial serum human chorionic gonadotropin (hCG) measurements. Patients are considered to have attained remission when their hCG level spontaneously declines to an undetectable level and remains there during a 6-month follow-up period. This standard effectively detects all disease recurrence; however, it is resource intensive, delays child bearing, and is subject to significant noncompliance. Our objective was to determine the risk of disease recurrence after hCG spontaneously declines to undetectable levels. We used a database from the New England Trophoblastic Disease Center to analyze hCG levels in patients with complete molar pregnancies. Among 1,029 women with complete molar pregnancy and complete data, 15% developed persistent gestational trophoblastic neoplasia. The rate of persistent neoplasm among those whose hCG level fell spontaneously to undetectable levels was 0.2% (2/876, 95% confidence interval 0-0.8%). No women developed persistent gestational trophoblastic neoplasia after their hCG level fell to undetectable levels using an assay with a sensitivity of 5 mIU/mL (n = 82, 95% confidence interval 0-4.5%). Based on our experience with women with complete hydatidiform molar pregnancies whose hCG values spontaneously fell to undetectable levels after molar evacuation, we conclude that the risk of recurrent neoplasm after hCG levels fall to less than 5 mIU/mL approaches zero. Although normal value of hCG (LH level) does not necessarily indicate eradication of viable trophoblast, its confirmation has been demonstrated as a clinically useful guide for the probable prevention of choriocarcinoma after hydatidiform mole by Takeuchi et al. Choriocarcinoma preceded by other pregnancies than hydatidiform mole which has the highest risk for choriocarcinoma has drawn more attention than before in connection with the decrease of postmolar choriocarcinoma. So that I have studied the regression rate of urinary gonadotropin (hCG) after the termination of various kinds of pregnancies. In 2,433 cases of induced abortion, 695 cases of spontaneous abortion, 1,724 cases of term delivery and 43 cases of hydatidiform mole, their urinary hCG were determined to the level of physiological range of LH. The rate of hCG regression was in the order of term delivery, spontaneous abortion, induced abortion and hydatidiform mole. The younger was the gestational age of trophoblast, the slower was the regression of hCG. At one month after the termination of pregnancy, 80.1%, 11%, 0.3%, 8% and 4.1%, and at two month 55.8%, 1.6%, 0.5%, 4% and 0.5% for hydatidiform mole, induced abortion of less than 12 week of gestation, spontaneous abortion of less than 12 week of gestation, spontaneous abortion of between 13 and 20 week of gestation respectively still showed abnormal hCG value. One percent of induced abortion at 5 month, 4% of spontaneous abortion at 3 month, 0.3% of term delivery at 4 month still maintained abnormal titer. No malignant sequelae in patients under the investigation have ever been observed in the follow up period between 3 and 8 years. A spontaneous fall in the radioimmunoassay for the beta subunit of hCG to less than 2 mIU/mL documents regression of hydatidiform mole following evacuation of a molar pregnancy. Continued negative hCG levels for the year after evacuation indicates the absence of risk for persistent gestational trophoblastic disease. This report describes an unusual case of recurrent nonmetastatic gestational trophoblastic disease 16 months after initial evacuation. A 29-year-old woman presented at 19 weeks' gestation with severe preeclampsia and vaginal bleeding. Pelvic ultrasonography demonstrated a molar pregnancy. Pathology following uterine evacuation confirmed a hydatidiform mole. Serial hCG levels fell progressively to less than 2 mIU/mL over the following 25 weeks. She remained compliant with oral contraceptive pills despite having no sexual activity. Sixteen months after uterine evacuation, recurrence of gestational trophoblastic disease was documented by a rising beta-hCG, negative pelvic ultrasound, normal liver function tests, and normal computed tomography of the head. Endometrial curettage showed no chorionic villi or molar tissue. She was treated with five courses of actinomycin D and has remained disease-free for the following 5 years. This late recurrence of gestational trophoblastic disease suggests that those with a molar pregnancy may benefit from surveillance beyond 1 year after uterine evacuation. Risk factors for molar pregnancy include extremes of age, ethnicity, and a prior history of a HM, suggesting a genetic etiology. The risk of a complete mole is higher for women older than 35 years and younger than 21 years and 7.5 times higher for women older than 40 years. The risk of repeat molar pregnancy in women with a history of molar pregnancy is approximately 1% which is 10 to 20 times the risk in the general population. [1] Interestingly, a history of prior spontaneous abortion has been reported to confer a 2- to 3-fold increased risk of molar pregnancy compared to women without a history of spontaneous abortion. [3] Following 2 molar gestations, the risk of having a third mole is > 10%. [7] It is also important to note that malignant transformation such as choriocarcinoma or placental-site trophoblastic tumor can occur following any pregnancy. Women diagnosed with complete hydatidiform molar pregnancy are at 15% to 28% risk of developing persistent gestational trophoblastic neoplasia (GTN) requiring further management with chemotherapy. Our objective was to develop human chorionic gonadotropin (hCG) criteria that establish a patient's risk of developing persistent GTN or achieving remission from their baseline risk within a few weeks of molar evacuation. We used a database from the New England Trophoblastic Disease Center to analyze hCG levels from 1,029 women with complete molar pregnancies. We conducted a retrospective cohort study using data from 1973 to 2001. Women whose hCG level declined below 50 mIU/mL during their follow-up were found to be at no more than 1.1% risk for developing persistent GTN, irrespective of when this level was reached. Women whose hCG levels was below 200 mIU/mL in the fourth week after evacuation (59.8% of all women), or below 100 mIU/mL in the sixth week after evacuation (65.8% of all women), had a risk of persistence below 9%. hCG levels above 2,000 mIU/mL in the fourth week after evacuation (13.3% of women) were associated with a 63.8% risk of developing persistent disease. These data may allow clinicians to evaluate the risk of persistence that their patients with complete molar pregnancy have based on early hCG results after molar evacuation. In the fourth week after molar evacuation, 59.8% of women may be counseled that their risk of developing persistent GTN is substantially reduced from their baseline, whereas 13.3% of women may be warned that their risk of developing persistent GTN is greater than 50%. II-2. The association between spontaneous abortion and gestational trophoblastic disease (GTD) has been investigated in a study based on 93 women with 2 consecutive (repeated) spontaneous abortions and 82 control subjects who delivered normal babies. Nine molar pregnancies were observed among 7 of the 93 cases of repeated abortion while no control reported previous GTD. This difference was statistically significant and was not explained by allowance for age and number of pregnancies between cases and controls (chi 2(1) = 4.20; P = 0.04). When the observed number (9) of hydatidiform mole in the 385 pregnancies of the women with repeated abortion was compared with the expected one (0.28) based on the regional frequency data, the estimated relative risk was 32.1 with a 95% confidence interval from 13.9 to 63.3. The present findings confirm the association between GTD and spontaneous abortion and indicate that the risk is larger in women with repeated abortions. To approach the efficiency and feasibility of preserving the fertility for patients with placental site trophoblastic tumor (PSTT). Totally 2 086 cases of gestational trophoblastic neoplasm (GTN) patients registered in Peking Union Medical College Hospital between 1998 and 2013. Fifty-seven of them were PSTT patients, 40 cases of which suffered hysterectomy, the rest 17 PSTT patients who preserved their fertility were analyzed retrospectively. The computerized database of clinical and pathological reports was reviewed in this cohort. The clinical manifestation of PSTT was not specific compared to other types of GTN. The average age of the 17 patients was 29.5 years old (range 22-39 years). The most common antecedent pregnancy was term birth (8 cases), the others were spontaneous abortion in 4 case, artificial abortion in 3 cases and molar pregnancy in 2 cases. The baseline serum β-hCG was slightly elevated and 12 patients (12/15) were less than 1 000 U/L. In this cohort, nine of the patients were in stage I, while the other eight cases were in stage III . The patients suffered conservative surgery, including dilation and curettage of uterus in 7 cases, open abdomen uterine lesion excision in 4 cases, laparoscopic uterine lesion excision in 3 cases, hysteroscopic uterine lesion excision in 1 case, and pulmonary lobectomy in 2 cases. Two of the patients didn't received chemotherapy, while the other 15 cases suffered combination chemotherapy. Compared with 40 patients who suffered hysterectomy during the same interval, fertility preservation group did not result in poor outcomes or high risk of relapse rate. Six subsequent pregnancies happened after the therapy, two of them were during their second-trimester, while four patients had healthy babies by vaginal delivery in two and cesarean section in two. The scar of the uterus was fairly well during the cesarean sections. Reservation of fertility therapy could be considered in highly-selected patients for young women who strongly desired to preserve their fertility and with localized lesion. Exactitude follow-up after therapy should be recommended. Contraception should also be recommended for at least one year after the chemotherapy. Vaginal delivery could be an option for the future pregnancies. The use of a reliable contraception method is very important during the entire follow up period, as patients are strongly advised against pregnancy at that time. If a reliable contraception method is not used during the follow-up, it could be initially unclear to clinicians as to whether a rising hCG level is caused by the patient becoming pregnant again, or by the continued presence of GTD. In women who have a malignant form of GTD, hCG concentrations stay the same (plateau) or they rise. Persistent elevation of serum hCG levels after a non molar pregnancy (i.e., normal pregnancy [term pregnancy], or preterm pregnancy, or ectopic pregnancy [pregnancy taking place in the wrong place, usually in the fallopian tube], or abortion) always indicate persistent GTD (very frequently due to choriocarcinoma or placental site trophoblastic tumour), but this is not common, because treatment mostly is successful. Traditional epidemiologic data suggest that persistent gestational trophoblastic disease (pGTD), may follow, and be derived from, either molar pregnancy, non-molar term pregnancy or first-trimester non-molar miscarriage. We examined a database of cases of possible or probable hydatidiform moles and proven pGTD derived from the Regional Trophoblastic Disease Unit, Charing Cross Hospital, London. There were 424 cases (6%), in whom the initial registered diagnosis was that of PHM or CHM but central histopathological review diagnosed a definite non-molar hydropic abortion (HA). In eight of the 424 (2%), although the histology of the most recent index pregnancy was that of non-molar miscarriage, there was a previous history of pregnancy affected by hydatidiform mole; two of these developed subsequent pGTD. Of a further 86 cases referred for a histopathological opinion prior to registration which demonstrated definite non-molar HA, none developed pGTD (zero of 510 (0%, 95% CI 0-0.7%)). During the same period there were 352 cases with pGTD requiring chemotherapy. In 31 cases, the only known pregnancy was the preceding apparent non-molar HA. However, of these, there were only three cases in whom the preceding histological products of conception had been centrally reviewed and were suggestive of non-molar pregnancy. However, in all three of these cases, the specimens were inadequate for definite exclusion of molar pregnancy. In one case in whom no material was available for review, molecular genetic analysis using restriction fragment length polymorphisms was carried out, and the choriocarcinoma was genetically derived from a previous molar pregnancy rather than the preceding HA. There were therefore no cases identified on the database of the trophoblastic disease unit of pGTD requiring treatment in whom the trophoblastic tumour could be genetically proven to have arisen from the preceding first trimester non-molar HA. We suggest that the risk of pGTD developing from a histologically confirmed non-molar HA is less than 1 in 50,000 and that the majority of pGTD cases previously reported to have been caused by a non-molar miscarriage probably represent disease due to an unrecognised early molar pregnancy. In this scoring system, women with a score of 7 or greater are considered at high risk. It is very important for malignant forms of GTD to be discovered in time. In Western countries, women with molar pregnancies are followed carefully; for instance, in the UK, all women who have had a molar pregnancy are registered at the National Trophoblastic Screening Centre. There are efforts in this direction in the developing countries too, and there have been improvements in these countries in the early detection of choriocarcinoma, thereby significantly reducing the mortality rate also in developing countries. Becoming pregnant again Most women with GTD can become pregnant again and can have children again. The risk of a further molar pregnancy is low. More than 98% of women who become pregnant following a molar pregnancy will not have a further hydatidiform mole or be at increased risk of complications. However, the incidence of rare diseases (such as GTD) is difficult to measure, because epidemiologic data on rare diseases is limited. Not all cases will be reported, and some cases will not be recognised. In addition, in GTD, this is especially difficult, because one would need to know all gestational events in the total population. Yet, it seems very likely that the estimated number of births that occur at home or outside of a hospital has been inflated in some reports. Terminology Gestational trophoblastic disease (GTD) may also be called gestational trophoblastic tumour (GTT). Hydatidiform mole (one type of GTD) may also be called molar pregnancy. Persistent disease; persistent GTD: If there is any evidence of persistence of GTD, usually defined as persistent elevation of beta hCG (see «Diagnosis» below), the condition may also be referred to as gestational trophoblastic neoplasia (GTN). See also Trophoblastic neoplasms References External links The aim of this study was to explore the risk of pregnancy of patients who conceived within 1 year after successful chemotherapy for gestational trophoblastic tumor (GTT). From 1966 to 1996, 22 patients who conceived within 1 year after chemotherapy were followed up and analyzed retrospectively. Among 22 patients, 9 had term deliveries and 1 had a premature birth, 6 had induced abortion at the patient's request, and 6 had therapeutic abortion because of various indications such as repeated hydatidiform mole (1 case), intrauterine death (1 case), inevitable abortion (1 case), and threatened abortion (3 cases). The fetal loss rate was 27.1% (6/22). The incidence rate of gestational trophoblastic disease (GTD) was 9.1% (2/22). The incidence rate of GTT was 4.5% (1/22). The average interval between completion of chemotherapy and pregnancy was 10.25 months in the group of term pregnancies and 5.86 months in that of fetal loss (P &lt; 0.05), indicating that the longer the interval, the lesser the risk of GTD. The results suggest that contraception for 1 year is necessary in patients with GTT after successful chemotherapy. However, in the case of a patient who conceives within 1 year, it is not necessary to terminate pregnancy, but the pregnancy must be carefully watched. All five closely related tumours develop in the placenta. All five tumours arise from trophoblastic cells. The trophoblast is the membrane that forms the wall of the blastocyst in the early development of the fetus. In a normal pregnancy, trophoblastic cells aid the implantation of the fertilised egg into the uterine wall. But in GTD, they develop into tumour cells. Cause Two main risk factors increase the likelihood for the development of GTD: 1) The woman being under 20 years of age, or over 35 years of age, and 2) previous GTD. Although molar pregnancies affect women of all ages, women under 16 and over 45 years of age have an increased risk of developing a molar pregnancy.Being from Asia/of Asian ethnicity is an important risk factor. Hydatidiform moles are abnormal conceptions with excessive placental development. Conception takes place, but placental tissue grows very fast, rather than supporting the growth of a fetus. Management of GTN requires pathology review, treatment options and monitoring of hCG. Therefore, it can be treated with curettage, hysterectomy and single agent or multi agent chemotherapy. Although this group of diseases are highly susceptible to chemotherapy, prognosis depends on the type of GTN and whether the tumor has spread to other areas of the body. Cause and Risk factors The exact cause of gestational trophoblastic neoplasia (GTN) is unknown. GTN often arises after molar pregnancies but can also occur after any gestation including miscarriages and term pregnancies. Although risk factors may impact on the development of the tumor, most do not directly cause of disease. According to the some studies, the risk of complete molar pregnancy is highest in women over age 35 and younger than 20. The risk is even higher for women over age 45. Signs and Symptoms The symptoms of GTN will vary from person to person. People with the same disease may not have all the symptoms listed. To investigate the slope of linear regression of postevacuation serum hCG as an independent risk factor for postmolar gestational trophoblastic neoplasia (GTN). Multicenter retrospective cohort study. Academic referral health care centers. All subjects with confirmed hydatidiform mole and at least four measurements of β-hCG titer. None. Type and magnitude of the relationship between the slope of linear regression of β-hCG as a new risk factor and GTN using Bayesian logistic regression with penalized log-likelihood estimation. Among the high-risk and low-risk molar pregnancy cases, 11 (18.6%) and 19 cases (13.3%) had GTN, respectively. No significant relationship was found between the components of a high-risk pregnancy and GTN. The β-hCG return slope was higher in the spontaneous cure group. However, the initial level of this hormone in the first measurement was higher in the GTN group compared with in the spontaneous recovery group. The average time for diagnosing GTN in the high-risk molar pregnancy group was 2 weeks less than that of the low-risk molar pregnancy group. In addition to slope of linear regression of β-hCG (odds ratio [OR], 12.74, confidence interval [CI], 5.42-29.2), abortion history (OR, 2.53; 95% CI, 1.27-5.04) and large uterine height for gestational age (OR, 1.26; CI, 1.04-1.54) had the maximum effects on GTN outcome, respectively. The slope of linear regression of β-hCG was introduced as an independent risk factor, which could be used for clinical decision making based on records of β-hCG titer and subsequent prevention program. To estimate the incidence of gestational trophoblastic neoplasia following complete and partial molar pregnancy after reaching normal human chorionic gonadotropin (hCG) levels to guide evidence-based follow-up recommendations. MEDLINE, EMBASE, Web of Science, POPLINE, Cochrane, and ClinicalTrials.gov were searched from inception to November 2018, using the intersection of \"gestational trophoblastic disease,\" \"molar pregnancy,\" and \"human chorionic gonadotropin\" themes. Search results were screened to identify cohort studies of molar pregnancy reporting gestational trophoblastic neoplasia development, with at least 6 months of intended normal hCG follow-up. Two reviewers independently identified articles for inclusion. Data were extracted using a standardized form. For meta-analysis, cumulative incidence of gestational trophoblastic neoplasia, with CIs by the Agresti-Coull method, and pooled risk ratios (RRs) comparing complete and partial mole were calculated. Among the 19 eligible studies that reported adequate data for inclusion in the primary meta-analysis, we found low incidence of gestational trophoblastic neoplasia after normal hCG level following both complete mole (64/18,357, 0.35%, 95% CI 0.27-0.45%), and partial mole (5/14,864, 0.03%, 95% CI 0.01-0.08%). There was a significantly higher risk of gestational trophoblastic neoplasia after complete compared with partial molar pregnancy (RR 4.72, 95% CI 1.81-12.3, P=.002). Among gestational trophoblastic neoplasia cases after normal hCG level following complete mole, 89.6% occurred when the time from evacuation to normalization was 56 days or longer, and 60.7% were diagnosed beyond the commonly recommended 6-month surveillance interval. Sensitivity analyses, including those limiting to studies at low risk of bias, did not significantly affect results. We found an overall incidence of gestational trophoblastic neoplasia of 15.7% for complete mole (1,354/8,611, 95% CI 15.0-16.5%) and 3.95% for partial mole (221/5,593, 95% CI 3.47-4.50%). Gestational trophoblastic neoplasia development after normal hCG level following molar pregnancy is rare. Recommendations for frequency and duration of hCG follow-up can be minimized to lessen burden on patients and informed by the type of molar pregnancy and time interval from uterine evacuation to hCG normalization. PROSPERO, CRD42019116414. To study the clinical presentations of gestational trophoblastic neoplasia and its response to chemotherapy. This is a retrospective study of 28 women of gestational trophoblastic neoplasia evaluated over a period of 6 years from January 2004 to December 2009. Patients were evaluated on the basis of their age, number of deliveries, history of abortion or molar pregnancy, and the treatment received. All patients were scored on the basis of WHO scoring system. Patients with low risk (score &lt;/=6) received single agent chemotherapy with methotrexate or actinomycin D. Patients with high risk (score &gt;/=7) received multiple agent chemotherapy with EMACO regimen. After completion of chemotherapy patients were followed for a minimum of 2 years. The response to treatment was evaluated during follow-up by clinical examination, beta hCG levels and imaging as and when required. Out of 28 women only 27 could be evaluated, because 1 patient was lost to follow-up. Out of 27 patients, 18 patients (66.67%) achieved complete remission with the first-line chemotherapy and additional 25.92% (7/27) achieved complete remission with second line chemotherapy resulting in complete remission of 92.5% (25/27). Gestational trophoblastic neoplasia is curable if patient is properly evaluated and scored. It shows good response to chemotherapy.\nHere is the question:\nGYNECOLOGY AND OBSTETRICS: A 24-year-old woman, primigestation, suffers a spontaneous abortion at 7 weeks gestation. The anatomopathological study of the abortive remains indicates molar disease. We should inform you that:\nHere are the potential choices:\n1. The risk of a new molar gestation in a future pregnancy is 50%.\n2. You should not become pregnant until periodic controls and have spent one year with negative BHCG levels.\n3. Subsequent controls are not necessary if the evacuation of the trophoblastic tissue was complete.\n4. It is necessary to perform periodic controls since 40% of the cases will develop a gestational trophoblastic neoplasia.\nThe correct answer is: ",
        "gold_answer": "2 You should not become pregnant until periodic controls and have spent one year with negative BHCG levels.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Recent clinical advances in the field of gestational trophoblastic diseases are described. WHO modified its risk factor scoring system. This change was proposed to combine both the basic FIGO anatomic staging with the modified WHO risk factor scoring system. Patients who score as low-risk are treated with single agent chemotherapy, such as methotrexate (MTX), and patients refractory to MTX are treated with a combination chemotherapy, EMA/CO. Patients who score as high-risk are treated with EMA/CO, and patients refractory to the first line chemotherapy may be successfully treated with EP/EMA. Recent epidemiological data showed that women with complete hydatidiform moles could anticipate normal reproduction in the future. Studies found that pregnancies after treatment of molar pregnancy resulted in 69% full-term, live births; 8% premature deliveries; 1% ectopic pregnancies, and 0.5% stillbirths. First-trimester spontaneous abortions occurred in 17% of pregnancies, and major and minor malformations were detected in 0.4% of infants. Patients with hydatidiform mole were at increased risk of developing molar pregnancy in subsequent conceptions. After having one molar pregnancy, the risk of having molar disease in a future gestation was about 1%. The risk of persistent gestational trophoblastic tumors was increased by long-term oral contraceptive use before conception. In a large, multicenter, case-control study, the risk was shown to be increased in women who had ever used oral contraceptives, but was highest for women taking oral contraceptives during the cycle in which they became pregnant. Partial hydatidiform moles were never previously proven to transform into choriocarcinoma; however, a recent study with molecular techniques clearly showed that partial moles could transform into choriocarcinoma. All patients with suspected partial moles should be reviewed centrally and require hCG follow-up. In the past, it was seen as important not to get pregnant straight away after a GTD. Specialists recommended a waiting period of 6 months after the hCG levels become normal. Recently, this standpoint has been questioned. New medical data suggest that a significantly shorter waiting period after the hCG levels become normal is reasonable for approximately 97% of the patients with hydatidiform mole. Risk of a repeat GTD The risk of a repeat GTD is approximately 1 in 100, compared with approximately 1 in 1000 risk in the general population. Especially women whose hCG levels remain significantly elevated are at risk of developing a repeat GTD. Persistent trophoblastic disease The term «persistent trophoblastic disease» (PTD) is used when after treatment of a molar pregnancy, some molar tissue is left behind and again starts growing into a tumour. Although PTD can spread within the body like a malignant cancer, the overall cure rate is nearly 100%. Placental site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic disease. Little is known about its pathogenesis and natural history. This report describes two cases that arose in patients with documented complete hydatidiform moles and summarizes the antecedent prenatal histories of PSTTs based on a detailed Medline literature analysis. A 28-year-old, G(2)P(2) female had a live, 12-week gestation fetus and a coexisting molar pregnancy. Her hCG levels dropped promptly from 1.5 million to 23,273 IU/ml after termination, but rose shortly thereafter together with the onset of recurrent vaginal bleeding. Curettage revealed persistent mole. Persistently elevated hCG led to hysterectomy disclosing a fundal PSTT. The second case was that of a 48-year-old, G(2) woman who presented with symptoms of preeclampsia, hyperthyroidism, and elevated hCG. Curettage yielded a complete hydatidiform mole. Although the hCG level decreased for a short period, it soon increased despite treatment with methotrexate. A second curettage revealed a PSTT. A Medline literature analysis of PSTT, which consists almost entirely of individual cases and several small series, disclosed that PSTT is preceded in 61% of cases by normal term pregnancy, 12% molar pregnancy, 9% spontaneous abortion, 8% therapeutic abortion, and 3% with ectopic pregnancy, stillbirths or preterm delivery. No information is known in 7%. This report describes two additional cases of PSTT preceded by complete molar pregnancy. PSTT is a well recognized, but uncommon form of gestational trophoblastic disease. Although little is known about its pathogenesis, it is preceded not uncommonly by an abnormal pregnancy, including a molar pregnancy. Clinical data of molar pregnancies found in women undergoing elective abortion (group 1, n = 39) were compared to those of molar pregnancies in women who experienced spontaneous abortions (group 2, n = 157) and women in whom molar pregnancy was discovered before symptoms of spontaneous abortion were evident (group 3, n = 209). Group 1 women were younger and experienced uterine evacuation at an earlier stage of amenorrhea than groups 2 and 3. Group 3 had larger uteri at evacuation and longer intervals of positive tests for the beta-subunit of human chorionic gonadotropin during the postmolar phase as compared with groups 1 and 2. On the basis of available provincial data for the number of elective abortions, the estimated incidence of molar pregnancies in this population was 1:2,699. The presence of malignant gestational trophoblastic neoplasia was documented in a single patient in group 1. The incidence of malignant gestational trophoblastic neoplasia in this group was not significantly different from that in groups 2 and 3. Routine pathologic examination of the products of conception in women undergoing elective abortion coupled with routine assays of the beta-subunit of human chorionic gonadotropin when molar pregnancy is found can identify both noninvasive and invasive trophoblastic disease in these women. Complete hydatidiform molar pregnancies occur in approximately 1 of 1,000 conceptions. After uterine evacuation of the trophoblastic tissue, women are followed up with serial serum human chorionic gonadotropin (hCG) measurements. Patients are considered to have attained remission when their hCG level spontaneously declines to an undetectable level and remains there during a 6-month follow-up period. This standard effectively detects all disease recurrence; however, it is resource intensive, delays child bearing, and is subject to significant noncompliance. Our objective was to determine the risk of disease recurrence after hCG spontaneously declines to undetectable levels. We used a database from the New England Trophoblastic Disease Center to analyze hCG levels in patients with complete molar pregnancies. Among 1,029 women with complete molar pregnancy and complete data, 15% developed persistent gestational trophoblastic neoplasia. The rate of persistent neoplasm among those whose hCG level fell spontaneously to undetectable levels was 0.2% (2/876, 95% confidence interval 0-0.8%). No women developed persistent gestational trophoblastic neoplasia after their hCG level fell to undetectable levels using an assay with a sensitivity of 5 mIU/mL (n = 82, 95% confidence interval 0-4.5%). Based on our experience with women with complete hydatidiform molar pregnancies whose hCG values spontaneously fell to undetectable levels after molar evacuation, we conclude that the risk of recurrent neoplasm after hCG levels fall to less than 5 mIU/mL approaches zero. Although normal value of hCG (LH level) does not necessarily indicate eradication of viable trophoblast, its confirmation has been demonstrated as a clinically useful guide for the probable prevention of choriocarcinoma after hydatidiform mole by Takeuchi et al. Choriocarcinoma preceded by other pregnancies than hydatidiform mole which has the highest risk for choriocarcinoma has drawn more attention than before in connection with the decrease of postmolar choriocarcinoma. So that I have studied the regression rate of urinary gonadotropin (hCG) after the termination of various kinds of pregnancies. In 2,433 cases of induced abortion, 695 cases of spontaneous abortion, 1,724 cases of term delivery and 43 cases of hydatidiform mole, their urinary hCG were determined to the level of physiological range of LH. The rate of hCG regression was in the order of term delivery, spontaneous abortion, induced abortion and hydatidiform mole. The younger was the gestational age of trophoblast, the slower was the regression of hCG. At one month after the termination of pregnancy, 80.1%, 11%, 0.3%, 8% and 4.1%, and at two month 55.8%, 1.6%, 0.5%, 4% and 0.5% for hydatidiform mole, induced abortion of less than 12 week of gestation, spontaneous abortion of less than 12 week of gestation, spontaneous abortion of between 13 and 20 week of gestation respectively still showed abnormal hCG value. One percent of induced abortion at 5 month, 4% of spontaneous abortion at 3 month, 0.3% of term delivery at 4 month still maintained abnormal titer. No malignant sequelae in patients under the investigation have ever been observed in the follow up period between 3 and 8 years. A spontaneous fall in the radioimmunoassay for the beta subunit of hCG to less than 2 mIU/mL documents regression of hydatidiform mole following evacuation of a molar pregnancy. Continued negative hCG levels for the year after evacuation indicates the absence of risk for persistent gestational trophoblastic disease. This report describes an unusual case of recurrent nonmetastatic gestational trophoblastic disease 16 months after initial evacuation. A 29-year-old woman presented at 19 weeks' gestation with severe preeclampsia and vaginal bleeding. Pelvic ultrasonography demonstrated a molar pregnancy. Pathology following uterine evacuation confirmed a hydatidiform mole. Serial hCG levels fell progressively to less than 2 mIU/mL over the following 25 weeks. She remained compliant with oral contraceptive pills despite having no sexual activity. Sixteen months after uterine evacuation, recurrence of gestational trophoblastic disease was documented by a rising beta-hCG, negative pelvic ultrasound, normal liver function tests, and normal computed tomography of the head. Endometrial curettage showed no chorionic villi or molar tissue. She was treated with five courses of actinomycin D and has remained disease-free for the following 5 years. This late recurrence of gestational trophoblastic disease suggests that those with a molar pregnancy may benefit from surveillance beyond 1 year after uterine evacuation. Risk factors for molar pregnancy include extremes of age, ethnicity, and a prior history of a HM, suggesting a genetic etiology. The risk of a complete mole is higher for women older than 35 years and younger than 21 years and 7.5 times higher for women older than 40 years. The risk of repeat molar pregnancy in women with a history of molar pregnancy is approximately 1% which is 10 to 20 times the risk in the general population. [1] Interestingly, a history of prior spontaneous abortion has been reported to confer a 2- to 3-fold increased risk of molar pregnancy compared to women without a history of spontaneous abortion. [3] Following 2 molar gestations, the risk of having a third mole is > 10%. [7] It is also important to note that malignant transformation such as choriocarcinoma or placental-site trophoblastic tumor can occur following any pregnancy. Women diagnosed with complete hydatidiform molar pregnancy are at 15% to 28% risk of developing persistent gestational trophoblastic neoplasia (GTN) requiring further management with chemotherapy. Our objective was to develop human chorionic gonadotropin (hCG) criteria that establish a patient's risk of developing persistent GTN or achieving remission from their baseline risk within a few weeks of molar evacuation. We used a database from the New England Trophoblastic Disease Center to analyze hCG levels from 1,029 women with complete molar pregnancies. We conducted a retrospective cohort study using data from 1973 to 2001. Women whose hCG level declined below 50 mIU/mL during their follow-up were found to be at no more than 1.1% risk for developing persistent GTN, irrespective of when this level was reached. Women whose hCG levels was below 200 mIU/mL in the fourth week after evacuation (59.8% of all women), or below 100 mIU/mL in the sixth week after evacuation (65.8% of all women), had a risk of persistence below 9%. hCG levels above 2,000 mIU/mL in the fourth week after evacuation (13.3% of women) were associated with a 63.8% risk of developing persistent disease. These data may allow clinicians to evaluate the risk of persistence that their patients with complete molar pregnancy have based on early hCG results after molar evacuation. In the fourth week after molar evacuation, 59.8% of women may be counseled that their risk of developing persistent GTN is substantially reduced from their baseline, whereas 13.3% of women may be warned that their risk of developing persistent GTN is greater than 50%. II-2. The association between spontaneous abortion and gestational trophoblastic disease (GTD) has been investigated in a study based on 93 women with 2 consecutive (repeated) spontaneous abortions and 82 control subjects who delivered normal babies. Nine molar pregnancies were observed among 7 of the 93 cases of repeated abortion while no control reported previous GTD. This difference was statistically significant and was not explained by allowance for age and number of pregnancies between cases and controls (chi 2(1) = 4.20; P = 0.04). When the observed number (9) of hydatidiform mole in the 385 pregnancies of the women with repeated abortion was compared with the expected one (0.28) based on the regional frequency data, the estimated relative risk was 32.1 with a 95% confidence interval from 13.9 to 63.3. The present findings confirm the association between GTD and spontaneous abortion and indicate that the risk is larger in women with repeated abortions. To approach the efficiency and feasibility of preserving the fertility for patients with placental site trophoblastic tumor (PSTT). Totally 2 086 cases of gestational trophoblastic neoplasm (GTN) patients registered in Peking Union Medical College Hospital between 1998 and 2013. Fifty-seven of them were PSTT patients, 40 cases of which suffered hysterectomy, the rest 17 PSTT patients who preserved their fertility were analyzed retrospectively. The computerized database of clinical and pathological reports was reviewed in this cohort. The clinical manifestation of PSTT was not specific compared to other types of GTN. The average age of the 17 patients was 29.5 years old (range 22-39 years). The most common antecedent pregnancy was term birth (8 cases), the others were spontaneous abortion in 4 case, artificial abortion in 3 cases and molar pregnancy in 2 cases. The baseline serum β-hCG was slightly elevated and 12 patients (12/15) were less than 1 000 U/L. In this cohort, nine of the patients were in stage I, while the other eight cases were in stage III . The patients suffered conservative surgery, including dilation and curettage of uterus in 7 cases, open abdomen uterine lesion excision in 4 cases, laparoscopic uterine lesion excision in 3 cases, hysteroscopic uterine lesion excision in 1 case, and pulmonary lobectomy in 2 cases. Two of the patients didn't received chemotherapy, while the other 15 cases suffered combination chemotherapy. Compared with 40 patients who suffered hysterectomy during the same interval, fertility preservation group did not result in poor outcomes or high risk of relapse rate. Six subsequent pregnancies happened after the therapy, two of them were during their second-trimester, while four patients had healthy babies by vaginal delivery in two and cesarean section in two. The scar of the uterus was fairly well during the cesarean sections. Reservation of fertility therapy could be considered in highly-selected patients for young women who strongly desired to preserve their fertility and with localized lesion. Exactitude follow-up after therapy should be recommended. Contraception should also be recommended for at least one year after the chemotherapy. Vaginal delivery could be an option for the future pregnancies. The use of a reliable contraception method is very important during the entire follow up period, as patients are strongly advised against pregnancy at that time. If a reliable contraception method is not used during the follow-up, it could be initially unclear to clinicians as to whether a rising hCG level is caused by the patient becoming pregnant again, or by the continued presence of GTD. In women who have a malignant form of GTD, hCG concentrations stay the same (plateau) or they rise. Persistent elevation of serum hCG levels after a non molar pregnancy (i.e., normal pregnancy [term pregnancy], or preterm pregnancy, or ectopic pregnancy [pregnancy taking place in the wrong place, usually in the fallopian tube], or abortion) always indicate persistent GTD (very frequently due to choriocarcinoma or placental site trophoblastic tumour), but this is not common, because treatment mostly is successful. Traditional epidemiologic data suggest that persistent gestational trophoblastic disease (pGTD), may follow, and be derived from, either molar pregnancy, non-molar term pregnancy or first-trimester non-molar miscarriage. We examined a database of cases of possible or probable hydatidiform moles and proven pGTD derived from the Regional Trophoblastic Disease Unit, Charing Cross Hospital, London. There were 424 cases (6%), in whom the initial registered diagnosis was that of PHM or CHM but central histopathological review diagnosed a definite non-molar hydropic abortion (HA). In eight of the 424 (2%), although the histology of the most recent index pregnancy was that of non-molar miscarriage, there was a previous history of pregnancy affected by hydatidiform mole; two of these developed subsequent pGTD. Of a further 86 cases referred for a histopathological opinion prior to registration which demonstrated definite non-molar HA, none developed pGTD (zero of 510 (0%, 95% CI 0-0.7%)). During the same period there were 352 cases with pGTD requiring chemotherapy. In 31 cases, the only known pregnancy was the preceding apparent non-molar HA. However, of these, there were only three cases in whom the preceding histological products of conception had been centrally reviewed and were suggestive of non-molar pregnancy. However, in all three of these cases, the specimens were inadequate for definite exclusion of molar pregnancy. In one case in whom no material was available for review, molecular genetic analysis using restriction fragment length polymorphisms was carried out, and the choriocarcinoma was genetically derived from a previous molar pregnancy rather than the preceding HA. There were therefore no cases identified on the database of the trophoblastic disease unit of pGTD requiring treatment in whom the trophoblastic tumour could be genetically proven to have arisen from the preceding first trimester non-molar HA. We suggest that the risk of pGTD developing from a histologically confirmed non-molar HA is less than 1 in 50,000 and that the majority of pGTD cases previously reported to have been caused by a non-molar miscarriage probably represent disease due to an unrecognised early molar pregnancy. In this scoring system, women with a score of 7 or greater are considered at high risk. It is very important for malignant forms of GTD to be discovered in time. In Western countries, women with molar pregnancies are followed carefully; for instance, in the UK, all women who have had a molar pregnancy are registered at the National Trophoblastic Screening Centre. There are efforts in this direction in the developing countries too, and there have been improvements in these countries in the early detection of choriocarcinoma, thereby significantly reducing the mortality rate also in developing countries. Becoming pregnant again Most women with GTD can become pregnant again and can have children again. The risk of a further molar pregnancy is low. More than 98% of women who become pregnant following a molar pregnancy will not have a further hydatidiform mole or be at increased risk of complications. However, the incidence of rare diseases (such as GTD) is difficult to measure, because epidemiologic data on rare diseases is limited. Not all cases will be reported, and some cases will not be recognised. In addition, in GTD, this is especially difficult, because one would need to know all gestational events in the total population. Yet, it seems very likely that the estimated number of births that occur at home or outside of a hospital has been inflated in some reports. Terminology Gestational trophoblastic disease (GTD) may also be called gestational trophoblastic tumour (GTT). Hydatidiform mole (one type of GTD) may also be called molar pregnancy. Persistent disease; persistent GTD: If there is any evidence of persistence of GTD, usually defined as persistent elevation of beta hCG (see «Diagnosis» below), the condition may also be referred to as gestational trophoblastic neoplasia (GTN). See also Trophoblastic neoplasms References External links The aim of this study was to explore the risk of pregnancy of patients who conceived within 1 year after successful chemotherapy for gestational trophoblastic tumor (GTT). From 1966 to 1996, 22 patients who conceived within 1 year after chemotherapy were followed up and analyzed retrospectively. Among 22 patients, 9 had term deliveries and 1 had a premature birth, 6 had induced abortion at the patient's request, and 6 had therapeutic abortion because of various indications such as repeated hydatidiform mole (1 case), intrauterine death (1 case), inevitable abortion (1 case), and threatened abortion (3 cases). The fetal loss rate was 27.1% (6/22). The incidence rate of gestational trophoblastic disease (GTD) was 9.1% (2/22). The incidence rate of GTT was 4.5% (1/22). The average interval between completion of chemotherapy and pregnancy was 10.25 months in the group of term pregnancies and 5.86 months in that of fetal loss (P &lt; 0.05), indicating that the longer the interval, the lesser the risk of GTD. The results suggest that contraception for 1 year is necessary in patients with GTT after successful chemotherapy. However, in the case of a patient who conceives within 1 year, it is not necessary to terminate pregnancy, but the pregnancy must be carefully watched. All five closely related tumours develop in the placenta. All five tumours arise from trophoblastic cells. The trophoblast is the membrane that forms the wall of the blastocyst in the early development of the fetus. In a normal pregnancy, trophoblastic cells aid the implantation of the fertilised egg into the uterine wall. But in GTD, they develop into tumour cells. Cause Two main risk factors increase the likelihood for the development of GTD: 1) The woman being under 20 years of age, or over 35 years of age, and 2) previous GTD. Although molar pregnancies affect women of all ages, women under 16 and over 45 years of age have an increased risk of developing a molar pregnancy.Being from Asia/of Asian ethnicity is an important risk factor. Hydatidiform moles are abnormal conceptions with excessive placental development. Conception takes place, but placental tissue grows very fast, rather than supporting the growth of a fetus. Management of GTN requires pathology review, treatment options and monitoring of hCG. Therefore, it can be treated with curettage, hysterectomy and single agent or multi agent chemotherapy. Although this group of diseases are highly susceptible to chemotherapy, prognosis depends on the type of GTN and whether the tumor has spread to other areas of the body. Cause and Risk factors The exact cause of gestational trophoblastic neoplasia (GTN) is unknown. GTN often arises after molar pregnancies but can also occur after any gestation including miscarriages and term pregnancies. Although risk factors may impact on the development of the tumor, most do not directly cause of disease. According to the some studies, the risk of complete molar pregnancy is highest in women over age 35 and younger than 20. The risk is even higher for women over age 45. Signs and Symptoms The symptoms of GTN will vary from person to person. People with the same disease may not have all the symptoms listed. To investigate the slope of linear regression of postevacuation serum hCG as an independent risk factor for postmolar gestational trophoblastic neoplasia (GTN). Multicenter retrospective cohort study. Academic referral health care centers. All subjects with confirmed hydatidiform mole and at least four measurements of β-hCG titer. None. Type and magnitude of the relationship between the slope of linear regression of β-hCG as a new risk factor and GTN using Bayesian logistic regression with penalized log-likelihood estimation. Among the high-risk and low-risk molar pregnancy cases, 11 (18.6%) and 19 cases (13.3%) had GTN, respectively. No significant relationship was found between the components of a high-risk pregnancy and GTN. The β-hCG return slope was higher in the spontaneous cure group. However, the initial level of this hormone in the first measurement was higher in the GTN group compared with in the spontaneous recovery group. The average time for diagnosing GTN in the high-risk molar pregnancy group was 2 weeks less than that of the low-risk molar pregnancy group. In addition to slope of linear regression of β-hCG (odds ratio [OR], 12.74, confidence interval [CI], 5.42-29.2), abortion history (OR, 2.53; 95% CI, 1.27-5.04) and large uterine height for gestational age (OR, 1.26; CI, 1.04-1.54) had the maximum effects on GTN outcome, respectively. The slope of linear regression of β-hCG was introduced as an independent risk factor, which could be used for clinical decision making based on records of β-hCG titer and subsequent prevention program. To estimate the incidence of gestational trophoblastic neoplasia following complete and partial molar pregnancy after reaching normal human chorionic gonadotropin (hCG) levels to guide evidence-based follow-up recommendations. MEDLINE, EMBASE, Web of Science, POPLINE, Cochrane, and ClinicalTrials.gov were searched from inception to November 2018, using the intersection of \"gestational trophoblastic disease,\" \"molar pregnancy,\" and \"human chorionic gonadotropin\" themes. Search results were screened to identify cohort studies of molar pregnancy reporting gestational trophoblastic neoplasia development, with at least 6 months of intended normal hCG follow-up. Two reviewers independently identified articles for inclusion. Data were extracted using a standardized form. For meta-analysis, cumulative incidence of gestational trophoblastic neoplasia, with CIs by the Agresti-Coull method, and pooled risk ratios (RRs) comparing complete and partial mole were calculated. Among the 19 eligible studies that reported adequate data for inclusion in the primary meta-analysis, we found low incidence of gestational trophoblastic neoplasia after normal hCG level following both complete mole (64/18,357, 0.35%, 95% CI 0.27-0.45%), and partial mole (5/14,864, 0.03%, 95% CI 0.01-0.08%). There was a significantly higher risk of gestational trophoblastic neoplasia after complete compared with partial molar pregnancy (RR 4.72, 95% CI 1.81-12.3, P=.002). Among gestational trophoblastic neoplasia cases after normal hCG level following complete mole, 89.6% occurred when the time from evacuation to normalization was 56 days or longer, and 60.7% were diagnosed beyond the commonly recommended 6-month surveillance interval. Sensitivity analyses, including those limiting to studies at low risk of bias, did not significantly affect results. We found an overall incidence of gestational trophoblastic neoplasia of 15.7% for complete mole (1,354/8,611, 95% CI 15.0-16.5%) and 3.95% for partial mole (221/5,593, 95% CI 3.47-4.50%). Gestational trophoblastic neoplasia development after normal hCG level following molar pregnancy is rare. Recommendations for frequency and duration of hCG follow-up can be minimized to lessen burden on patients and informed by the type of molar pregnancy and time interval from uterine evacuation to hCG normalization. PROSPERO, CRD42019116414. To study the clinical presentations of gestational trophoblastic neoplasia and its response to chemotherapy. This is a retrospective study of 28 women of gestational trophoblastic neoplasia evaluated over a period of 6 years from January 2004 to December 2009. Patients were evaluated on the basis of their age, number of deliveries, history of abortion or molar pregnancy, and the treatment received. All patients were scored on the basis of WHO scoring system. Patients with low risk (score &lt;/=6) received single agent chemotherapy with methotrexate or actinomycin D. Patients with high risk (score &gt;/=7) received multiple agent chemotherapy with EMACO regimen. After completion of chemotherapy patients were followed for a minimum of 2 years. The response to treatment was evaluated during follow-up by clinical examination, beta hCG levels and imaging as and when required. Out of 28 women only 27 could be evaluated, because 1 patient was lost to follow-up. Out of 27 patients, 18 patients (66.67%) achieved complete remission with the first-line chemotherapy and additional 25.92% (7/27) achieved complete remission with second line chemotherapy resulting in complete remission of 92.5% (25/27). Gestational trophoblastic neoplasia is curable if patient is properly evaluated and scored. It shows good response to chemotherapy.\nHere is the question:\nGYNECOLOGY AND OBSTETRICS: A 24-year-old woman, primigestation, suffers a spontaneous abortion at 7 weeks gestation. The anatomopathological study of the abortive remains indicates molar disease. We should inform you that:\nHere are the potential choices:\n1. The risk of a new molar gestation in a future pregnancy is 50%.\n2. You should not become pregnant until periodic controls and have spent one year with negative BHCG levels.\n3. Subsequent controls are not necessary if the evacuation of the trophoblastic tissue was complete.\n4. It is necessary to perform periodic controls since 40% of the cases will develop a gestational trophoblastic neoplasia.\nThe correct answer is: 2. You should not become pregnant until periodic controls and have spent one year with negative BHCG levels."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Pregnancy does not appear to have a consistent effect on the frequency or severity of asthma. The most common cause of worsening asthma in pregnancy is likely to be noncompliance with medication. Emphasizing to the patient in advance that fetal well-being is dependent on maternal well-being may help prevent this.In general, well controlled asthma is not associated with a higher risk of adverse pregnancy outcomes. Essential to successful asthma management is patient education that helps to ensure effective medication use, avoidance of triggers, and prompt treatment. This education should include measurement of peak expiratory flow rate and a written asthma action plan. Most of the medications that are used to control asthma in the general population can be safely used in pregnant women. Inhaled beta-adrenoceptor agonists (beta-agonists), cromolyn sodium (sodium cromoglycate), and inhaled and systemic corticosteroids all appear to be very well tolerated by the fetus. Budesonide and beclomethasone should be considered as the preferred inhaled corticosteroids for the treatment of asthma in pregnancy. Use of the leukotriene receptor antagonists zafirlukast and montelukast in pregnancy is probably safe but should be limited to special circumstances, where they are viewed essential for asthma control. Zileuton should not be used in pregnancy.Acute asthma exacerbations in pregnant women should be treated in a similar manner to that in non-pregnant patients. Maternal blood glucose levels should be monitored periodically in pregnant women receiving systemic corticosteroids because of the deleterious effects of hyperglycemia upon embryos and fetuses. During pregnancy, maternal arterial oxygen saturations should be kept above 95% if possible for fetal well-being. Ambulatory oxygenation should be checked prior to discharge to ensure that women do not desaturate with their daily activities.Acute exacerbations of asthma during labor and delivery are rare. Dinoprost, ergometrine, and other ergot derivatives can cause severe bronchospasm, especially when used in combination with general anesthesia, and should be avoided in asthmatic patients. Pregnant women who have been treated with corticosteroids in the past year may require stress-dose corticosteroids during labor and delivery. Most asthma medications, including oral prednisone, are considered compatible with breast-feeding. Budesonide is the only inhaled corticosteroid to be given a category B pregnancy rating by the US Food and Drug Administration, based on observational data from the Swedish Medical Birth Registry. However, data from large randomized controlled trials are lacking. To compare pregnancy outcomes among patients with recent-onset mild-to-moderate persistent asthma receiving low-dose budesonide vs placebo. In a randomized, double-blind, placebo-controlled trial, 7241 patients aged 5 to 66 years with mild-to-moderate persistent asthma for less than 2 years and no previous regular corticosteroid therapy received once-daily budesonide or placebo via dry powder inhaler in addition to their usual asthma medication for 3 years. This trial was followed by a 2-year open-label treatment period. The daily dose of budesonide was 400 microg for adults. The study included 2473 females aged 15 to 50 years at randomization. Pregnancy was not an exclusion criterion (except for U.S. patients). Of 319 pregnancies reported, 313 were analyzed. Healthy children were delivered in 81% and 77% of all pregnancies in the budesonide and placebo groups, respectively. Of the 196 pregnancies reported by participants taking budesonide, 38 (19%) had adverse outcomes: 23 (12%) had miscarriages, 3 (2%) had congenital malformations, and 12 (6%) had other outcomes. Of the 117 pregnancies reported in the placebo group, 27 (23%) had adverse outcomes: 11 (9%) had miscarriages, 4 (3%) had congenital malformations, and 12 (10%) had other outcomes. Treatment with low-dose inhaled budesonide in females with mild-to-moderate persistent asthma does not seem to affect the outcome of pregnancy. The course of asthma during pregnancy may be affected by maternal physiological changes and triggers of asthma such as viral infections, exposure to allergens, and nonadherence with therapy. If asthma is uncontrolled, there are recognized harmful effects not only to the mother but also  to the fetus. However, with effective asthma control, most women have outcomes, at or near that of the general population. Many medications are considered appropriate for use in pregnancy including inhaled corticosteroids (ICSs) such as budesonide, beclomethasone dipropionate, and fluticasone  and the leukotriene receptor antagonists montelukast and zafirlukast. When ICSs or ICS/long-acting beta(2)-adrenergic agonist combinations are not effective during exacerbations of asthma, short courses of oral corticosteroids should be administered earlier rather than later. Spirometry  and flow volume loop tracings are useful measures of pulmonary function for gravidas. Results may be compared with nonpregnant reference values. Vocal cord dysfunction may be suspected when the inspiratory loop is truncated. The gravida does not reject the fetus because of lack of vascular  continuity, a trophoblast layer causing separation, and suppressive mechanisms at the placental interface. The secretion of IL-10 increases in pregnancy and is lower in women with recurrent spontaneous abortions. Only immunoglobulin G (IgG) subclasses are transported across the placenta, especially  IgG1, IgG3, and IgG4. Fetal B cells can produce endogenous IgE by 20 weeks of gestation. Asthma and rhinitis frequently complicate pregnancy. The course of asthma may be adversely altered by gestation, placing the mother and fetus at risk. Therefore, pregnant patients with persistent asthma require an aggressive asthma management plan that includes environmental control measures and the use of long-term controller medications. Inhaled corticosteroids (ICSs) are the preferred long-term controller medication for persistent asthma, based on efficacy. However, safety concerns regarding corticosteroids may cause physicians or patients to seek an alternate, less effective treatment during pregnancy. The Food and Drug Administration's pregnancy category ratings are based on animal and human safety data. Because ICSs were previously rated pregnancy category C (i.e., with human studies lacking and animal studies either lacking or positive for fetal risk), other asthma controllers, such as cromolyn and nedocromil, that carry a pregnancy category B rating (i.e., showing no evidence of fetal risk in humans or animal studies negative for fetal risk) appeared to be more desirable for use during pregnancy. One ICS, budesonide, was reclassified as pregnancy category B based on human data supporting its use during pregnancy. In moderate and severe persistent asthma, add-on therapy may be considered, including long-acting beta2-adrenergic agonists, leukotriene receptor antagonists, and theophylline. Because rhinitis may adversely affect quality of life and the course of asthma, recommendations for aggressive management also apply. Bronchial asthma is one of the most common medical problems in pregnancy, with prevalance around 4-7 %. Asthma clinical course is variable, with worsening of symptoms in one third of the cases. The most critical period occurs between the 24th and 36th week of gestation. Symptoms usually regress completely after delivery during the following three months and they are expected to recur, with the same pattern, in subsequent pregnancies. Asthma control during pregnancy depends on pregnant patient education and safe medication, preferably inhaled, that prevents crises. In chronic asthma, usually prescribed drugs (inhaled corticosteroids: beclometasone and budesonide) are effective and safe to the fetus. There are several drugs to be added to inhaled steroids -- beta agonists bronchodilators: short and long acting -- according to the severity of bronchial constriction and frequency of crises. Treatment of acute asthma should follow recommended guidelines, since uncontrolled asthma increases more the risk of pregnancy complications (low birth weight and premature delivery) than the eventual medication risks to pregnancy. Pregnancy Approximately one-third of asthmatic patients who are pregnant improve during the course of a pregnancy, one-third deteriorate, and one-third are unchanged. It is important to maintain good control of asthma because poor control may have adverse effects on fetal development. Compliance may be a problem because there is often concern about the effects of antiasthma medications on fetal development. The drugs that have been used for many years in asthma therapy have now been shown to be safe and without teratogenic potential. These drugs include SABA, ICS, and theophylline; there is less safety information about newer classes of drugs such as LABA, antileukotrienes, and anti-IgE. If an OCS is needed, it is better to use prednisone rather than prednisolone because it cannot be converted to the active prednisolone by the fetal liver, thus protecting the fetus from systemic effects of the corticosteroid. There is no contraindication to breast-feeding when patients are using these Omalizumab is a recombinant humanized anti-IgE monoclonal antibody approved in the US for moderate to severe persistent allergic asthma (severe persistent asthma in the European Union), uncontrolled despite treatment with inhaled corticosteroids and long-acting beta2 agonists. It reduces asthma exacerbations, symptoms, oral corticosteroid doses, and improves quality of life. Omalizumab may have an antiviral effect when used as a preventive therapy for fall exacerbations in children and teenagers. Two proof-of-concept studies have evaluated omalizumab in nonatopic asthma and showed that it is safe and possibly efficacious in some patients. Omalizumab has been successfully studied as add-on to specific immunotherapy in moderate allergic asthma. Its safety in pregnancy has been assessed in the EXPECT registry. Case series also report positive effects in cases of allergic bronchopulmonary aspergillosis, and in nasal disorders frequently associated with asthma. Last, omalizumab may have corticosteroid-sparing effect in a subset of patients with eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome). Recent studies argue in favor of positive effects of omalizumab beyond its current indications in asthma. Well-designed studies are needed in order to demonstrate the safety and efficacy of omalizumab in these possible novel indications. Leukotriene receptor antagonists (anti-leukotriene agents such as montelukast and zafirlukast) may be used in addition to inhaled corticosteroids, typically also in conjunction with a LABA. For adults or adolescents who have persistent asthma that is not controlled very well, the addition of anti-leukotriene agents along with daily inhaled corticosteriods improves lung function and reduces the risk of moderate and severe asthma exacerbations. Anti-leukotriene agents may be effective alone for adolescents and adults, however there is no clear research suggesting which people with asthma would benefit from anti-leukotriene receptor alone. In those under five years of age, anti-leukotriene agents were the preferred add-on therapy after inhaled corticosteroids. A 2013 Cochrane systematic review concluded that anti-leukotriene agents appear to be of little benefit when added to inhaled steroids for treating children. A similar class of drugs, 5-LOX inhibitors, may be used as an Mast cell stabilizers (such as cromolyn sodium) are safe alternatives to corticosteroids but not preferred because they have to be administered frequently. Oral Theophyllines are sometimes used for controlling chronic asthma, but their used is minimized because of their side effects. Omalizumab, a monoclonal Antibody Against IgE, is a novel way to lessen exacerbations by lessening the levels of circulating IgE that play a significant role at allergic asthma. Anticholinergic medications such as ipratropium bromide have not been shown to be beneficial for treating chronic asthma in children over 2 years old, but is not suggested for routine treatment of chronic asthma in adults. Allergic rhinitis is a frequent problem during pregnancy. In addition, physiological changes associated with pregnancy can affect the upper airways. Evidence-based guidelines on the management of allergic rhinitis have recently been published, the most recent being the Allergic Rhinitis and its Impact on Asthma (ARIA)--World Health Organization consensus. Many pregnant women experience allergic rhinitis and particular attention is required when prescribing drugs to these patients. Medication can be prescribed during pregnancy when the apparent benefit of the drug is greater than the apparent risk. Usually, there is at least one drug from each major class that can be safely utilised to control symptoms. All glucocorticosteroids are teratogenic in animals but, when the indication is clear (for diseases possibly associated, such as severe asthma exacerbation), the benefit of the drug is far greater than the risk. Inhaled glucocorticosteroids (e.g. beclomethasone or budesonide) have not been incriminated as teratogens in humans and are used by pregnant women who have asthma. A few histamine H(1)-receptor antagonists (H(1)-antihistamines) can safely be used as well. Most oral decongestants (except pseudoephedrine) are teratogenic in animals. There are no such data available for intra-nasal decongestants. Finally, pregnancy is not considered as a contraindication for the continuation of allergen specific immunotherapy. Corticosteroids are generally considered the most effective treatment available for long-term control. Inhaled forms are usually used except in the case of severe persistent disease, in which oral corticosteroids may be needed. Dosage depends on the severity of symptoms. High dosage and long term use might lead to the appearance of common adverse effects which are growth delay, adrenal suppression, and osteoporosis. Continuous (daily) use of an inhaled corticosteroid, rather than its intermitted use, seems to provide better results in controlling asthma exacerbations. Commonly used corticosteroids are budesonide, fluticasone, mometasone and ciclesonide. either because optimum doses of asthma medications do not work (called \"refractory\" asthma) or because individuals are either unable (e.g. inability to afford treatment, poor inhaler technique) or unwilling (e.g., wish to avoid side effects of corticosteroids) to take optimum doses of prescribed asthma medications (called \"difficult to treat\" asthma). In practice, it is not possible to distinguish \"refractory\" from \"difficult to treat\" categories for patients who have never taken optimum doses of asthma medications. A related issue is that the asthma efficacy trials upon which the pharmacological treatment guidelines are based have systematically excluded the majority of people with asthma. For example, asthma efficacy treatment trials always exclude otherwise eligible people who smoke, and smoking blunts the efficacy of inhaled corticosteroids, the mainstay of asthma control management. Common (≥1/100 to <1/10) side effects include candidiasis, headache, tremor, palpitations, throat irritation, coughing, and dysphonia. Pneumonia is a common side effect in people with COPD, and other, less common side effects have been documented. There were concerns that the LABA component increases the risk of death in children with asthma, however these concerns were removed in 2017. Therefore, this combination is only recommended in those who are not controlled on an inhaled steroid alone. There is tentative evidence that typical doses of inhaled steroids and LABAs are safe in pregnancy. Both formoterol and budesonide are excreted in breast-milk. Montelukast, sold under the brand name Singulair among others, is a medication used in the maintenance treatment of asthma. It is generally less preferred for this use than inhaled corticosteroids. It is not useful for acute asthma attacks. Other uses include allergic rhinitis and hives of long duration. For allergic rhinitis it is a second-line treatment. Common side effects include abdominal pain, cough, and headache. Severe side effects may include allergic reactions, such as anaphylaxis and eosinophilia. Use in pregnancy appears to be safe. Montelukast is in the leukotriene receptor antagonist family of medications. It works by blocking the action of leukotriene D4 in the lungs resulting in decreased inflammation and relaxation of smooth muscle. Salbutamol is the preferred reliever due to its high safety profile. Inhaled corticosteroids (ICS) are the preferred controller medications. It is safe to use ICS, theophylline, and montelukast during pregnancy. Prolonged use of systemic steroids has been associated with pregnancy-related complications, especially in the first trimester. But systemic steroids if indicated they should be used the same as in non-pregnancy (Evidence C). Research has suggested that management of asthma in pregnancy based on the fraction of exhaled nitric oxide (FENO) and symptoms significantly reduces asthma exacerbations. [9] In moderate-persistent asthma, a long-acting beta 2 agonist combined with an inhaled anti-inflammatory agent or inhaled corticosteroid is recommended for treatment. In severe asthma, oral corticosteroids and long-acting beta agonists are recommended. Inhaled glucocorticoids are relatively safe although there is a potential risk for endocrine and metabolic disturbances in fetuses. Sustained use of systemic steroids may increase the risk of congenital malformation, prematurity, neonatal insufficiency, low birth weight, preeclampsia, and gestational diabetes. [10] If anesthesia is indicated during labor, regional anesthesia is preferred. [11] [7] Medical uses Asthma Budesonide is given by metered-dose inhaler or nebulizer for maintenance and prophylactic treatment of asthma, including patients who require oral corticosteroids and those who may benefit from a systemic dose reduction. Inflammatory bowel disease Formulations of delayed-release budesonide are an effective treatment for mild-to-moderately active Crohn's disease involving the ileum and/or ascending colon. A Cochrane review found evidence for up to three months (but not longer) of maintenance of remission in Crohn's disease. Budesonide assists in the induction of remission in people with active ulcerative colitis. Budesonide is highly effective and recommended as the drug of choice in microscopic colitis, for induction and maintenance of remission, and for both the lymphocytic colitis and collagenous colitis forms. Allergic rhinitis Budesonide in the form of nasal sprays is a treatment for allergic rhinitis. The article presents case reports of 2 women who became pregnant during therapy with omalizumab. Both subjects suffered from very severe asthma and were treated chronically with all available medications including systemic steroids (first - 20 mg prednisolone/day, second - 40 mg prednisolone/day). Both were enrolled into treatment with omalizumab and started regular therapy in 2007. The course of asthma significantly improved in both cases (withdrawal of oral steroids or significant reduction of their dose, better asthma control). The first woman, 32-year-old, became pregnant in 2010 and gave birth in Oct 2010 - it was her 3(rd) pregnancy, and 3(rd) labor. The second woman, 31-year-old, also became pregnant in 2010 and gave birth in Jan 2011 - it was her 5(th) pregnancy and 2(nd) labor. Both had severe asthma exacerbations during previous pregnancies and labors, and decided to continue therapy with omalizumab. The first woman, besides omalizumab, was treated with high doses of inhaled corticosteroids (ICS) and long-acting β agonists (LABA) while the second one was treated with high doses of ICS, LABA and 2.5 mg to 5 mg prednisone/day. The pregnancies proceeded without asthma exacerbations. The first woman delivered a healthy girl (Apgar 9, weight 3200 g, length 56 cm) in the 40(th) week of pregnancy by caesarean section due to the narrow pelvis. The second one delivered a healthy boy (Apgar 9, weight 3800 g, length 56 cm) in week 40 by caesarean section due to the aggravating obstetrical history. In both cases, treatment with omalizumab did not affect pregnancies and newborns.  Allergic bronchial asthma can be treated with any of the following: inhaled short- and long-acting bronchodilators (anticholinergics) along with inhaled corticosteroids, leukotriene antagonists, use of disodium cromoglycate, and environmental control. Experimentally, a low dose of methotrexate or cyclosporin and omalizumab (a monoclonal anti-IgE antibody) has been used. Treatment of autoimmune disorders (e.g., SLE) include one or a combination of NSAIDs and hydroxychloroquine, azathioprine, methotrexate, mycophenolate, cyclophosphamide, low dose IL-2, intravenous immunoglobulins, and belimumab. Omalizumab is a monoclonal antibody that interacts with the binding site of the high-affinity IgE receptor on mast cells. It is an engineered, humanized recombinant immunoglobulin. Moderate to severe allergic bronchial asthma can improve with omalizumab. Delayed hypersensitivity reactions Treatment of type 4 HR involves the treatment of the eliciting cause. We describe the first report in Japan of a woman who received omalizumab during pregnancy and delivery. Her asthma was so severe that she had been taking systemic corticosteroids since 22 years old, but asthma was poorly controlled. She had been pregnant seven times before, but almost every time asthma control had worsened and spontaneous abortion resulted, so she had only one child. She confirmed that she was not intending to become pregnant, and initiated use of omalizumab in August 2009. However, pregnancy was identified after she had taken the drug 3 times. We explained the risks in detail, but the patient wanted to keep taking omalizumab, as her asthma control was improved and she thought she could continue the pregnancy. We therefore decided to continue with omalizumab therapy. In October, she caught a cold and experienced asthma exacerbation. Despite the risk, she decided to suspend omalizumab therapy after taking the drug 7 times, as she was not feeling any benefit from therapy. Threat of abortion was identified in February 2010, so a 544-g female baby was delivered at 26 weeks gestation by Cesarean section. The baby had to be hospitalized in the neonatal intensive care unit because of low birth weight, but she has been developing and growing without handicap. We report this case as the first known case of pregnancy and delivery for a woman receiving omalizumab in Japan. Omalizumab may be safe to use in pregnant women with difficult-to-control asthma. (1) Long-term therapy for severe asthma (stage 4) currently consists of a high-dose inhaled steroid plus a long-acting beta-2 agonist. (2) Omalizumab is a recombinant anti-IgE antibody marketed for the treatment of severe allergic asthma associated with high circulating IgE levels, as an adjunct to inadequate ongoing treatment. Omalizumab is administered subcutaneously every 2 to 4 weeks. (3) Omalizumab has been evaluated in many clinical trials but only one, a double-blind randomised placebo-controlled trial lasting 28 weeks and involving 419 patients, corresponded to the approved indications. Omalizumab adjunction to ongoing treatment prevented one emergency department admission for asthma every 2.5 years on average, but this trial provided weak evidence as it suffered from several biases. In particular, the two groups were not identical at baseline in terms of prior frequency of asthma exacerbations. These were more frequent in the omalizumab group. In addition, many analyses were retrospective, few events occurred, and the protocol was modified 4 times. (4) A combined analysis of this and 4 other trials involving slightly different patients suggests that omalizumab prevents one asthma emergency approximately every 3 patient-years. (5) During comparative trials, the main adverse effects were anaphylaxis and local injection site reactions. Omalizumab may increase the risk of parasitic infections. Cases of laryngeal oedema and angioedema have been reported. (6) The possibility of an increased risk of cancer is to be examined in a post-marketing cohort study. (7) Treatment can cost more than 1700 euros a month. (8) In practice, in view of the potentially severe adverse effects of omalizumab, the evidence supporting its efficacy is too weak. It is better to carefully tailor existing treatments to the individual patient. We report a case of a pregnant woman with severe asthma that was not controlled with ordinary medications but was effectively treated by inhalational lidocaine treatment. The case was a 27-year-old woman who had been repeatedly hospitalized due to acute asthma since her infancy. The patient had an episode of asthma attack caused by the use of aspirin. The daily medication for controlling her asthma included 1.5mg betamethasone. In February, 2004, she was hospitalized because of asthma exacerbation during her 11th week of pregnancy. Despite intensive treatments including repetition of inhaled beta2-agonist and anti-cholinergic drugs, intravenous injection of betamethasone and theophylline, and a leukotriene receptor-antagonist, no obvious improvement in severe cough, wheeze, or hypoxemia was observed for more than 3 weeks. Then inhalational lidocaine was introduced according to the method described by Mayo Clinic, USA. Namely, following inhalation of beta2-agonist, 40 to 100mg lidocaine was given via an ultrasonic nebulizer 5 times a day. Interestingly, symptoms such as wheezing or cough and also her hypoxemia dramatically improved following this treatment and reduction of systemic corticosteroid became possible. Finally, she was delivered of a girl by caesarean section. Nebulized lidocaine treatment may be an useful option as supplementary treatment for refractory asthma especially in pregnant cases. Asthma is estimated to affect up to 4% of pregnancies. Management of asthma during pregnancy follows the same approach as in the general population. Aggressive treatment should be entertained because asthma under poor control during pregnancy can lead to poor outcomes for the mother and child. The foundations of management are environmental avoidance procedures, proper pharmacologic agents, and specific allergen immunotherapy. For pregnant women with persistent asthma, the use of inhaled cromolyn or inhaled budesonide should be considered as first-line agents. Short-acting beta-agonists can be used as needed in all asthma categories. Other agents such as salmeterol, leukotriene modifiers, newer inhaled corticosteroids, and omalizumab may be considered in women who showed a good response to these agents before pregnancy. A Combination of Mepolizumab and Omaluzimab injections for severe asthma. Patients with severe persistent asthma account for a large proportion of asthma morbidity and health care expenditures. In this case report we describe the use of a combination of omalizumab and mepolizumab in severe asthma with elevated IgE levels and eosinophilic phenotype. We are treating a 55 year old woman with severe persistent eosinophilic asthma and elevated IgE levels. Her regimen included salmeterol/fluticasone propionate inhaler 500/50 one puff twice a day, budesonide nebulizer twice a day, tiotropium respimat inhaler two puffs daily, montelukast 10 mg daily, Albuterol as needed, Azithromycin 250 mg three times a week, and also omalizumab injections. She was having recurrent asthma exacerbations requiring the use of oral corticosteroids. Due to frequent exacerbations, we referred her for Bronchial Thermoplasty. This procedure was denied by insurance and therefore the patient was started on 20 mg PO prednisone daily. Mepolizumab was added approximately 4 months after starting chronic PO prednisone. We were able to taper down the steroids and she is currently on 4 mg daily. Since we added the mepolizumab injections along with the omalizumab injections, we have been able to decrease the prednisone steadily and currently the patient is on 4 mg daily. The plan is to taper off the corticosteroids slowly as the clinical status allows. Combination of omalizumab and mepolizumab could become the gold standard for severe asthma patients that have elevated IgE levels and an eosinophilic phenotype. A Combination of Mepolizumab and Omaluzimab injections for severe asthma. A 26-year-old female with steroid dependent eosinophilic asthma and nasal polyps who had successfully been treated with mepolizumab for 17 consecutive months with complete steroid withdrawal and symptoms control, stopped biologic treatment due to pregnancy efforts. Mepolizumab discontinuation resulted in frequent exacerbations and daily symptoms despite high dose ICS/LABA and re-initiation of oral steroids. Mepolizumab was initiated again, followed by improvement of asthma control and gradual withdrawal of steroids within 2 months. The patient became pregnant during the fourth month of mepolizumab re-initiation. The patient presented two asthma exacerbations during pregnancy treated with short course (3 days) oral steroids and delivery was uneventful (female, Apgar 9, weight 2750 g, length 59 cm) in week 40 by caesarean section.\nHere is the question:\nGYNECOLOGY AND OBSTETRICS: A 27-year-old woman, 10 weeks pregnant, with persistent severe allergic asthma. She is currently adequately controlled with daily inhaled budesonide and rescue inhaled salbutamol on demand. She comes to your office concerned about the possible teratogenic effects of her anti-asthma medication. Which of the following would be the correct approach?\nHere are the potential choices:\n1. Given that asthma improves during pregnancy in most patients, the best thing for the patient and the fetus is to suspend anti-asthma treatment.\n2. Discontinue budesonide because it has been associated with an increased risk of fetal malformations and replace it with an oral anti-leukotriene (montelukast).\n3. Withdraw current treatment and replace it with oral prednisone at the lowest possible dose.\n4. Maintain the current treatment and reassure the patient about its side effects and the need for adequate asthma control during pregnancy.\n5. Replace budesonide with an anti-IgE monoclonal antibody (omalizumab) because of its greater safety in pregnancy since it is not a drug.\nThe correct answer is: ",
        "gold_answer": "4 Maintain the current treatment and reassure the patient about its side effects and the need for adequate asthma control during pregnancy.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Pregnancy does not appear to have a consistent effect on the frequency or severity of asthma. The most common cause of worsening asthma in pregnancy is likely to be noncompliance with medication. Emphasizing to the patient in advance that fetal well-being is dependent on maternal well-being may help prevent this.In general, well controlled asthma is not associated with a higher risk of adverse pregnancy outcomes. Essential to successful asthma management is patient education that helps to ensure effective medication use, avoidance of triggers, and prompt treatment. This education should include measurement of peak expiratory flow rate and a written asthma action plan. Most of the medications that are used to control asthma in the general population can be safely used in pregnant women. Inhaled beta-adrenoceptor agonists (beta-agonists), cromolyn sodium (sodium cromoglycate), and inhaled and systemic corticosteroids all appear to be very well tolerated by the fetus. Budesonide and beclomethasone should be considered as the preferred inhaled corticosteroids for the treatment of asthma in pregnancy. Use of the leukotriene receptor antagonists zafirlukast and montelukast in pregnancy is probably safe but should be limited to special circumstances, where they are viewed essential for asthma control. Zileuton should not be used in pregnancy.Acute asthma exacerbations in pregnant women should be treated in a similar manner to that in non-pregnant patients. Maternal blood glucose levels should be monitored periodically in pregnant women receiving systemic corticosteroids because of the deleterious effects of hyperglycemia upon embryos and fetuses. During pregnancy, maternal arterial oxygen saturations should be kept above 95% if possible for fetal well-being. Ambulatory oxygenation should be checked prior to discharge to ensure that women do not desaturate with their daily activities.Acute exacerbations of asthma during labor and delivery are rare. Dinoprost, ergometrine, and other ergot derivatives can cause severe bronchospasm, especially when used in combination with general anesthesia, and should be avoided in asthmatic patients. Pregnant women who have been treated with corticosteroids in the past year may require stress-dose corticosteroids during labor and delivery. Most asthma medications, including oral prednisone, are considered compatible with breast-feeding. Budesonide is the only inhaled corticosteroid to be given a category B pregnancy rating by the US Food and Drug Administration, based on observational data from the Swedish Medical Birth Registry. However, data from large randomized controlled trials are lacking. To compare pregnancy outcomes among patients with recent-onset mild-to-moderate persistent asthma receiving low-dose budesonide vs placebo. In a randomized, double-blind, placebo-controlled trial, 7241 patients aged 5 to 66 years with mild-to-moderate persistent asthma for less than 2 years and no previous regular corticosteroid therapy received once-daily budesonide or placebo via dry powder inhaler in addition to their usual asthma medication for 3 years. This trial was followed by a 2-year open-label treatment period. The daily dose of budesonide was 400 microg for adults. The study included 2473 females aged 15 to 50 years at randomization. Pregnancy was not an exclusion criterion (except for U.S. patients). Of 319 pregnancies reported, 313 were analyzed. Healthy children were delivered in 81% and 77% of all pregnancies in the budesonide and placebo groups, respectively. Of the 196 pregnancies reported by participants taking budesonide, 38 (19%) had adverse outcomes: 23 (12%) had miscarriages, 3 (2%) had congenital malformations, and 12 (6%) had other outcomes. Of the 117 pregnancies reported in the placebo group, 27 (23%) had adverse outcomes: 11 (9%) had miscarriages, 4 (3%) had congenital malformations, and 12 (10%) had other outcomes. Treatment with low-dose inhaled budesonide in females with mild-to-moderate persistent asthma does not seem to affect the outcome of pregnancy. The course of asthma during pregnancy may be affected by maternal physiological changes and triggers of asthma such as viral infections, exposure to allergens, and nonadherence with therapy. If asthma is uncontrolled, there are recognized harmful effects not only to the mother but also  to the fetus. However, with effective asthma control, most women have outcomes, at or near that of the general population. Many medications are considered appropriate for use in pregnancy including inhaled corticosteroids (ICSs) such as budesonide, beclomethasone dipropionate, and fluticasone  and the leukotriene receptor antagonists montelukast and zafirlukast. When ICSs or ICS/long-acting beta(2)-adrenergic agonist combinations are not effective during exacerbations of asthma, short courses of oral corticosteroids should be administered earlier rather than later. Spirometry  and flow volume loop tracings are useful measures of pulmonary function for gravidas. Results may be compared with nonpregnant reference values. Vocal cord dysfunction may be suspected when the inspiratory loop is truncated. The gravida does not reject the fetus because of lack of vascular  continuity, a trophoblast layer causing separation, and suppressive mechanisms at the placental interface. The secretion of IL-10 increases in pregnancy and is lower in women with recurrent spontaneous abortions. Only immunoglobulin G (IgG) subclasses are transported across the placenta, especially  IgG1, IgG3, and IgG4. Fetal B cells can produce endogenous IgE by 20 weeks of gestation. Asthma and rhinitis frequently complicate pregnancy. The course of asthma may be adversely altered by gestation, placing the mother and fetus at risk. Therefore, pregnant patients with persistent asthma require an aggressive asthma management plan that includes environmental control measures and the use of long-term controller medications. Inhaled corticosteroids (ICSs) are the preferred long-term controller medication for persistent asthma, based on efficacy. However, safety concerns regarding corticosteroids may cause physicians or patients to seek an alternate, less effective treatment during pregnancy. The Food and Drug Administration's pregnancy category ratings are based on animal and human safety data. Because ICSs were previously rated pregnancy category C (i.e., with human studies lacking and animal studies either lacking or positive for fetal risk), other asthma controllers, such as cromolyn and nedocromil, that carry a pregnancy category B rating (i.e., showing no evidence of fetal risk in humans or animal studies negative for fetal risk) appeared to be more desirable for use during pregnancy. One ICS, budesonide, was reclassified as pregnancy category B based on human data supporting its use during pregnancy. In moderate and severe persistent asthma, add-on therapy may be considered, including long-acting beta2-adrenergic agonists, leukotriene receptor antagonists, and theophylline. Because rhinitis may adversely affect quality of life and the course of asthma, recommendations for aggressive management also apply. Bronchial asthma is one of the most common medical problems in pregnancy, with prevalance around 4-7 %. Asthma clinical course is variable, with worsening of symptoms in one third of the cases. The most critical period occurs between the 24th and 36th week of gestation. Symptoms usually regress completely after delivery during the following three months and they are expected to recur, with the same pattern, in subsequent pregnancies. Asthma control during pregnancy depends on pregnant patient education and safe medication, preferably inhaled, that prevents crises. In chronic asthma, usually prescribed drugs (inhaled corticosteroids: beclometasone and budesonide) are effective and safe to the fetus. There are several drugs to be added to inhaled steroids -- beta agonists bronchodilators: short and long acting -- according to the severity of bronchial constriction and frequency of crises. Treatment of acute asthma should follow recommended guidelines, since uncontrolled asthma increases more the risk of pregnancy complications (low birth weight and premature delivery) than the eventual medication risks to pregnancy. Pregnancy Approximately one-third of asthmatic patients who are pregnant improve during the course of a pregnancy, one-third deteriorate, and one-third are unchanged. It is important to maintain good control of asthma because poor control may have adverse effects on fetal development. Compliance may be a problem because there is often concern about the effects of antiasthma medications on fetal development. The drugs that have been used for many years in asthma therapy have now been shown to be safe and without teratogenic potential. These drugs include SABA, ICS, and theophylline; there is less safety information about newer classes of drugs such as LABA, antileukotrienes, and anti-IgE. If an OCS is needed, it is better to use prednisone rather than prednisolone because it cannot be converted to the active prednisolone by the fetal liver, thus protecting the fetus from systemic effects of the corticosteroid. There is no contraindication to breast-feeding when patients are using these Omalizumab is a recombinant humanized anti-IgE monoclonal antibody approved in the US for moderate to severe persistent allergic asthma (severe persistent asthma in the European Union), uncontrolled despite treatment with inhaled corticosteroids and long-acting beta2 agonists. It reduces asthma exacerbations, symptoms, oral corticosteroid doses, and improves quality of life. Omalizumab may have an antiviral effect when used as a preventive therapy for fall exacerbations in children and teenagers. Two proof-of-concept studies have evaluated omalizumab in nonatopic asthma and showed that it is safe and possibly efficacious in some patients. Omalizumab has been successfully studied as add-on to specific immunotherapy in moderate allergic asthma. Its safety in pregnancy has been assessed in the EXPECT registry. Case series also report positive effects in cases of allergic bronchopulmonary aspergillosis, and in nasal disorders frequently associated with asthma. Last, omalizumab may have corticosteroid-sparing effect in a subset of patients with eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome). Recent studies argue in favor of positive effects of omalizumab beyond its current indications in asthma. Well-designed studies are needed in order to demonstrate the safety and efficacy of omalizumab in these possible novel indications. Leukotriene receptor antagonists (anti-leukotriene agents such as montelukast and zafirlukast) may be used in addition to inhaled corticosteroids, typically also in conjunction with a LABA. For adults or adolescents who have persistent asthma that is not controlled very well, the addition of anti-leukotriene agents along with daily inhaled corticosteriods improves lung function and reduces the risk of moderate and severe asthma exacerbations. Anti-leukotriene agents may be effective alone for adolescents and adults, however there is no clear research suggesting which people with asthma would benefit from anti-leukotriene receptor alone. In those under five years of age, anti-leukotriene agents were the preferred add-on therapy after inhaled corticosteroids. A 2013 Cochrane systematic review concluded that anti-leukotriene agents appear to be of little benefit when added to inhaled steroids for treating children. A similar class of drugs, 5-LOX inhibitors, may be used as an Mast cell stabilizers (such as cromolyn sodium) are safe alternatives to corticosteroids but not preferred because they have to be administered frequently. Oral Theophyllines are sometimes used for controlling chronic asthma, but their used is minimized because of their side effects. Omalizumab, a monoclonal Antibody Against IgE, is a novel way to lessen exacerbations by lessening the levels of circulating IgE that play a significant role at allergic asthma. Anticholinergic medications such as ipratropium bromide have not been shown to be beneficial for treating chronic asthma in children over 2 years old, but is not suggested for routine treatment of chronic asthma in adults. Allergic rhinitis is a frequent problem during pregnancy. In addition, physiological changes associated with pregnancy can affect the upper airways. Evidence-based guidelines on the management of allergic rhinitis have recently been published, the most recent being the Allergic Rhinitis and its Impact on Asthma (ARIA)--World Health Organization consensus. Many pregnant women experience allergic rhinitis and particular attention is required when prescribing drugs to these patients. Medication can be prescribed during pregnancy when the apparent benefit of the drug is greater than the apparent risk. Usually, there is at least one drug from each major class that can be safely utilised to control symptoms. All glucocorticosteroids are teratogenic in animals but, when the indication is clear (for diseases possibly associated, such as severe asthma exacerbation), the benefit of the drug is far greater than the risk. Inhaled glucocorticosteroids (e.g. beclomethasone or budesonide) have not been incriminated as teratogens in humans and are used by pregnant women who have asthma. A few histamine H(1)-receptor antagonists (H(1)-antihistamines) can safely be used as well. Most oral decongestants (except pseudoephedrine) are teratogenic in animals. There are no such data available for intra-nasal decongestants. Finally, pregnancy is not considered as a contraindication for the continuation of allergen specific immunotherapy. Corticosteroids are generally considered the most effective treatment available for long-term control. Inhaled forms are usually used except in the case of severe persistent disease, in which oral corticosteroids may be needed. Dosage depends on the severity of symptoms. High dosage and long term use might lead to the appearance of common adverse effects which are growth delay, adrenal suppression, and osteoporosis. Continuous (daily) use of an inhaled corticosteroid, rather than its intermitted use, seems to provide better results in controlling asthma exacerbations. Commonly used corticosteroids are budesonide, fluticasone, mometasone and ciclesonide. either because optimum doses of asthma medications do not work (called \"refractory\" asthma) or because individuals are either unable (e.g. inability to afford treatment, poor inhaler technique) or unwilling (e.g., wish to avoid side effects of corticosteroids) to take optimum doses of prescribed asthma medications (called \"difficult to treat\" asthma). In practice, it is not possible to distinguish \"refractory\" from \"difficult to treat\" categories for patients who have never taken optimum doses of asthma medications. A related issue is that the asthma efficacy trials upon which the pharmacological treatment guidelines are based have systematically excluded the majority of people with asthma. For example, asthma efficacy treatment trials always exclude otherwise eligible people who smoke, and smoking blunts the efficacy of inhaled corticosteroids, the mainstay of asthma control management. Common (≥1/100 to <1/10) side effects include candidiasis, headache, tremor, palpitations, throat irritation, coughing, and dysphonia. Pneumonia is a common side effect in people with COPD, and other, less common side effects have been documented. There were concerns that the LABA component increases the risk of death in children with asthma, however these concerns were removed in 2017. Therefore, this combination is only recommended in those who are not controlled on an inhaled steroid alone. There is tentative evidence that typical doses of inhaled steroids and LABAs are safe in pregnancy. Both formoterol and budesonide are excreted in breast-milk. Montelukast, sold under the brand name Singulair among others, is a medication used in the maintenance treatment of asthma. It is generally less preferred for this use than inhaled corticosteroids. It is not useful for acute asthma attacks. Other uses include allergic rhinitis and hives of long duration. For allergic rhinitis it is a second-line treatment. Common side effects include abdominal pain, cough, and headache. Severe side effects may include allergic reactions, such as anaphylaxis and eosinophilia. Use in pregnancy appears to be safe. Montelukast is in the leukotriene receptor antagonist family of medications. It works by blocking the action of leukotriene D4 in the lungs resulting in decreased inflammation and relaxation of smooth muscle. Salbutamol is the preferred reliever due to its high safety profile. Inhaled corticosteroids (ICS) are the preferred controller medications. It is safe to use ICS, theophylline, and montelukast during pregnancy. Prolonged use of systemic steroids has been associated with pregnancy-related complications, especially in the first trimester. But systemic steroids if indicated they should be used the same as in non-pregnancy (Evidence C). Research has suggested that management of asthma in pregnancy based on the fraction of exhaled nitric oxide (FENO) and symptoms significantly reduces asthma exacerbations. [9] In moderate-persistent asthma, a long-acting beta 2 agonist combined with an inhaled anti-inflammatory agent or inhaled corticosteroid is recommended for treatment. In severe asthma, oral corticosteroids and long-acting beta agonists are recommended. Inhaled glucocorticoids are relatively safe although there is a potential risk for endocrine and metabolic disturbances in fetuses. Sustained use of systemic steroids may increase the risk of congenital malformation, prematurity, neonatal insufficiency, low birth weight, preeclampsia, and gestational diabetes. [10] If anesthesia is indicated during labor, regional anesthesia is preferred. [11] [7] Medical uses Asthma Budesonide is given by metered-dose inhaler or nebulizer for maintenance and prophylactic treatment of asthma, including patients who require oral corticosteroids and those who may benefit from a systemic dose reduction. Inflammatory bowel disease Formulations of delayed-release budesonide are an effective treatment for mild-to-moderately active Crohn's disease involving the ileum and/or ascending colon. A Cochrane review found evidence for up to three months (but not longer) of maintenance of remission in Crohn's disease. Budesonide assists in the induction of remission in people with active ulcerative colitis. Budesonide is highly effective and recommended as the drug of choice in microscopic colitis, for induction and maintenance of remission, and for both the lymphocytic colitis and collagenous colitis forms. Allergic rhinitis Budesonide in the form of nasal sprays is a treatment for allergic rhinitis. The article presents case reports of 2 women who became pregnant during therapy with omalizumab. Both subjects suffered from very severe asthma and were treated chronically with all available medications including systemic steroids (first - 20 mg prednisolone/day, second - 40 mg prednisolone/day). Both were enrolled into treatment with omalizumab and started regular therapy in 2007. The course of asthma significantly improved in both cases (withdrawal of oral steroids or significant reduction of their dose, better asthma control). The first woman, 32-year-old, became pregnant in 2010 and gave birth in Oct 2010 - it was her 3(rd) pregnancy, and 3(rd) labor. The second woman, 31-year-old, also became pregnant in 2010 and gave birth in Jan 2011 - it was her 5(th) pregnancy and 2(nd) labor. Both had severe asthma exacerbations during previous pregnancies and labors, and decided to continue therapy with omalizumab. The first woman, besides omalizumab, was treated with high doses of inhaled corticosteroids (ICS) and long-acting β agonists (LABA) while the second one was treated with high doses of ICS, LABA and 2.5 mg to 5 mg prednisone/day. The pregnancies proceeded without asthma exacerbations. The first woman delivered a healthy girl (Apgar 9, weight 3200 g, length 56 cm) in the 40(th) week of pregnancy by caesarean section due to the narrow pelvis. The second one delivered a healthy boy (Apgar 9, weight 3800 g, length 56 cm) in week 40 by caesarean section due to the aggravating obstetrical history. In both cases, treatment with omalizumab did not affect pregnancies and newborns.  Allergic bronchial asthma can be treated with any of the following: inhaled short- and long-acting bronchodilators (anticholinergics) along with inhaled corticosteroids, leukotriene antagonists, use of disodium cromoglycate, and environmental control. Experimentally, a low dose of methotrexate or cyclosporin and omalizumab (a monoclonal anti-IgE antibody) has been used. Treatment of autoimmune disorders (e.g., SLE) include one or a combination of NSAIDs and hydroxychloroquine, azathioprine, methotrexate, mycophenolate, cyclophosphamide, low dose IL-2, intravenous immunoglobulins, and belimumab. Omalizumab is a monoclonal antibody that interacts with the binding site of the high-affinity IgE receptor on mast cells. It is an engineered, humanized recombinant immunoglobulin. Moderate to severe allergic bronchial asthma can improve with omalizumab. Delayed hypersensitivity reactions Treatment of type 4 HR involves the treatment of the eliciting cause. We describe the first report in Japan of a woman who received omalizumab during pregnancy and delivery. Her asthma was so severe that she had been taking systemic corticosteroids since 22 years old, but asthma was poorly controlled. She had been pregnant seven times before, but almost every time asthma control had worsened and spontaneous abortion resulted, so she had only one child. She confirmed that she was not intending to become pregnant, and initiated use of omalizumab in August 2009. However, pregnancy was identified after she had taken the drug 3 times. We explained the risks in detail, but the patient wanted to keep taking omalizumab, as her asthma control was improved and she thought she could continue the pregnancy. We therefore decided to continue with omalizumab therapy. In October, she caught a cold and experienced asthma exacerbation. Despite the risk, she decided to suspend omalizumab therapy after taking the drug 7 times, as she was not feeling any benefit from therapy. Threat of abortion was identified in February 2010, so a 544-g female baby was delivered at 26 weeks gestation by Cesarean section. The baby had to be hospitalized in the neonatal intensive care unit because of low birth weight, but she has been developing and growing without handicap. We report this case as the first known case of pregnancy and delivery for a woman receiving omalizumab in Japan. Omalizumab may be safe to use in pregnant women with difficult-to-control asthma. (1) Long-term therapy for severe asthma (stage 4) currently consists of a high-dose inhaled steroid plus a long-acting beta-2 agonist. (2) Omalizumab is a recombinant anti-IgE antibody marketed for the treatment of severe allergic asthma associated with high circulating IgE levels, as an adjunct to inadequate ongoing treatment. Omalizumab is administered subcutaneously every 2 to 4 weeks. (3) Omalizumab has been evaluated in many clinical trials but only one, a double-blind randomised placebo-controlled trial lasting 28 weeks and involving 419 patients, corresponded to the approved indications. Omalizumab adjunction to ongoing treatment prevented one emergency department admission for asthma every 2.5 years on average, but this trial provided weak evidence as it suffered from several biases. In particular, the two groups were not identical at baseline in terms of prior frequency of asthma exacerbations. These were more frequent in the omalizumab group. In addition, many analyses were retrospective, few events occurred, and the protocol was modified 4 times. (4) A combined analysis of this and 4 other trials involving slightly different patients suggests that omalizumab prevents one asthma emergency approximately every 3 patient-years. (5) During comparative trials, the main adverse effects were anaphylaxis and local injection site reactions. Omalizumab may increase the risk of parasitic infections. Cases of laryngeal oedema and angioedema have been reported. (6) The possibility of an increased risk of cancer is to be examined in a post-marketing cohort study. (7) Treatment can cost more than 1700 euros a month. (8) In practice, in view of the potentially severe adverse effects of omalizumab, the evidence supporting its efficacy is too weak. It is better to carefully tailor existing treatments to the individual patient. We report a case of a pregnant woman with severe asthma that was not controlled with ordinary medications but was effectively treated by inhalational lidocaine treatment. The case was a 27-year-old woman who had been repeatedly hospitalized due to acute asthma since her infancy. The patient had an episode of asthma attack caused by the use of aspirin. The daily medication for controlling her asthma included 1.5mg betamethasone. In February, 2004, she was hospitalized because of asthma exacerbation during her 11th week of pregnancy. Despite intensive treatments including repetition of inhaled beta2-agonist and anti-cholinergic drugs, intravenous injection of betamethasone and theophylline, and a leukotriene receptor-antagonist, no obvious improvement in severe cough, wheeze, or hypoxemia was observed for more than 3 weeks. Then inhalational lidocaine was introduced according to the method described by Mayo Clinic, USA. Namely, following inhalation of beta2-agonist, 40 to 100mg lidocaine was given via an ultrasonic nebulizer 5 times a day. Interestingly, symptoms such as wheezing or cough and also her hypoxemia dramatically improved following this treatment and reduction of systemic corticosteroid became possible. Finally, she was delivered of a girl by caesarean section. Nebulized lidocaine treatment may be an useful option as supplementary treatment for refractory asthma especially in pregnant cases. Asthma is estimated to affect up to 4% of pregnancies. Management of asthma during pregnancy follows the same approach as in the general population. Aggressive treatment should be entertained because asthma under poor control during pregnancy can lead to poor outcomes for the mother and child. The foundations of management are environmental avoidance procedures, proper pharmacologic agents, and specific allergen immunotherapy. For pregnant women with persistent asthma, the use of inhaled cromolyn or inhaled budesonide should be considered as first-line agents. Short-acting beta-agonists can be used as needed in all asthma categories. Other agents such as salmeterol, leukotriene modifiers, newer inhaled corticosteroids, and omalizumab may be considered in women who showed a good response to these agents before pregnancy. A Combination of Mepolizumab and Omaluzimab injections for severe asthma. Patients with severe persistent asthma account for a large proportion of asthma morbidity and health care expenditures. In this case report we describe the use of a combination of omalizumab and mepolizumab in severe asthma with elevated IgE levels and eosinophilic phenotype. We are treating a 55 year old woman with severe persistent eosinophilic asthma and elevated IgE levels. Her regimen included salmeterol/fluticasone propionate inhaler 500/50 one puff twice a day, budesonide nebulizer twice a day, tiotropium respimat inhaler two puffs daily, montelukast 10 mg daily, Albuterol as needed, Azithromycin 250 mg three times a week, and also omalizumab injections. She was having recurrent asthma exacerbations requiring the use of oral corticosteroids. Due to frequent exacerbations, we referred her for Bronchial Thermoplasty. This procedure was denied by insurance and therefore the patient was started on 20 mg PO prednisone daily. Mepolizumab was added approximately 4 months after starting chronic PO prednisone. We were able to taper down the steroids and she is currently on 4 mg daily. Since we added the mepolizumab injections along with the omalizumab injections, we have been able to decrease the prednisone steadily and currently the patient is on 4 mg daily. The plan is to taper off the corticosteroids slowly as the clinical status allows. Combination of omalizumab and mepolizumab could become the gold standard for severe asthma patients that have elevated IgE levels and an eosinophilic phenotype. A Combination of Mepolizumab and Omaluzimab injections for severe asthma. A 26-year-old female with steroid dependent eosinophilic asthma and nasal polyps who had successfully been treated with mepolizumab for 17 consecutive months with complete steroid withdrawal and symptoms control, stopped biologic treatment due to pregnancy efforts. Mepolizumab discontinuation resulted in frequent exacerbations and daily symptoms despite high dose ICS/LABA and re-initiation of oral steroids. Mepolizumab was initiated again, followed by improvement of asthma control and gradual withdrawal of steroids within 2 months. The patient became pregnant during the fourth month of mepolizumab re-initiation. The patient presented two asthma exacerbations during pregnancy treated with short course (3 days) oral steroids and delivery was uneventful (female, Apgar 9, weight 2750 g, length 59 cm) in week 40 by caesarean section.\nHere is the question:\nGYNECOLOGY AND OBSTETRICS: A 27-year-old woman, 10 weeks pregnant, with persistent severe allergic asthma. She is currently adequately controlled with daily inhaled budesonide and rescue inhaled salbutamol on demand. She comes to your office concerned about the possible teratogenic effects of her anti-asthma medication. Which of the following would be the correct approach?\nHere are the potential choices:\n1. Given that asthma improves during pregnancy in most patients, the best thing for the patient and the fetus is to suspend anti-asthma treatment.\n2. Discontinue budesonide because it has been associated with an increased risk of fetal malformations and replace it with an oral anti-leukotriene (montelukast).\n3. Withdraw current treatment and replace it with oral prednisone at the lowest possible dose.\n4. Maintain the current treatment and reassure the patient about its side effects and the need for adequate asthma control during pregnancy.\n5. Replace budesonide with an anti-IgE monoclonal antibody (omalizumab) because of its greater safety in pregnancy since it is not a drug.\nThe correct answer is: 4. Maintain the current treatment and reassure the patient about its side effects and the need for adequate asthma control during pregnancy."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Thyroglobulin (Tg) assay of material from fine-needle aspiration of neck masses can help distinguish neck masses of thyroid origin from other masses. We describe its utility in a patient with an unusual constellation of findings, a neck lump identified as a lymph node metastasis from a contralateral occult papillary thyroid carcinoma (PTC). A 56-year-old woman was referred to our center for evaluation of a 15-mm right lateral cervical neck mass which was strongly hypoechoic, not homogenous and contained several microcalcifications. There was no family history of thyroid disease, the patient was euthyroid and was not taking medications for thyroid disorders. On physical examination the thyroid was slightly enlarged and was normal on ultrasound except for a 1 x 3 mm hypoechoic nodule in the middle of the left lobe. Ultrasound-guided fine-needle aspiration biopsy (FNAB) of the right lateral cervical mass was performed with the Tg concentration of the FNAB washout liquid being &gt;300 ng/mL and the cytology showing lymphoid elements mixed with polymorphous epithelial cells with atypical nuclei, suggesting lymph node metastasis from a cancer of epithelial origin. A lymph node metastasis from a papillary thyroid microcarcinoma (micro-PTC) was the presumptive diagnosis with the preoperative staging being Tx N1b. The patient underwent total thyroidectomy and bilateral lymph node dissection. At pathology, the right cervical mass was confirmed as lymph node metastasis of a PTC, and a unifocal micro-PTC was found in the middle left lobe. The patient was readmitted for a therapeutic (131)I dose (4810 MBq). At the time of (131)I administration, the whole-body scan showed only minimal thyroid bed uptake and serum Tg was &lt;1 ng/mL. She was maintained on l-thyroxine treatment (150 microg/d). Five year later she did not have evidence of recurrent or residual PTC. We describe the first case of contralateral lymph node metastasis from a unifocal micro-PTC identified by the detection of high Tg levels in the wash-out liquid of FNAB. We report a case in which the appearance of a progressively rising titer of thyroglobulin (Tg) antibodies was the most sensitive marker of papillary thyroid cancer relapse at loco-regional lymph nodes. The patient, a 60-year-old man, had been treated with total thyroidectomy plus lymphadenectomy and radioiodine ablation for a 1-cm papillary thyroid cancer. Twelve years after surgery, while undergoing levothyroxine (LT4) therapy, Tg antibodies were first detected and progressively rose from 99 to 1,697 U/mL in 18 months, while serum Tg remained undetectable. Both neck ultrasonography and 131I whole-body scan (WBS) were unremarkable. Enlarged lymph nodes became palpable at the left laterocervical region only 2 years after the first appearance of Tg antibodies and were surgically removed after cancer relapse was confirmed by fine-needle aspiration cytology. This case emphasizes the possibility that in thyroid cancer patients who have undergone total thyroidectomy, the appearance of Tg antibodies may indicate metastatic lymph nodes even when serum Tg is undetectable and WBS negative. A neck mass or neck lump is an ambiguous mass found in the neck area. There are many different possible causes, including congenital conditions like branchial anomalies and thyroglossal duct cysts. Workup Workup of a neck mass includes a medical history and a physical examination, where important characteristics are location, size, shape, consistency, tenderness, mobility, and color. When this is not conclusive, further workup includes: Blood tests Medical imaging: Contrast CT is generally the initial study of choice for adults. Medical ultrasound of the neck is useful in children because it avoids the radiation dose of CT. In some cases, fine needle aspiration may assist in the diagnosis. See also Cervical lymphadenopathy References External links Human head and neck Malignancy Only a small percentage of lumps in the neck are malignant (around 4 – 6.5%), and most thyroid nodules are benign colloid nodules. There are many factors to consider when diagnosing a malignant lump. Trouble swallowing or speaking, swollen cervical lymph nodes or a firm, immobile nodule are more indicative of malignancy, whereas a family history of autoimmune disease or goiter, thyroid hormonal dysfunction or a soft, painful nodule are more indicative of benignancy. The prevalence of cancer is higher in males, patients under 20 years old or over 70 years old, and patients with a history of head and neck irradiation or a family history of thyroid cancer. Solitary thyroid nodule A 73-year-old African American female presented to our clinic with painful lower extremity lesions of 2 weeks duration. She was in her usual state of health until 3 months prior to presentation when she reported symptoms of fatigue and weakness. She also noticed an enlarging mass on the left side of her neck. She denied fevers, chills, night sweats or cough. Her symptoms were unresponsive to a course of oral dicloxacillin. The neck mass enlarged over 8 weeks and she was referred to our institution for evaluation. CT scan of the neck showed an enlarged lymph node. Ten days prior to her presentation in dermatology, a fine needle aspirate of the enlarging lymph node revealed necrotizing granulomas. Tissue was sent for routine mycobacterial and fungal cultures. Routine blood work, chest radiograph, and a tuberculin skin test were also performed. At the time of her dermatology visit she described the development of multiple new painful, non-pruritic lesions, bilaterally on the lower extremities. She also reported a red crusted area that appeared at the site of her tuberculin test that was placed subsequent to the development of her lower extremity lesions. Her past medical history was significant for Parkinson's disease, hypothyroidism and hypertension. Her current medications included l-thyroxine, estrogen and diltiazem. Her travel history was only remarkable for a trip to Jamaica the previous spring. She was born and raised in Haiti. She reported a history of a positive tuberculin skin test 20 years ago, but received no therapy. Physical examination revealed a 2 x 3 centimeter firm, nontender left lateral neck mass (Fig. 1). Her right forearm revealed an erythematous, ulcerated, indurated plaque 1.5 cm in diameter (Fig. 2.). Her lower extremities revealed tender 0.5 to 1 cm erythematous nodules below the knees bilaterally (Fig. 3). A punch biopsy of a lower extremity nodule revealed a mild pervisacular dermal infiltrate. Within the subcutaneous tissue there was septal widening. There was also a lymphohistiocytic infiltrate with a slight admixture of neutrophils within the septa of the fat lobules. There was no evidence of necrotizing vasculitis or collagen necrosis. An acid-fast stain was not performed. The histologic findings were consistent with a diagnosis of erythema nodosum. Her laboratory evaluation including CBC, electrolytes, thyroid studies, angiotensin converting enzyme level and chest radiograph were normal. Approximately 1 week after her dermatological evaluation, the fine-needle aspirate culture grew Mycobacterium tuberculosis. A diagnosis of tuberculous lymphadenitis associated with erythema nodosum was confirmed. The patient was started on quadruple therapy of isoniazid, rifampin, ethambutol and pyrazinamide. Her lower limb skins lesions rapidly resolved over the subsequent month and her neck mass also diminished in size. She completed 6 months of antituberculous therapy with complete resolution of her lymphadenopathy. The aim of this study is to evaluate the additional diagnostic significance of immunocytochemical staining of thyreoglobulin (TG) in Fine Needle Aspiration Biopsy (FNAB) of neck lymph-nodes, in patients with a previous history of thyroid carcinoma. Twenty-five smears performed by ultrasound-guided FNAB on laterocervical nodes with a 21-23 gauge needle were evaluates. All smears were stained according to Papanicolaou and microscopically examined. Of these 25 smears, 15 were diagnostic and 10 were non diagnostic. Of the 15 diagnostic cases, 10 were positive for metastatic lesions from thyroid neoplasm and the other 4 were classified as reactive lymphoadenitis. One smear for each case was selected for the immunohistochemical stain. All the 10 non-diagnostic cases showed no reaction to thyreoglobulin. Neoplastic cells, from 9 out of 11 cytologically positive smears, expressed thyreoglobulin in the cytoplasm. In one case no reaction was evident and the other one was discarded for technical reasons. In 3 of the 4 cases cytologically classified as lymphoadenitis, immunoreactive thyreoglobulin was not found. In the fourth case, blastic-like cells showed a scanty cytoplasmic rime which was immunoreactive for TG and thus was classified as a metastatic tumour. On this basis, it is suggested that FNAB should be performed routinelly in the diagnostic evaluation of neck masses of unknown origin in patients with a previous history of thyroid neoplasm. If the FNAB is inconclusive, a second aspiration should be performed while immunoperoxidase stain to evidentiate TG may be an adjuntive diagnostic tool in cytologically negative cases. We studied 4 cases of Graves' disease with anti-thyroid hormone antibodies. Changes in the serum levels of triiodothyronine(T3), thyroxine(T4), free T4, thyrotropin(TSH), and thyroglobulin(Tg), as well as titers of anti-Tg antibodies, anti-thyroid hormone antibodies, anti-TSH receptor antibodies(TRAb) and anti-microsomal antibodies(MCHA) during 2 10 years' treatment periods were examined in each case. Case 1; A woman, who was diagnosed as having Graves' disease when she was 10 years old, had been treated with methimazole(MMI) or propylthiouracil(PTU). Treatment with the antithyroid drug had been discontinued by herself when she was 19 years old until she was 24 years old, when she was pregnant and consulted our hospital. Since her serum levels of T3 were unusually high, examination of her serum for the presence of anti-T3 antibodies was done. The presence of anti-T3 antibodies in her serum was confirmed. Case 2; A woman, who was diagnosed as having Graves' disease at the age of 41, had been treated with MMI or PTU. Presence of serum anti-T3 antibodies was found in a screening test for the antibodies. Serial sera were obtained during the 5 year observation period when she was treated with MMI, PTU, and subtotal thyroidectomy. Titers of anti-Tg antibodies in her sera were in the normal range. Case 3; A woman, who was diagnosed as having Graves' disease at the age of 11, had been treated with MMI or PTU. Presence of anti-T3 and anti-T4 antibodies were found in her sera in a screening test. Serial sera obtained during the 4 year treatment period were tested. Case 4; A woman, who was diagnosed as having Graves' disease at the age of 14, had been treated with MMI. Presence of anti-T3 and anti-T4 antibodies was found in her sera in a screening test. Serial sera obtained during the 2 year treatment period were tested. Titers of anti-Tg were increased when the levels of TSH or titers of TRAb were increased. The results suggested that TSH and TRAb, which are thyroid stimulating substances, increased serum levels of Tg, which resulted in the increase of titers of anti-Tg. Because of the possibility that administration of PSL could modify B lymphocyte functions, periods during which PSL was administered were excluded from the examination of the correlation between Tg concentrations or titers of anti-Tg and titers of anti-thyroid hormone antibodies, as in Cases 2 and 4, respectively.(ABSTRACT TRUNCATED AT 400 WORDS) We wanted to study the utility of thyroglobulin determination in the washout of fine needle aspiration (FNAB-Tg) of lymph metastatic nodes in patients with papillar thyroid carcinoma (PTC) and positive serum thyroglobulin antibodies (AbTg). We have studied 11 patients (49.9+/-11.8 years old, 70% females) with PTC and positive AbTg in which a whole-body scanning (WBS) after (131)I treatment showed pathological uptake in lymph cervical nodes. An ultrasound-guided fine-needle aspiration biopsy (US-FNAB) was performed for cytological research. Needle-washout with 1 ml ClNa 0.9% was employed to determine FNAB-Tg. In 16/17 suspicious nodes Tg-FNAB concentration was higher than 7 ng/dl (223.3+/-314.2 [7-1009]). AbTg were negative in the washout obtained. WBS was able to detect 94% lymphadenopathies, whereas 76.5% were detected with ultrasound and 70.6% using cytology. The FNAB-Tg was positive in 94% of nodules, which was higher than combining US and FNAB-cytology both together (88.2%). One hundred per cent of pathological nodules were detected using US plus FNAB-Tg. FNAB-Tg determination is an useful technique for diagnosis of metastatic lymph nodes of patients with PTC and is unaffected by the presence of serum AbTg. Solid pseudopapillary tumor of the pancreas, otherwise known as solid and cystic tumor or Frantz tumor, is an unusual form of pancreatic carcinoma, with unknown etiopathogenesis, that accounts for 0.2 to 2.7% of all pancreatic tumors. It is defined as an exocrine pancreatic neoplasia that mainly affects women between the second and third decade of life, and its management is not well defined. Endoscopic ultrasound offers a key anatomical advantage in accessing the pancreas and endoscopic ultrasound fine-needle aspiration has become the gold standard method for the diagnosis of pancreatic lesions. Case 1: A 31-year-old white Hispanic woman presented with epigastric pain for 5 months. An abdominal ultrasound revealed a single 2 cm nodule in the uncinate process of her pancreas. Endoscopic ultrasound showed a regular, well-defined solid lesion with alternating cystic areas at the uncinate process of her pancreas, measuring 1.7 × 1.4 cm; endoscopic ultrasound fine-needle aspiration was then performed with cytopathological analysis compatible with solid pseudopapillary tumor. Body computed tomography confirmed the absence of metastases and she underwent conventional duodenopancreatectomy. However, she died 4 days after surgery due to postoperative surgical complications. Case 2: A 35-year-old Hispanic woman presented with left upper quadrant abdominal pain for 3 months, associated with a palpable mass at this region. A computed tomography scan showed a solitary nodule in the pancreatic body. Endoscopic ultrasound showed a regular, well-defined, homogeneous lesion with small anechoic (cystic) areas, measuring 2 × 2 cm, in between the pancreatic body and neck. Endoscopic ultrasound fine-needle aspiration was performed and cytopathological analysis was suggestive of a pseudopapillary solid tumor. She underwent a body-tail laparoscopic pancreatectomy with splenectomy. Nine months after the diagnosis, she remains asymptomatic, continuing regular follow-up in the oncology out-patient clinic. Solid pseudopapillary tumor is a rare pancreatic malignancy. Endoscopic ultrasound fine-needle aspiration is the gold standard method to characterize and diagnose this type of pancreatic lesion, making this an invaluable tool to help guide clinical management and improve the preoperative diagnostic yield. Follow-Up Whole-Body Thyroid Scanning and Thyroglobulin Determinations Serum thyroglobulin is a sensitive marker of residual/ recurrent thyroid cancer after ablation of the residual postsurgical thyroid tissue. However, newer Tg assays have functional sensitivities as low as 0.1 ng/mL, as opposed to older assays with functional sensitivities of 1 ng/mL, reducing the number of patients with truly undetectable serum Tg levels. Because the vast majority of papillary thyroid cancer recurrences are in cervical lymph nodes, a neck ultrasound should be performed about 6 months after thyroid ablation; ultrasound has been shown to be more sensitive than WBS in this scenario. Lymphadenopathy is a common finding in toxoplasmosis. A breast mass due to toxoplasmosis is very rare, and only a few cases have been reported. We present a case of toxoplasmosis that presented as a swelling in the axillary tail of the breast with a palpable axillary lymph node which mimicked breast cancer. A 45-year-old otherwise healthy Caucasian woman presented with a lump on the lateral aspect of her left breast. Her mother had breast cancer that was diagnosed at the age of 66 years. During an examination, we discovered that our patient had a discrete, firm lump in the axillary tail of her left breast and an enlarged, palpable lymph node in her left axilla. Her right breast and axilla were normal. The clinical diagnosis was malignancy in the left breast. Ultrasound and mammographic examinations of her breast suggested a pathological process but were not conclusive. She had targeted fine-needle aspiration cytology (FNAC) and core biopsy of the lesions. FNAC was indeterminate (C3) but suggested a possibility of toxoplasmosis. The core biopsy was not suggestive of malignancy but showed granulomatous inflammation. She had a wide local excision of the breast lump and an axillary lymph node biopsy. Histopathology and immunohistochemical studies excluded carcinoma or lymphoma but suggested the possibility of intramammary and axillary toxoplasmic lymphadenopathy. The results of Toxoplasma gondii IgM and IgG serology tests were positive, supporting a diagnosis of toxoplasmosis. Toxoplasmosis rarely presents as a pseudotumor of the breast. FNAC and histology are valuable tools for a diagnosis of toxoplasmosis, and serology is an important adjunct for confirmation. In thyroid diseases, the place of fine needle aspiration biopsy still continues to be discussed: the sensibility and specificity vary greatly in the literature. Frozen section diagnosis is necessary to form a diagnostic strategy. The objective of this study was compare the results of fine needle aspiration biopsy, frozen section diagnosis, and definitive histologic results in a population of 163 patients and to draw conclusions about treatment. From 1994 to 1999, 163 patients (132 females and, 31 males) undergoing thyroid surgery were included in this retrospective study, after a standard preoperative work-up. Those with a single palpable nodule and hypofixation on scintigraphy underwent fine needle aspiration before surgery. These results were compared with the definitive histologic results. A loboisthmectomy was performed in 88 cases (54%), a subtotal thyroidectomy in 34 cases (21%), and a total thyrodectomy in 41 cases (25%). In the latter group, an associated neck dissection was performed in 18 cases (11%); a frozen section diagnosis was obtained in all cases of thyroid nodules. This study demonstrated a single nodule in 97 cases (60%), multiple nodules in 27 cases (17%), multinodular goitre in 34 cases (21%), and 5 Basedow diseases (3%). Sixty-two cases (38%) of thyroid nodules underwent fine needle aspiration before surgery. In 25 cases (15%), definitive pathology showed a malignant lesion. The frozen section diagnosis had a sensitivity of 73% and a specificity of 99%, and the fine needle aspiration biopsy had a sensitivity of 40% and a specificity of 100%. The authors propose fine needle aspiration biopsy in the following cases: a single palpable nodule and hypofixation on scintigraphy or a surgical contra indication; and direct surgery in symptomatic thyroid disease or if there are one or several full nodules &gt; 2 cm. In near future, these indications will be modified with the increasing reliability of fine needle aspiration biopsy. The patient was a 41-year-old, premenopausal woman with a chief complaint of well-circumscribed palpable, right breast mass without nipple discharge. Although she noticed the lump 3 months previously, the size of the tumor (1.1 × 0.9 cm(2)) had been stable. The patient's mother suffered from gastric cancer. Her previous history of the triple different malignancies was as follows: (1) left osteosarcoma [amputation of left lower leg at 15 years old (y/o)]. After the operation, she was treated with various kinds of anticancer drugs including a total of 45 g ifosphamide and 342 g methotrexate; (2) tongue cancer (right radical neck resection; 23 y/o); and (3) thyroid cancer (right lobectomy; 40 y/o). There was no evidence of recurrence of these malignancies at the present consultation. At the time of tongue cancer operation, chromosome abnormality was investigated, but the results were normal. Physical examination showed a well-delimited, elastic-firm, mobile tumor in the central outer right breast. Regional lymph nodes were not palpable. Mammography showed a focal asymmetry in the right upper breast on the mediolateral oblique view. Ultrasonography revealed a hypoechoic mass with irregular margins. Distant metastases could not be detected by whole-body computed tomography scan. The histology of the Mammotome(®) (vacuum-assisted core needle biopsy) specimen revealed that this tumor was low-grade ductal carcinoma in situ (DCIS). She underwent breast-conserving surgery with sentinel lymph node biopsy. On permanent histopathological examination, the diagnosis of the tumor was intracystic papilloma with low-grade DCIS. Surgical margin was negative, and sentinel lymph node metastases could not be observed. Estrogen and progesterone receptor (ER/PR) were strongly positive, but human epidermal growth factor receptor-2 (HER-2) overexpression was not tested because the lesion was DCIS. She has received no adjuvant therapy and is currently disease free 3 months after surgery. We studied the feasibility of employing the measurement of thyroglobulin (Tg) in the washout of the needle used to perform the fine needle aspiration cytology (FNA-Tg) for the differential diagnosis of nonthyroidal neck masses of unknown etiology. We studied 35 patients presenting for 1 or more neck lumps outside the thyroid gland. A previous history of treated differentiated thyroid cancer (DTC) was given by 23 patients and of nonthyroidal malignancy by 3 patients. FNA-Tg was measured in the Tg-free serum used to wash out the needle employed for the cytology. Finally, all patients were treated by surgery. FNA-Tg was always detectable in 14 patients with thyroid cancer metastases demonstrated by histology, with a mean (+/- SD) of 27,087 +/- 37,622 ng/FNA (P less than 0.002) compared to patients without thyroid cancer metastases (mean +/- SD, 12.1 +/- 4.8 ng/FNA in 7 cases; undetectable in 14 cases). Assuming 21.7 ng/FNA (the mean +/- 2 SD of the negative patients) as the cut-off value, all patients with metastases from DTC were detected by FNA-Tg. FNA-Tg had better negative predictive value than cytology, since this last technique gave 10 inconclusive results, comprising 2 false negative results in patients with metastases from DTC. Our results indicate that elevated concentrations of FNA-Tg in nonthyroidal neck nodes strongly suggest the diagnosis of metastases from DTC. This report highlights the difficulties associated with diagnosing cervical spine injuries in children especially as the history and mechanism of injury may often be unclear and the normal variations in roentgenographic appearance may be confusing. As far as we are aware this is only the second case of traumatic Hangman's fracture in a child under the age of 3 years and the only case where there is a strong probability of child abuse. A female child aged 23 months was admitted with a 5-day history of irritability and general malaise. Her father reported noticing that she was reluctant to move her neck. He denied any possibility of trauma. On admission she had neck stiffness with a temperature of 37 degrees C and supported her neck with her hands. There was evidence of otitis media of her right ear. Her physical examination was otherwise normal. A full blood count and lumbar puncture were within normal limits. Cervical spine x rays suggested a Hangman's fracture of C2 with slight anterior subluxation of C2 on C3 and a kyphus at that level. Computerized Tomography demonstrated no significant canal encroachment. An isotope bone scan was non-diagnostic. She was treated in a moulded cervical collar with neck held in slight extension. Her symptoms resolved and further radiographs showed improved alignment. Repeat CT scans seven weeks post admission showed callus formation. At follow-up at one year she remains asymptomatic. Hangman's fracture is very rare in children under 3 years and the considerable normal variations further complicate diagnosis. Swischuk described the posterior cervical line connecting the spinous process of C1-C3 vertebrae on the lateral projection to differentiate a true fracture dislocation from physiological anterior displacement. A detailed history, roentgenograms, bone scans, CT scans and MRI scans are often required for accurate diagnosis. Fine-needle aspiration cytology is frequently used for differential diagnosis of neck masses of unknown origin. Inconclusive and even false-negative results are not uncommon. To evaluate the utility of thyroglobulin (Tg) measurement in fine-needle aspirates (FNA-Tg) for detecting cervical lymph node (CLNs) metastases from differentiated thyroid carcinomas. An ultrasound-guided fine-needle aspiration was done in 67 patients with 83 suspicious enlarged CLNs to obtain material for cytology and Tg measurement in the needle washout, using an immunometric chemiluminescent assay. Measurement of anti-Tg antibodies (FNA-TgAb) was also carried out in half of all the aspirates. Subjects were divided into two groups: one of 16 patients awaiting thyroidectomy and the other of 51 patients in follow-up after surgery. The first group of patients had positive FNA biopsy (FNAB-Tg) in 14 out of the 18 studied CLNs with a range of 3.2-43 352 ng/ml, while FNAB-cytology indicated metastasis in only 8 out of the 14 CLNs with positive histology. A total of 65 CLNs were studied in the follow-up group. Lymphadenectomy was performed in 23 patients and 28 aspirated CLNs were removed. Histology confirmed the diagnosis of metastasis suggested by FNAB-Tg in 20 CLNs and of reactive lymphadenitis in the remaining 8 CLNs. FNAB-cytology was positive in only 11 CLNs. Sensitivity of FNAB-Tg was not affected by the studied FNAB-TgAb. The FNAB-Tg achieved a sensitivity of 100% in both groups. FNAB-Tg is an easy and inexpensive technique which proved to increase the diagnostic of cytology in the early diagnosis of papillary carcinoma recurrence to CLN even in the presence of serum TgAb.\nHere is the question:\nENDOCRINOLOGY: A 52-year-old woman from a village on the Costa Brava notices an otherwise asymptomatic lump in the anterior region when applying cream to her neck; she goes to her general practitioner who confirms the presence of a firm, smooth mass, 2 cm in maximum diameter, which rises with swallowing. No palpable lymphadenopathy. What tests would you order at the outset?\nHere are the potential choices:\n1. A determination of thyroglobulin in blood.\n2. A cervical CT scan.\n3. A determination of circulating antithyroid antibodies (antithyroglubulin and antiperoxidase).\n4. A fine needle puncture.\n5. A determination of free T3.\nThe correct answer is: ",
        "gold_answer": "4 A fine needle puncture.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Thyroglobulin (Tg) assay of material from fine-needle aspiration of neck masses can help distinguish neck masses of thyroid origin from other masses. We describe its utility in a patient with an unusual constellation of findings, a neck lump identified as a lymph node metastasis from a contralateral occult papillary thyroid carcinoma (PTC). A 56-year-old woman was referred to our center for evaluation of a 15-mm right lateral cervical neck mass which was strongly hypoechoic, not homogenous and contained several microcalcifications. There was no family history of thyroid disease, the patient was euthyroid and was not taking medications for thyroid disorders. On physical examination the thyroid was slightly enlarged and was normal on ultrasound except for a 1 x 3 mm hypoechoic nodule in the middle of the left lobe. Ultrasound-guided fine-needle aspiration biopsy (FNAB) of the right lateral cervical mass was performed with the Tg concentration of the FNAB washout liquid being &gt;300 ng/mL and the cytology showing lymphoid elements mixed with polymorphous epithelial cells with atypical nuclei, suggesting lymph node metastasis from a cancer of epithelial origin. A lymph node metastasis from a papillary thyroid microcarcinoma (micro-PTC) was the presumptive diagnosis with the preoperative staging being Tx N1b. The patient underwent total thyroidectomy and bilateral lymph node dissection. At pathology, the right cervical mass was confirmed as lymph node metastasis of a PTC, and a unifocal micro-PTC was found in the middle left lobe. The patient was readmitted for a therapeutic (131)I dose (4810 MBq). At the time of (131)I administration, the whole-body scan showed only minimal thyroid bed uptake and serum Tg was &lt;1 ng/mL. She was maintained on l-thyroxine treatment (150 microg/d). Five year later she did not have evidence of recurrent or residual PTC. We describe the first case of contralateral lymph node metastasis from a unifocal micro-PTC identified by the detection of high Tg levels in the wash-out liquid of FNAB. We report a case in which the appearance of a progressively rising titer of thyroglobulin (Tg) antibodies was the most sensitive marker of papillary thyroid cancer relapse at loco-regional lymph nodes. The patient, a 60-year-old man, had been treated with total thyroidectomy plus lymphadenectomy and radioiodine ablation for a 1-cm papillary thyroid cancer. Twelve years after surgery, while undergoing levothyroxine (LT4) therapy, Tg antibodies were first detected and progressively rose from 99 to 1,697 U/mL in 18 months, while serum Tg remained undetectable. Both neck ultrasonography and 131I whole-body scan (WBS) were unremarkable. Enlarged lymph nodes became palpable at the left laterocervical region only 2 years after the first appearance of Tg antibodies and were surgically removed after cancer relapse was confirmed by fine-needle aspiration cytology. This case emphasizes the possibility that in thyroid cancer patients who have undergone total thyroidectomy, the appearance of Tg antibodies may indicate metastatic lymph nodes even when serum Tg is undetectable and WBS negative. A neck mass or neck lump is an ambiguous mass found in the neck area. There are many different possible causes, including congenital conditions like branchial anomalies and thyroglossal duct cysts. Workup Workup of a neck mass includes a medical history and a physical examination, where important characteristics are location, size, shape, consistency, tenderness, mobility, and color. When this is not conclusive, further workup includes: Blood tests Medical imaging: Contrast CT is generally the initial study of choice for adults. Medical ultrasound of the neck is useful in children because it avoids the radiation dose of CT. In some cases, fine needle aspiration may assist in the diagnosis. See also Cervical lymphadenopathy References External links Human head and neck Malignancy Only a small percentage of lumps in the neck are malignant (around 4 – 6.5%), and most thyroid nodules are benign colloid nodules. There are many factors to consider when diagnosing a malignant lump. Trouble swallowing or speaking, swollen cervical lymph nodes or a firm, immobile nodule are more indicative of malignancy, whereas a family history of autoimmune disease or goiter, thyroid hormonal dysfunction or a soft, painful nodule are more indicative of benignancy. The prevalence of cancer is higher in males, patients under 20 years old or over 70 years old, and patients with a history of head and neck irradiation or a family history of thyroid cancer. Solitary thyroid nodule A 73-year-old African American female presented to our clinic with painful lower extremity lesions of 2 weeks duration. She was in her usual state of health until 3 months prior to presentation when she reported symptoms of fatigue and weakness. She also noticed an enlarging mass on the left side of her neck. She denied fevers, chills, night sweats or cough. Her symptoms were unresponsive to a course of oral dicloxacillin. The neck mass enlarged over 8 weeks and she was referred to our institution for evaluation. CT scan of the neck showed an enlarged lymph node. Ten days prior to her presentation in dermatology, a fine needle aspirate of the enlarging lymph node revealed necrotizing granulomas. Tissue was sent for routine mycobacterial and fungal cultures. Routine blood work, chest radiograph, and a tuberculin skin test were also performed. At the time of her dermatology visit she described the development of multiple new painful, non-pruritic lesions, bilaterally on the lower extremities. She also reported a red crusted area that appeared at the site of her tuberculin test that was placed subsequent to the development of her lower extremity lesions. Her past medical history was significant for Parkinson's disease, hypothyroidism and hypertension. Her current medications included l-thyroxine, estrogen and diltiazem. Her travel history was only remarkable for a trip to Jamaica the previous spring. She was born and raised in Haiti. She reported a history of a positive tuberculin skin test 20 years ago, but received no therapy. Physical examination revealed a 2 x 3 centimeter firm, nontender left lateral neck mass (Fig. 1). Her right forearm revealed an erythematous, ulcerated, indurated plaque 1.5 cm in diameter (Fig. 2.). Her lower extremities revealed tender 0.5 to 1 cm erythematous nodules below the knees bilaterally (Fig. 3). A punch biopsy of a lower extremity nodule revealed a mild pervisacular dermal infiltrate. Within the subcutaneous tissue there was septal widening. There was also a lymphohistiocytic infiltrate with a slight admixture of neutrophils within the septa of the fat lobules. There was no evidence of necrotizing vasculitis or collagen necrosis. An acid-fast stain was not performed. The histologic findings were consistent with a diagnosis of erythema nodosum. Her laboratory evaluation including CBC, electrolytes, thyroid studies, angiotensin converting enzyme level and chest radiograph were normal. Approximately 1 week after her dermatological evaluation, the fine-needle aspirate culture grew Mycobacterium tuberculosis. A diagnosis of tuberculous lymphadenitis associated with erythema nodosum was confirmed. The patient was started on quadruple therapy of isoniazid, rifampin, ethambutol and pyrazinamide. Her lower limb skins lesions rapidly resolved over the subsequent month and her neck mass also diminished in size. She completed 6 months of antituberculous therapy with complete resolution of her lymphadenopathy. The aim of this study is to evaluate the additional diagnostic significance of immunocytochemical staining of thyreoglobulin (TG) in Fine Needle Aspiration Biopsy (FNAB) of neck lymph-nodes, in patients with a previous history of thyroid carcinoma. Twenty-five smears performed by ultrasound-guided FNAB on laterocervical nodes with a 21-23 gauge needle were evaluates. All smears were stained according to Papanicolaou and microscopically examined. Of these 25 smears, 15 were diagnostic and 10 were non diagnostic. Of the 15 diagnostic cases, 10 were positive for metastatic lesions from thyroid neoplasm and the other 4 were classified as reactive lymphoadenitis. One smear for each case was selected for the immunohistochemical stain. All the 10 non-diagnostic cases showed no reaction to thyreoglobulin. Neoplastic cells, from 9 out of 11 cytologically positive smears, expressed thyreoglobulin in the cytoplasm. In one case no reaction was evident and the other one was discarded for technical reasons. In 3 of the 4 cases cytologically classified as lymphoadenitis, immunoreactive thyreoglobulin was not found. In the fourth case, blastic-like cells showed a scanty cytoplasmic rime which was immunoreactive for TG and thus was classified as a metastatic tumour. On this basis, it is suggested that FNAB should be performed routinelly in the diagnostic evaluation of neck masses of unknown origin in patients with a previous history of thyroid neoplasm. If the FNAB is inconclusive, a second aspiration should be performed while immunoperoxidase stain to evidentiate TG may be an adjuntive diagnostic tool in cytologically negative cases. We studied 4 cases of Graves' disease with anti-thyroid hormone antibodies. Changes in the serum levels of triiodothyronine(T3), thyroxine(T4), free T4, thyrotropin(TSH), and thyroglobulin(Tg), as well as titers of anti-Tg antibodies, anti-thyroid hormone antibodies, anti-TSH receptor antibodies(TRAb) and anti-microsomal antibodies(MCHA) during 2 10 years' treatment periods were examined in each case. Case 1; A woman, who was diagnosed as having Graves' disease when she was 10 years old, had been treated with methimazole(MMI) or propylthiouracil(PTU). Treatment with the antithyroid drug had been discontinued by herself when she was 19 years old until she was 24 years old, when she was pregnant and consulted our hospital. Since her serum levels of T3 were unusually high, examination of her serum for the presence of anti-T3 antibodies was done. The presence of anti-T3 antibodies in her serum was confirmed. Case 2; A woman, who was diagnosed as having Graves' disease at the age of 41, had been treated with MMI or PTU. Presence of serum anti-T3 antibodies was found in a screening test for the antibodies. Serial sera were obtained during the 5 year observation period when she was treated with MMI, PTU, and subtotal thyroidectomy. Titers of anti-Tg antibodies in her sera were in the normal range. Case 3; A woman, who was diagnosed as having Graves' disease at the age of 11, had been treated with MMI or PTU. Presence of anti-T3 and anti-T4 antibodies were found in her sera in a screening test. Serial sera obtained during the 4 year treatment period were tested. Case 4; A woman, who was diagnosed as having Graves' disease at the age of 14, had been treated with MMI. Presence of anti-T3 and anti-T4 antibodies was found in her sera in a screening test. Serial sera obtained during the 2 year treatment period were tested. Titers of anti-Tg were increased when the levels of TSH or titers of TRAb were increased. The results suggested that TSH and TRAb, which are thyroid stimulating substances, increased serum levels of Tg, which resulted in the increase of titers of anti-Tg. Because of the possibility that administration of PSL could modify B lymphocyte functions, periods during which PSL was administered were excluded from the examination of the correlation between Tg concentrations or titers of anti-Tg and titers of anti-thyroid hormone antibodies, as in Cases 2 and 4, respectively.(ABSTRACT TRUNCATED AT 400 WORDS) We wanted to study the utility of thyroglobulin determination in the washout of fine needle aspiration (FNAB-Tg) of lymph metastatic nodes in patients with papillar thyroid carcinoma (PTC) and positive serum thyroglobulin antibodies (AbTg). We have studied 11 patients (49.9+/-11.8 years old, 70% females) with PTC and positive AbTg in which a whole-body scanning (WBS) after (131)I treatment showed pathological uptake in lymph cervical nodes. An ultrasound-guided fine-needle aspiration biopsy (US-FNAB) was performed for cytological research. Needle-washout with 1 ml ClNa 0.9% was employed to determine FNAB-Tg. In 16/17 suspicious nodes Tg-FNAB concentration was higher than 7 ng/dl (223.3+/-314.2 [7-1009]). AbTg were negative in the washout obtained. WBS was able to detect 94% lymphadenopathies, whereas 76.5% were detected with ultrasound and 70.6% using cytology. The FNAB-Tg was positive in 94% of nodules, which was higher than combining US and FNAB-cytology both together (88.2%). One hundred per cent of pathological nodules were detected using US plus FNAB-Tg. FNAB-Tg determination is an useful technique for diagnosis of metastatic lymph nodes of patients with PTC and is unaffected by the presence of serum AbTg. Solid pseudopapillary tumor of the pancreas, otherwise known as solid and cystic tumor or Frantz tumor, is an unusual form of pancreatic carcinoma, with unknown etiopathogenesis, that accounts for 0.2 to 2.7% of all pancreatic tumors. It is defined as an exocrine pancreatic neoplasia that mainly affects women between the second and third decade of life, and its management is not well defined. Endoscopic ultrasound offers a key anatomical advantage in accessing the pancreas and endoscopic ultrasound fine-needle aspiration has become the gold standard method for the diagnosis of pancreatic lesions. Case 1: A 31-year-old white Hispanic woman presented with epigastric pain for 5 months. An abdominal ultrasound revealed a single 2 cm nodule in the uncinate process of her pancreas. Endoscopic ultrasound showed a regular, well-defined solid lesion with alternating cystic areas at the uncinate process of her pancreas, measuring 1.7 × 1.4 cm; endoscopic ultrasound fine-needle aspiration was then performed with cytopathological analysis compatible with solid pseudopapillary tumor. Body computed tomography confirmed the absence of metastases and she underwent conventional duodenopancreatectomy. However, she died 4 days after surgery due to postoperative surgical complications. Case 2: A 35-year-old Hispanic woman presented with left upper quadrant abdominal pain for 3 months, associated with a palpable mass at this region. A computed tomography scan showed a solitary nodule in the pancreatic body. Endoscopic ultrasound showed a regular, well-defined, homogeneous lesion with small anechoic (cystic) areas, measuring 2 × 2 cm, in between the pancreatic body and neck. Endoscopic ultrasound fine-needle aspiration was performed and cytopathological analysis was suggestive of a pseudopapillary solid tumor. She underwent a body-tail laparoscopic pancreatectomy with splenectomy. Nine months after the diagnosis, she remains asymptomatic, continuing regular follow-up in the oncology out-patient clinic. Solid pseudopapillary tumor is a rare pancreatic malignancy. Endoscopic ultrasound fine-needle aspiration is the gold standard method to characterize and diagnose this type of pancreatic lesion, making this an invaluable tool to help guide clinical management and improve the preoperative diagnostic yield. Follow-Up Whole-Body Thyroid Scanning and Thyroglobulin Determinations Serum thyroglobulin is a sensitive marker of residual/ recurrent thyroid cancer after ablation of the residual postsurgical thyroid tissue. However, newer Tg assays have functional sensitivities as low as 0.1 ng/mL, as opposed to older assays with functional sensitivities of 1 ng/mL, reducing the number of patients with truly undetectable serum Tg levels. Because the vast majority of papillary thyroid cancer recurrences are in cervical lymph nodes, a neck ultrasound should be performed about 6 months after thyroid ablation; ultrasound has been shown to be more sensitive than WBS in this scenario. Lymphadenopathy is a common finding in toxoplasmosis. A breast mass due to toxoplasmosis is very rare, and only a few cases have been reported. We present a case of toxoplasmosis that presented as a swelling in the axillary tail of the breast with a palpable axillary lymph node which mimicked breast cancer. A 45-year-old otherwise healthy Caucasian woman presented with a lump on the lateral aspect of her left breast. Her mother had breast cancer that was diagnosed at the age of 66 years. During an examination, we discovered that our patient had a discrete, firm lump in the axillary tail of her left breast and an enlarged, palpable lymph node in her left axilla. Her right breast and axilla were normal. The clinical diagnosis was malignancy in the left breast. Ultrasound and mammographic examinations of her breast suggested a pathological process but were not conclusive. She had targeted fine-needle aspiration cytology (FNAC) and core biopsy of the lesions. FNAC was indeterminate (C3) but suggested a possibility of toxoplasmosis. The core biopsy was not suggestive of malignancy but showed granulomatous inflammation. She had a wide local excision of the breast lump and an axillary lymph node biopsy. Histopathology and immunohistochemical studies excluded carcinoma or lymphoma but suggested the possibility of intramammary and axillary toxoplasmic lymphadenopathy. The results of Toxoplasma gondii IgM and IgG serology tests were positive, supporting a diagnosis of toxoplasmosis. Toxoplasmosis rarely presents as a pseudotumor of the breast. FNAC and histology are valuable tools for a diagnosis of toxoplasmosis, and serology is an important adjunct for confirmation. In thyroid diseases, the place of fine needle aspiration biopsy still continues to be discussed: the sensibility and specificity vary greatly in the literature. Frozen section diagnosis is necessary to form a diagnostic strategy. The objective of this study was compare the results of fine needle aspiration biopsy, frozen section diagnosis, and definitive histologic results in a population of 163 patients and to draw conclusions about treatment. From 1994 to 1999, 163 patients (132 females and, 31 males) undergoing thyroid surgery were included in this retrospective study, after a standard preoperative work-up. Those with a single palpable nodule and hypofixation on scintigraphy underwent fine needle aspiration before surgery. These results were compared with the definitive histologic results. A loboisthmectomy was performed in 88 cases (54%), a subtotal thyroidectomy in 34 cases (21%), and a total thyrodectomy in 41 cases (25%). In the latter group, an associated neck dissection was performed in 18 cases (11%); a frozen section diagnosis was obtained in all cases of thyroid nodules. This study demonstrated a single nodule in 97 cases (60%), multiple nodules in 27 cases (17%), multinodular goitre in 34 cases (21%), and 5 Basedow diseases (3%). Sixty-two cases (38%) of thyroid nodules underwent fine needle aspiration before surgery. In 25 cases (15%), definitive pathology showed a malignant lesion. The frozen section diagnosis had a sensitivity of 73% and a specificity of 99%, and the fine needle aspiration biopsy had a sensitivity of 40% and a specificity of 100%. The authors propose fine needle aspiration biopsy in the following cases: a single palpable nodule and hypofixation on scintigraphy or a surgical contra indication; and direct surgery in symptomatic thyroid disease or if there are one or several full nodules &gt; 2 cm. In near future, these indications will be modified with the increasing reliability of fine needle aspiration biopsy. The patient was a 41-year-old, premenopausal woman with a chief complaint of well-circumscribed palpable, right breast mass without nipple discharge. Although she noticed the lump 3 months previously, the size of the tumor (1.1 × 0.9 cm(2)) had been stable. The patient's mother suffered from gastric cancer. Her previous history of the triple different malignancies was as follows: (1) left osteosarcoma [amputation of left lower leg at 15 years old (y/o)]. After the operation, she was treated with various kinds of anticancer drugs including a total of 45 g ifosphamide and 342 g methotrexate; (2) tongue cancer (right radical neck resection; 23 y/o); and (3) thyroid cancer (right lobectomy; 40 y/o). There was no evidence of recurrence of these malignancies at the present consultation. At the time of tongue cancer operation, chromosome abnormality was investigated, but the results were normal. Physical examination showed a well-delimited, elastic-firm, mobile tumor in the central outer right breast. Regional lymph nodes were not palpable. Mammography showed a focal asymmetry in the right upper breast on the mediolateral oblique view. Ultrasonography revealed a hypoechoic mass with irregular margins. Distant metastases could not be detected by whole-body computed tomography scan. The histology of the Mammotome(®) (vacuum-assisted core needle biopsy) specimen revealed that this tumor was low-grade ductal carcinoma in situ (DCIS). She underwent breast-conserving surgery with sentinel lymph node biopsy. On permanent histopathological examination, the diagnosis of the tumor was intracystic papilloma with low-grade DCIS. Surgical margin was negative, and sentinel lymph node metastases could not be observed. Estrogen and progesterone receptor (ER/PR) were strongly positive, but human epidermal growth factor receptor-2 (HER-2) overexpression was not tested because the lesion was DCIS. She has received no adjuvant therapy and is currently disease free 3 months after surgery. We studied the feasibility of employing the measurement of thyroglobulin (Tg) in the washout of the needle used to perform the fine needle aspiration cytology (FNA-Tg) for the differential diagnosis of nonthyroidal neck masses of unknown etiology. We studied 35 patients presenting for 1 or more neck lumps outside the thyroid gland. A previous history of treated differentiated thyroid cancer (DTC) was given by 23 patients and of nonthyroidal malignancy by 3 patients. FNA-Tg was measured in the Tg-free serum used to wash out the needle employed for the cytology. Finally, all patients were treated by surgery. FNA-Tg was always detectable in 14 patients with thyroid cancer metastases demonstrated by histology, with a mean (+/- SD) of 27,087 +/- 37,622 ng/FNA (P less than 0.002) compared to patients without thyroid cancer metastases (mean +/- SD, 12.1 +/- 4.8 ng/FNA in 7 cases; undetectable in 14 cases). Assuming 21.7 ng/FNA (the mean +/- 2 SD of the negative patients) as the cut-off value, all patients with metastases from DTC were detected by FNA-Tg. FNA-Tg had better negative predictive value than cytology, since this last technique gave 10 inconclusive results, comprising 2 false negative results in patients with metastases from DTC. Our results indicate that elevated concentrations of FNA-Tg in nonthyroidal neck nodes strongly suggest the diagnosis of metastases from DTC. This report highlights the difficulties associated with diagnosing cervical spine injuries in children especially as the history and mechanism of injury may often be unclear and the normal variations in roentgenographic appearance may be confusing. As far as we are aware this is only the second case of traumatic Hangman's fracture in a child under the age of 3 years and the only case where there is a strong probability of child abuse. A female child aged 23 months was admitted with a 5-day history of irritability and general malaise. Her father reported noticing that she was reluctant to move her neck. He denied any possibility of trauma. On admission she had neck stiffness with a temperature of 37 degrees C and supported her neck with her hands. There was evidence of otitis media of her right ear. Her physical examination was otherwise normal. A full blood count and lumbar puncture were within normal limits. Cervical spine x rays suggested a Hangman's fracture of C2 with slight anterior subluxation of C2 on C3 and a kyphus at that level. Computerized Tomography demonstrated no significant canal encroachment. An isotope bone scan was non-diagnostic. She was treated in a moulded cervical collar with neck held in slight extension. Her symptoms resolved and further radiographs showed improved alignment. Repeat CT scans seven weeks post admission showed callus formation. At follow-up at one year she remains asymptomatic. Hangman's fracture is very rare in children under 3 years and the considerable normal variations further complicate diagnosis. Swischuk described the posterior cervical line connecting the spinous process of C1-C3 vertebrae on the lateral projection to differentiate a true fracture dislocation from physiological anterior displacement. A detailed history, roentgenograms, bone scans, CT scans and MRI scans are often required for accurate diagnosis. Fine-needle aspiration cytology is frequently used for differential diagnosis of neck masses of unknown origin. Inconclusive and even false-negative results are not uncommon. To evaluate the utility of thyroglobulin (Tg) measurement in fine-needle aspirates (FNA-Tg) for detecting cervical lymph node (CLNs) metastases from differentiated thyroid carcinomas. An ultrasound-guided fine-needle aspiration was done in 67 patients with 83 suspicious enlarged CLNs to obtain material for cytology and Tg measurement in the needle washout, using an immunometric chemiluminescent assay. Measurement of anti-Tg antibodies (FNA-TgAb) was also carried out in half of all the aspirates. Subjects were divided into two groups: one of 16 patients awaiting thyroidectomy and the other of 51 patients in follow-up after surgery. The first group of patients had positive FNA biopsy (FNAB-Tg) in 14 out of the 18 studied CLNs with a range of 3.2-43 352 ng/ml, while FNAB-cytology indicated metastasis in only 8 out of the 14 CLNs with positive histology. A total of 65 CLNs were studied in the follow-up group. Lymphadenectomy was performed in 23 patients and 28 aspirated CLNs were removed. Histology confirmed the diagnosis of metastasis suggested by FNAB-Tg in 20 CLNs and of reactive lymphadenitis in the remaining 8 CLNs. FNAB-cytology was positive in only 11 CLNs. Sensitivity of FNAB-Tg was not affected by the studied FNAB-TgAb. The FNAB-Tg achieved a sensitivity of 100% in both groups. FNAB-Tg is an easy and inexpensive technique which proved to increase the diagnostic of cytology in the early diagnosis of papillary carcinoma recurrence to CLN even in the presence of serum TgAb.\nHere is the question:\nENDOCRINOLOGY: A 52-year-old woman from a village on the Costa Brava notices an otherwise asymptomatic lump in the anterior region when applying cream to her neck; she goes to her general practitioner who confirms the presence of a firm, smooth mass, 2 cm in maximum diameter, which rises with swallowing. No palpable lymphadenopathy. What tests would you order at the outset?\nHere are the potential choices:\n1. A determination of thyroglobulin in blood.\n2. A cervical CT scan.\n3. A determination of circulating antithyroid antibodies (antithyroglubulin and antiperoxidase).\n4. A fine needle puncture.\n5. A determination of free T3.\nThe correct answer is: 4. A fine needle puncture."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The aim was to assess the association of histological tumor grade with other clinical features and epidemiological factors of women with invasive breast carcinoma. A retrospective study of 103 Mizo breast cancer patients visiting hospitals was made in Aizawl, Mizoram, Northeast India. With a prior consent, information on epidemiological factors and family history in relation to cancer was obtained. Clinical reports were obtained from their medical records. The frequency of distribution was calculated for age at diagnosis and tumor characteristics. Statistical analysis for different variables was done using a chi-square test. p &lt; 0.05 was considered significant. The histological tumor grades in our studies were found to be associated with lymph node invasion (p &lt; 0.021), different subtype of hormone receptor such as ER status (p &lt; 0.004), ER/PR status (p &lt; 0.007), HER2/neu status (p &lt; 0.014), and ER/PR/HER2 status (p &lt; 0.025). A patient with a family history of breast cancer in their 1st degree relative is also seen to have association in determining the tumor grade (p &lt; 0.003). Reproductive history, lifestyle and dietary habits, tobacco, and alcohol consumption were found to have no influence on breast cancer tumor grade. Our results showing significant correlation between status of lymph node, ER, PR, and HER2/neu oncoprotein and family history with 1st degree relative breast cancer are the first time report to target and focus on the possible role of biomarkers for diagnosis among the Mizo tribal breast cancer patients. Since the risk of carcinoma of the breast is increased in women with a family history of the disease, new primary carcinomas of the breast may be increased after treatment. Women with several relatives with carcinoma of the breast are thought to be at higher risk of having a second primary carcinoma of the breast develop and mastectomy is more frequently recommended. The computerized registry of the Mount Sinai Medical Center Breast Service was used to identify 1,337 patients with complete information concerning family history. Three hundred fifty-nine patients with a family history of carcinoma of the breast were compared with women with no family history. Compared with patients with no family history of carcinoma of the breast, patients with a family history of carcinoma of the breast were significantly younger (54.0 versus 55.8 years of age, p &lt; 0.01), were significantly more likely to have used oral contraceptives (26 versus 13 percent, p &lt; 0.001), had significantly more ductal carcinoma in situ (10 versus 4 percent, p &lt; 0.01), and were significantly more often treated with breast conservation (42 versus 31 percent, p &lt; 0.001). Simultaneous contralateral carcinoma of the breast was diagnosed more frequently in patients with a family history (3 versus 1 percent, p &lt; 0.025), but metachronous contralateral carcinomas were not increased. In comparing the two groups, there were no significant differences in proportion premenopausal, parity, use of postmenopausal hormones, tumor size, tumor differentiation, nodal involvement, TNM stage, estrogen receptor status, or use of adjuvant radiation, chemotherapy, or tamoxifen. Complete five-year follow-up evaluation for 748 patients, 179 with a family history, found no differences in local, distant, or disease-free survival rates for mastectomy or breast conservation in relation to family history. Outcome for patients with first-degree affected relatives and those with more than one affected relative was the same as those with no family history. These results indicate that women with a family history of carcinoma of the breast should be treated no differently than women with no family history. Relative indications for testing for a mutation in BRCA1 or BRCA2 for newly diagnosed or family members include a family history among 1st (FDR), 2nd (SDR), or 3rd(TDR) degree relatives usually on the same side of the family but not limited: A known mutation (BRCA1 or BRCA2) in a cancer susceptibility gene within the family Women affected with any breast cancer diagnosed under the age of 30 Women affected with triple negative breast cancer (TNBC) (estrogen receptor negative, progesterone receptor negative, and HER2/neu negative) under the age of 50 Two relatives (FDR/SDR) diagnosed under the age of 45 Three relatives (FDR/SDR) diagnosed with average age of 50 or less Four relatives at any ages Ovarian cancer with either an additional diagnosed relative or a relative with male breast cancer A single family member with both breast and ovarian cancer Male breast cancer Pancreatic cancer with breast or ovarian cancer in the same individual or on the same side of the family Triple-negative breast cancer accounts for less than 20% of breast cancers overall, but is the predominant subtype among carriers of mutations in BRCA1. However, few studies have assessed the association between breast cancer family history and risk of triple-negative breast cancer. We examined the relationship between having a family history of breast cancer in first-degree relatives and risk of triple-negative breast cancer, and risk of two other breast cancer subtypes defined by tumor marker expression. We evaluated data collected by the Breast Cancer Surveillance Consortium from 2,599,946 mammograms on 1,054,466 women, among whom 15% reported a first-degree family history of breast cancer. Using Cox regression in this cohort, we evaluated subtype-specific associations between family history and risk of triple-negative (N = 705), estrogen receptor-positive (ER+, N = 10,026), and hormone receptor-negative/HER2-expressing (ER-/PR-/HER2+, N = 308) breast cancer among women aged 40-84 years. First-degree family history was similarly and significantly associated with an increased risk of all the subtypes [hazard ratio (HR) = 1.73, 95% confidence interval (CI): 1.43-2.09, HR = 1.62, 95% CI: 1.54-1.70, and HR = 1.56, 95% CI: 1.15-2.13, for triple-negative, ER+, and ER-/PR-/HER2+, respectively]. Risk of all the subtypes was most pronounced among women with at least two affected first-degree relatives (versus women with no affected first-degree relatives, HR(triple-negative) = 2.66, 95% CI: 1.66-4.27, HR(ER+) = 2.05, 95% CI: 1.79-2.36, HR(ER)-(/PR)-(/HER2+) = 2.25, 95% CI: 0.99-5.08). Having a first-degree family history of breast cancer was associated with an increased risk of triple-negative breast cancer with a magnitude of association similar to that for the predominant ER+ subtype and ER-/PR-/HER2+ breast cancer. The objective of this study was to examine the association of: (i) diagnosis at age &lt;/=35, (ii) first-degree family history of breast or ovarian cancer (BOC) and (iii) a research based definition of genetic risk, with tumor characteristics, treatment and survival in breast cancer (BC). Consenting female participants in the population-based Ontario Familial Breast Cancer Registry diagnosed with primary invasive BC between 1996 and 1998 were followed prospectively until 2005. Among 967 women, 105 were &lt;/=35 years old at diagnosis and 686 were classified as genetic risk cases, including 349 with a first-degree family history. Individuals diagnosed at age &lt;/=35 were more likely to self-detect tumors, to present with inflammatory BC, to have invasive ductal carcinoma of no special type, high T stage, and tumors with lymphovascular invasion (LVI), high grade and negative estrogen receptors. Younger women were more likely to receive chemotherapy and less likely to receive hormonal therapy. Diagnosis &lt;/=35 years old was associated with significantly reduced distant recurrence free survival, an effect that did not persist after adjustment for tumor and treatment related variables. Poor outcomes were restricted to younger women with hormone responsive BC. Family history was associated with increased rates of mammographic detection of BC, lower tumor stage and less frequent inflammatory BC, but had no association with BC outcomes. Women diagnosed with BC at age &lt;/=35 have more aggressive tumors; these adverse tumor characteristics, rather than age, lead to poor outcomes. Family history was not associated with survival. The HER2 gene, located on the long arm of chromosome 17, codes for a protein with the characteristics of a growth factor receptor. In a preliminary study, we reported that high levels of tumor HER2 (erbB-2/neu) protein are associated with a family history of breast cancer (that is, one or more female blood relatives with breast cancer). We have now collected a larger number of subjects (94) and performed a multivariate analysis of the independent variables family history of breast cancer, tumor estrogen receptor, age, and tumor DNA index. Family history of breast cancer was assessed by questioning the patient, in many cases by telephone. HER2 levels were significantly higher in women with a family history of breast cancer (p = 0.015, two-tailed t-test). The 27 women with family history were predominantly postmenopausal, mean age 61 +/- 2.3 (mean +/- SEM), versus a mean age of 56 +/- 1.7 for the 67 women with no family history. Of the 27 women with a family history of breast cancer, 13 had a first-degree relative (mother or sister) with the disease. The remaining 14 women had other relatives (grandmothers, aunts, cousins, or a niece) with breast cancer. The results of multiple linear regression analysis, with HER2 as the dependent variable, showed that family history of breast cancer was significantly associated with elevated HER2 levels in the tumors (p = 0.0038), after controlling for the effects of age, tumor estrogen receptor, and DNA index. The association of family history of breast cancer and elevated tumor HER2 protein suggests that postmenopausal familial breast cancer may be associated with altered HER2 expression. Double heterozygosity (DH) for BRCA1 and BRCA2 mutations is a very rare finding, particularly in non-Ashkenazi individuals, and only a few cases have been reported to date. In addition, little is known on the pathological features of the tumors that occur in DH cases and on their family history of cancer. Four carriers of pathogenic mutations in both BRCA1 and BRCA2 were identified among women who underwent genetic counseling for hereditary susceptibility to breast and ovarian carcinoma at three different Italian institutions. Clinical, pathological, and family history data were collected from medical records and during genetic counseling sessions. All identified DH cases developed breast carcinoma and three of them were also diagnosed with ovarian carcinoma. Mean ages of breast and ovarian cancer diagnosis were 42.7 and 48.6 years, respectively. The majority of breast cancers showed a BRCA1-related phenotype, being negative for hormone receptors and HER2. Two cases reported different gastrointestinal tumors among relatives. Although the individuals described in this study show more severe clinical features in comparison to previously reported BRCA1 and BRCA2 DH cases, our observations support the hypothesis of a non specific phenotype of DH cases in terms of age of disease onset. In addition, our observations indicate that in DH patients breast carcinogenesis appears to be driven mainly by the mutations in BRCA1. The possible association of DH for BRCA gene mutations with gastrointestinal tumors is in keeping with previous reports, but needs to be confirmed by further analyses. Eight-hundred and thirteen patients were prospectively studied to examine the influence of family history and the prior use of exogenous hormones as covariables in the subsequent expression of estrogen receptor protein (ERP) in the primary tumor of patients with breast cancer. Cases were divided by menstrual status; there were 385 pre- and perimenopausal and 428 postmenopausal patients. The influence of prior exposure to estrogen replacement therapy (ERT) in postmenopausal patients or oral contraceptives (OC) in pre- and perimenopausal patients on tumor ERP was analyzed controlling for family history: none, first degree (1 degree, mother or sister), second degree (2 degrees, grandmother or aunt), or both 1 degree and 2 degrees relatives. The results showed no influence of the prior use of ERT in postmenopausal women on subsequent tumor ERP. Among pre- and perimenopausal women, those with a family history of breast cancer in only a 1 degree relative, showed a borderline significant association between prior OC usage and subsequent tumor ERP. The use of OC was consistently associated with ERP negative tumors (9/9) whereas of 29 patients who had no prior OC exposure 17 had ERP negative tumors (P = 0.04, Fisher's Exact Test). Analysis of the prior exposure to OC, verified with the primary care physician or pharmacist, showed that these patients first used OC at the mean age of 32.2 years, had used OC for a mean duration of 41.9 months and stopped OC use a mean of 79.5 months before being diagnosed as having breast cancer. These results suggest that in a subset of patients with breast cancer, and a first degree relative only who had breast cancer, prior exposure to OC may influence the subsequent ERP status of the tumor. This is not due to exogenous estrogen saturation of receptors as there was a long latent period between exposure and diagnosis. Alternative hypotheses as to the mechanism of selection of subsequent tumor ERP may be either inhibition of ERP positive preneoplastic or tumor cell clones early in the evolution of the tumor or early selection of a tumor capable of endogenous estrogen synthesis with receptor saturation. Ductal carcinoma in situ (DCIS) is considered a component of the clinical spectrum of breast cancer even in those with BRCA1/2 mutation. The aim of this study was to report the feature of DCIS raised in Japanese women with BRCA1/2 mutations. A total of 325 Japanese women with breast cancer (BC) (with or without invasive cancer) were referred for genetic counseling and underwent genetic testing for mutations in the BRCA1 and BRCA2 genes in Showa University Hospital between December 2011 and August 2016. And 49 of them who were pathologically diagnosed as DCIS were included in this study. Logistic regression models were fit to determine the associations between potential predictive factors and BRCA status. A Cox proportional hazards model is used to predictive value of parameters for Ipsilateral breast tumor recurrence (IBTR) and contralateral breast tumor recurrence (CBTR). (a) Of 325 patients (with or without invasive cancer), 19.1% (62/325) tested positive for BRCA1/BRCA2 mutations. And 18.4% (9/49) was positive for BRCA1/BRCA2 mutations in DCIS, compared with 19.2% (53/276) in IDC (p = 1.000). Among BRCA mutations, 14.5% (9/62) had DCIS compared with nonmutations (15.2%, 40/263). Incidence of DCIS was 3.0% (1/33) of BRCA1 mutations and 27.5% (8/29) of BRCA2 mutation (p = 0.009). (b) Median age of diagnosis in BRCA mutation carriers was 39 years, compared with 46 years in noncarriers. Age, Family history (FH) of BC, FH of first or second BC and total number of relatives with BC diagnosis (DX) has significant difference between BRCA mutation carriers and noncarriers in univariate analysis. In a multivariate logistic model, total relatives with BC DX ≥ 2 (odds ratio [OR], 5.128; 95% confidence interval [CI], 1.266-20.763; p = 0.022), age at diagnosis ≤35 years (OR 0.149, 95% CI 0.023-0.954, p = 0.045) and ER+/HER2+ status (OR 5.034, 95% CI 1.092-23.210, p = 0.038) remained as independent significant predictors for BRCA mutation. Ki67 index (cut off by 14% or 30%) did not differ between BRCA mutation carriers and noncarriers (p = 0.459 and p = 0.651). (c) There was a significant difference in ER-positive tumors among BRCA2 carriers and noncarriers (p = 0.042). Subgroup analysis showed BRCA2 carriers tend to be of higher grade (Grade 2 and 3), more frequently ER+/PR+ (p = 0.041) and lower proliferation (Ki67 index) than noncarriers, whereas differences in nuclear grade and ki67 index were not found significantly in our study. (d) BRCA mutation was not associated with an increased risk of IBTR and CBTR. DCIS is equally as prevalent in patients who were BRCA mutation carriers as in high familial-risk women who were noncarriers, but occurs at earlier age. BRCA2 carriers have higher incidence in DCIS than that of BRCA1 carriers, and tend to be higher grade and more frequently ER positive and lower proliferation. Total relatives with BC DX ≥2, age at diagnosis ≤35 years and ER+/HER2+ might be independent predictors for BRCA mutation in Japanese women with DCIS and patients of these risk factors should be recommended to receive genetic counseling and BRCA testing. other components of the endocrine system and nervous system, so it can be drawn that the receptor family has great influence among these systems. The family was first discovered in a segment of a rat's pituitary gland known as the tumor cell line. A cell line is grown as a culture under controlled conditions, so the first discovery was found by culturing these cells in controlled conditions and in an environment outside of its norm. There, researchers found that the tumor cell line expresses a cell dividing inhibitor known as the transforming growth factor beta (TGF-beta) and also acts as an inhibitor to the milk producing hormone in female mammals, prolactin, and growth hormones. Researchers studied the activity of the receptors by conducting an assay with Ligand binding studies, which basically means they were conducting studies to see how prevalent the binding of the receptors occurred. Differences in how prevalently they receptors bonded revealed the existence of multiple A few studies have suggested a relatively better prognosis for breast cancer (BC) cases reporting a positive family history (FH). We aimed at comparing the survival of patients according to FH in a large hospital-based series of 1,278 BC cases. Information on FH for BC was obtained at diagnosis by interview. All cases reporting a first- or second-degree FH for breast carcinoma were compared with cases without FH. Overall survival was estimated using a product-limit method. Hazard ratios (HRs) and the corresponding 95% confidence intervals (95% CIs), adjusted for confounding factors, were computed using proportional hazard models. Overall, 240 (18.8%) cases reporting, at diagnosis, a positive FH (156 with at least 1 first-degree relative and 84 with at least 1 second-degree relative) were compared with 1,038 patients without FH for BC. No significant differences were found in terms of distribution of age at diagnosis, tumor stage, nodal involvement, receptor status and histology. Cumulative survival rates at 5 years for cases without FH and with first-degree and second-degree FH for BC were 79.8 (95% CI 77.0-83.0), 78.6 (95% CI 70.0-88.0) and 80.2 (95% CI 68.0-92.0), respectively (log-rank test, chi(2) (2) = 0.02, p = 1.0). After adjustment for age, pathologic size and nodal involvement, the HR among cases of invasive cancer with a first-degree FH of BC was 0.91 (95% CI 0.55-1.48); however, the HR for cases with second-degree FH was 1.18 (95% CI 0.62-2.25) compared to cases without FH. Our study, based on a large series of consecutive invasive BC cases, did not find any significant survival differences associated with a positive FH for breast carcinoma, suggesting the existence of a large heterogeneity among BC cases with FH. Pemetrexed has been shown to improve survival in non-squamous cell NSCLC, and is the first drug to reveal differential survival benefit in large cell lung carcinoma. C-SCLC appear to express female hormone (i.e. estrogen and/or progesterone) receptors in a high (50–67%) proportion of cases, similar to breast carcinomas. However, it is at present unknown whether blockade of these receptors affects the growth of c-SCLC. Prognosis Current consensus is that the long-term prognosis of c-SCLC patients is determined by the SCLC component of their tumor, given that \"pure\" SCLC seems to have the worst long-term prognosis of all forms of lung cancer. Although data on c-SCLC is very sparse, some studies suggest that survival rates in c-SCLC may be even worse than that of pure SCLC, likely due to the lower rate of complete response to chemoradiation in c-SCLC, although not all studies have shown a significant difference in survival. This study was conducted to acquire information as to the clinicopathological characteristics of breast cancer patients with family history. Of 583 patients with breast cancer, 60 (10.3%) had family history in at least one relative within the second-degree. The affected family member was most frequently a sister (43%), followed by the mother (23%) and an aunt (20%). Comparison of the data for the patients between with and without family history revealed no significant differences for any of mean age, menopausal status, histological type, histological staging, and estrogen receptor status. Although the sample size was small, neither the survival rate nor the bilaterality of disease was influenced by the family history of breast cancer. Few studies have systematically reported the relationship between the risk of breast cancer and family history of other cancers. This study was designed to systematically determine the relationship between breast cancer risk and family history of other cancers in first-degree relatives. Between January 2006 and June 2011, 823 women diagnosed with breast cancer were included, and age-matched women diagnosed with benign breast disease were selected as controls. Family history of other cancers in first-degree relatives was recorded by trained reviewers. Multivariate logistic regression was applied to analyze the relationships. A family history of esophagus cancer (OR: 2.70, 95% CI: 1.11 - 6.57), lung cancer (OR: 2.49 95% CI: 1.10 - 5.65), digestive system cancer (OR: 1.79, 95% CI: 1.14 - 2.79) and any cancer (OR: 2.13, 95% CI: 1.49 - 3.04) in first-degree relatives was directly associated with increased breast cancer risk. In subgroup analysis, the risk of hormone receptor positive breast cancer was increased in subjects with a family history of lung cancer (OR: 3.37, 95% CI: 1.45 - 7.82), while the risk of hormone receptor negative breast cancer was increased in subjects with a family history of esophagus cancer (OR: 6.19, 95% CI: 2.30 - 16.71), uterus cancer (OR: 6.92, 95% CI: 1.12 - 42.89), digestive tract cancer (OR: 2.05, 95% CI: 1.03 - 4.10) and gynecology cancer (OR: 6.79, 95% CI: 1.46 - 31.65). Additionally, a significant increase in breast cancer was observed with a family history of digestive system cancer for subjects 50 y and younger (OR: 1.88, 95% CI: 1.03 - 3.43), not for subjects 50 y older (OR: 1.67, 95% CI: 0.86 - 3.25). Breast cancer aggregates in families with several types of cancer especially for digestive system cancer. The influence of a family history of other cancers seems more likely to be limited to hormone receptor negative breast cancer. Tamoxifen is a first-line hormonal treatment of ER-positive metastatic breast cancer. It is used for breast cancer risk reduction in women at high risk, and as adjuvant treatment of axillary node-negative and node-positive, ductal carcinoma in situ. Tamoxifen treatment is also useful in the treatment of bone density and blood lipids in postmenopausal women. Adverse effects include hot flushes and more serious is two to three times higher relative risk of developing endometrial cancer compared to women of an age-matched population. Toremifene, a chlorinated tamoxifen derivative, causes fewer DNA adducts in liver than seen with tamoxifen in preclinical studies and was developed to avoid hepatic carcinomas. It is used as endocrine therapy in women with ER/PR-positive stage 4 or recurrent metastatic breast cancer and has demonstrated similar efficacy compared to tamoxifen as adjuvant treatment of breast cancer and in the treatment of metastatic breast cancer. Breast cancer patients were classified in the family history positive (FHP) group when they had at least one second-degree relative who was a breast cancer patient. The results of a comparative study with patients classified in the family history negative (FHN) group showed the prognosis of the FHP group was significantly better than that of the FHN group. However, when those patients were classified according to their menopausal status at onset, there were no significant differences in survival rates between the FHP and FHN groups with onset before menopause, whereas the survival rate of the FHP group was significantly higher than that of the FHN group with onset after menopause. The same results were found when the FHP group was subgrouped into the FHP group with first-degree relatives and the FHP group with second-degree relatives. Further investigations on background factors revealed that the patients with onset before menopause showed no significant differences between the FHP and FHN groups in age at surgery, diameter of the tumor, histologic grade, the number of metastatic lymph nodes, body weight, estrogen receptor (ER) status, and the values of CEA and CA15-3 before surgery. On the other hand, the FHP patients with onset after menopause showed significantly lower numbers of metastatic lymph nodes and trends showing higher ER values and lower CA15-3-values. Therefore the favorable prognosis in the FHP group seems to be attributable to the higher survival rate of the FHP patients with onset after menopause. Metaplastic carcinoma, otherwise known as metaplastic carcinoma of the breast (MCB), is a heterogeneous group of cancers that exhibit varied patterns of metaplasia and differentiation along multiple cell lines. This rare and aggressive form of breast cancer is characterized as being composed of a mixed group of neoplasms containing both glandular and non-glandular patterns with epithelial and/or mesenchymal components. It accounts for fewer than 1% of all breast cancer diagnoses. It is most closely associated with invasive ductal carcinoma of no special type. (IDC), and shares similar treatment approaches. Relative to IDC, MCB generally has higher histological grade and larger tumor size at time of diagnosis, with a lower incidence of axillary lymph node involvement. MCB tumors are typically estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor-2 (HER-2) negative, meaning hormone therapy is generally not an effective treatment option, which correlates to As of early 2016, abemaciclib was involved in 3 Phase III clinical trials: The JUNIPER Study is comparing abemaciclib against erlotinib in patients with stage IV non-small-cell lung carcinoma Due to collect data until September 2017. The MONARCH 2 study is investigating the effectiveness of abemaciclib in combination with fulvestrant for women with breast cancer. It is due to end in Feb 2017. In March 2017, Eli Lilly announced that it had met its primary endpoint of superior progression-free survival (PFS) over placebo plus fulvestrant in patients with estrogen receptor positive and HER2 negative advanced or metastatic breast cancer. This result led to the September 2017 FDA approval. The MONARCH 3 study is investigating the effectiveness of abemaciclib, plus either anastrozole or letrozole, as a first-line treatment for women with breast cancer. The trial is expected to end in June 2017. <bBackground:</b Incidence rates of <iin situ</i breast carcinomas have increased due to widespread adoption of mammography. Very little is known about why some women with <iin situ</i breast cancer later develop second primary breast cancers.<bMethods:</b In this population-based nested case-control study among <iin situ</i breast cancer survivors, including 539 cases with a second primary breast cancer and 994 matched controls, we evaluated the association between first-degree family history of breast cancer and risk of developing a second primary breast cancer.<bResults:</b First-degree family history of breast cancer was associated with an increased risk of developing a second primary breast cancer among women with a previous <iin situ</i breast cancer [odds ratio (OR) = 1.33, 95% confidence interval (CI), 1.05-1.69] and those with two or more affected first-degree relatives had an even higher risk (OR = 1.94; 95% CI, 1.15-3.28). Those whose relative was diagnosed at less than 50 years old were more likely to develop a second primary breast cancer (OR = 1.78; 95% CI, 1.24-2.57). No difference in risks associated with number or age of affected relatives was observed by menopausal status.<bConclusions:</b Results from this study suggest that first-degree family history of breast cancer may be an important risk factor for development of a second primary breast cancer among women with a previous <iin situ</i breast cancer.<bImpact:</b Given the growing population of <iin situ</i breast cancer survivors, a better understanding of risk factors associated with development of a second primary breast cancer is needed to further understand risk. <iCancer Epidemiol Biomarkers Prev; 27(3); 315-20. ©2018 AACR</i.\nHere is the question:\nONCOLOGY (ECTOPIC): A 67-year-old woman diagnosed with an infiltrating ductal carcinoma of the breast with no family history of neoplasia. What additional studies should be performed on the tumor because of its clinical and therapeutic implications:\nHere are the potential choices:\n1. Complete phenotypic study by flow cytometry.\n2. Study of hormone receptors and HER2.\n3. Study of hormone receptors, ecadherin and study of first degree relatives.\n4. BRCA l-2 study and study of first-degree relatives.\nThe correct answer is: ",
        "gold_answer": "2 Study of hormone receptors and HER2.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The aim was to assess the association of histological tumor grade with other clinical features and epidemiological factors of women with invasive breast carcinoma. A retrospective study of 103 Mizo breast cancer patients visiting hospitals was made in Aizawl, Mizoram, Northeast India. With a prior consent, information on epidemiological factors and family history in relation to cancer was obtained. Clinical reports were obtained from their medical records. The frequency of distribution was calculated for age at diagnosis and tumor characteristics. Statistical analysis for different variables was done using a chi-square test. p &lt; 0.05 was considered significant. The histological tumor grades in our studies were found to be associated with lymph node invasion (p &lt; 0.021), different subtype of hormone receptor such as ER status (p &lt; 0.004), ER/PR status (p &lt; 0.007), HER2/neu status (p &lt; 0.014), and ER/PR/HER2 status (p &lt; 0.025). A patient with a family history of breast cancer in their 1st degree relative is also seen to have association in determining the tumor grade (p &lt; 0.003). Reproductive history, lifestyle and dietary habits, tobacco, and alcohol consumption were found to have no influence on breast cancer tumor grade. Our results showing significant correlation between status of lymph node, ER, PR, and HER2/neu oncoprotein and family history with 1st degree relative breast cancer are the first time report to target and focus on the possible role of biomarkers for diagnosis among the Mizo tribal breast cancer patients. Since the risk of carcinoma of the breast is increased in women with a family history of the disease, new primary carcinomas of the breast may be increased after treatment. Women with several relatives with carcinoma of the breast are thought to be at higher risk of having a second primary carcinoma of the breast develop and mastectomy is more frequently recommended. The computerized registry of the Mount Sinai Medical Center Breast Service was used to identify 1,337 patients with complete information concerning family history. Three hundred fifty-nine patients with a family history of carcinoma of the breast were compared with women with no family history. Compared with patients with no family history of carcinoma of the breast, patients with a family history of carcinoma of the breast were significantly younger (54.0 versus 55.8 years of age, p &lt; 0.01), were significantly more likely to have used oral contraceptives (26 versus 13 percent, p &lt; 0.001), had significantly more ductal carcinoma in situ (10 versus 4 percent, p &lt; 0.01), and were significantly more often treated with breast conservation (42 versus 31 percent, p &lt; 0.001). Simultaneous contralateral carcinoma of the breast was diagnosed more frequently in patients with a family history (3 versus 1 percent, p &lt; 0.025), but metachronous contralateral carcinomas were not increased. In comparing the two groups, there were no significant differences in proportion premenopausal, parity, use of postmenopausal hormones, tumor size, tumor differentiation, nodal involvement, TNM stage, estrogen receptor status, or use of adjuvant radiation, chemotherapy, or tamoxifen. Complete five-year follow-up evaluation for 748 patients, 179 with a family history, found no differences in local, distant, or disease-free survival rates for mastectomy or breast conservation in relation to family history. Outcome for patients with first-degree affected relatives and those with more than one affected relative was the same as those with no family history. These results indicate that women with a family history of carcinoma of the breast should be treated no differently than women with no family history. Relative indications for testing for a mutation in BRCA1 or BRCA2 for newly diagnosed or family members include a family history among 1st (FDR), 2nd (SDR), or 3rd(TDR) degree relatives usually on the same side of the family but not limited: A known mutation (BRCA1 or BRCA2) in a cancer susceptibility gene within the family Women affected with any breast cancer diagnosed under the age of 30 Women affected with triple negative breast cancer (TNBC) (estrogen receptor negative, progesterone receptor negative, and HER2/neu negative) under the age of 50 Two relatives (FDR/SDR) diagnosed under the age of 45 Three relatives (FDR/SDR) diagnosed with average age of 50 or less Four relatives at any ages Ovarian cancer with either an additional diagnosed relative or a relative with male breast cancer A single family member with both breast and ovarian cancer Male breast cancer Pancreatic cancer with breast or ovarian cancer in the same individual or on the same side of the family Triple-negative breast cancer accounts for less than 20% of breast cancers overall, but is the predominant subtype among carriers of mutations in BRCA1. However, few studies have assessed the association between breast cancer family history and risk of triple-negative breast cancer. We examined the relationship between having a family history of breast cancer in first-degree relatives and risk of triple-negative breast cancer, and risk of two other breast cancer subtypes defined by tumor marker expression. We evaluated data collected by the Breast Cancer Surveillance Consortium from 2,599,946 mammograms on 1,054,466 women, among whom 15% reported a first-degree family history of breast cancer. Using Cox regression in this cohort, we evaluated subtype-specific associations between family history and risk of triple-negative (N = 705), estrogen receptor-positive (ER+, N = 10,026), and hormone receptor-negative/HER2-expressing (ER-/PR-/HER2+, N = 308) breast cancer among women aged 40-84 years. First-degree family history was similarly and significantly associated with an increased risk of all the subtypes [hazard ratio (HR) = 1.73, 95% confidence interval (CI): 1.43-2.09, HR = 1.62, 95% CI: 1.54-1.70, and HR = 1.56, 95% CI: 1.15-2.13, for triple-negative, ER+, and ER-/PR-/HER2+, respectively]. Risk of all the subtypes was most pronounced among women with at least two affected first-degree relatives (versus women with no affected first-degree relatives, HR(triple-negative) = 2.66, 95% CI: 1.66-4.27, HR(ER+) = 2.05, 95% CI: 1.79-2.36, HR(ER)-(/PR)-(/HER2+) = 2.25, 95% CI: 0.99-5.08). Having a first-degree family history of breast cancer was associated with an increased risk of triple-negative breast cancer with a magnitude of association similar to that for the predominant ER+ subtype and ER-/PR-/HER2+ breast cancer. The objective of this study was to examine the association of: (i) diagnosis at age &lt;/=35, (ii) first-degree family history of breast or ovarian cancer (BOC) and (iii) a research based definition of genetic risk, with tumor characteristics, treatment and survival in breast cancer (BC). Consenting female participants in the population-based Ontario Familial Breast Cancer Registry diagnosed with primary invasive BC between 1996 and 1998 were followed prospectively until 2005. Among 967 women, 105 were &lt;/=35 years old at diagnosis and 686 were classified as genetic risk cases, including 349 with a first-degree family history. Individuals diagnosed at age &lt;/=35 were more likely to self-detect tumors, to present with inflammatory BC, to have invasive ductal carcinoma of no special type, high T stage, and tumors with lymphovascular invasion (LVI), high grade and negative estrogen receptors. Younger women were more likely to receive chemotherapy and less likely to receive hormonal therapy. Diagnosis &lt;/=35 years old was associated with significantly reduced distant recurrence free survival, an effect that did not persist after adjustment for tumor and treatment related variables. Poor outcomes were restricted to younger women with hormone responsive BC. Family history was associated with increased rates of mammographic detection of BC, lower tumor stage and less frequent inflammatory BC, but had no association with BC outcomes. Women diagnosed with BC at age &lt;/=35 have more aggressive tumors; these adverse tumor characteristics, rather than age, lead to poor outcomes. Family history was not associated with survival. The HER2 gene, located on the long arm of chromosome 17, codes for a protein with the characteristics of a growth factor receptor. In a preliminary study, we reported that high levels of tumor HER2 (erbB-2/neu) protein are associated with a family history of breast cancer (that is, one or more female blood relatives with breast cancer). We have now collected a larger number of subjects (94) and performed a multivariate analysis of the independent variables family history of breast cancer, tumor estrogen receptor, age, and tumor DNA index. Family history of breast cancer was assessed by questioning the patient, in many cases by telephone. HER2 levels were significantly higher in women with a family history of breast cancer (p = 0.015, two-tailed t-test). The 27 women with family history were predominantly postmenopausal, mean age 61 +/- 2.3 (mean +/- SEM), versus a mean age of 56 +/- 1.7 for the 67 women with no family history. Of the 27 women with a family history of breast cancer, 13 had a first-degree relative (mother or sister) with the disease. The remaining 14 women had other relatives (grandmothers, aunts, cousins, or a niece) with breast cancer. The results of multiple linear regression analysis, with HER2 as the dependent variable, showed that family history of breast cancer was significantly associated with elevated HER2 levels in the tumors (p = 0.0038), after controlling for the effects of age, tumor estrogen receptor, and DNA index. The association of family history of breast cancer and elevated tumor HER2 protein suggests that postmenopausal familial breast cancer may be associated with altered HER2 expression. Double heterozygosity (DH) for BRCA1 and BRCA2 mutations is a very rare finding, particularly in non-Ashkenazi individuals, and only a few cases have been reported to date. In addition, little is known on the pathological features of the tumors that occur in DH cases and on their family history of cancer. Four carriers of pathogenic mutations in both BRCA1 and BRCA2 were identified among women who underwent genetic counseling for hereditary susceptibility to breast and ovarian carcinoma at three different Italian institutions. Clinical, pathological, and family history data were collected from medical records and during genetic counseling sessions. All identified DH cases developed breast carcinoma and three of them were also diagnosed with ovarian carcinoma. Mean ages of breast and ovarian cancer diagnosis were 42.7 and 48.6 years, respectively. The majority of breast cancers showed a BRCA1-related phenotype, being negative for hormone receptors and HER2. Two cases reported different gastrointestinal tumors among relatives. Although the individuals described in this study show more severe clinical features in comparison to previously reported BRCA1 and BRCA2 DH cases, our observations support the hypothesis of a non specific phenotype of DH cases in terms of age of disease onset. In addition, our observations indicate that in DH patients breast carcinogenesis appears to be driven mainly by the mutations in BRCA1. The possible association of DH for BRCA gene mutations with gastrointestinal tumors is in keeping with previous reports, but needs to be confirmed by further analyses. Eight-hundred and thirteen patients were prospectively studied to examine the influence of family history and the prior use of exogenous hormones as covariables in the subsequent expression of estrogen receptor protein (ERP) in the primary tumor of patients with breast cancer. Cases were divided by menstrual status; there were 385 pre- and perimenopausal and 428 postmenopausal patients. The influence of prior exposure to estrogen replacement therapy (ERT) in postmenopausal patients or oral contraceptives (OC) in pre- and perimenopausal patients on tumor ERP was analyzed controlling for family history: none, first degree (1 degree, mother or sister), second degree (2 degrees, grandmother or aunt), or both 1 degree and 2 degrees relatives. The results showed no influence of the prior use of ERT in postmenopausal women on subsequent tumor ERP. Among pre- and perimenopausal women, those with a family history of breast cancer in only a 1 degree relative, showed a borderline significant association between prior OC usage and subsequent tumor ERP. The use of OC was consistently associated with ERP negative tumors (9/9) whereas of 29 patients who had no prior OC exposure 17 had ERP negative tumors (P = 0.04, Fisher's Exact Test). Analysis of the prior exposure to OC, verified with the primary care physician or pharmacist, showed that these patients first used OC at the mean age of 32.2 years, had used OC for a mean duration of 41.9 months and stopped OC use a mean of 79.5 months before being diagnosed as having breast cancer. These results suggest that in a subset of patients with breast cancer, and a first degree relative only who had breast cancer, prior exposure to OC may influence the subsequent ERP status of the tumor. This is not due to exogenous estrogen saturation of receptors as there was a long latent period between exposure and diagnosis. Alternative hypotheses as to the mechanism of selection of subsequent tumor ERP may be either inhibition of ERP positive preneoplastic or tumor cell clones early in the evolution of the tumor or early selection of a tumor capable of endogenous estrogen synthesis with receptor saturation. Ductal carcinoma in situ (DCIS) is considered a component of the clinical spectrum of breast cancer even in those with BRCA1/2 mutation. The aim of this study was to report the feature of DCIS raised in Japanese women with BRCA1/2 mutations. A total of 325 Japanese women with breast cancer (BC) (with or without invasive cancer) were referred for genetic counseling and underwent genetic testing for mutations in the BRCA1 and BRCA2 genes in Showa University Hospital between December 2011 and August 2016. And 49 of them who were pathologically diagnosed as DCIS were included in this study. Logistic regression models were fit to determine the associations between potential predictive factors and BRCA status. A Cox proportional hazards model is used to predictive value of parameters for Ipsilateral breast tumor recurrence (IBTR) and contralateral breast tumor recurrence (CBTR). (a) Of 325 patients (with or without invasive cancer), 19.1% (62/325) tested positive for BRCA1/BRCA2 mutations. And 18.4% (9/49) was positive for BRCA1/BRCA2 mutations in DCIS, compared with 19.2% (53/276) in IDC (p = 1.000). Among BRCA mutations, 14.5% (9/62) had DCIS compared with nonmutations (15.2%, 40/263). Incidence of DCIS was 3.0% (1/33) of BRCA1 mutations and 27.5% (8/29) of BRCA2 mutation (p = 0.009). (b) Median age of diagnosis in BRCA mutation carriers was 39 years, compared with 46 years in noncarriers. Age, Family history (FH) of BC, FH of first or second BC and total number of relatives with BC diagnosis (DX) has significant difference between BRCA mutation carriers and noncarriers in univariate analysis. In a multivariate logistic model, total relatives with BC DX ≥ 2 (odds ratio [OR], 5.128; 95% confidence interval [CI], 1.266-20.763; p = 0.022), age at diagnosis ≤35 years (OR 0.149, 95% CI 0.023-0.954, p = 0.045) and ER+/HER2+ status (OR 5.034, 95% CI 1.092-23.210, p = 0.038) remained as independent significant predictors for BRCA mutation. Ki67 index (cut off by 14% or 30%) did not differ between BRCA mutation carriers and noncarriers (p = 0.459 and p = 0.651). (c) There was a significant difference in ER-positive tumors among BRCA2 carriers and noncarriers (p = 0.042). Subgroup analysis showed BRCA2 carriers tend to be of higher grade (Grade 2 and 3), more frequently ER+/PR+ (p = 0.041) and lower proliferation (Ki67 index) than noncarriers, whereas differences in nuclear grade and ki67 index were not found significantly in our study. (d) BRCA mutation was not associated with an increased risk of IBTR and CBTR. DCIS is equally as prevalent in patients who were BRCA mutation carriers as in high familial-risk women who were noncarriers, but occurs at earlier age. BRCA2 carriers have higher incidence in DCIS than that of BRCA1 carriers, and tend to be higher grade and more frequently ER positive and lower proliferation. Total relatives with BC DX ≥2, age at diagnosis ≤35 years and ER+/HER2+ might be independent predictors for BRCA mutation in Japanese women with DCIS and patients of these risk factors should be recommended to receive genetic counseling and BRCA testing. other components of the endocrine system and nervous system, so it can be drawn that the receptor family has great influence among these systems. The family was first discovered in a segment of a rat's pituitary gland known as the tumor cell line. A cell line is grown as a culture under controlled conditions, so the first discovery was found by culturing these cells in controlled conditions and in an environment outside of its norm. There, researchers found that the tumor cell line expresses a cell dividing inhibitor known as the transforming growth factor beta (TGF-beta) and also acts as an inhibitor to the milk producing hormone in female mammals, prolactin, and growth hormones. Researchers studied the activity of the receptors by conducting an assay with Ligand binding studies, which basically means they were conducting studies to see how prevalent the binding of the receptors occurred. Differences in how prevalently they receptors bonded revealed the existence of multiple A few studies have suggested a relatively better prognosis for breast cancer (BC) cases reporting a positive family history (FH). We aimed at comparing the survival of patients according to FH in a large hospital-based series of 1,278 BC cases. Information on FH for BC was obtained at diagnosis by interview. All cases reporting a first- or second-degree FH for breast carcinoma were compared with cases without FH. Overall survival was estimated using a product-limit method. Hazard ratios (HRs) and the corresponding 95% confidence intervals (95% CIs), adjusted for confounding factors, were computed using proportional hazard models. Overall, 240 (18.8%) cases reporting, at diagnosis, a positive FH (156 with at least 1 first-degree relative and 84 with at least 1 second-degree relative) were compared with 1,038 patients without FH for BC. No significant differences were found in terms of distribution of age at diagnosis, tumor stage, nodal involvement, receptor status and histology. Cumulative survival rates at 5 years for cases without FH and with first-degree and second-degree FH for BC were 79.8 (95% CI 77.0-83.0), 78.6 (95% CI 70.0-88.0) and 80.2 (95% CI 68.0-92.0), respectively (log-rank test, chi(2) (2) = 0.02, p = 1.0). After adjustment for age, pathologic size and nodal involvement, the HR among cases of invasive cancer with a first-degree FH of BC was 0.91 (95% CI 0.55-1.48); however, the HR for cases with second-degree FH was 1.18 (95% CI 0.62-2.25) compared to cases without FH. Our study, based on a large series of consecutive invasive BC cases, did not find any significant survival differences associated with a positive FH for breast carcinoma, suggesting the existence of a large heterogeneity among BC cases with FH. Pemetrexed has been shown to improve survival in non-squamous cell NSCLC, and is the first drug to reveal differential survival benefit in large cell lung carcinoma. C-SCLC appear to express female hormone (i.e. estrogen and/or progesterone) receptors in a high (50–67%) proportion of cases, similar to breast carcinomas. However, it is at present unknown whether blockade of these receptors affects the growth of c-SCLC. Prognosis Current consensus is that the long-term prognosis of c-SCLC patients is determined by the SCLC component of their tumor, given that \"pure\" SCLC seems to have the worst long-term prognosis of all forms of lung cancer. Although data on c-SCLC is very sparse, some studies suggest that survival rates in c-SCLC may be even worse than that of pure SCLC, likely due to the lower rate of complete response to chemoradiation in c-SCLC, although not all studies have shown a significant difference in survival. This study was conducted to acquire information as to the clinicopathological characteristics of breast cancer patients with family history. Of 583 patients with breast cancer, 60 (10.3%) had family history in at least one relative within the second-degree. The affected family member was most frequently a sister (43%), followed by the mother (23%) and an aunt (20%). Comparison of the data for the patients between with and without family history revealed no significant differences for any of mean age, menopausal status, histological type, histological staging, and estrogen receptor status. Although the sample size was small, neither the survival rate nor the bilaterality of disease was influenced by the family history of breast cancer. Few studies have systematically reported the relationship between the risk of breast cancer and family history of other cancers. This study was designed to systematically determine the relationship between breast cancer risk and family history of other cancers in first-degree relatives. Between January 2006 and June 2011, 823 women diagnosed with breast cancer were included, and age-matched women diagnosed with benign breast disease were selected as controls. Family history of other cancers in first-degree relatives was recorded by trained reviewers. Multivariate logistic regression was applied to analyze the relationships. A family history of esophagus cancer (OR: 2.70, 95% CI: 1.11 - 6.57), lung cancer (OR: 2.49 95% CI: 1.10 - 5.65), digestive system cancer (OR: 1.79, 95% CI: 1.14 - 2.79) and any cancer (OR: 2.13, 95% CI: 1.49 - 3.04) in first-degree relatives was directly associated with increased breast cancer risk. In subgroup analysis, the risk of hormone receptor positive breast cancer was increased in subjects with a family history of lung cancer (OR: 3.37, 95% CI: 1.45 - 7.82), while the risk of hormone receptor negative breast cancer was increased in subjects with a family history of esophagus cancer (OR: 6.19, 95% CI: 2.30 - 16.71), uterus cancer (OR: 6.92, 95% CI: 1.12 - 42.89), digestive tract cancer (OR: 2.05, 95% CI: 1.03 - 4.10) and gynecology cancer (OR: 6.79, 95% CI: 1.46 - 31.65). Additionally, a significant increase in breast cancer was observed with a family history of digestive system cancer for subjects 50 y and younger (OR: 1.88, 95% CI: 1.03 - 3.43), not for subjects 50 y older (OR: 1.67, 95% CI: 0.86 - 3.25). Breast cancer aggregates in families with several types of cancer especially for digestive system cancer. The influence of a family history of other cancers seems more likely to be limited to hormone receptor negative breast cancer. Tamoxifen is a first-line hormonal treatment of ER-positive metastatic breast cancer. It is used for breast cancer risk reduction in women at high risk, and as adjuvant treatment of axillary node-negative and node-positive, ductal carcinoma in situ. Tamoxifen treatment is also useful in the treatment of bone density and blood lipids in postmenopausal women. Adverse effects include hot flushes and more serious is two to three times higher relative risk of developing endometrial cancer compared to women of an age-matched population. Toremifene, a chlorinated tamoxifen derivative, causes fewer DNA adducts in liver than seen with tamoxifen in preclinical studies and was developed to avoid hepatic carcinomas. It is used as endocrine therapy in women with ER/PR-positive stage 4 or recurrent metastatic breast cancer and has demonstrated similar efficacy compared to tamoxifen as adjuvant treatment of breast cancer and in the treatment of metastatic breast cancer. Breast cancer patients were classified in the family history positive (FHP) group when they had at least one second-degree relative who was a breast cancer patient. The results of a comparative study with patients classified in the family history negative (FHN) group showed the prognosis of the FHP group was significantly better than that of the FHN group. However, when those patients were classified according to their menopausal status at onset, there were no significant differences in survival rates between the FHP and FHN groups with onset before menopause, whereas the survival rate of the FHP group was significantly higher than that of the FHN group with onset after menopause. The same results were found when the FHP group was subgrouped into the FHP group with first-degree relatives and the FHP group with second-degree relatives. Further investigations on background factors revealed that the patients with onset before menopause showed no significant differences between the FHP and FHN groups in age at surgery, diameter of the tumor, histologic grade, the number of metastatic lymph nodes, body weight, estrogen receptor (ER) status, and the values of CEA and CA15-3 before surgery. On the other hand, the FHP patients with onset after menopause showed significantly lower numbers of metastatic lymph nodes and trends showing higher ER values and lower CA15-3-values. Therefore the favorable prognosis in the FHP group seems to be attributable to the higher survival rate of the FHP patients with onset after menopause. Metaplastic carcinoma, otherwise known as metaplastic carcinoma of the breast (MCB), is a heterogeneous group of cancers that exhibit varied patterns of metaplasia and differentiation along multiple cell lines. This rare and aggressive form of breast cancer is characterized as being composed of a mixed group of neoplasms containing both glandular and non-glandular patterns with epithelial and/or mesenchymal components. It accounts for fewer than 1% of all breast cancer diagnoses. It is most closely associated with invasive ductal carcinoma of no special type. (IDC), and shares similar treatment approaches. Relative to IDC, MCB generally has higher histological grade and larger tumor size at time of diagnosis, with a lower incidence of axillary lymph node involvement. MCB tumors are typically estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor-2 (HER-2) negative, meaning hormone therapy is generally not an effective treatment option, which correlates to As of early 2016, abemaciclib was involved in 3 Phase III clinical trials: The JUNIPER Study is comparing abemaciclib against erlotinib in patients with stage IV non-small-cell lung carcinoma Due to collect data until September 2017. The MONARCH 2 study is investigating the effectiveness of abemaciclib in combination with fulvestrant for women with breast cancer. It is due to end in Feb 2017. In March 2017, Eli Lilly announced that it had met its primary endpoint of superior progression-free survival (PFS) over placebo plus fulvestrant in patients with estrogen receptor positive and HER2 negative advanced or metastatic breast cancer. This result led to the September 2017 FDA approval. The MONARCH 3 study is investigating the effectiveness of abemaciclib, plus either anastrozole or letrozole, as a first-line treatment for women with breast cancer. The trial is expected to end in June 2017. <bBackground:</b Incidence rates of <iin situ</i breast carcinomas have increased due to widespread adoption of mammography. Very little is known about why some women with <iin situ</i breast cancer later develop second primary breast cancers.<bMethods:</b In this population-based nested case-control study among <iin situ</i breast cancer survivors, including 539 cases with a second primary breast cancer and 994 matched controls, we evaluated the association between first-degree family history of breast cancer and risk of developing a second primary breast cancer.<bResults:</b First-degree family history of breast cancer was associated with an increased risk of developing a second primary breast cancer among women with a previous <iin situ</i breast cancer [odds ratio (OR) = 1.33, 95% confidence interval (CI), 1.05-1.69] and those with two or more affected first-degree relatives had an even higher risk (OR = 1.94; 95% CI, 1.15-3.28). Those whose relative was diagnosed at less than 50 years old were more likely to develop a second primary breast cancer (OR = 1.78; 95% CI, 1.24-2.57). No difference in risks associated with number or age of affected relatives was observed by menopausal status.<bConclusions:</b Results from this study suggest that first-degree family history of breast cancer may be an important risk factor for development of a second primary breast cancer among women with a previous <iin situ</i breast cancer.<bImpact:</b Given the growing population of <iin situ</i breast cancer survivors, a better understanding of risk factors associated with development of a second primary breast cancer is needed to further understand risk. <iCancer Epidemiol Biomarkers Prev; 27(3); 315-20. ©2018 AACR</i.\nHere is the question:\nONCOLOGY (ECTOPIC): A 67-year-old woman diagnosed with an infiltrating ductal carcinoma of the breast with no family history of neoplasia. What additional studies should be performed on the tumor because of its clinical and therapeutic implications:\nHere are the potential choices:\n1. Complete phenotypic study by flow cytometry.\n2. Study of hormone receptors and HER2.\n3. Study of hormone receptors, ecadherin and study of first degree relatives.\n4. BRCA l-2 study and study of first-degree relatives.\nThe correct answer is: 2. Study of hormone receptors and HER2."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The Apixaban for the Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE), Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY), and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trials demonstrated that the oral anticoagulants (OACs), apixaban, dabigatran, and rivaroxaban, respectively, are efficacious for stroke prevention among nonvalvular atrial fibrillation (NVAF) patients. Based on clinical trial results this study evaluated medical costs of clinical events associated with use of individual OACs relative to those of warfarin in NVAF patients with moderate and high stroke risk. Rates for primary and secondary efficacy and safety outcomes (i.e., clinical events) among NVAF patients with CHADS2 = 2 and ≥3 were determined from the three OAC trials. One-year incremental costs among patients with clinical events from a US payer perspective were obtained from the literature and inflation adjusted to 2010 costs. Medical costs for clinical events associated with each OAC vs. warfarin were estimated and compared. For NVAF patients with moderate stroke risk (CHADS2 = 2) differences in clinical event medical costs vs. warfarin were -$298, -$143, and +$117 per patient year for apixaban, dabigatran (150 mg), and rivaroxaban, respectively (negative numbers indicate cost reduction). For NVAF patients with high stroke risk (CHADS2 ≥ 3) differences in clinical event medical costs vs. warfarin were -$697, +$2, and -$100 for apixaban, dabigatran (150 mg), and rivaroxaban, respectively. Medical cost differences associated with OACs vs. warfarin vary according to stroke risk. Of the three OACs, apixaban demonstrated consistent medical cost reductions vs. warfarin for NVAF patients with moderate and high stroke risks. Atrial fibrillation affects approximately 5 million patients in the United States. The rate of stroke in adults with atrial fibrillation depending on their risk factors varies between 1-20% annually. Anticoagulation with vitamin K antagonists such as warfarin has been the mainstay therapy but it is cumbersome and requires close follow-up. Since 2010, three new oral anticoagulants have received Food and Drug Administration approval for stroke prevention in atrial fibrillation. This review summarizes data from three landmark trials: RE-LY, ROCKET-AF, and ARISTOTLE. In addition, issues relating to cost, reversal, drug interactions, and perioperative discontinuation are discussed. Compared to Warfarin, Dabigatran 150 mg twice daily lowered the primary outcome of stroke/systemic embolism by 34% (number needed to treat/yr 169) and had similar incidence of major bleeding. Rivaroxaban demonstrated non inferiority compared to the warfarin group for the primary outcome of stroke and systemic embolism and major bleeding. Apixaban showed a relative risk reduction for the primary outcome of 21% (number needed to treat 300), and lowered major bleeding down by 31% (number needed to treat /yr 104). Apixaban also showed a mortality benefit compared to warfarin (3.52 vs. 3.94%/year, p 0.047). All 3 oral anticoagulants lowered rates of intracranial hemorrhage. The use of Rivaroxaban and Apixaban has been projected to reduce medical costs when compared to warfarin, and Dabigatran is projected to have similar costs. All the 3 oral anticoagulants have robust randomized controlled trials supporting their comparability to warfarin therapy for stroke prevention in non valvular atrial fibrillation, with Apixaban showing superiority in incidence of strokes, major bleeding and mortality. Nonvalvular atrial fibrillation (NVAF) is frequently seen in elderly people and has become a main cause of cardioembolic stroke. The efficacy of anticoagulation for primary prevention of stroke or transient ischaemic attacks (TIAs) in patients with NVAF has been established by prospective, randomised and controlled trials. Warfarin decreased the frequency of all strokes by 68% and the rate of the combined outcome of stroke, systemic embolism or death by 48%. Anticoagulation with warfarin using international normalised ratios (INRs) ranging from 2.0 to 3.0 is recommended for patients with NVAF, who have any of the risk factors identified by the Atrial Fibrillation Investigators (AFI) [previous stroke or TIA, history of hypertension, diabetes mellitus, advanced age (&gt; or = 65 years old), congestive heart failure and coronary artery disease], the American College of Chest Physicians (ACCP) [increased age (&gt; 75 years old), prior stroke, hypertension and heart failure], or the Stroke Prevention in Atrial Fibrillation (SPAF) investigators [women &gt; 75 years old, prior stroke, systolic blood pressure &gt; 160mm Hg, recent heart failure, and fractional shortening &lt; 25% on echocardiography]. For the secondary prevention of stroke, the efficacy of adjusted-dose warfarin therapy has been demonstrated by 2 major randomised trials. SPAF III (INR 2.0 to 3.0) demonstrated a lower incidence of ischaemic stroke or systemic embolism (3.4 %/year) compared with low fixed-dose warfarin plus aspirin (acetylsalicylic acid) [11.9%]. The European Atrial Fibrillation Trial [EAFT] (INR 2.5 to 4.0) showed a lower incidence of all stroke (4.0 %/year) with adjusted-dose warfarin compared with placebo (12.0 %/year). The incidence of major bleeding in the adjusted-dose warfarin group in SPAF III and EAFT was 2.4 and 2.8 %/year, respectively. EAFT incidence rates for the occurrence of a first ischaemic or haemorrhagic complication analysed by INR range indicated that the rate was lowest at INRs of 2.0 to 2.9, and higher with INRs of 3.0 to 3.9. Therefore, the optimal intensity of anticoagulation for prevention of recurrent stroke seems to be an INR of between 2.0 and 3.0, as for primary prevention. Retrospective and prospective studies from Japan reported that in the elderly, haemorrhagic complications occur frequently with INRs above 2.6 and major ischaemic events cannot be prevented at INRs below 1.6. Therefore, an INR target between 1.6 and 2.6 may be an alternative for secondary prevention of stroke in elderly patients with NVAF who have a potential risk of bleeding, to avoid both major ischaemic and haemorrhagic events. Antiplatelets may be administered in patients who are unable to manage taking warfarin properly or who have a high risk of falling and subsequently sustaining a head injury, although the efficacy of antiplatelets for secondary prevention of stroke in NVAF has not yet been established. Chronic anticoagulation Among patients with nonvalvular AF, anticoagulation with warfarin can reduce stroke by 60% while antiplatelet agents can reduce stroke by 20%. The combination of aspirin and clopidogrel reduced the risk of stroke by 25%, but increased the risk of major bleeding by 57%, which means that this combination is inferior to warfarin, and is not an alternative for patients who are judged to be at high risk of bleeding on warfarin therapy. Previous stroke or TIA Keeping blood pressure below 140/90 mmHg is recommended. Anticoagulation can prevent recurrent ischemic strokes. Among people with nonvalvular atrial fibrillation, anticoagulation can reduce stroke by 60% while antiplatelet agents can reduce stroke by 20%. However, a recent meta-analysis suggests harm from anticoagulation started early after an embolic stroke. Stroke prevention treatment for atrial fibrillation is determined according to the CHA2DS2–VASc score. The most widely used anticoagulant to prevent thromboembolic stroke in people with nonvalvular atrial fibrillation is the oral agent warfarin while a number of newer agents including dabigatran are alternatives which do not require prothrombin time monitoring. Anticoagulants, when used following stroke, should not be stopped for dental procedures. Latest ESC guidelines on atrial fibrillation recommend assessment of bleeding risk in AF using the HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile International Normalized Ratio, Elderly, Drugs/alcohol concomitantly) bleeding risk schema as a simple, easy calculation, whereby a score of ≥3 indicates \"high risk\" and some caution and regular review of the patient is needed. The HAS-BLED score has also been validated in an anticoagulated trial cohort of 7329 patients with AF – in this study, the HAS-BLED score offered some improvement in predictive capability for bleeding risk over previously published bleeding risk assessment schemas and was simpler to apply. With the likely availability of new oral anticoagulants that avoid the limitations of warfarin (and may even be safer), more widespread use of oral anticoagulation therapy for stroke prevention in AF is likely. To evaluate the current status of anticoagulation therapy in patients with atrial fibrillation(AF)in Xinjiang, and compare the two scoring systems(CHADS2 and CHA2DS2-VASc scores) in determining the risk of strokes in AF patients in Xinjiang. Subjects with AF were collected by searching the electronic and paper medical records from 35 hospitals in Xinjiang area during October 2013 to October 2014, and followed up for the incident strokes after 10 to 12 months. Totally, 5 953 AF patients were enrolled in the study with the age of (67.9±12.0) years old, and men to women ratio of 1.44. Most patients were in age groups of 60-69 (23.92%) and 70-79 years (37.81%). Among patients with a CHADS2 score of 1 or less, the CHA2DS2-VASc scores of these subjects ranged from 0 to 3. After 10 to 12 months of follow-up, 22 patients developed new strokes. Only 30.79% patients ( n=1 460) received the anticoagulation treatment among those (n=4 742) who need to be treated with anticoagulation drugs. In patients receiving anticoagulant therapy, 1 162 patients were treated with warfarin, and 298 patients with new oral anticoagulant drugs.Totally 1 110 patients treated with warfarin were monitored with international normalized ratio (INR). The median INR was 1.14 with only 97 cases meeting the recommended INR ranging of 2.0-3.0 in the guidelines. The compliance rate was 8.74%. The current status of anticoagulation for AF in Xinjiang area is characterized by \"low anticoagulation rate\" and \"low compliance rate\". The CHA2DS2-VASc score is more suitable for predicting the risk of strokes in patients with non valvular atrial fibrillation in Xinjiang area. Direct oral anticoagulants (DOACs) are increasingly used as an alternative to warfarin in patients with nonvalvular atrial fibrillation (NVAF). However, whether there is sufficient prescription of oral anticoagulants (OACs) to decrease the incidence of embolic stroke remains unclear. We conducted a retrospective observational study of patients hospitalized with ischemic stroke between January 1, 2010 and December 31, 2018. During the 8 years, the annual incidence ratio of embolic stroke to all ischemic strokes did not decrease over time (21-33%) except for that in 2018. The proportion of OAC users did not also change over time (from 23% to 45% [overall 31%], <iP</i = .78). Among the OAC users, 19% patients were warfarin users, and 12% patients were DOAC users. In 73% of warfarin users, prothrombin time was subtherapeutic, whereas in 60% of DOAC users, the dose was adequately prescribed. OACs were prescribed more often in patients with high CHADS2 score than in those with low score (<iP</i = .01). The number of patients who had no medical history of a doctor visit before admission increased significantly in the recent period of 2015-2018 (22% vs 8% in the previous period of 2010-2014) (<iP</i = .01). The incidence of embolic stroke patients without OACs did not decrease over time, and OACs in patients with NVAF have not been sufficient, even in DOAC era. In recent years, the incidence of undiagnosed AF has increased. To prevent embolic stroke, a correct AF diagnosis beforehand is important. Direct oral anticoagulants (DOACs) are surpassing warfarin as the anticoagulant of choice for stroke prevention in nonvalvular atrial fibrillation. DOAC outcomes in elective periprocedural settings have not been well elucidated and remain a source of concern for clinicians. The aim of this meta-analysis was to evaluate the periprocedural safety and efficacy of DOACs versus warfarin in patients with nonvalvular atrial fibrillation. We reviewed the literature for data from phase III randomized controlled trials comparing DOACs with warfarin in the periprocedural period among patients with nonvalvular atrial fibrillation. Substudies from 4 trials (RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation], and ENGAGE-AF [Effective Anticoagulation With Factor xA Next Generation in Atrial Fibrillation]) were included in the meta-analysis. DOACs as a group and warfarin were compared in terms of the 30-day pooled risk for stroke/systemic embolism, major bleeding, and death, according to whether the study drug was interrupted or not periprocedurally. The overall relative risk (RR) was estimated with a random-effects model. The I<sup2</sup test was used to assess heterogeneity in RR among the studies. In the uninterrupted anticoagulant strategy, there were no differences in the rates of stroke/systemic embolism (pooled risk, 0.6% [29 events/4519 procedures] versus 1.1% [31/2971]; RR, 0.70; 95% confidence interval [CI], 0.41-1.18) and death (1.4% versus 1.8%; RR, 0.77; 95% CI, 0.53-1.12) between DOACs and warfarin and significantly fewer major bleeding events (2.0% versus 3.3%; RR, 0.62; 95% CI, 0.47-0.82) with DOACs compared to warfarin. Under an interrupted strategy, there was no significant difference between DOACs versus warfarin for stroke/systemic embolism (0.4% [41/9260] versus 0.5% [31/7168]; RR, 0.95; 95% CI, 0.59-1.55), major bleeding (2.1% versus 2.0%; RR, 1.05; 95% CI, 0.85-1.30), and death (0.7% versus 0.6%; RR, 1.24; 95% CI, 0.76-2.04). The studies were homogeneous ( I<sup2</sup=0.0%) for all calculated pooled associations except for the RR of death in the interrupted strategy ( I<sup2</sup=26.3%). The short-term safety and efficacy of DOACs and warfarin are not different in patients with nonvalvular atrial fibrillation periprocedurally. Under an uninterrupted anticoagulation strategy, DOACs are associated with a 38% lower risk of major bleeding compared with warfarin. For those with non-valvular atrial fibrillation, DOACs are at least as effective as warfarin for preventing strokes and blood clots embolizing to the systemic circulation (if not more so) and are generally preferred over warfarin. DOACs carry a lower risk of bleeding in the brain compared to warfarin, although dabigatran is associated with a higher risk of intestinal bleeding. Dual antiplatelet therapy with aspirin and clopidogrel is inferior to warfarin for preventing strokes and has comparable bleeding risk in people with atrial fibrillation. In those who are also on aspirin, however, DOACs appear to be better than warfarin. In patients with non-valvular atrial fibrillation (AF), direct-acting oral anticoagulants (DOACs) are at least non-inferior to warfarin for the prevention of stroke and systemic embolism. The main objective of this study was to obtain reliable and precise estimates for all-cause mortality, vascular mortality and bleeding mortality in patients with AF receiving a DOAC or warfarin for stroke prevention. A meta-analysis was performed on phase 3 randomized trials that compared a DOAC with warfarin for stroke prevention in AF. Published data were pooled by use of the DerSimonian random-effect model, with revman 5.2 and comprehensive meta analysis software version 2. The results were presented as risk ratios (RRs), absolute risk reduction (ARR), and number-needed-to-treat (NNT). A total of 71 683 patients were included in this meta-analysis from four randomized controlled trials (median patient follow-up: 1.8-2.8 years) that compared a DOAC with warfarin for stroke prevention in AF. As compared with warfarin, DOACs significantly reduced all-cause mortality (RR 0.89, 95% confidence interval [CI] 0.85-0.94; ARR 0.76%, 95% CI 0.39-1.13%; NNT = 132), vascular mortality (RR 0.88, 95% CI 0.82-0.94; ARR 0.53%, 95% CI 0.23-0.83%; NNT = 189), and bleeding mortality (RR 0.54, 95% CI 0.44-0.67; ARR 0.32%, 95% CI 0.21-0.43%; NNT = 313). As compared with warfarin therapy for stroke prevention in patients with AF, DOACs significantly reduce all-cause mortality, vascular mortality, and bleeding mortality. This mortality benefit appears to be driven by the reduction in vascular-related and bleeding-related mortality, which, in turn, may be related to the reduction in intracranial bleeding. Although several new antithrombotic agents have been developed for stroke prevention in patients with nonvalvular atrial fibrillation (AF), many patients will continue to be treated with warfarin worldwide. We performed a meta-analysis of safety and efficacy outcomes in patients with AF treated with warfarin for stroke prevention in large contemporary randomized controlled trials (RCTs). We searched the MEDLINE, EMBASE, and Cochrane databases for relevant studies; RCTs comparing warfarin with an alternative thromboprophylaxis strategy with at least 400 patients in the warfarin arm and reporting stroke as an efficacy outcome were included. Eight RCTs with 55,789 patient-years of warfarin therapy follow-up were included. Overall time spent in the therapeutic range was 55% to 68%. The annual incidence of stroke or systemic embolism in patients with AF taking warfarin was estimated to be 1.66% (95% CI, 1.41%-1.91%). Major bleeding rates varied from 1.40% to 3.40% per year across the studies. The risk of stroke per year was significantly higher in elderly patients (2.27%), female patients (2.12%), patients with a history of stroke (2.64%), and patients reporting no previous exposure to vitamin K antagonists (1.96%). There was a significant increase in the annual incidence of stroke with progressively increasing CHADS(2) (congestive heart failure, hypertension, age, diabetes, and prior stroke) scores. Current use of warfarin as a stroke prevention agent in patients with AF is associated with a low rate of residual stroke or systemic embolism estimated to be 1.66% per year. Compared with a previous meta-analysis, there has been significant improvement in the proportion of time spent in therapeutic anticoagulation, with a resultant decline in observed stroke rates. 2020 ESC guidelines on atrial fibrillation recommend assessment of bleeding risk in AF using the HAS-BLED bleeding risk schema as a simple, easy calculation, whereby a score of ≥3 indicates \"high risk\" and some caution and regular review of the patient is needed. The HAS-BLED score has also been validated in an anticoagulated trial cohort of 7329 people with AF - in this study, the HAS-BLED score offered some improvement in predictive capability for bleeding risk over previously published bleeding risk assessment schemas and was simpler to apply. With the likely availability of new oral anticoagulants that avoid the limitations of warfarin (and may even be safer), more widespread use of oral anticoagulation therapy for stroke prevention in AF is likely. The SAMe-TT2R2 score is a clinical prediction rule to predict the quality of vitamin K antagonist anticoagulation therapy as measured by time in therapeutic INR range (TTR) (VKA e.g. warfarin). It has been suggested that it can aid in the medical decision making between VKAs and new oral anticoagulant/non-VKA oral anticoagulant (NOAC e.g. dabigatran, rivaroxaban, apixaban or edoxaban) in patients with atrial fibrillation (AF). This score can be used with patients with ≥1 additional stroke risk factors using the CHA2DS2-VASc score, where oral anticoagulation is recommended or should be considered. This score reflects the need to offer an improved patient care pathway when using oral anticoagulants. While NOACs avoid the need for drug monitoring (e.g. INR monitoring), they have an unstable bioavailability and are not indicated for patients with chronic kidney failure or in patients with valvular replacement surgery. Anticoagulants may be started if the TIA is thought to be attributable to atrial fibrillation. Atrial fibrillation is an abnormal heart rhythm that may cause the formation of blood clots that can travel to the brain, resulting in TIAs or ischemic strokes. Atrial fibrillation increases stroke risk by five times, and is thought to cause 10-12% of all ischemic strokes in the US. Anticoagulant therapy can decrease the relative risk of ischemic stroke in those with atrial fibrillation by 67% Warfarin is a common anticoagulant used, but direct acting oral anticoagulants (DOACs), such as apixaban, have been shown to be equally effective while also conferring a lower risk of bleeding. Generally, anticoagulants and antiplatelets are not used in combination, as they result in increased bleeding risk without a decrease in stroke risk. However, combined antiplatelet and anticoagulant therapy may be warranted if the patient has symptomatic coronary artery disease in addition to atrial Warfarin is a commonly prescribed oral anticoagulant, or blood thinner used to treat blood clots such as deep vein thrombosis and pulmonary embolism and to prevent stroke in people who have atrial fibrillation, valvular heart disease or artificial heart valves. Warfarin causes inhibition on VKORC1 activities and leads to a reduced amount of vitamin K available to serve as a cofactor for clotting proteins. Inappropriate dosing of warfarin has been associated with a substantial risk of both major and minor hemorrhage. As the pharmacological target of warfarin, VKORC1 is considered a candidate gene for the variability in warfarin response. Previous researches have shown that the CYP2C9 genotype of patients also played a role in warfarin metabolism and response. Gene The human gene is located on chromosome 16. Two pseudogenes have been identified on chromosome 1 and the X chromosome. Clinical relevance Warfarin has been shown to be highly efficacious for preventing thromboembolism in atrial fibrillation in randomized trials, but its effectiveness and safety in clinical practice is less clear. To evaluate the effect of warfarin on risk of thromboembolism, hemorrhage, and death in atrial fibrillation within a usual care setting. Cohort study assembled between July 1, 1996, and December 31, 1997, and followed up through August 31, 1999. Large integrated health care system in Northern California. Of 13,559 adults with nonvalvular atrial fibrillation, 11,526 were studied, 43% of whom were women, mean age 71 years, with no known contraindications to anticoagulation at baseline. Ischemic stroke, peripheral embolism, hemorrhage, and death according to warfarin use and comorbidity status, as determined by automated databases, review of medical records, and state mortality files. Among 11,526 patients, 397 incident thromboembolic events (372 ischemic strokes, 25 peripheral embolism) occurred during 25,341 person-years of follow-up, and warfarin therapy was associated with a 51% (95% confidence interval [CI], 39%-60%) lower risk of thromboembolism compared with no warfarin therapy (either no antithrombotic therapy or aspirin) after adjusting for potential confounders and likelihood of receiving warfarin. Warfarin was effective in reducing thromboembolic risk in the presence or absence of risk factors for stroke. A nested case-control analysis estimated a 64% reduction in odds of thromboembolism with warfarin compared with no antithrombotic therapy. Warfarin was also associated with a reduced risk of all-cause mortality (adjusted hazard ratio, 0.69; 95% CI, 0.61-0.77). Intracranial hemorrhage was uncommon, but the rate was moderately higher among those taking vs those not taking warfarin (0.46 vs 0.23 per 100 person-years, respectively; P =.003, adjusted hazard ratio, 1.97; 95% CI, 1.24-3.13). However, warfarin therapy was not associated with an increased adjusted risk of nonintracranial major hemorrhage. The effects of warfarin were similar when patients with contraindications at baseline were analyzed separately or combined with those without contraindications (total cohort of 13,559). Warfarin is very effective for preventing ischemic stroke in patients with atrial fibrillation in clinical practice while the absolute increase in the risk of intracranial hemorrhage is small. Results of randomized trials of anticoagulation translate well into clinical care for patients with atrial fibrillation. Compared with warfarin it has fewer drug interactions. It was developed by Daiichi Sankyo and approved in July 2011, in Japan for prevention of venous thromboembolisms following lower-limb orthopedic surgery. It was also approved in the United States by the Food and Drug Administration (FDA) in January 2015, for the prevention of stroke and non–central-nervous-system systemic embolism. It was approved for use in the European Union in June 2015. It is on the World Health Organization's List of Essential Medicines. Medical uses In the United States, edoxaban is approved for treating deep vein thrombosis and pulmonary embolism following five to ten days of initial therapy with a parenteral anticoagulant. It is also approved for reducing the risk of blood clots in people with nonvalvular atrial fibrillation. Benefits and/or harms (including costs) of non-vitamin K oral anticoagulants (NOACs) versus warfarin therapy need appreciation in relative and absolute terms. Accordingly, we derived clinically relevant relative and absolute benefit/harm parameters for NOACs (apixaban, dabigatran, rivaroxaban, edoxaban) compared to warfarin from four clinical trials involving atrial fibrillation (AF) patients. For each trial, we tabulated patient numbers enduring four important outcomes and calculated unadjusted relative risk reduction (RRR) and number needed to treat (NNT)/year values (and 95% confidence intervals) for the NAOC compared to warfarin. These outcomes were as follows: stroke/systemic embolism (primary endpoint), hemorrhagic stroke, major bleeds, and death. We also addressed drug acquisition costs. Each NOAC was noninferior to warfarin for primary-outcome prevention; RRRs were 12-33% and NNT/year values were 182-481, and all but one indicated statistically significant superiority. All the NOACs yielded statistically significant reductions in hemorrhagic stroke risk; RRRs were 42-74% and NNT/year values were 364-528. Major bleeding risk was comparable in both groups. Apixaban yielded a lower NNT/year for preventing death than for primary-outcome prevention. Compared to warfarin, NOAC acquisition costs were 70- to 140-fold greater. For the primary outcome, the absolute benefits of NOACs were modest (NNT/year values being large). Reduced hemorrhagic stroke rates with NOACs could be due to superior embolic infarct prevention and fewer consequential hemorrhagic transformations. Among apixaban recipients, the absolute mortality benefit exceeded that for the primary outcome, indicating prevention of additional unrelated deaths. The substantially greater NOAC acquisition costs need viewing against probable greater safety and the avoidance of monitoring bleeding risks.\nHere is the question:\nPREVENTIVE MEDICINE: An 86-year-old woman in whom nonvalvular atrial fibrillation has been detected. She has a CHADS2 score of 3 points. In the literature, similar patients on warfarin therapy have a stroke risk of 2.2% versus 5.2% in patients without warfarin. What would be the number needed to treat (NNT) to prevent embolic stroke with anticoagulation therapy?\nHere are the potential choices:\n1. 3\n2. 19,2.\n3. 33,3.\n4. 49,5.\nThe correct answer is: ",
        "gold_answer": "3 33,3.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The Apixaban for the Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE), Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY), and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trials demonstrated that the oral anticoagulants (OACs), apixaban, dabigatran, and rivaroxaban, respectively, are efficacious for stroke prevention among nonvalvular atrial fibrillation (NVAF) patients. Based on clinical trial results this study evaluated medical costs of clinical events associated with use of individual OACs relative to those of warfarin in NVAF patients with moderate and high stroke risk. Rates for primary and secondary efficacy and safety outcomes (i.e., clinical events) among NVAF patients with CHADS2 = 2 and ≥3 were determined from the three OAC trials. One-year incremental costs among patients with clinical events from a US payer perspective were obtained from the literature and inflation adjusted to 2010 costs. Medical costs for clinical events associated with each OAC vs. warfarin were estimated and compared. For NVAF patients with moderate stroke risk (CHADS2 = 2) differences in clinical event medical costs vs. warfarin were -$298, -$143, and +$117 per patient year for apixaban, dabigatran (150 mg), and rivaroxaban, respectively (negative numbers indicate cost reduction). For NVAF patients with high stroke risk (CHADS2 ≥ 3) differences in clinical event medical costs vs. warfarin were -$697, +$2, and -$100 for apixaban, dabigatran (150 mg), and rivaroxaban, respectively. Medical cost differences associated with OACs vs. warfarin vary according to stroke risk. Of the three OACs, apixaban demonstrated consistent medical cost reductions vs. warfarin for NVAF patients with moderate and high stroke risks. Atrial fibrillation affects approximately 5 million patients in the United States. The rate of stroke in adults with atrial fibrillation depending on their risk factors varies between 1-20% annually. Anticoagulation with vitamin K antagonists such as warfarin has been the mainstay therapy but it is cumbersome and requires close follow-up. Since 2010, three new oral anticoagulants have received Food and Drug Administration approval for stroke prevention in atrial fibrillation. This review summarizes data from three landmark trials: RE-LY, ROCKET-AF, and ARISTOTLE. In addition, issues relating to cost, reversal, drug interactions, and perioperative discontinuation are discussed. Compared to Warfarin, Dabigatran 150 mg twice daily lowered the primary outcome of stroke/systemic embolism by 34% (number needed to treat/yr 169) and had similar incidence of major bleeding. Rivaroxaban demonstrated non inferiority compared to the warfarin group for the primary outcome of stroke and systemic embolism and major bleeding. Apixaban showed a relative risk reduction for the primary outcome of 21% (number needed to treat 300), and lowered major bleeding down by 31% (number needed to treat /yr 104). Apixaban also showed a mortality benefit compared to warfarin (3.52 vs. 3.94%/year, p 0.047). All 3 oral anticoagulants lowered rates of intracranial hemorrhage. The use of Rivaroxaban and Apixaban has been projected to reduce medical costs when compared to warfarin, and Dabigatran is projected to have similar costs. All the 3 oral anticoagulants have robust randomized controlled trials supporting their comparability to warfarin therapy for stroke prevention in non valvular atrial fibrillation, with Apixaban showing superiority in incidence of strokes, major bleeding and mortality. Nonvalvular atrial fibrillation (NVAF) is frequently seen in elderly people and has become a main cause of cardioembolic stroke. The efficacy of anticoagulation for primary prevention of stroke or transient ischaemic attacks (TIAs) in patients with NVAF has been established by prospective, randomised and controlled trials. Warfarin decreased the frequency of all strokes by 68% and the rate of the combined outcome of stroke, systemic embolism or death by 48%. Anticoagulation with warfarin using international normalised ratios (INRs) ranging from 2.0 to 3.0 is recommended for patients with NVAF, who have any of the risk factors identified by the Atrial Fibrillation Investigators (AFI) [previous stroke or TIA, history of hypertension, diabetes mellitus, advanced age (&gt; or = 65 years old), congestive heart failure and coronary artery disease], the American College of Chest Physicians (ACCP) [increased age (&gt; 75 years old), prior stroke, hypertension and heart failure], or the Stroke Prevention in Atrial Fibrillation (SPAF) investigators [women &gt; 75 years old, prior stroke, systolic blood pressure &gt; 160mm Hg, recent heart failure, and fractional shortening &lt; 25% on echocardiography]. For the secondary prevention of stroke, the efficacy of adjusted-dose warfarin therapy has been demonstrated by 2 major randomised trials. SPAF III (INR 2.0 to 3.0) demonstrated a lower incidence of ischaemic stroke or systemic embolism (3.4 %/year) compared with low fixed-dose warfarin plus aspirin (acetylsalicylic acid) [11.9%]. The European Atrial Fibrillation Trial [EAFT] (INR 2.5 to 4.0) showed a lower incidence of all stroke (4.0 %/year) with adjusted-dose warfarin compared with placebo (12.0 %/year). The incidence of major bleeding in the adjusted-dose warfarin group in SPAF III and EAFT was 2.4 and 2.8 %/year, respectively. EAFT incidence rates for the occurrence of a first ischaemic or haemorrhagic complication analysed by INR range indicated that the rate was lowest at INRs of 2.0 to 2.9, and higher with INRs of 3.0 to 3.9. Therefore, the optimal intensity of anticoagulation for prevention of recurrent stroke seems to be an INR of between 2.0 and 3.0, as for primary prevention. Retrospective and prospective studies from Japan reported that in the elderly, haemorrhagic complications occur frequently with INRs above 2.6 and major ischaemic events cannot be prevented at INRs below 1.6. Therefore, an INR target between 1.6 and 2.6 may be an alternative for secondary prevention of stroke in elderly patients with NVAF who have a potential risk of bleeding, to avoid both major ischaemic and haemorrhagic events. Antiplatelets may be administered in patients who are unable to manage taking warfarin properly or who have a high risk of falling and subsequently sustaining a head injury, although the efficacy of antiplatelets for secondary prevention of stroke in NVAF has not yet been established. Chronic anticoagulation Among patients with nonvalvular AF, anticoagulation with warfarin can reduce stroke by 60% while antiplatelet agents can reduce stroke by 20%. The combination of aspirin and clopidogrel reduced the risk of stroke by 25%, but increased the risk of major bleeding by 57%, which means that this combination is inferior to warfarin, and is not an alternative for patients who are judged to be at high risk of bleeding on warfarin therapy. Previous stroke or TIA Keeping blood pressure below 140/90 mmHg is recommended. Anticoagulation can prevent recurrent ischemic strokes. Among people with nonvalvular atrial fibrillation, anticoagulation can reduce stroke by 60% while antiplatelet agents can reduce stroke by 20%. However, a recent meta-analysis suggests harm from anticoagulation started early after an embolic stroke. Stroke prevention treatment for atrial fibrillation is determined according to the CHA2DS2–VASc score. The most widely used anticoagulant to prevent thromboembolic stroke in people with nonvalvular atrial fibrillation is the oral agent warfarin while a number of newer agents including dabigatran are alternatives which do not require prothrombin time monitoring. Anticoagulants, when used following stroke, should not be stopped for dental procedures. Latest ESC guidelines on atrial fibrillation recommend assessment of bleeding risk in AF using the HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile International Normalized Ratio, Elderly, Drugs/alcohol concomitantly) bleeding risk schema as a simple, easy calculation, whereby a score of ≥3 indicates \"high risk\" and some caution and regular review of the patient is needed. The HAS-BLED score has also been validated in an anticoagulated trial cohort of 7329 patients with AF – in this study, the HAS-BLED score offered some improvement in predictive capability for bleeding risk over previously published bleeding risk assessment schemas and was simpler to apply. With the likely availability of new oral anticoagulants that avoid the limitations of warfarin (and may even be safer), more widespread use of oral anticoagulation therapy for stroke prevention in AF is likely. To evaluate the current status of anticoagulation therapy in patients with atrial fibrillation(AF)in Xinjiang, and compare the two scoring systems(CHADS2 and CHA2DS2-VASc scores) in determining the risk of strokes in AF patients in Xinjiang. Subjects with AF were collected by searching the electronic and paper medical records from 35 hospitals in Xinjiang area during October 2013 to October 2014, and followed up for the incident strokes after 10 to 12 months. Totally, 5 953 AF patients were enrolled in the study with the age of (67.9±12.0) years old, and men to women ratio of 1.44. Most patients were in age groups of 60-69 (23.92%) and 70-79 years (37.81%). Among patients with a CHADS2 score of 1 or less, the CHA2DS2-VASc scores of these subjects ranged from 0 to 3. After 10 to 12 months of follow-up, 22 patients developed new strokes. Only 30.79% patients ( n=1 460) received the anticoagulation treatment among those (n=4 742) who need to be treated with anticoagulation drugs. In patients receiving anticoagulant therapy, 1 162 patients were treated with warfarin, and 298 patients with new oral anticoagulant drugs.Totally 1 110 patients treated with warfarin were monitored with international normalized ratio (INR). The median INR was 1.14 with only 97 cases meeting the recommended INR ranging of 2.0-3.0 in the guidelines. The compliance rate was 8.74%. The current status of anticoagulation for AF in Xinjiang area is characterized by \"low anticoagulation rate\" and \"low compliance rate\". The CHA2DS2-VASc score is more suitable for predicting the risk of strokes in patients with non valvular atrial fibrillation in Xinjiang area. Direct oral anticoagulants (DOACs) are increasingly used as an alternative to warfarin in patients with nonvalvular atrial fibrillation (NVAF). However, whether there is sufficient prescription of oral anticoagulants (OACs) to decrease the incidence of embolic stroke remains unclear. We conducted a retrospective observational study of patients hospitalized with ischemic stroke between January 1, 2010 and December 31, 2018. During the 8 years, the annual incidence ratio of embolic stroke to all ischemic strokes did not decrease over time (21-33%) except for that in 2018. The proportion of OAC users did not also change over time (from 23% to 45% [overall 31%], <iP</i = .78). Among the OAC users, 19% patients were warfarin users, and 12% patients were DOAC users. In 73% of warfarin users, prothrombin time was subtherapeutic, whereas in 60% of DOAC users, the dose was adequately prescribed. OACs were prescribed more often in patients with high CHADS2 score than in those with low score (<iP</i = .01). The number of patients who had no medical history of a doctor visit before admission increased significantly in the recent period of 2015-2018 (22% vs 8% in the previous period of 2010-2014) (<iP</i = .01). The incidence of embolic stroke patients without OACs did not decrease over time, and OACs in patients with NVAF have not been sufficient, even in DOAC era. In recent years, the incidence of undiagnosed AF has increased. To prevent embolic stroke, a correct AF diagnosis beforehand is important. Direct oral anticoagulants (DOACs) are surpassing warfarin as the anticoagulant of choice for stroke prevention in nonvalvular atrial fibrillation. DOAC outcomes in elective periprocedural settings have not been well elucidated and remain a source of concern for clinicians. The aim of this meta-analysis was to evaluate the periprocedural safety and efficacy of DOACs versus warfarin in patients with nonvalvular atrial fibrillation. We reviewed the literature for data from phase III randomized controlled trials comparing DOACs with warfarin in the periprocedural period among patients with nonvalvular atrial fibrillation. Substudies from 4 trials (RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation], and ENGAGE-AF [Effective Anticoagulation With Factor xA Next Generation in Atrial Fibrillation]) were included in the meta-analysis. DOACs as a group and warfarin were compared in terms of the 30-day pooled risk for stroke/systemic embolism, major bleeding, and death, according to whether the study drug was interrupted or not periprocedurally. The overall relative risk (RR) was estimated with a random-effects model. The I<sup2</sup test was used to assess heterogeneity in RR among the studies. In the uninterrupted anticoagulant strategy, there were no differences in the rates of stroke/systemic embolism (pooled risk, 0.6% [29 events/4519 procedures] versus 1.1% [31/2971]; RR, 0.70; 95% confidence interval [CI], 0.41-1.18) and death (1.4% versus 1.8%; RR, 0.77; 95% CI, 0.53-1.12) between DOACs and warfarin and significantly fewer major bleeding events (2.0% versus 3.3%; RR, 0.62; 95% CI, 0.47-0.82) with DOACs compared to warfarin. Under an interrupted strategy, there was no significant difference between DOACs versus warfarin for stroke/systemic embolism (0.4% [41/9260] versus 0.5% [31/7168]; RR, 0.95; 95% CI, 0.59-1.55), major bleeding (2.1% versus 2.0%; RR, 1.05; 95% CI, 0.85-1.30), and death (0.7% versus 0.6%; RR, 1.24; 95% CI, 0.76-2.04). The studies were homogeneous ( I<sup2</sup=0.0%) for all calculated pooled associations except for the RR of death in the interrupted strategy ( I<sup2</sup=26.3%). The short-term safety and efficacy of DOACs and warfarin are not different in patients with nonvalvular atrial fibrillation periprocedurally. Under an uninterrupted anticoagulation strategy, DOACs are associated with a 38% lower risk of major bleeding compared with warfarin. For those with non-valvular atrial fibrillation, DOACs are at least as effective as warfarin for preventing strokes and blood clots embolizing to the systemic circulation (if not more so) and are generally preferred over warfarin. DOACs carry a lower risk of bleeding in the brain compared to warfarin, although dabigatran is associated with a higher risk of intestinal bleeding. Dual antiplatelet therapy with aspirin and clopidogrel is inferior to warfarin for preventing strokes and has comparable bleeding risk in people with atrial fibrillation. In those who are also on aspirin, however, DOACs appear to be better than warfarin. In patients with non-valvular atrial fibrillation (AF), direct-acting oral anticoagulants (DOACs) are at least non-inferior to warfarin for the prevention of stroke and systemic embolism. The main objective of this study was to obtain reliable and precise estimates for all-cause mortality, vascular mortality and bleeding mortality in patients with AF receiving a DOAC or warfarin for stroke prevention. A meta-analysis was performed on phase 3 randomized trials that compared a DOAC with warfarin for stroke prevention in AF. Published data were pooled by use of the DerSimonian random-effect model, with revman 5.2 and comprehensive meta analysis software version 2. The results were presented as risk ratios (RRs), absolute risk reduction (ARR), and number-needed-to-treat (NNT). A total of 71 683 patients were included in this meta-analysis from four randomized controlled trials (median patient follow-up: 1.8-2.8 years) that compared a DOAC with warfarin for stroke prevention in AF. As compared with warfarin, DOACs significantly reduced all-cause mortality (RR 0.89, 95% confidence interval [CI] 0.85-0.94; ARR 0.76%, 95% CI 0.39-1.13%; NNT = 132), vascular mortality (RR 0.88, 95% CI 0.82-0.94; ARR 0.53%, 95% CI 0.23-0.83%; NNT = 189), and bleeding mortality (RR 0.54, 95% CI 0.44-0.67; ARR 0.32%, 95% CI 0.21-0.43%; NNT = 313). As compared with warfarin therapy for stroke prevention in patients with AF, DOACs significantly reduce all-cause mortality, vascular mortality, and bleeding mortality. This mortality benefit appears to be driven by the reduction in vascular-related and bleeding-related mortality, which, in turn, may be related to the reduction in intracranial bleeding. Although several new antithrombotic agents have been developed for stroke prevention in patients with nonvalvular atrial fibrillation (AF), many patients will continue to be treated with warfarin worldwide. We performed a meta-analysis of safety and efficacy outcomes in patients with AF treated with warfarin for stroke prevention in large contemporary randomized controlled trials (RCTs). We searched the MEDLINE, EMBASE, and Cochrane databases for relevant studies; RCTs comparing warfarin with an alternative thromboprophylaxis strategy with at least 400 patients in the warfarin arm and reporting stroke as an efficacy outcome were included. Eight RCTs with 55,789 patient-years of warfarin therapy follow-up were included. Overall time spent in the therapeutic range was 55% to 68%. The annual incidence of stroke or systemic embolism in patients with AF taking warfarin was estimated to be 1.66% (95% CI, 1.41%-1.91%). Major bleeding rates varied from 1.40% to 3.40% per year across the studies. The risk of stroke per year was significantly higher in elderly patients (2.27%), female patients (2.12%), patients with a history of stroke (2.64%), and patients reporting no previous exposure to vitamin K antagonists (1.96%). There was a significant increase in the annual incidence of stroke with progressively increasing CHADS(2) (congestive heart failure, hypertension, age, diabetes, and prior stroke) scores. Current use of warfarin as a stroke prevention agent in patients with AF is associated with a low rate of residual stroke or systemic embolism estimated to be 1.66% per year. Compared with a previous meta-analysis, there has been significant improvement in the proportion of time spent in therapeutic anticoagulation, with a resultant decline in observed stroke rates. 2020 ESC guidelines on atrial fibrillation recommend assessment of bleeding risk in AF using the HAS-BLED bleeding risk schema as a simple, easy calculation, whereby a score of ≥3 indicates \"high risk\" and some caution and regular review of the patient is needed. The HAS-BLED score has also been validated in an anticoagulated trial cohort of 7329 people with AF - in this study, the HAS-BLED score offered some improvement in predictive capability for bleeding risk over previously published bleeding risk assessment schemas and was simpler to apply. With the likely availability of new oral anticoagulants that avoid the limitations of warfarin (and may even be safer), more widespread use of oral anticoagulation therapy for stroke prevention in AF is likely. The SAMe-TT2R2 score is a clinical prediction rule to predict the quality of vitamin K antagonist anticoagulation therapy as measured by time in therapeutic INR range (TTR) (VKA e.g. warfarin). It has been suggested that it can aid in the medical decision making between VKAs and new oral anticoagulant/non-VKA oral anticoagulant (NOAC e.g. dabigatran, rivaroxaban, apixaban or edoxaban) in patients with atrial fibrillation (AF). This score can be used with patients with ≥1 additional stroke risk factors using the CHA2DS2-VASc score, where oral anticoagulation is recommended or should be considered. This score reflects the need to offer an improved patient care pathway when using oral anticoagulants. While NOACs avoid the need for drug monitoring (e.g. INR monitoring), they have an unstable bioavailability and are not indicated for patients with chronic kidney failure or in patients with valvular replacement surgery. Anticoagulants may be started if the TIA is thought to be attributable to atrial fibrillation. Atrial fibrillation is an abnormal heart rhythm that may cause the formation of blood clots that can travel to the brain, resulting in TIAs or ischemic strokes. Atrial fibrillation increases stroke risk by five times, and is thought to cause 10-12% of all ischemic strokes in the US. Anticoagulant therapy can decrease the relative risk of ischemic stroke in those with atrial fibrillation by 67% Warfarin is a common anticoagulant used, but direct acting oral anticoagulants (DOACs), such as apixaban, have been shown to be equally effective while also conferring a lower risk of bleeding. Generally, anticoagulants and antiplatelets are not used in combination, as they result in increased bleeding risk without a decrease in stroke risk. However, combined antiplatelet and anticoagulant therapy may be warranted if the patient has symptomatic coronary artery disease in addition to atrial Warfarin is a commonly prescribed oral anticoagulant, or blood thinner used to treat blood clots such as deep vein thrombosis and pulmonary embolism and to prevent stroke in people who have atrial fibrillation, valvular heart disease or artificial heart valves. Warfarin causes inhibition on VKORC1 activities and leads to a reduced amount of vitamin K available to serve as a cofactor for clotting proteins. Inappropriate dosing of warfarin has been associated with a substantial risk of both major and minor hemorrhage. As the pharmacological target of warfarin, VKORC1 is considered a candidate gene for the variability in warfarin response. Previous researches have shown that the CYP2C9 genotype of patients also played a role in warfarin metabolism and response. Gene The human gene is located on chromosome 16. Two pseudogenes have been identified on chromosome 1 and the X chromosome. Clinical relevance Warfarin has been shown to be highly efficacious for preventing thromboembolism in atrial fibrillation in randomized trials, but its effectiveness and safety in clinical practice is less clear. To evaluate the effect of warfarin on risk of thromboembolism, hemorrhage, and death in atrial fibrillation within a usual care setting. Cohort study assembled between July 1, 1996, and December 31, 1997, and followed up through August 31, 1999. Large integrated health care system in Northern California. Of 13,559 adults with nonvalvular atrial fibrillation, 11,526 were studied, 43% of whom were women, mean age 71 years, with no known contraindications to anticoagulation at baseline. Ischemic stroke, peripheral embolism, hemorrhage, and death according to warfarin use and comorbidity status, as determined by automated databases, review of medical records, and state mortality files. Among 11,526 patients, 397 incident thromboembolic events (372 ischemic strokes, 25 peripheral embolism) occurred during 25,341 person-years of follow-up, and warfarin therapy was associated with a 51% (95% confidence interval [CI], 39%-60%) lower risk of thromboembolism compared with no warfarin therapy (either no antithrombotic therapy or aspirin) after adjusting for potential confounders and likelihood of receiving warfarin. Warfarin was effective in reducing thromboembolic risk in the presence or absence of risk factors for stroke. A nested case-control analysis estimated a 64% reduction in odds of thromboembolism with warfarin compared with no antithrombotic therapy. Warfarin was also associated with a reduced risk of all-cause mortality (adjusted hazard ratio, 0.69; 95% CI, 0.61-0.77). Intracranial hemorrhage was uncommon, but the rate was moderately higher among those taking vs those not taking warfarin (0.46 vs 0.23 per 100 person-years, respectively; P =.003, adjusted hazard ratio, 1.97; 95% CI, 1.24-3.13). However, warfarin therapy was not associated with an increased adjusted risk of nonintracranial major hemorrhage. The effects of warfarin were similar when patients with contraindications at baseline were analyzed separately or combined with those without contraindications (total cohort of 13,559). Warfarin is very effective for preventing ischemic stroke in patients with atrial fibrillation in clinical practice while the absolute increase in the risk of intracranial hemorrhage is small. Results of randomized trials of anticoagulation translate well into clinical care for patients with atrial fibrillation. Compared with warfarin it has fewer drug interactions. It was developed by Daiichi Sankyo and approved in July 2011, in Japan for prevention of venous thromboembolisms following lower-limb orthopedic surgery. It was also approved in the United States by the Food and Drug Administration (FDA) in January 2015, for the prevention of stroke and non–central-nervous-system systemic embolism. It was approved for use in the European Union in June 2015. It is on the World Health Organization's List of Essential Medicines. Medical uses In the United States, edoxaban is approved for treating deep vein thrombosis and pulmonary embolism following five to ten days of initial therapy with a parenteral anticoagulant. It is also approved for reducing the risk of blood clots in people with nonvalvular atrial fibrillation. Benefits and/or harms (including costs) of non-vitamin K oral anticoagulants (NOACs) versus warfarin therapy need appreciation in relative and absolute terms. Accordingly, we derived clinically relevant relative and absolute benefit/harm parameters for NOACs (apixaban, dabigatran, rivaroxaban, edoxaban) compared to warfarin from four clinical trials involving atrial fibrillation (AF) patients. For each trial, we tabulated patient numbers enduring four important outcomes and calculated unadjusted relative risk reduction (RRR) and number needed to treat (NNT)/year values (and 95% confidence intervals) for the NAOC compared to warfarin. These outcomes were as follows: stroke/systemic embolism (primary endpoint), hemorrhagic stroke, major bleeds, and death. We also addressed drug acquisition costs. Each NOAC was noninferior to warfarin for primary-outcome prevention; RRRs were 12-33% and NNT/year values were 182-481, and all but one indicated statistically significant superiority. All the NOACs yielded statistically significant reductions in hemorrhagic stroke risk; RRRs were 42-74% and NNT/year values were 364-528. Major bleeding risk was comparable in both groups. Apixaban yielded a lower NNT/year for preventing death than for primary-outcome prevention. Compared to warfarin, NOAC acquisition costs were 70- to 140-fold greater. For the primary outcome, the absolute benefits of NOACs were modest (NNT/year values being large). Reduced hemorrhagic stroke rates with NOACs could be due to superior embolic infarct prevention and fewer consequential hemorrhagic transformations. Among apixaban recipients, the absolute mortality benefit exceeded that for the primary outcome, indicating prevention of additional unrelated deaths. The substantially greater NOAC acquisition costs need viewing against probable greater safety and the avoidance of monitoring bleeding risks.\nHere is the question:\nPREVENTIVE MEDICINE: An 86-year-old woman in whom nonvalvular atrial fibrillation has been detected. She has a CHADS2 score of 3 points. In the literature, similar patients on warfarin therapy have a stroke risk of 2.2% versus 5.2% in patients without warfarin. What would be the number needed to treat (NNT) to prevent embolic stroke with anticoagulation therapy?\nHere are the potential choices:\n1. 3\n2. 19,2.\n3. 33,3.\n4. 49,5.\nThe correct answer is: 3. 33,3."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The best approach for screening patients hinges on the number, degree, and age of relatives diagnosed with colorectal cancer (CRC) or adenomatous polyps (AP). Screening should begin at 40 years of age for patients with a family history of CRC or AP in at least 1 first-degree relative or CRC in at least 2 second-degree relatives. Patients at highest risk-who have 1 first-degree relative diagnosed with CRC or AP before 60 years of age or multiple first-degree relatives diagnosed at any age-should begin screening with colonoscopy at 40 years of age or 10 years younger than the earliest affected relative and undergo a repeat colonoscopy every 5 years. Patients who have a first-degree relative diagnosed with CRC or AP after 60 years of age or 2 or more second-degree relatives with CRC should start screening at 40 years of age, with routine options and follow-up intervals. (Routine options and follow-up intervals include any of the following 3 regimens: annual high-sensitivity fecal occult blood testing, sigmoidoscopy every 5 years combined with high-sensitivity fecal occult blood testing every 3 years, or screening colonoscopy every 10 years.). Familial adenomatous polyposis (FAP) is a dominantly inherited predisposition to the development of many hundreds to thousands of adenomatous polyps of the colon. The mean age of onset is around 15 years, symptoms may arise in the third decade, and the median age for the development of colonic cancer is 35-40 years. Prophylactic colectomy reduces the risk of death from colorectal cancer to such an extent that late sequelae such as upper gastrointestinal tumours have become the main cause of mortality in appropriately managed patients. The age at which colonic surveillance begins reflects the natural history of the disease. Onset of polyp formation and cancer in childhood is very unusual, but has recently been associated with a specific mutation at codon 1309 in exon 15 where a more severe phenotype is sometimes observed. The case histories of two families are reported in which there is childhood onset of polyps in the youngest generation and in one case a carcinoma, in whom mutations have been identified in exon 11 of the APC gene. Several other affected relatives were diagnosed at ages ranging from 5-48 years, some already with a cancer at the time of first screening. Since the aim of screening for colonic polyps is prevention of colonic cancer, family members at risk should be offered genetic assessment and direct mutation testing where this is possible, usually in the early teens. In the absence of a genetic test (the situation in about one third of families) or in a known gene carrier, annual colonoscopy examination is advised from the same age. Clinicians should take note of the family history and be prepared to consider much earlier intervention if symptoms occur in a child with a family history of FAP. Where childhood onset of polyps has occurred, other children at risk in the family must be offered earlier genetic testing and endoscopic surveillance. Individuals at increased risk of developing colorectal cancer include those with a personal or family history of advanced adenomas or colorectal cancer, a personal history of inflammatory bowel disease, or genetic polyposis syndromes. In general, these persons should undergo more frequent or earlier testing than individuals at average risk. Individuals who have a first-degree relative with colorectal cancer or advanced adenoma diagnosed before 60 years of age or two first-degree relatives diagnosed at any age should be advised to start screening colonoscopy at 40 years of age or 10 years younger than the earliest diagnosis in their family, whichever comes first. In individuals with ulcerative colitis or Crohn disease with colonic involvement, colonoscopy should begin eight to 10 years after the onset of symptoms and be repeated every one to three years. Individuals who have a first-degree relative with hereditary nonpolyposis colorectal cancer should begin colonoscopy at 25 years of age and repeat colonoscopy every one to two years. In persons with a family history of adenomatous polyposis syndromes, screening should begin at 10 years of age or in a person's mid-20s, depending on the syndrome; repeat colonoscopy is typically required every one to two years. Screening colonoscopy should begin at eight years of age in individuals with Peutz-Jeghers syndrome. If results are normal, colonoscopy can be repeated at 18 years of age and then every three years. Persons with sessile serrated adenomatous polyposis should begin annual colonoscopy as soon as the diagnosis is established. Familial adenomatous polyposis represents approximately 1% of all colorectal tumours and is caused by germline mutations in the adenomatous polyposis coli (APC) gene. A 38-year-old lady presented with abdominal pain, diarrhoea and iron deficiency anemia. There was no history of colorectal cancer in the family. Colonoscopy showed hundreds of polyps throughout the colon sparing the rectum, and an ulcerative tumour of the sigmoid colon. The diagnosis was familial adenomatous polyposis (FAP) and adenocarcinoma of the sigmoid colon. Colectomy with ileorectal anastomosis was performed and later on she was given chemotherapy and advice life long surveillance. The patient had one brother and one sister, without clinical symptoms. The brother had a single hyperplastic rectal polyp, while the sister refused colonoscopy. The patient has 2 sons, the elder son had normal colonoscopic findings, and the younger son was also diagnosed as a patient of FAP and referred for colectomy. To determine the minimum family history of colorectal cancer (CRC), which justifies colonoscopy and to establish whether further colonic assessment is necessary after a negative screening colonoscopy. A retrospective review of every colonoscopy undertaken for family screening at the Royal Berkshire and Battle Hospitals, Reading between October 1996 and July 2004. Four hundred and thirty-two patients (261 women) with an average age of 48 years (range 14-84) were screened. Three cancers in patients over the age of 60 years and 49 adenomas were found in 37 patients. Twenty three of 281 (8%) patients with a 'low-risk' family history (one in 12 or less lifetime risk of developing CRC) had either a cancer or an adenoma. Eighteen of 151 (12%) patients with a 'high-risk' family history (one in 10 or greater) had a similar positive colonoscopy. Thirteen of 15 patients who had an adenoma aged under 45 years had a high-risk family history. Seventy-three patients subsequently underwent two or more follow-up colonoscopies. There were 22 adenomatous polyps found in 12 patients (16%) at the first screening, nine adenomas in seven patients in the second colonoscopy and four adenomas found in four patients in all subsequent colonoscopies. Patients with a low-risk family history have a similar adenoma pick-up to that of the general population. These patients need not be screened below the age of 50 unless symptomatic. Follow up of low-risk family history (FH) patients with a negative screening colonoscopy is unlikely to be beneficial. Screening colonoscopy is always indicated when rectosigmoidoscopy reveals an adenoma, since this lesion roughly doubles the patient's risk of contracting colonic cancer. Follow-up should be performed at intervals of about three years after endoscopic removal of all colorectal polyps. Repeated screening examinations are recommended for the following genetic diseases that carry an increased risk of colorectal carcinoma: familial adenomatous polyposis (FAP) and its genetic variant, hereditary non-polyposis colorectal cancer syndrome (HNPCC) and hamartomatous polyposis syndromes (e.g. Peutz-Jeghers). Also in the case of familial \"sporadic\" carcinoma of the colon, regular screening colonoscopies for first degree relatives are recommended. Although the use of regular screening colonoscopies in patients with a long history of extensive ulcerative colitis is controversial, the recent results support such examinations. While the benefit of screening colonoscopy or sigmoidoscopy of the general population from the age of 50 onward must be affirmed, it should be weighed against the costs involved in such an undertaking. At the present time, the American Cancer Society recommends that from the age of 50 onward, the annual fecal test for occult blood should be supplemented by sigmoidoscopy performed every three to five years. Several genes have been associated with polyposis, such as GREM1, MSH3, MLH3, NTHL1, RNF43 and RPS20. Familial adenomatous polyposis Familial adenomatous polyposis (FAP) is a form of hereditary cancer syndrome involving the APC gene located on chromosome q521. The syndrome was first described in 1863 by Virchow on a 15-year-old boy with multiple polyps in his colon. The syndrome involves development of multiple polyps at an early age and those left untreated will all eventually develop cancer. The gene is expressed 100% in those with the mutation and it is autosomal dominant. 10% to 20% of patients have negative family history and acquire the syndrome from spontaneous germline mutation. The average age of newly diagnosed patient is 29 and the average age of newly discovered colorectal cancer is 39. It is recommended that those affected undergo colorectal cancer screening at younger age with treatment and prevention are surgical with removal of affected tissues. Familial adenomatous polyposis coli is a hereditary autosomal dominant disease which spontaneously and inevitably leads to degeneration of colorectal adenomas and requires preventive surgical treatment. The aim of this study was to evaluate the age of colorectal degeneration and the need for a screening technique in family members. Between 1983 and 1989, 141 patients were treated for familial adenomatous polyposis in our surgical center. Mean age at surgery was 32 years and 64 patients (45.4 percent) had a colorectal carcinoma. Thirty had an in situ tumor (mean age: 30 years) and 34 had an invasive adenocarcinoma (mean age: 45 years), 7 of whom died of their cancer. No colonic cancer was found in patients younger than 20. Thirty-eight percent of the patients under 40 years of age, 73 percent of the patients older than 40 years and 81 percent of those older than 50 had an adenocarcinoma. Fifty percent of the patients with carcinoma were younger than 40 years and 7 percent were less than 25 years old. Seventy-one patients were symptomatic at the time of operation (mean age: 40 years), 32 (45 percent) had a colonic cancer. In 70 patients, familial adenomatous polyposis was detected by screening (mean age: 24) and 2.8 percent had a colonic carcinoma. We conclude that the age-related risk of developing colonic carcinoma requires prophylactic surgery in asymptomatic patients before 20 years of age, and that routine familial screening would be of some benefit. We describe a patient who had precancerous colonic symptoms and a positive family history of multiple occurrences of early-onset colorectal cancer in her first-degree and second-degree relatives consistent with hereditary nonpolyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer diagnosis had not been made before her diagnosis of carcinoma of the cecum with liver metastasis. She died at age 20, leading to litigation. Controversies about standards of care, their malpractice implications, and pertinent legal issues are discussed. Review of the medical and family history was made by the expert witness (HTL) with appropriate documentation of the chronology of symptoms, as derived from depositions. These documents revealed that the patient's mother had repeatedly discussed with the caregivers her concern about the family history of colon cancer and the need for appropriate surveillance. The patient's colonic symptoms progressed for a period of three years. Flexible sigmoidoscopy was performed by a nonphysician. The physician who ordered the procedure considered this appropriate because isolated polyps were reported in the patient's father and paternal uncle, which apparently led him to believe that the diagnosis was familial adenomatous polyposis. During litigation procedures, a pedigree was constructed and found to be consistent with hereditary nonpolyposis colorectal cancer. The case was settled in favor of the plaintiff before trial. It is essential to understand the natural history of hereditary nonpolyposis colorectal cancer, inclusive of the need for surveillance colonoscopy in patients at increased risk by virtue of their position in their family pedigree. A family cancer screening clinic was set up to screen and counsel subjects at above average risk of developing colorectal cancer. Criteria for referral were one first degree relative under 50 years or two of any age with colorectal cancer. Pedigree information was used to estimate lifetime risks of developing colorectal cancer and offer appropriate screening: colonoscopy for high risks (greater than 1 in 10), faecal occult blood testing for lower risks. One hundred and eleven subjects from 76 families were seen over four years. Forty two families gave a pedigree consistent with dominantly inherited non-polyposis colorectal cancer syndrome (HNPCC). Three subjects from one family were found to have familial adenomatous polyposis. Ninety two colonoscopies yielded 21 patients with polyps (12 had tubular adenomas, including one with early malignant invasion). Thirty three per cent (four of 12) of the tubular adenomas were beyond the reach of a flexible sigmoidoscope. Three hundred and forty two further high risk relatives were identified from the family history. Average risk (no first-degree relative to colon cancer): Colonoscopy at age 50 No adenoma or carcinoma, repeat in 10 years One to two small (no more than 1 cm) tubular adenomas with low-grade dysplasia, repeat in 5 to 10 years Three to ten adenomas, or a large (at least 1 cm) adenoma, or any adenomas with high-grade dysplasia or villous features, repeat in 3 years. More than ten adenomas on a single exam, repeat within 3 years Increased risk (positive family history in the first-degree relative before age 60, or in two or more first-degree relatives at any age if not a hereditary syndrome) Colonoscopy at age 40, or 10 years before the youngest case in the immediate family (whichever is earlier). Repeat with above surveillance guidelines with the caveat that maximum time between screening should be 5 years. High-risk (hereditary colon cancer/polyposis syndromes): FAP: Annual flexible sigmoidoscopy; if genetically proven FAP, consider colectomy. Those with a family history in two or more first-degree relatives (such as a parent or sibling) have a two to threefold greater risk of disease and this group accounts for about 20% of all cases. A number of genetic syndromes are also associated with higher rates of colorectal cancer. The most common of these is hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome) which is present in about 3% of people with colorectal cancer. Other syndromes that are strongly associated with colorectal cancer include Gardner syndrome and familial adenomatous polyposis (FAP). For people with these syndromes, cancer almost always occurs and makes up 1% of the cancer cases. A total proctocolectomy may be recommended for people with FAP as a preventive measure due to the high risk of malignancy. Colectomy, removal of the colon, may not suffice as a preventive measure because of the high risk of rectal cancer if the rectum remains. The most common polyposis syndrome affecting the colon is First degree relatives of people with SPS are at a higher risk of colorectal cancer and SPS. As such, these individuals should undergo screening with colonoscopy beginning at the earliest of the following: 40 years of age, the age of the youngest diagnosis of SPS in the family, or 10 years younger than the earliest CRC related to SPS. Repeat colonoscopy should be performed at 5 year intervals. Prognosis The overall risk of colorectal cancer is about 19.9%. However, the risk of cancer varies widely and depends on age, polyp burden, phenotype and the presence of dysplasia on histology. Endoscopic surveillance can decrease the risk of progression to cancer. Patients with a high risk of developing colorectal cancer receive the screening procedure before the age of 50 years, and it is repeated every 1, 2, or 5 years based upon the primary risk and findings during the procedure. Examples of high-risk populations include a history of inflammatory bowel disease, a family history of colorectal cancer at age <60 years, hereditary polyposis (Such as Peutz Jegher syndrome and Familial Adenomatous Polyposis, caused by an APC gene mutation) and non-polyposis syndromes (LYNCH I and II), and surveillance after resection of colorectal cancer. Individuals with first degree relatives diagnosed with colon cancer are encouraged to undergo their first colonoscopy at age 40, or 10 years prior to the age the relative was diagnosed, whichever comes first. Elective colonoscopy is performed for reasons such as known or occult gastrointestinal bleeding or stool positive for occult blood, unexplained changes in bowel habits, patterns, iron deficiency anemia or weight loss in elderly patients, persistent abdominal pain, suspected inflammatory or infectious colitis and barium enema showing radiographic structural abnormalities. Children with familial adenomatous polyposis have a greater mortality and morbidity in the first decade of life compared with the general population. Some children with a more severe disease phenotype present early with colorectal adenomata and may require colectomy at an early age. We present our multidisciplinary clinic experience with familial adenomatous polyposis in children younger than age ten years at the time of presentation. A cross-sectional analysis was performed on all patients with suspected or confirmed familial adenomatous polyposis presenting in the first decade of life and followed by the multidisciplinary Pediatric Hereditary Polyposis Clinic at our institutions. Analysis included demographics, clinical presentation and course, gene mutation testing, endoscopic-histologic findings, and surgical outcome. Twenty-two children (11 males) presented with suspected or confirmed familial adenomatous polyposis. Two were discharged from follow-up after negative adenomatous polyposis coli gene mutation testing. The rest underwent annual hepatoblastoma surveillance through age ten years with negative findings. Twelve patients presented with symptoms: six had de novo familial adenomatous polyposis. Seven had gastrointestinal hemorrhage and went on to colonoscopy. Four patients with adenomatous polyposis coli gene mutation at codon 1309 were referred for colectomy before age ten years. Referral to colectomy was earlier in patients with 1309 mutation and with de novo familial adenomatous polyposis. Children with familial adenomatous polyposis younger than age ten years may present presymptomatically for disease surveillance. Familial adenomatous polyposis with adenomatous polyposis coli gene mutation at codon 1309 entails a risk of a more aggressive phenotype; early colectomy may be indicated in children harboring this gene mutation. Hyperplastic polyposis (HP) is a rare condition characterized by the presence of multiple hyperplastic polyps in the colon, which has been associated to an increased risk of colorectal cancer (CRC). Guidelines for management of this disease remain, so far, undefined. To evaluate, in symptomatic patients with HP, phenotypic characteristics as well as results of a screening program in their at-risk first-degree relatives. Pedigree information and clinical and endoscopic data of 14 patients with HP was studied. SEVENTEEN AND METHODS: at-risk first-degree relatives from six families were also invited to perform screening colonoscopy. Twelve of fourteen (86%) patients had fewer than 100 colorectal polyps. Polyps' sizes ranged from 2 to 25 mm and were uniformly distributed through the whole colon in 43% of the patients. Hyperplastic polyps predominated, but 11/14 (79%) patients also harbored serrated as well as classic adenomatous polyps. CRC was present in 6/14 (43%) of the patients at the time of diagnosis. Familial history of CRC/polyps was positive in 6/12 (50%) of cases. Colonoscopy in at-risk relatives disclosed polyps in 10/17 (59%) of cases with at least one additional patient having criteria for HP. Although small, this series demonstrates that a high level of suspicion is needed to diagnose the HP syndrome, in which serrated adenomas seem to be the hallmark. Although an elevated percentage of CRC was observed in this series of symptomatic patients with HP, prospective studies in asymptomatic individuals are needed to clearly quantify the risk of CRC in patients with HP. Because familial aggregation of HP was present in 3/12 (25%) of kindreds, screening colonoscopy should be offered to first-degree relatives. Understanding the natural history of Familial Adenomatous Polyposis (FAP) will guide screening and aid clinical management. Patients with FAP, age ≤20years presenting between 1987 and 2011, were reviewed for presentation, diagnosis, extraintestinal manifestations, polyp burden, family history, histology, gene mutation, surgical intervention, and outcome. One hundred sixty-three FAP patients were identified. Diagnosis was made by colonoscopy (69%) or genetic screening (25%) at mean age of 12.5years. Most children (58%) were asymptomatic and diagnosed via screening due to family history. Rectal bleeding was the most common (37%) symptom prompting evaluation. Colon polyps appeared by mean age of 13.4years with &gt;50 polyps at the time of diagnosis in 60%. Cancer was found in 1 colonoscopy biopsy and 5 colectomy specimens. Family history of FAP was known in 85%. 53% had genetic testing, which confirmed APC mutation in 88%. Extraintestinal manifestations included congenital hypertrophy of the retinal pigment epithelium (11.3%), desmoids (10.6%), osteomas (6.7%), epidermal cysts (5.5%), extranumerary teeth (3.7%), papillary thyroid cancer (3.1%), and hepatoblastoma (2.5%). Six patients died secondary to FAP. Clinical presentation and manifestations in pediatric FAP are variable. We suggest an individualized patient-oriented screening algorithm that allows for earlier screening and appropriate management. of first-degree relatives of FAP patients beginning at age 10 to 15 years has been the traditional mainstay of screening. Today, following genetic counseling, APC gene testing may be used to screen family members, pro-viding an APC mutation has been identified. If APC testing is positive in a relative of a patient with a known APC mutation, annual flexible sigmoidoscopy beginning at age 10 to 15 years is done until polyps are identified. If APC testing is negative, the relative can be screened starting at age 50 years per average-risk guidelines. If APC testing is refused or unavailable, or if a mutation cannot be identified, annual flexible sigmoidoscopy beginning at age 10 to 15 years is performed until age 24 years. Screening flexible sigmoidoscopy is then done every 2 years until age 34 years, every 3 years until age 44 years, and then every 3 to 5 years.FAP patients are also at risk for the development of adeno-mas anywhere in the gastrointestinal tract, particularly in the Most colorectal cancers (CRCs) arise from adenomatous polyps, but the effects of CRC family history on adenoma risk are not well known. This issue is clinically relevant since several medical societies currently recommend earlier and more rigorous colorectal screening for individuals with a strong family history of CRC. Colonoscopies were performed in 236 first-, second-, and third-degree relatives of 40 index CRC cases from six large kindreds selected from a large population database. The kindreds were selected for significantly greater risk of CRCs compared with the overall population. Known hereditary colon cancer syndromes were clinically and genetically excluded. Thirty-seven percent of relatives were found to have adenomas on colonoscopy. The average age of diagnosis for colon cancer was 63 yr and advanced adenomas 56 yr. Independent predictors of adenomatous polyps in the relatives were advancing age (P &lt; 0.0001), male gender (P &lt; 0.001), and greater degree of relation to CRC cases (P &lt; 0.01). There was no significant predilection of colorectal tumors for the right or left colon. A higher degree of relationship to CRC cases was a significant predictor of having simple and advanced adenomas, but not hyperplastic polyps after adjustment for age and gender. These data support the current recommendations for colonoscopy starting before the age of 50 yr in individuals with a strong family history of CRC. The risk for colorectal cancer among family members of patients with colorectal cancer is well established, but the risk among family members of patients with colorectal adenomas is less well established. To examine the risk for colorectal cancer among first-degree relatives of patients with adenoma compared with that among first-degree relatives of controls without adenoma. Reconstructed cohort study. Three university-based colonoscopy practices in New York City. 1554 first-degree relatives of 244 patients with newly diagnosed adenomas and 2173 first-degree relatives of 362 endoscopically normal controls. Structured interviews were used to obtain family history. Adjusted relative risks (RR) were estimated from Cox proportional hazards regression models. The risk for colorectal cancer was elevated (RR, 1.74 [95% CI, 1.24 to 2.45]) among first-degree relatives of patients with newly diagnosed adenomas compared with the risk among first-degree relatives of controls. This increased risk was the same for parents (RR, 1.58 [CI, 1.07 to 2.34]) and siblings (RR, 1.58 [CI, 0.81 to 3.08]). First-degree relatives of patients with adenomas did not have elevated risk for other cancers. The risk for colorectal cancer among family members increased with decreasing age at diagnosis of adenoma in probands. Among first-degree relatives of patients who were 50 years of age or younger when the adenoma was diagnosed, the risk was more than four times greater (RR, 4.36 [CI, 2.24 to 8.51]) than that among first-degree relatives of patients who were older than 60 years of age when the adenoma was diagnosed. First-degree relatives of patients with newly diagnosed adenomas, particularly of patients who are 50 years of age or younger at diagnosis, are at increased risk for colorectal cancer and should undergo screening similar to that recommended for relatives of patients with colorectal cancer. Lynch syndrome families have a substantial risk of developing colorectal cancer (CRC). The recommended surveillance protocol includes colonoscopy every 2 years from age 20-25 years. It is yet unknown whether annual screening of patients aged 40-60 years is more effective than bi-annual screening, whether patients who had an adenoma removed should be re-examined after a year and whether surveillance of second-degree relatives is indicated. The aim of this study was to address these issues. All carriers of a mismatch repair gene mutation who participated in the surveillance program were selected from the Dutch Lynch syndrome registry. The results of colonoscopy were prospectively collected. A total of 666 mutation carriers were identified in 110 families. Fourty-one CRCs were detected during endoscopic follow-up, of which 34 (83%) were diagnosed between age 40 and 60 years. In five of 34 patients, CRC was diagnosed within 1 year after colonoscopy, eight cancers were diagnosed between 1 and 2 years and the remaining tumors more than 2 years after colonoscopy. All eight CRCs detected between 1 and 2 years were at local stage. At least one adenoma was diagnosed at 141 examinations. The risk of developing CRC during follow-up in carriers with an adenoma was similar as in carriers without an adenoma at the previous colonoscopy. 280 parent-child couples with at least one Lynch syndrome-related carcinoma were identified in 110 families. In only 19 (6.8%) of these couples, CRC developed earlier in the child than an Lynch syndrome-associated cancer in the parent. The current surveillance protocol, i.e., bi-annual colonoscopy in first-degree relatives independent of age and endoscopic findings, appears to be appropriate. Attenuated familial adenomatous polyposis is a form of familial adenomatous polyposis, a cancer syndrome. It is a pre-malignant disease that can develop into colorectal cancer. A patient will have fewer than a hundred polyps located typically in right side of the colon. Cancer might develop as early as the age of five, though typically presents later than classical FAP. See also Familial adenomatous polyposis Birt–Hogg–Dubé syndrome Cowden syndrome Cronkhite–Canada syndrome Juvenile polyposis MUTYH Peutz–Jeghers syndrome References External links Gastrointestinal cancer Hereditary cancers Epidemiology The incidence of the mutation is between 1 in 10,000 and 1 in 15,000 births. By age 35 years, 95% of individuals with FAP (>100 adenomas) have polyps. Without colectomy, colon cancer is virtually inevitable. The mean age of colon cancer in untreated individuals is 39 years (range 34–43 years). Attenuated FAP arises when APC is defective but still somewhat functional. As a result, it retains part of its ability to suppress polyps. Therefore, attenuated FAP manifests as colorectal cancer unusually late (age 40–70, average=55), and typically with few, or at least far fewer polyps (typically 30), than the more usual version of FAP, at an age when FAP is no longer considered much of a likelihood or risk according to usual FAP epidemiology. Comparison of FAP variants This table compares the different subtypes of FAP:\nHere is the question:\nDIGESTIVE: A 30-year-old man with a family history of a father who died at 38 years of age from colon cancer. A colonoscopy is performed and shows hundreds of adenomas throughout the colon. Which of the following statements is false?\nHere are the potential choices:\n1. The patient has familial adenomatous polyposis.\n2. The most appropriate management is annual follow-up colonoscopy and colectomy at age 40.\n3. If the patient does not undergo surgical treatment, he/she will almost certainly develop colorectal cancer.\n4. First degree relatives should be studied.\n5. The patient's children have a 50% risk of suffering the same disease.\nThe correct answer is: ",
        "gold_answer": "2 The most appropriate management is annual follow-up colonoscopy and colectomy at age 40.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The best approach for screening patients hinges on the number, degree, and age of relatives diagnosed with colorectal cancer (CRC) or adenomatous polyps (AP). Screening should begin at 40 years of age for patients with a family history of CRC or AP in at least 1 first-degree relative or CRC in at least 2 second-degree relatives. Patients at highest risk-who have 1 first-degree relative diagnosed with CRC or AP before 60 years of age or multiple first-degree relatives diagnosed at any age-should begin screening with colonoscopy at 40 years of age or 10 years younger than the earliest affected relative and undergo a repeat colonoscopy every 5 years. Patients who have a first-degree relative diagnosed with CRC or AP after 60 years of age or 2 or more second-degree relatives with CRC should start screening at 40 years of age, with routine options and follow-up intervals. (Routine options and follow-up intervals include any of the following 3 regimens: annual high-sensitivity fecal occult blood testing, sigmoidoscopy every 5 years combined with high-sensitivity fecal occult blood testing every 3 years, or screening colonoscopy every 10 years.). Familial adenomatous polyposis (FAP) is a dominantly inherited predisposition to the development of many hundreds to thousands of adenomatous polyps of the colon. The mean age of onset is around 15 years, symptoms may arise in the third decade, and the median age for the development of colonic cancer is 35-40 years. Prophylactic colectomy reduces the risk of death from colorectal cancer to such an extent that late sequelae such as upper gastrointestinal tumours have become the main cause of mortality in appropriately managed patients. The age at which colonic surveillance begins reflects the natural history of the disease. Onset of polyp formation and cancer in childhood is very unusual, but has recently been associated with a specific mutation at codon 1309 in exon 15 where a more severe phenotype is sometimes observed. The case histories of two families are reported in which there is childhood onset of polyps in the youngest generation and in one case a carcinoma, in whom mutations have been identified in exon 11 of the APC gene. Several other affected relatives were diagnosed at ages ranging from 5-48 years, some already with a cancer at the time of first screening. Since the aim of screening for colonic polyps is prevention of colonic cancer, family members at risk should be offered genetic assessment and direct mutation testing where this is possible, usually in the early teens. In the absence of a genetic test (the situation in about one third of families) or in a known gene carrier, annual colonoscopy examination is advised from the same age. Clinicians should take note of the family history and be prepared to consider much earlier intervention if symptoms occur in a child with a family history of FAP. Where childhood onset of polyps has occurred, other children at risk in the family must be offered earlier genetic testing and endoscopic surveillance. Individuals at increased risk of developing colorectal cancer include those with a personal or family history of advanced adenomas or colorectal cancer, a personal history of inflammatory bowel disease, or genetic polyposis syndromes. In general, these persons should undergo more frequent or earlier testing than individuals at average risk. Individuals who have a first-degree relative with colorectal cancer or advanced adenoma diagnosed before 60 years of age or two first-degree relatives diagnosed at any age should be advised to start screening colonoscopy at 40 years of age or 10 years younger than the earliest diagnosis in their family, whichever comes first. In individuals with ulcerative colitis or Crohn disease with colonic involvement, colonoscopy should begin eight to 10 years after the onset of symptoms and be repeated every one to three years. Individuals who have a first-degree relative with hereditary nonpolyposis colorectal cancer should begin colonoscopy at 25 years of age and repeat colonoscopy every one to two years. In persons with a family history of adenomatous polyposis syndromes, screening should begin at 10 years of age or in a person's mid-20s, depending on the syndrome; repeat colonoscopy is typically required every one to two years. Screening colonoscopy should begin at eight years of age in individuals with Peutz-Jeghers syndrome. If results are normal, colonoscopy can be repeated at 18 years of age and then every three years. Persons with sessile serrated adenomatous polyposis should begin annual colonoscopy as soon as the diagnosis is established. Familial adenomatous polyposis represents approximately 1% of all colorectal tumours and is caused by germline mutations in the adenomatous polyposis coli (APC) gene. A 38-year-old lady presented with abdominal pain, diarrhoea and iron deficiency anemia. There was no history of colorectal cancer in the family. Colonoscopy showed hundreds of polyps throughout the colon sparing the rectum, and an ulcerative tumour of the sigmoid colon. The diagnosis was familial adenomatous polyposis (FAP) and adenocarcinoma of the sigmoid colon. Colectomy with ileorectal anastomosis was performed and later on she was given chemotherapy and advice life long surveillance. The patient had one brother and one sister, without clinical symptoms. The brother had a single hyperplastic rectal polyp, while the sister refused colonoscopy. The patient has 2 sons, the elder son had normal colonoscopic findings, and the younger son was also diagnosed as a patient of FAP and referred for colectomy. To determine the minimum family history of colorectal cancer (CRC), which justifies colonoscopy and to establish whether further colonic assessment is necessary after a negative screening colonoscopy. A retrospective review of every colonoscopy undertaken for family screening at the Royal Berkshire and Battle Hospitals, Reading between October 1996 and July 2004. Four hundred and thirty-two patients (261 women) with an average age of 48 years (range 14-84) were screened. Three cancers in patients over the age of 60 years and 49 adenomas were found in 37 patients. Twenty three of 281 (8%) patients with a 'low-risk' family history (one in 12 or less lifetime risk of developing CRC) had either a cancer or an adenoma. Eighteen of 151 (12%) patients with a 'high-risk' family history (one in 10 or greater) had a similar positive colonoscopy. Thirteen of 15 patients who had an adenoma aged under 45 years had a high-risk family history. Seventy-three patients subsequently underwent two or more follow-up colonoscopies. There were 22 adenomatous polyps found in 12 patients (16%) at the first screening, nine adenomas in seven patients in the second colonoscopy and four adenomas found in four patients in all subsequent colonoscopies. Patients with a low-risk family history have a similar adenoma pick-up to that of the general population. These patients need not be screened below the age of 50 unless symptomatic. Follow up of low-risk family history (FH) patients with a negative screening colonoscopy is unlikely to be beneficial. Screening colonoscopy is always indicated when rectosigmoidoscopy reveals an adenoma, since this lesion roughly doubles the patient's risk of contracting colonic cancer. Follow-up should be performed at intervals of about three years after endoscopic removal of all colorectal polyps. Repeated screening examinations are recommended for the following genetic diseases that carry an increased risk of colorectal carcinoma: familial adenomatous polyposis (FAP) and its genetic variant, hereditary non-polyposis colorectal cancer syndrome (HNPCC) and hamartomatous polyposis syndromes (e.g. Peutz-Jeghers). Also in the case of familial \"sporadic\" carcinoma of the colon, regular screening colonoscopies for first degree relatives are recommended. Although the use of regular screening colonoscopies in patients with a long history of extensive ulcerative colitis is controversial, the recent results support such examinations. While the benefit of screening colonoscopy or sigmoidoscopy of the general population from the age of 50 onward must be affirmed, it should be weighed against the costs involved in such an undertaking. At the present time, the American Cancer Society recommends that from the age of 50 onward, the annual fecal test for occult blood should be supplemented by sigmoidoscopy performed every three to five years. Several genes have been associated with polyposis, such as GREM1, MSH3, MLH3, NTHL1, RNF43 and RPS20. Familial adenomatous polyposis Familial adenomatous polyposis (FAP) is a form of hereditary cancer syndrome involving the APC gene located on chromosome q521. The syndrome was first described in 1863 by Virchow on a 15-year-old boy with multiple polyps in his colon. The syndrome involves development of multiple polyps at an early age and those left untreated will all eventually develop cancer. The gene is expressed 100% in those with the mutation and it is autosomal dominant. 10% to 20% of patients have negative family history and acquire the syndrome from spontaneous germline mutation. The average age of newly diagnosed patient is 29 and the average age of newly discovered colorectal cancer is 39. It is recommended that those affected undergo colorectal cancer screening at younger age with treatment and prevention are surgical with removal of affected tissues. Familial adenomatous polyposis coli is a hereditary autosomal dominant disease which spontaneously and inevitably leads to degeneration of colorectal adenomas and requires preventive surgical treatment. The aim of this study was to evaluate the age of colorectal degeneration and the need for a screening technique in family members. Between 1983 and 1989, 141 patients were treated for familial adenomatous polyposis in our surgical center. Mean age at surgery was 32 years and 64 patients (45.4 percent) had a colorectal carcinoma. Thirty had an in situ tumor (mean age: 30 years) and 34 had an invasive adenocarcinoma (mean age: 45 years), 7 of whom died of their cancer. No colonic cancer was found in patients younger than 20. Thirty-eight percent of the patients under 40 years of age, 73 percent of the patients older than 40 years and 81 percent of those older than 50 had an adenocarcinoma. Fifty percent of the patients with carcinoma were younger than 40 years and 7 percent were less than 25 years old. Seventy-one patients were symptomatic at the time of operation (mean age: 40 years), 32 (45 percent) had a colonic cancer. In 70 patients, familial adenomatous polyposis was detected by screening (mean age: 24) and 2.8 percent had a colonic carcinoma. We conclude that the age-related risk of developing colonic carcinoma requires prophylactic surgery in asymptomatic patients before 20 years of age, and that routine familial screening would be of some benefit. We describe a patient who had precancerous colonic symptoms and a positive family history of multiple occurrences of early-onset colorectal cancer in her first-degree and second-degree relatives consistent with hereditary nonpolyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer diagnosis had not been made before her diagnosis of carcinoma of the cecum with liver metastasis. She died at age 20, leading to litigation. Controversies about standards of care, their malpractice implications, and pertinent legal issues are discussed. Review of the medical and family history was made by the expert witness (HTL) with appropriate documentation of the chronology of symptoms, as derived from depositions. These documents revealed that the patient's mother had repeatedly discussed with the caregivers her concern about the family history of colon cancer and the need for appropriate surveillance. The patient's colonic symptoms progressed for a period of three years. Flexible sigmoidoscopy was performed by a nonphysician. The physician who ordered the procedure considered this appropriate because isolated polyps were reported in the patient's father and paternal uncle, which apparently led him to believe that the diagnosis was familial adenomatous polyposis. During litigation procedures, a pedigree was constructed and found to be consistent with hereditary nonpolyposis colorectal cancer. The case was settled in favor of the plaintiff before trial. It is essential to understand the natural history of hereditary nonpolyposis colorectal cancer, inclusive of the need for surveillance colonoscopy in patients at increased risk by virtue of their position in their family pedigree. A family cancer screening clinic was set up to screen and counsel subjects at above average risk of developing colorectal cancer. Criteria for referral were one first degree relative under 50 years or two of any age with colorectal cancer. Pedigree information was used to estimate lifetime risks of developing colorectal cancer and offer appropriate screening: colonoscopy for high risks (greater than 1 in 10), faecal occult blood testing for lower risks. One hundred and eleven subjects from 76 families were seen over four years. Forty two families gave a pedigree consistent with dominantly inherited non-polyposis colorectal cancer syndrome (HNPCC). Three subjects from one family were found to have familial adenomatous polyposis. Ninety two colonoscopies yielded 21 patients with polyps (12 had tubular adenomas, including one with early malignant invasion). Thirty three per cent (four of 12) of the tubular adenomas were beyond the reach of a flexible sigmoidoscope. Three hundred and forty two further high risk relatives were identified from the family history. Average risk (no first-degree relative to colon cancer): Colonoscopy at age 50 No adenoma or carcinoma, repeat in 10 years One to two small (no more than 1 cm) tubular adenomas with low-grade dysplasia, repeat in 5 to 10 years Three to ten adenomas, or a large (at least 1 cm) adenoma, or any adenomas with high-grade dysplasia or villous features, repeat in 3 years. More than ten adenomas on a single exam, repeat within 3 years Increased risk (positive family history in the first-degree relative before age 60, or in two or more first-degree relatives at any age if not a hereditary syndrome) Colonoscopy at age 40, or 10 years before the youngest case in the immediate family (whichever is earlier). Repeat with above surveillance guidelines with the caveat that maximum time between screening should be 5 years. High-risk (hereditary colon cancer/polyposis syndromes): FAP: Annual flexible sigmoidoscopy; if genetically proven FAP, consider colectomy. Those with a family history in two or more first-degree relatives (such as a parent or sibling) have a two to threefold greater risk of disease and this group accounts for about 20% of all cases. A number of genetic syndromes are also associated with higher rates of colorectal cancer. The most common of these is hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome) which is present in about 3% of people with colorectal cancer. Other syndromes that are strongly associated with colorectal cancer include Gardner syndrome and familial adenomatous polyposis (FAP). For people with these syndromes, cancer almost always occurs and makes up 1% of the cancer cases. A total proctocolectomy may be recommended for people with FAP as a preventive measure due to the high risk of malignancy. Colectomy, removal of the colon, may not suffice as a preventive measure because of the high risk of rectal cancer if the rectum remains. The most common polyposis syndrome affecting the colon is First degree relatives of people with SPS are at a higher risk of colorectal cancer and SPS. As such, these individuals should undergo screening with colonoscopy beginning at the earliest of the following: 40 years of age, the age of the youngest diagnosis of SPS in the family, or 10 years younger than the earliest CRC related to SPS. Repeat colonoscopy should be performed at 5 year intervals. Prognosis The overall risk of colorectal cancer is about 19.9%. However, the risk of cancer varies widely and depends on age, polyp burden, phenotype and the presence of dysplasia on histology. Endoscopic surveillance can decrease the risk of progression to cancer. Patients with a high risk of developing colorectal cancer receive the screening procedure before the age of 50 years, and it is repeated every 1, 2, or 5 years based upon the primary risk and findings during the procedure. Examples of high-risk populations include a history of inflammatory bowel disease, a family history of colorectal cancer at age <60 years, hereditary polyposis (Such as Peutz Jegher syndrome and Familial Adenomatous Polyposis, caused by an APC gene mutation) and non-polyposis syndromes (LYNCH I and II), and surveillance after resection of colorectal cancer. Individuals with first degree relatives diagnosed with colon cancer are encouraged to undergo their first colonoscopy at age 40, or 10 years prior to the age the relative was diagnosed, whichever comes first. Elective colonoscopy is performed for reasons such as known or occult gastrointestinal bleeding or stool positive for occult blood, unexplained changes in bowel habits, patterns, iron deficiency anemia or weight loss in elderly patients, persistent abdominal pain, suspected inflammatory or infectious colitis and barium enema showing radiographic structural abnormalities. Children with familial adenomatous polyposis have a greater mortality and morbidity in the first decade of life compared with the general population. Some children with a more severe disease phenotype present early with colorectal adenomata and may require colectomy at an early age. We present our multidisciplinary clinic experience with familial adenomatous polyposis in children younger than age ten years at the time of presentation. A cross-sectional analysis was performed on all patients with suspected or confirmed familial adenomatous polyposis presenting in the first decade of life and followed by the multidisciplinary Pediatric Hereditary Polyposis Clinic at our institutions. Analysis included demographics, clinical presentation and course, gene mutation testing, endoscopic-histologic findings, and surgical outcome. Twenty-two children (11 males) presented with suspected or confirmed familial adenomatous polyposis. Two were discharged from follow-up after negative adenomatous polyposis coli gene mutation testing. The rest underwent annual hepatoblastoma surveillance through age ten years with negative findings. Twelve patients presented with symptoms: six had de novo familial adenomatous polyposis. Seven had gastrointestinal hemorrhage and went on to colonoscopy. Four patients with adenomatous polyposis coli gene mutation at codon 1309 were referred for colectomy before age ten years. Referral to colectomy was earlier in patients with 1309 mutation and with de novo familial adenomatous polyposis. Children with familial adenomatous polyposis younger than age ten years may present presymptomatically for disease surveillance. Familial adenomatous polyposis with adenomatous polyposis coli gene mutation at codon 1309 entails a risk of a more aggressive phenotype; early colectomy may be indicated in children harboring this gene mutation. Hyperplastic polyposis (HP) is a rare condition characterized by the presence of multiple hyperplastic polyps in the colon, which has been associated to an increased risk of colorectal cancer (CRC). Guidelines for management of this disease remain, so far, undefined. To evaluate, in symptomatic patients with HP, phenotypic characteristics as well as results of a screening program in their at-risk first-degree relatives. Pedigree information and clinical and endoscopic data of 14 patients with HP was studied. SEVENTEEN AND METHODS: at-risk first-degree relatives from six families were also invited to perform screening colonoscopy. Twelve of fourteen (86%) patients had fewer than 100 colorectal polyps. Polyps' sizes ranged from 2 to 25 mm and were uniformly distributed through the whole colon in 43% of the patients. Hyperplastic polyps predominated, but 11/14 (79%) patients also harbored serrated as well as classic adenomatous polyps. CRC was present in 6/14 (43%) of the patients at the time of diagnosis. Familial history of CRC/polyps was positive in 6/12 (50%) of cases. Colonoscopy in at-risk relatives disclosed polyps in 10/17 (59%) of cases with at least one additional patient having criteria for HP. Although small, this series demonstrates that a high level of suspicion is needed to diagnose the HP syndrome, in which serrated adenomas seem to be the hallmark. Although an elevated percentage of CRC was observed in this series of symptomatic patients with HP, prospective studies in asymptomatic individuals are needed to clearly quantify the risk of CRC in patients with HP. Because familial aggregation of HP was present in 3/12 (25%) of kindreds, screening colonoscopy should be offered to first-degree relatives. Understanding the natural history of Familial Adenomatous Polyposis (FAP) will guide screening and aid clinical management. Patients with FAP, age ≤20years presenting between 1987 and 2011, were reviewed for presentation, diagnosis, extraintestinal manifestations, polyp burden, family history, histology, gene mutation, surgical intervention, and outcome. One hundred sixty-three FAP patients were identified. Diagnosis was made by colonoscopy (69%) or genetic screening (25%) at mean age of 12.5years. Most children (58%) were asymptomatic and diagnosed via screening due to family history. Rectal bleeding was the most common (37%) symptom prompting evaluation. Colon polyps appeared by mean age of 13.4years with &gt;50 polyps at the time of diagnosis in 60%. Cancer was found in 1 colonoscopy biopsy and 5 colectomy specimens. Family history of FAP was known in 85%. 53% had genetic testing, which confirmed APC mutation in 88%. Extraintestinal manifestations included congenital hypertrophy of the retinal pigment epithelium (11.3%), desmoids (10.6%), osteomas (6.7%), epidermal cysts (5.5%), extranumerary teeth (3.7%), papillary thyroid cancer (3.1%), and hepatoblastoma (2.5%). Six patients died secondary to FAP. Clinical presentation and manifestations in pediatric FAP are variable. We suggest an individualized patient-oriented screening algorithm that allows for earlier screening and appropriate management. of first-degree relatives of FAP patients beginning at age 10 to 15 years has been the traditional mainstay of screening. Today, following genetic counseling, APC gene testing may be used to screen family members, pro-viding an APC mutation has been identified. If APC testing is positive in a relative of a patient with a known APC mutation, annual flexible sigmoidoscopy beginning at age 10 to 15 years is done until polyps are identified. If APC testing is negative, the relative can be screened starting at age 50 years per average-risk guidelines. If APC testing is refused or unavailable, or if a mutation cannot be identified, annual flexible sigmoidoscopy beginning at age 10 to 15 years is performed until age 24 years. Screening flexible sigmoidoscopy is then done every 2 years until age 34 years, every 3 years until age 44 years, and then every 3 to 5 years.FAP patients are also at risk for the development of adeno-mas anywhere in the gastrointestinal tract, particularly in the Most colorectal cancers (CRCs) arise from adenomatous polyps, but the effects of CRC family history on adenoma risk are not well known. This issue is clinically relevant since several medical societies currently recommend earlier and more rigorous colorectal screening for individuals with a strong family history of CRC. Colonoscopies were performed in 236 first-, second-, and third-degree relatives of 40 index CRC cases from six large kindreds selected from a large population database. The kindreds were selected for significantly greater risk of CRCs compared with the overall population. Known hereditary colon cancer syndromes were clinically and genetically excluded. Thirty-seven percent of relatives were found to have adenomas on colonoscopy. The average age of diagnosis for colon cancer was 63 yr and advanced adenomas 56 yr. Independent predictors of adenomatous polyps in the relatives were advancing age (P &lt; 0.0001), male gender (P &lt; 0.001), and greater degree of relation to CRC cases (P &lt; 0.01). There was no significant predilection of colorectal tumors for the right or left colon. A higher degree of relationship to CRC cases was a significant predictor of having simple and advanced adenomas, but not hyperplastic polyps after adjustment for age and gender. These data support the current recommendations for colonoscopy starting before the age of 50 yr in individuals with a strong family history of CRC. The risk for colorectal cancer among family members of patients with colorectal cancer is well established, but the risk among family members of patients with colorectal adenomas is less well established. To examine the risk for colorectal cancer among first-degree relatives of patients with adenoma compared with that among first-degree relatives of controls without adenoma. Reconstructed cohort study. Three university-based colonoscopy practices in New York City. 1554 first-degree relatives of 244 patients with newly diagnosed adenomas and 2173 first-degree relatives of 362 endoscopically normal controls. Structured interviews were used to obtain family history. Adjusted relative risks (RR) were estimated from Cox proportional hazards regression models. The risk for colorectal cancer was elevated (RR, 1.74 [95% CI, 1.24 to 2.45]) among first-degree relatives of patients with newly diagnosed adenomas compared with the risk among first-degree relatives of controls. This increased risk was the same for parents (RR, 1.58 [CI, 1.07 to 2.34]) and siblings (RR, 1.58 [CI, 0.81 to 3.08]). First-degree relatives of patients with adenomas did not have elevated risk for other cancers. The risk for colorectal cancer among family members increased with decreasing age at diagnosis of adenoma in probands. Among first-degree relatives of patients who were 50 years of age or younger when the adenoma was diagnosed, the risk was more than four times greater (RR, 4.36 [CI, 2.24 to 8.51]) than that among first-degree relatives of patients who were older than 60 years of age when the adenoma was diagnosed. First-degree relatives of patients with newly diagnosed adenomas, particularly of patients who are 50 years of age or younger at diagnosis, are at increased risk for colorectal cancer and should undergo screening similar to that recommended for relatives of patients with colorectal cancer. Lynch syndrome families have a substantial risk of developing colorectal cancer (CRC). The recommended surveillance protocol includes colonoscopy every 2 years from age 20-25 years. It is yet unknown whether annual screening of patients aged 40-60 years is more effective than bi-annual screening, whether patients who had an adenoma removed should be re-examined after a year and whether surveillance of second-degree relatives is indicated. The aim of this study was to address these issues. All carriers of a mismatch repair gene mutation who participated in the surveillance program were selected from the Dutch Lynch syndrome registry. The results of colonoscopy were prospectively collected. A total of 666 mutation carriers were identified in 110 families. Fourty-one CRCs were detected during endoscopic follow-up, of which 34 (83%) were diagnosed between age 40 and 60 years. In five of 34 patients, CRC was diagnosed within 1 year after colonoscopy, eight cancers were diagnosed between 1 and 2 years and the remaining tumors more than 2 years after colonoscopy. All eight CRCs detected between 1 and 2 years were at local stage. At least one adenoma was diagnosed at 141 examinations. The risk of developing CRC during follow-up in carriers with an adenoma was similar as in carriers without an adenoma at the previous colonoscopy. 280 parent-child couples with at least one Lynch syndrome-related carcinoma were identified in 110 families. In only 19 (6.8%) of these couples, CRC developed earlier in the child than an Lynch syndrome-associated cancer in the parent. The current surveillance protocol, i.e., bi-annual colonoscopy in first-degree relatives independent of age and endoscopic findings, appears to be appropriate. Attenuated familial adenomatous polyposis is a form of familial adenomatous polyposis, a cancer syndrome. It is a pre-malignant disease that can develop into colorectal cancer. A patient will have fewer than a hundred polyps located typically in right side of the colon. Cancer might develop as early as the age of five, though typically presents later than classical FAP. See also Familial adenomatous polyposis Birt–Hogg–Dubé syndrome Cowden syndrome Cronkhite–Canada syndrome Juvenile polyposis MUTYH Peutz–Jeghers syndrome References External links Gastrointestinal cancer Hereditary cancers Epidemiology The incidence of the mutation is between 1 in 10,000 and 1 in 15,000 births. By age 35 years, 95% of individuals with FAP (>100 adenomas) have polyps. Without colectomy, colon cancer is virtually inevitable. The mean age of colon cancer in untreated individuals is 39 years (range 34–43 years). Attenuated FAP arises when APC is defective but still somewhat functional. As a result, it retains part of its ability to suppress polyps. Therefore, attenuated FAP manifests as colorectal cancer unusually late (age 40–70, average=55), and typically with few, or at least far fewer polyps (typically 30), than the more usual version of FAP, at an age when FAP is no longer considered much of a likelihood or risk according to usual FAP epidemiology. Comparison of FAP variants This table compares the different subtypes of FAP:\nHere is the question:\nDIGESTIVE: A 30-year-old man with a family history of a father who died at 38 years of age from colon cancer. A colonoscopy is performed and shows hundreds of adenomas throughout the colon. Which of the following statements is false?\nHere are the potential choices:\n1. The patient has familial adenomatous polyposis.\n2. The most appropriate management is annual follow-up colonoscopy and colectomy at age 40.\n3. If the patient does not undergo surgical treatment, he/she will almost certainly develop colorectal cancer.\n4. First degree relatives should be studied.\n5. The patient's children have a 50% risk of suffering the same disease.\nThe correct answer is: 2. The most appropriate management is annual follow-up colonoscopy and colectomy at age 40."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Parkinson's disease, a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech. Huntington's disease, a rare inherited neurological disorder whose most obvious symptoms are abnormal body movements and a lack of coordination. It also affects a number of mental abilities and some aspects of personality. Alzheimer's disease, a neurodegenerative disease that, in its most common form, is found in people over the age of 65 and is characterized by progressive cognitive deterioration, together with declining activities of daily living and by neuropsychiatric symptoms or behavioral changes. Clinical depression, a common psychiatric disorder, characterized by a persistent lowering of mood, loss of interest in usual activities and diminished ability to experience pleasure. Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, self-neglect, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years. To investigate the frequency and longitudinal course of symptoms of depression, agitation, and psychosis in a longitudinally studied sample of patients with Alzheimer's disease (AD). Longitudinal study of AD patients with follow-up assessments at 6-month intervals for an average of more than 3 years. Alzheimer's Disease Research Center of the Mount Sinai Medical Center and the Bronx VA Medical Center, New York. A total of 153 AD patients. Blessed Test of Information, Memory and Concentration (BIMC) and the Alzheimer's Disease Assessment Scale cognitive (ADAS-Cog) and noncognitive (ADAS-NC) subscales. At entry into the study, more than 90% of patients had a behavioral disturbance that was rated as mild or worse on one of the 10 ADAS noncognitive items; and 40% had at least one rating that was moderate or severe. Correlational analyses indicated that, with the exception of the two mood-related items, noncognitive symptoms on the ADAS were not highly correlated with one another. Only one of the noncognitive items, concentration, was strongly correlated with the severity of cognitive impairment. On average, patients showed progressively worse cognitive functioning over time as measured both by the ADAS-Cog and the BIMC. The mean severity of noncognitive symptoms did not change during the course of a 5-year follow up. The severity of behavioral disturbance at any one evaluation was negatively correlated with change in behavior during the next 6 months and was not correlated with cognitive decline. Mild behavioral disturbances are common, whereas moderate to severe behavioral symptoms are less frequent in this population of AD patients. Disturbances in mood and manifestations of agitation and psychotic symptoms are not closely related to one another and show little progressive worsening over time. Rather, they tend to be episodic such that increasing severity at one time is usually followed by improvement later. Concentration problems are a manifestation of cognitive dysfunction rather than behavioral disturbance in AD. Implications of these results for treatment of noncognitive disturbances in AD are discussed. Dementia manifests as a set of related symptoms, which usually surface when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively impact a person's ability to function and carry out everyday activities. Aside from memory impairment and a disruption in thought patterns, the most common symptoms include emotional problems, difficulties with language, and decreased motivation. The symptoms may be described as occurring in a continuum over several stages. Consciousness is not affected. Dementia ultimately has a significant effect on the individual, caregivers, and relationships in general. A diagnosis of dementia requires a change from a person's usual mental functioning and a greater cognitive decline than what is caused by normal aging. Several diseases and injuries to the brain, such as a stroke, can give rise to dementia. However, the most common cause is Alzheimer's disease, a neurodegenerative Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease characterized by progressive cognitive deterioration, together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. The most striking early symptom is loss of short-term memory (amnesia), which usually manifests as minor forgetfulness that becomes steadily more pronounced with illness progression, with relative preservation of older memories. As the disorder progresses, cognitive (intellectual) impairment extends to the domains of language (aphasia), skilled movements (apraxia), and recognition (agnosia), and functions such as decision-making and planning become impaired. We carried out a prospective longitudinal study of 41 patients diagnosed as probably having a mild form of Alzheimer's disease according to the data of an investigation of prevalence done in 1991 in the municipality of Habana Vieja. The research covered two phases, with an interval of one year between them. During both phases the patients were interviewed by the same neurology resident in a door-to-door survey using the Mini-Mental State, Hughes scale (CDR) and Blessed scale, to evaluate higher mental functions. We determined the progress of the disease over the course of two years (1991-1992 and 1992-1993) and the frequency and degree of deterioration of cognitive functions during a period of one year. There was evidence of progressive worsening of the illness in 46.4% of the patients. In 34.2% this was to a moderate form and in 12.2% to a severe form. There was no progression in 46.3%. In this group 17.0% continued with a diagnosis of doubtful dementia and 29.3% as having slight dementia. The other 7.3% of the total number of patients (n = 41) were reclassified as normal. Cognitive functions almost always showed a tendency to deteriorate over time, but in a small percentage of patients they did not deteriorate and some even improved. The cognitive functions which deteriorated most were those of orientation, language and copying, with an average deterioration of 28% and 24% respectively with regard to their initial values. After ten years' treatment with cholinesterase inhibitors (AcheI) in Alzheimer's disease (AD), we report here the activity of the Alzheimer's Disease Assessment Unit of IRCCS C. Mondino, Pavia, Italy. From September 2000 to December 2007, 794 out-patients (of 2236 referred to our Assessment Unit for cognitive disturbances) with AD of mild to moderate degree were treated with cholinesterase inhibitors (M/F: 273/521, mean age 73.6+/- 8.4 yrs, range 52-85 yrs). Outcome measures were scores on Mini Mental State Examination (MMSE), ADL, IADL and Neuropsychiatric Inventory (NPI). Mean treatment duration was 36.9+/-16.1 months. After three months' treatment, MMSE scores remained stable (responders) in 60% of cases and improved (increase of 3 or more points - good responders) in 15%, with good preservation of autonomy. After 15 months, the percentage of \"good responders\" decreased to 7%, while after 15, 27 and 39 months the percentage of responders progressively decreased to 40%, 30% and 8%, respectively; greater impairment in instrumental with respect to basic everyday activities was noted. No variables capable of predicting the response to treatment were detected. The onset of behavioral disturbances caused significant (p&lt;0.02) worsening of both cognition and function and, in 12% of cases, suspension of treatment. Our results therefore confirm the efficacy of AcheI in AD of mild to moderate degree even in a nonselected population; efficacy also seems to persist in long-term treatment. This report, although brief and mainly descriptive, can make a contribution to better knowledge of the usefulness of these drugs in AD of mild to moderate extent in everyday clinical practice. Psychotic symptoms associated with Alzheimer Disease (AD) contribute to excess functional dependence. Longitudinal studies have generally examined the association between rates of functional decline and the occurrence of psychotic symptoms from either a single evaluation or from multiple evaluations rather than through changes in frequency and severity of symptoms. Although the presence or absence of psychotic symptoms at initial or follow-up examinations may be associated with changes in functional status, the nature of the relationship between changes in these domains cannot be inferred. We examine the association between changes in the frequency of psychotic symptoms and changes in dependence in activities of daily living (ADL) over a period ranging from 1 to 74 months (median = 17.7). Data from a cohort of 234 individuals referred to a memory clinic were analyzed using multilevel linear regression. Information on ADL, behavioral and psychological symptoms, depression, and cognition was collected. An increase in the frequency of psychotic symptoms had a unique influence on the deterioration of basic ADL, after controlling for demographic variables, changes in cognition, depression, and other behavioral and psychological symptoms (B = -.017, p = .003). However, changes in psychotic symptoms did not significantly contribute to declines in the ability to perform instrumental ADL (B = -.008, p = .439). Changes in psychotic symptoms may influence basic but not instrumental ADL over time. These findings may have ramifications for studies and treatment plans for individuals with AD who demonstrate psychotic symptoms. Patients present with behavioral and psychiatric symptoms, speech deficits (aphasia and/or dysarthria) and progressive cognitive and motor decline (dementia, ataxia, parkinsonism, psychosis, aphasia and mood disorder). Average age at onset is 70 years, and duration of survival is 24 months. About 40% of patients have a family history of dementia. Like CJD, it can be mistaken for Alzheimer's dementia. The diagnosis of Alzheimer's disease must be considered in all subjects over 40 years of age whose mental functions have insidiously become altered and are progressively getting worse. The initial phase of the disease, which precedes dementia, is characterized by disorders of memory often associated with changes in personality and behaviour and with subtle disorders of speech, reasoning and abstraction ability and visuo-constructive capabilities. The results of neurological and paraclinical examinations are normal. This phase lasts from two to four years and may be diagnosed as \"possible Alzheimer's disease\". When the disease is established the patient has lost his autonomy and can only be kept at home with the help of his relatives. Dementia gradually becomes worse, with a combination of memory disturbance, aphasia-apraxia-agnosia syndrome, impaired intellectual faculties and disorders of behaviour. Computerized tomography shows evidence of cerebral atrophy. This phase lasts from three to six years and may be called \"probable Alzheimer's disease\". The terminal phase of the disease includes somatic lesions, and all mental functions are profoundly altered. Death occurs seven to ten years after the first symptoms. Histopathological data are necessary to make a diagnosis of \"confirmed Alzheimer's disease\", since there is no clinical, morphological, electrophysiological or radiological sign that is pathognomonic of that disease. Signs and symptoms Signs and symptoms of Huntington's disease most commonly become noticeable between the ages of 30 and 50 years, but they can begin at any age, and present as a triad of motor, cognitive, and psychiatric symptoms. In 50% of cases, the psychiatric symptoms appear first. Their progression is often described in early stages, middle stages, and late stages with an earlier prodromal phase. In the early stages, subtle personality changes, problems in cognition, and physical skills, irritability, and mood swings occur, all of which may go unnoticed, and these usually precede the motor symptoms. Almost everyone with HD eventually exhibits similar physical symptoms, but the onset, progression, and extent of cognitive and behavioral symptoms vary significantly between individuals. The decline in the Mini-Mental State Exam (MMSE) over 2 years was assessed in males with Alzheimer's disease (AD; N = 136) seen in a dementia clinic. The average initial MMSE was 21.0 (SD+/-3.9; range 14--29) and declined 2.8 points (+/-4.7; range -17 to +6) over 2 years. The mode for change on the MMSE was 0 (N = 22) while the median fell between 2 and 3 points lost. Fifty-five of 136 patients (39.7%) had unchanged or better scores. There was no significant correlation between the initial MMSE and rate of change (r = -0.16; p = 0.06). While the progression of AD is quite variable from patient to patient, our data indicate that in most it is associated with little if any change in the MMSE even over 2 years. The MMSE is not an adequate tool to monitor change in the individual patient with AD. The confusion between Alzheimer's and FTD is justifiable due to the similarities between their initial symptoms. Patients do not have difficulty with movement and other motor tasks. As FTD symptoms appear, it is difficult to differentiate between a diagnosis of Alzheimer's disease and FTD. There are distinct differences in the behavioral and emotional symptoms of the two dementias, notably, the blunting of emotions seen in FTD patients. In the early stages of FTD, anxiety and depression are common, which may result in an ambiguous diagnosis. However, over time, these ambiguities fade away as this dementia progresses and defining symptoms of apathy, unique to FTD, start to appear. The aim of the study which was based on a five year prospective scheme was the evaluation of progressive changes in persons with a diagnosed mild cognitive impairment (MCI). A result of 3 in the Global Deterioration Scale (Reisberg's criteria), allowed for mild cognitive impairment diagnosis. The CGI scale result in the 5th year of observation was the bases to divide the studied population into a group with a stable MCI course and a group with progressive symptoms. 41 persons finished the five years of observation, out of a total 46 chosen for the study. After 5 years, 26 persons had no changes in the CGI result, whilst 15 persons showed a worsening in their clinical picture. At the initial qualification to the study the two groups of patients did not differ in their psychiatric state. However differences in the ADAS-kog could be seen in the second measurement done after the first year of the observation. Amongst those persons who had a worsening above 1.68 in the first year of the observation, Alzheimer's disease could be diagnosed definitely more frequently in the further stages of the observation. Evaluation of cognitive function impairment progression seems to be one of the most important diagnostic elements and should be included in the diagnostic criteria of MCI. Although adult attention-deficit/hyperactivity disorder has recently gained increased attention, few reports on attention-deficit/hyperactivity disorder in the pre-elderly or elderly have been published. Here, we present the case of a patient with attention-deficit/hyperactivity disorder who gradually developed dementia-like symptoms as she aged, which initially made her condition difficult to distinguish from early onset Alzheimer's disease. This report illustrates that some types of attention-deficit/hyperactivity disorder may be misdiagnosed as dementia. The patient was a 58-year-old woman. Although she presented with a tendency for inattentiveness and forgetfulness since childhood, she did not have a history of psychiatric disorders prior to consultation. Around the age of 52 years, her inattentiveness and forgetfulness gradually progressed, and at 57 years of age, she became inattentive and forgetful that it interfered with her work and daily life. For example, she forgot meetings with important clients and transferred money to the wrong bank account; these failures resulted in poor management of her company. At home, she experienced increasing difficulties with remembering prior commitments with her family and misplacing items, which her family members noticed. With the encouragement of her family and employees, who worried that she was suffering from dementia, she visited our memory clinic, whereby she was suspected of having early onset Alzheimer's disease. However, neuropsychological tests and brain imaging evaluations did not reveal any significant abnormalities. After dismissing various possible diagnoses, including dementia, other organic diseases, mood disorders, and delirium, we diagnosed her with attention-deficit/hyperactivity disorder. Treatment with 18 mg of methylphenidate was initiated, and significant improvements in her symptoms were observed within a few days; for example, she stopped losing her things, was able to concentrate for long durations, and could complete more tasks than she could before treatment. Since initiating treatment, she has returned to work and has been able to perform her daily activities without difficulty. This case supports that some patients with late-onset attention-deficit/hyperactivity disorder may gradually develop dementia-like symptoms during the pre-elderly and elderly stages of life. Therefore, clinicians should consider late-onset attention-deficit/hyperactivity disorder as a differential diagnosis of some types of dementias. We examined the pattern of cognitive impairment and rate of cognitive and functional decline as a function of age at symptom onset in 127 patients with probable Alzheimer's disease (AD). At baseline, early-onset (before age 65) and late-onset groups were mildly and comparably impaired on the modified Mini-Mental State Examination (mMMS) and the Blessed Dementia Rating Scale-Part 1 (BDRS). Repeated-measures analysis of variance revealed significantly more rapid decline in early-onset subjects over a 2-year follow-up period. Multivariate linear regression analyses indicated that age at symptom onset strongly predicted rate of decline on the mMMS and the BDRS, even after controlling for symptom duration, gender, family history of dementia, and baseline mMMS and BDRS scores. Early- and late-onset AD subjects also differed in terms of pattern of performance on the mMMS. Early-onset subjects scored significantly lower than late-onset subjects on attentional items of the mMMS at baseline and follow-up. Conversely, late-onset subjects scored significantly lower than early-onset subjects on memory and naming items at baseline, and the two groups were comparable on these tasks at follow-up. Results provide longitudinal evidence of more rapid cognitive and functional decline in subjects with early-onset AD and suggest that early-onset AD may be characterized by predominant impairment of attentional skills. Dear Editor, Next to focal neurological symptoms, epileptic seizures and head aches, brain tumors can less frequently bring about cognitive changes, slowed speech, difficulty sustaining mental functioning and psychiatric symptoms of personality changes and. loss of interest in daily activities, these symptoms may be evaluated as anxiety or depression. Depression is known to be a complication of brain tumours and may sometimes be seen after the presentation of neurological symptoms linked to brain tumours, and sometimes after tumor treatment (Oğuz et al. 2005, Litofsky et al. 2004, Moise and Madhusoodanan 2006, Oreskovic M et al. 2007, Rooney A et al. 2010). The dorsolateral prefrontal, orbitofrontal and medial frontal circuits constitute the three subcortical neuronal circuits in the frontal cortex. The dorsolateral prefrontal circuit is associated with planning and operational functions and lesions on it may give rise to apathy, abulia, perseveration, personality changes and planning disorder. Lesions involving the orbitofrontal circuit, which is associated with response suppression and disinhibition, may involve emotional lability and memory problems. Whereas lesions affecting the right orbitofrontal circuit give rise to elevated mood, lesions on the left orbitofrontal circuit lead to depressed mood. In cases with medial frontal circuit involvement, akinetic mutism may result from lesions in the superior medial region and anteroretrograde amnesia and confabulation are observed with lesions in the inferior medial region (Tosun et al. 2016, Chirchiglia 2018). A diagnosis of psychiatric disorder may be given during the first examination of patieants with primary brain tumours, especially if localized in the frontal lobe. Thorough history taking and physical examination are necessary for early diagnosis. The case reported here concerns a 29-year-old university graduate female patient, living with her partner and children, who consulted the clinic with complaints of tendency to frequent crying, anhedonia, having difficulty with speech fluency, forgetfulness and distractedness that had presented suddenly, 2 months previously, without any causative stressor. In her mental status examination, she appeared having normal self-care with appearance at her actual age. She was fully conscious and oriented, not willing to cooperate with the interview, had distinct difficulty in maintaining attention and with fluency of speech. Her mood was depressive. She described loss of appetite, fatigue and energy loss. Her difficulty in paying attention was pronounced. She did not have a history of psychotropic medication use or family history of psychiatric disease. She did not smoke or use alcohol or substance. After evaluating the clinical interview, a preliminary diagnosis of major depressive disorder was considered on the basis of the DSM-5 criteria. Routine blood tests were requested. Given the continuation of her complaints, the difficulty with fluent speech and the increase in tendency to sleep at the first week follow up, cranial MRI was planned. The MRI results showed on the right, in the frontal lobe a multilocular mass with precallosal extension, undiscernable margins with the right lateral aspect of the corpus callosum genu and dispersed cystic-necrotic areas with T2 signal series. The dimensions of the mass were nearly 5 x 3 cm causing a 1-cm right-to-left shift of the midline (Figure 1) DEPRESSION AS THE FIRST SYMPTOM OF FRONTAL LOBE GRADE 2 MALIGNANT GLIOMA 2 Türk Psikiyatri Dergisi 2 Turkish Journal of Psychiatry Letter to the Editor 143 144 The patient was referred for surgery with the preliminary diagnosis of high-grade glial tumour. Pathology results identified a grade 2 glioma. It was learned that radiotherapy sessions were begun after surgery. The patient did not have any symptoms of psychopathology during the 2 monthly psychiatric interviews made after surgery. Brain tumours generally indicate their presence with headache, seizures and other neurological symptoms and very rarely with depression as seen in the case of our patient. It should be kept in mind that atypical psychiatric symptoms may have an underlying organic lesion and subtle neurological symptoms should be investigated in detail. A recent meta-analysis on 37 observational studies determined a 21.7% prevalence of depression in a total of 4518 patients with intracranial tumours. Comorbidity of depression with brain tumor was demonstrated to worsen the quality of life, increase suicidal risk and lower the chance of survival (Huang et al. 2017). The possibility of psychiatric symptoms being the clinical clues for brain cancer was noted and the necessity of neuroimaging tests in cases of recent-onset psychosis or mood disorder symptoms, atypical personality changes and anorexia without body dysmorphic disorder was emphasized (Madhusoodanan et al. 2015). Loss of interest, tendency to frequent weeping, introversion and anhedonia were the sole complaints in the case discussed here. The increase in psychomotor retardation and slowing down of movements at the very first weekly control follow up necessitated neuroimaging. Despite the reports in the literature on the frequent association of unpreventable excessive behavior, disinhibition and irritability with right frontal injury and lesions (Okumuş and Hocaoğlu 2018), depression was the dominant symptom in the case presented here. There are differences between primary major depression and depression presenting with underlying somatic diseases which is known to occur at later ages (Rouchell et al. 2002). However, our patient was aged 29 years. Also, cases of depression due to somatic disease are less associated with family history of depression and suicidal ideation and attempts, while cognitive symptoms come to the foreground during mental status examination. (Sertöz and Mete 2004, Rouchell et al. 2002). Our patient did not have suicidal ideation or attempts, or a family history of depression. In apathy, which may be explained as emotional blunting, indifference or detachment from the external world, targeted behavior is also reduced next to the lack of emotional expression. The individual discussed here was learned not to sit at the table or change the television channel unless reminded to do so. When the reason was asked, she could not think of one. The reduction in emotional expression accompanies reduced insight, abulia and lack of empathy (Sözeri Varma et al. 2019). In depression, apathy is defined as 'sorrowless depression'. Our patient cried but had very blunted mimics and gestures. She explained that she could not help weeping even at times when she did not feel internally distressed. The seriousness of apathy, as a symptom difficult to differentiate from depression, is still not understood. Neuroimaging Figure 1- Cranial MRI of the patient 145 Received: 16.08.2020, Accepted: 04.12.2020, Available Online Date: 05.10.2021 1MD., Antalya Kepez State Hospital, Department of Psychiatry, Antalya, 2MD., Ordu University Training and Research Hospital, Department of Psychiatry, Ordu, Turkey e-mail: bosbora@yahoo.com https://doi.org/10.5080/u25957 studies indicate apathy to be a reflect of impaired frontal-subcortical circuits and the functional disorder of the connections between the ventromedial prefrontal cortex and the basal ganglia (Chase 2011). Comparison of 45 individuals with depression due to aging and 43 healthy individuals showed apathy to be associated with fronto-limbic gray and white matter abnormalities which continued after antidepressant treatment. The structural anomalies of the posterior subgenual cingulate gyrus and the uncinate fasciculus were discussed (Yuen 2014). The case discussed here is presented to emphasize the importance of brain imaging methods and detailed investigation of atypical symptoms for diagnostic approaches to psychiatric disorders. Especially, complaints at young age of depression with psychomotor retardation, reduced fluency of speech and sudden onset withdrawal without stressors should be a warning of secondary depression. Yours sincerely... Şerif Bora Nazlı1 , Muhammet Sevindik2 REFERENCES Chase TN (2011) Apathy in Neuropsychiatric Disease: Diagnosis, Pathophysiology, and Treatment. Neurotox Res 19:266-78. Chirchiglia D (2018) Pseudodepression as an Anticipatory Symptom of Frontal Lobe Brain Tumors. Int J Depress Anxiety 1:007. Huang J, Zeng C, Xiao J et al (2017) Association between depression and brain tumor: a systematic review and meta-analysis. Oncotarget 8:94932-43. Litofsky NS, Farace E, Anderson F et al (2004) Depression in patients with high-grade glioma: Results of the glioma outcomes project. Neurosurgery 54:358-67. Madhusoodanan S, Ting MB, Farah T et al (2015) Pyschiatric aspects of brain tumors: A review. World J Psychiatry 5:273-85. Moise D, Madhusoodanan S (2006) Psychiatric symptoms associated with brain tumors: a clinical enigma. CNS Spectr 2006;11:28-31. Oğuz N, Ilnem C, Yener F (2005) Psychiatric symptoms in brain tumors: Case reports. Bulletin of Clinical Psychopharmacology 15:18-21. Hocaoğlu Ç, Okumuş B (2018) Psychiatric manifestations and brain tumor: A case report and brief review. The Medical Journal of Mustafa Kemal University 9:42-9. Oreskovic NM, Strother CG, Zibners LM (2007) An unusual case of a central nervous system tumor presenting as a chief complaint of depression. Pediatric Emergency Care 23:486-8. Rooney A, Carson A, Grant R (2011) Depression in cerebral glioma patients: a systematic review of observational studies. J Natl Cancer Inst103:61-76. Rouchell AM, Pounds R, Tierney JG (2002) Depression Textbook of Consultation-Liaison Psychiatry, 2nd Edition, Volume 1. MG Wise, JR Rundell (Ed), Washington DC American Psychiatric Publishing, Inc, p.307-38. Özen SÖ, Hayriye ME (2004) Bedensel Hastalıklarda Depresyon. Klinik Psikiyatri Ek 2:63-9. Sözeri Varma G , Bingöl C , Topak O et al (2019) Relationship of apathy with depressive symptom severity and cognitive functions in geriatric depression. Arch Neuropsychiatry 56:133-8. Yuen GS, Gunning FM, Woods E et al (2014) Neuroanatomical correlates of apathy in late-life depression and antidepressant treatment response. J Affect Disord 166:179-86.\nHere is the question:\nNEUROLOGY: A 75-year-old woman brought for consultation by her family because they have been finding her depressed and with memory lapses for months. They are concerned that she may have Alzheimer's disease. The patient refers that she does not think anything is wrong with her and that she is as usual. In what order do the following symptoms generally occur in the progression of Alzheimer's disease:\nHere are the potential choices:\n1. Mood changes, behavioral symptoms, cognitive deficits.\n2. Behavioral symptoms, motor symptoms, decline of functional independence.\n3. Mood changes, cognitive deficit, decline of functional independence.\n4. Behavioral symptoms, mood changes, motor symptoms.\nThe correct answer is: ",
        "gold_answer": "3 Mood changes, cognitive deficit, decline of functional independence.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Parkinson's disease, a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech. Huntington's disease, a rare inherited neurological disorder whose most obvious symptoms are abnormal body movements and a lack of coordination. It also affects a number of mental abilities and some aspects of personality. Alzheimer's disease, a neurodegenerative disease that, in its most common form, is found in people over the age of 65 and is characterized by progressive cognitive deterioration, together with declining activities of daily living and by neuropsychiatric symptoms or behavioral changes. Clinical depression, a common psychiatric disorder, characterized by a persistent lowering of mood, loss of interest in usual activities and diminished ability to experience pleasure. Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, self-neglect, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years. To investigate the frequency and longitudinal course of symptoms of depression, agitation, and psychosis in a longitudinally studied sample of patients with Alzheimer's disease (AD). Longitudinal study of AD patients with follow-up assessments at 6-month intervals for an average of more than 3 years. Alzheimer's Disease Research Center of the Mount Sinai Medical Center and the Bronx VA Medical Center, New York. A total of 153 AD patients. Blessed Test of Information, Memory and Concentration (BIMC) and the Alzheimer's Disease Assessment Scale cognitive (ADAS-Cog) and noncognitive (ADAS-NC) subscales. At entry into the study, more than 90% of patients had a behavioral disturbance that was rated as mild or worse on one of the 10 ADAS noncognitive items; and 40% had at least one rating that was moderate or severe. Correlational analyses indicated that, with the exception of the two mood-related items, noncognitive symptoms on the ADAS were not highly correlated with one another. Only one of the noncognitive items, concentration, was strongly correlated with the severity of cognitive impairment. On average, patients showed progressively worse cognitive functioning over time as measured both by the ADAS-Cog and the BIMC. The mean severity of noncognitive symptoms did not change during the course of a 5-year follow up. The severity of behavioral disturbance at any one evaluation was negatively correlated with change in behavior during the next 6 months and was not correlated with cognitive decline. Mild behavioral disturbances are common, whereas moderate to severe behavioral symptoms are less frequent in this population of AD patients. Disturbances in mood and manifestations of agitation and psychotic symptoms are not closely related to one another and show little progressive worsening over time. Rather, they tend to be episodic such that increasing severity at one time is usually followed by improvement later. Concentration problems are a manifestation of cognitive dysfunction rather than behavioral disturbance in AD. Implications of these results for treatment of noncognitive disturbances in AD are discussed. Dementia manifests as a set of related symptoms, which usually surface when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively impact a person's ability to function and carry out everyday activities. Aside from memory impairment and a disruption in thought patterns, the most common symptoms include emotional problems, difficulties with language, and decreased motivation. The symptoms may be described as occurring in a continuum over several stages. Consciousness is not affected. Dementia ultimately has a significant effect on the individual, caregivers, and relationships in general. A diagnosis of dementia requires a change from a person's usual mental functioning and a greater cognitive decline than what is caused by normal aging. Several diseases and injuries to the brain, such as a stroke, can give rise to dementia. However, the most common cause is Alzheimer's disease, a neurodegenerative Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease characterized by progressive cognitive deterioration, together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. The most striking early symptom is loss of short-term memory (amnesia), which usually manifests as minor forgetfulness that becomes steadily more pronounced with illness progression, with relative preservation of older memories. As the disorder progresses, cognitive (intellectual) impairment extends to the domains of language (aphasia), skilled movements (apraxia), and recognition (agnosia), and functions such as decision-making and planning become impaired. We carried out a prospective longitudinal study of 41 patients diagnosed as probably having a mild form of Alzheimer's disease according to the data of an investigation of prevalence done in 1991 in the municipality of Habana Vieja. The research covered two phases, with an interval of one year between them. During both phases the patients were interviewed by the same neurology resident in a door-to-door survey using the Mini-Mental State, Hughes scale (CDR) and Blessed scale, to evaluate higher mental functions. We determined the progress of the disease over the course of two years (1991-1992 and 1992-1993) and the frequency and degree of deterioration of cognitive functions during a period of one year. There was evidence of progressive worsening of the illness in 46.4% of the patients. In 34.2% this was to a moderate form and in 12.2% to a severe form. There was no progression in 46.3%. In this group 17.0% continued with a diagnosis of doubtful dementia and 29.3% as having slight dementia. The other 7.3% of the total number of patients (n = 41) were reclassified as normal. Cognitive functions almost always showed a tendency to deteriorate over time, but in a small percentage of patients they did not deteriorate and some even improved. The cognitive functions which deteriorated most were those of orientation, language and copying, with an average deterioration of 28% and 24% respectively with regard to their initial values. After ten years' treatment with cholinesterase inhibitors (AcheI) in Alzheimer's disease (AD), we report here the activity of the Alzheimer's Disease Assessment Unit of IRCCS C. Mondino, Pavia, Italy. From September 2000 to December 2007, 794 out-patients (of 2236 referred to our Assessment Unit for cognitive disturbances) with AD of mild to moderate degree were treated with cholinesterase inhibitors (M/F: 273/521, mean age 73.6+/- 8.4 yrs, range 52-85 yrs). Outcome measures were scores on Mini Mental State Examination (MMSE), ADL, IADL and Neuropsychiatric Inventory (NPI). Mean treatment duration was 36.9+/-16.1 months. After three months' treatment, MMSE scores remained stable (responders) in 60% of cases and improved (increase of 3 or more points - good responders) in 15%, with good preservation of autonomy. After 15 months, the percentage of \"good responders\" decreased to 7%, while after 15, 27 and 39 months the percentage of responders progressively decreased to 40%, 30% and 8%, respectively; greater impairment in instrumental with respect to basic everyday activities was noted. No variables capable of predicting the response to treatment were detected. The onset of behavioral disturbances caused significant (p&lt;0.02) worsening of both cognition and function and, in 12% of cases, suspension of treatment. Our results therefore confirm the efficacy of AcheI in AD of mild to moderate degree even in a nonselected population; efficacy also seems to persist in long-term treatment. This report, although brief and mainly descriptive, can make a contribution to better knowledge of the usefulness of these drugs in AD of mild to moderate extent in everyday clinical practice. Psychotic symptoms associated with Alzheimer Disease (AD) contribute to excess functional dependence. Longitudinal studies have generally examined the association between rates of functional decline and the occurrence of psychotic symptoms from either a single evaluation or from multiple evaluations rather than through changes in frequency and severity of symptoms. Although the presence or absence of psychotic symptoms at initial or follow-up examinations may be associated with changes in functional status, the nature of the relationship between changes in these domains cannot be inferred. We examine the association between changes in the frequency of psychotic symptoms and changes in dependence in activities of daily living (ADL) over a period ranging from 1 to 74 months (median = 17.7). Data from a cohort of 234 individuals referred to a memory clinic were analyzed using multilevel linear regression. Information on ADL, behavioral and psychological symptoms, depression, and cognition was collected. An increase in the frequency of psychotic symptoms had a unique influence on the deterioration of basic ADL, after controlling for demographic variables, changes in cognition, depression, and other behavioral and psychological symptoms (B = -.017, p = .003). However, changes in psychotic symptoms did not significantly contribute to declines in the ability to perform instrumental ADL (B = -.008, p = .439). Changes in psychotic symptoms may influence basic but not instrumental ADL over time. These findings may have ramifications for studies and treatment plans for individuals with AD who demonstrate psychotic symptoms. Patients present with behavioral and psychiatric symptoms, speech deficits (aphasia and/or dysarthria) and progressive cognitive and motor decline (dementia, ataxia, parkinsonism, psychosis, aphasia and mood disorder). Average age at onset is 70 years, and duration of survival is 24 months. About 40% of patients have a family history of dementia. Like CJD, it can be mistaken for Alzheimer's dementia. The diagnosis of Alzheimer's disease must be considered in all subjects over 40 years of age whose mental functions have insidiously become altered and are progressively getting worse. The initial phase of the disease, which precedes dementia, is characterized by disorders of memory often associated with changes in personality and behaviour and with subtle disorders of speech, reasoning and abstraction ability and visuo-constructive capabilities. The results of neurological and paraclinical examinations are normal. This phase lasts from two to four years and may be diagnosed as \"possible Alzheimer's disease\". When the disease is established the patient has lost his autonomy and can only be kept at home with the help of his relatives. Dementia gradually becomes worse, with a combination of memory disturbance, aphasia-apraxia-agnosia syndrome, impaired intellectual faculties and disorders of behaviour. Computerized tomography shows evidence of cerebral atrophy. This phase lasts from three to six years and may be called \"probable Alzheimer's disease\". The terminal phase of the disease includes somatic lesions, and all mental functions are profoundly altered. Death occurs seven to ten years after the first symptoms. Histopathological data are necessary to make a diagnosis of \"confirmed Alzheimer's disease\", since there is no clinical, morphological, electrophysiological or radiological sign that is pathognomonic of that disease. Signs and symptoms Signs and symptoms of Huntington's disease most commonly become noticeable between the ages of 30 and 50 years, but they can begin at any age, and present as a triad of motor, cognitive, and psychiatric symptoms. In 50% of cases, the psychiatric symptoms appear first. Their progression is often described in early stages, middle stages, and late stages with an earlier prodromal phase. In the early stages, subtle personality changes, problems in cognition, and physical skills, irritability, and mood swings occur, all of which may go unnoticed, and these usually precede the motor symptoms. Almost everyone with HD eventually exhibits similar physical symptoms, but the onset, progression, and extent of cognitive and behavioral symptoms vary significantly between individuals. The decline in the Mini-Mental State Exam (MMSE) over 2 years was assessed in males with Alzheimer's disease (AD; N = 136) seen in a dementia clinic. The average initial MMSE was 21.0 (SD+/-3.9; range 14--29) and declined 2.8 points (+/-4.7; range -17 to +6) over 2 years. The mode for change on the MMSE was 0 (N = 22) while the median fell between 2 and 3 points lost. Fifty-five of 136 patients (39.7%) had unchanged or better scores. There was no significant correlation between the initial MMSE and rate of change (r = -0.16; p = 0.06). While the progression of AD is quite variable from patient to patient, our data indicate that in most it is associated with little if any change in the MMSE even over 2 years. The MMSE is not an adequate tool to monitor change in the individual patient with AD. The confusion between Alzheimer's and FTD is justifiable due to the similarities between their initial symptoms. Patients do not have difficulty with movement and other motor tasks. As FTD symptoms appear, it is difficult to differentiate between a diagnosis of Alzheimer's disease and FTD. There are distinct differences in the behavioral and emotional symptoms of the two dementias, notably, the blunting of emotions seen in FTD patients. In the early stages of FTD, anxiety and depression are common, which may result in an ambiguous diagnosis. However, over time, these ambiguities fade away as this dementia progresses and defining symptoms of apathy, unique to FTD, start to appear. The aim of the study which was based on a five year prospective scheme was the evaluation of progressive changes in persons with a diagnosed mild cognitive impairment (MCI). A result of 3 in the Global Deterioration Scale (Reisberg's criteria), allowed for mild cognitive impairment diagnosis. The CGI scale result in the 5th year of observation was the bases to divide the studied population into a group with a stable MCI course and a group with progressive symptoms. 41 persons finished the five years of observation, out of a total 46 chosen for the study. After 5 years, 26 persons had no changes in the CGI result, whilst 15 persons showed a worsening in their clinical picture. At the initial qualification to the study the two groups of patients did not differ in their psychiatric state. However differences in the ADAS-kog could be seen in the second measurement done after the first year of the observation. Amongst those persons who had a worsening above 1.68 in the first year of the observation, Alzheimer's disease could be diagnosed definitely more frequently in the further stages of the observation. Evaluation of cognitive function impairment progression seems to be one of the most important diagnostic elements and should be included in the diagnostic criteria of MCI. Although adult attention-deficit/hyperactivity disorder has recently gained increased attention, few reports on attention-deficit/hyperactivity disorder in the pre-elderly or elderly have been published. Here, we present the case of a patient with attention-deficit/hyperactivity disorder who gradually developed dementia-like symptoms as she aged, which initially made her condition difficult to distinguish from early onset Alzheimer's disease. This report illustrates that some types of attention-deficit/hyperactivity disorder may be misdiagnosed as dementia. The patient was a 58-year-old woman. Although she presented with a tendency for inattentiveness and forgetfulness since childhood, she did not have a history of psychiatric disorders prior to consultation. Around the age of 52 years, her inattentiveness and forgetfulness gradually progressed, and at 57 years of age, she became inattentive and forgetful that it interfered with her work and daily life. For example, she forgot meetings with important clients and transferred money to the wrong bank account; these failures resulted in poor management of her company. At home, she experienced increasing difficulties with remembering prior commitments with her family and misplacing items, which her family members noticed. With the encouragement of her family and employees, who worried that she was suffering from dementia, she visited our memory clinic, whereby she was suspected of having early onset Alzheimer's disease. However, neuropsychological tests and brain imaging evaluations did not reveal any significant abnormalities. After dismissing various possible diagnoses, including dementia, other organic diseases, mood disorders, and delirium, we diagnosed her with attention-deficit/hyperactivity disorder. Treatment with 18 mg of methylphenidate was initiated, and significant improvements in her symptoms were observed within a few days; for example, she stopped losing her things, was able to concentrate for long durations, and could complete more tasks than she could before treatment. Since initiating treatment, she has returned to work and has been able to perform her daily activities without difficulty. This case supports that some patients with late-onset attention-deficit/hyperactivity disorder may gradually develop dementia-like symptoms during the pre-elderly and elderly stages of life. Therefore, clinicians should consider late-onset attention-deficit/hyperactivity disorder as a differential diagnosis of some types of dementias. We examined the pattern of cognitive impairment and rate of cognitive and functional decline as a function of age at symptom onset in 127 patients with probable Alzheimer's disease (AD). At baseline, early-onset (before age 65) and late-onset groups were mildly and comparably impaired on the modified Mini-Mental State Examination (mMMS) and the Blessed Dementia Rating Scale-Part 1 (BDRS). Repeated-measures analysis of variance revealed significantly more rapid decline in early-onset subjects over a 2-year follow-up period. Multivariate linear regression analyses indicated that age at symptom onset strongly predicted rate of decline on the mMMS and the BDRS, even after controlling for symptom duration, gender, family history of dementia, and baseline mMMS and BDRS scores. Early- and late-onset AD subjects also differed in terms of pattern of performance on the mMMS. Early-onset subjects scored significantly lower than late-onset subjects on attentional items of the mMMS at baseline and follow-up. Conversely, late-onset subjects scored significantly lower than early-onset subjects on memory and naming items at baseline, and the two groups were comparable on these tasks at follow-up. Results provide longitudinal evidence of more rapid cognitive and functional decline in subjects with early-onset AD and suggest that early-onset AD may be characterized by predominant impairment of attentional skills. Dear Editor, Next to focal neurological symptoms, epileptic seizures and head aches, brain tumors can less frequently bring about cognitive changes, slowed speech, difficulty sustaining mental functioning and psychiatric symptoms of personality changes and. loss of interest in daily activities, these symptoms may be evaluated as anxiety or depression. Depression is known to be a complication of brain tumours and may sometimes be seen after the presentation of neurological symptoms linked to brain tumours, and sometimes after tumor treatment (Oğuz et al. 2005, Litofsky et al. 2004, Moise and Madhusoodanan 2006, Oreskovic M et al. 2007, Rooney A et al. 2010). The dorsolateral prefrontal, orbitofrontal and medial frontal circuits constitute the three subcortical neuronal circuits in the frontal cortex. The dorsolateral prefrontal circuit is associated with planning and operational functions and lesions on it may give rise to apathy, abulia, perseveration, personality changes and planning disorder. Lesions involving the orbitofrontal circuit, which is associated with response suppression and disinhibition, may involve emotional lability and memory problems. Whereas lesions affecting the right orbitofrontal circuit give rise to elevated mood, lesions on the left orbitofrontal circuit lead to depressed mood. In cases with medial frontal circuit involvement, akinetic mutism may result from lesions in the superior medial region and anteroretrograde amnesia and confabulation are observed with lesions in the inferior medial region (Tosun et al. 2016, Chirchiglia 2018). A diagnosis of psychiatric disorder may be given during the first examination of patieants with primary brain tumours, especially if localized in the frontal lobe. Thorough history taking and physical examination are necessary for early diagnosis. The case reported here concerns a 29-year-old university graduate female patient, living with her partner and children, who consulted the clinic with complaints of tendency to frequent crying, anhedonia, having difficulty with speech fluency, forgetfulness and distractedness that had presented suddenly, 2 months previously, without any causative stressor. In her mental status examination, she appeared having normal self-care with appearance at her actual age. She was fully conscious and oriented, not willing to cooperate with the interview, had distinct difficulty in maintaining attention and with fluency of speech. Her mood was depressive. She described loss of appetite, fatigue and energy loss. Her difficulty in paying attention was pronounced. She did not have a history of psychotropic medication use or family history of psychiatric disease. She did not smoke or use alcohol or substance. After evaluating the clinical interview, a preliminary diagnosis of major depressive disorder was considered on the basis of the DSM-5 criteria. Routine blood tests were requested. Given the continuation of her complaints, the difficulty with fluent speech and the increase in tendency to sleep at the first week follow up, cranial MRI was planned. The MRI results showed on the right, in the frontal lobe a multilocular mass with precallosal extension, undiscernable margins with the right lateral aspect of the corpus callosum genu and dispersed cystic-necrotic areas with T2 signal series. The dimensions of the mass were nearly 5 x 3 cm causing a 1-cm right-to-left shift of the midline (Figure 1) DEPRESSION AS THE FIRST SYMPTOM OF FRONTAL LOBE GRADE 2 MALIGNANT GLIOMA 2 Türk Psikiyatri Dergisi 2 Turkish Journal of Psychiatry Letter to the Editor 143 144 The patient was referred for surgery with the preliminary diagnosis of high-grade glial tumour. Pathology results identified a grade 2 glioma. It was learned that radiotherapy sessions were begun after surgery. The patient did not have any symptoms of psychopathology during the 2 monthly psychiatric interviews made after surgery. Brain tumours generally indicate their presence with headache, seizures and other neurological symptoms and very rarely with depression as seen in the case of our patient. It should be kept in mind that atypical psychiatric symptoms may have an underlying organic lesion and subtle neurological symptoms should be investigated in detail. A recent meta-analysis on 37 observational studies determined a 21.7% prevalence of depression in a total of 4518 patients with intracranial tumours. Comorbidity of depression with brain tumor was demonstrated to worsen the quality of life, increase suicidal risk and lower the chance of survival (Huang et al. 2017). The possibility of psychiatric symptoms being the clinical clues for brain cancer was noted and the necessity of neuroimaging tests in cases of recent-onset psychosis or mood disorder symptoms, atypical personality changes and anorexia without body dysmorphic disorder was emphasized (Madhusoodanan et al. 2015). Loss of interest, tendency to frequent weeping, introversion and anhedonia were the sole complaints in the case discussed here. The increase in psychomotor retardation and slowing down of movements at the very first weekly control follow up necessitated neuroimaging. Despite the reports in the literature on the frequent association of unpreventable excessive behavior, disinhibition and irritability with right frontal injury and lesions (Okumuş and Hocaoğlu 2018), depression was the dominant symptom in the case presented here. There are differences between primary major depression and depression presenting with underlying somatic diseases which is known to occur at later ages (Rouchell et al. 2002). However, our patient was aged 29 years. Also, cases of depression due to somatic disease are less associated with family history of depression and suicidal ideation and attempts, while cognitive symptoms come to the foreground during mental status examination. (Sertöz and Mete 2004, Rouchell et al. 2002). Our patient did not have suicidal ideation or attempts, or a family history of depression. In apathy, which may be explained as emotional blunting, indifference or detachment from the external world, targeted behavior is also reduced next to the lack of emotional expression. The individual discussed here was learned not to sit at the table or change the television channel unless reminded to do so. When the reason was asked, she could not think of one. The reduction in emotional expression accompanies reduced insight, abulia and lack of empathy (Sözeri Varma et al. 2019). In depression, apathy is defined as 'sorrowless depression'. Our patient cried but had very blunted mimics and gestures. She explained that she could not help weeping even at times when she did not feel internally distressed. The seriousness of apathy, as a symptom difficult to differentiate from depression, is still not understood. Neuroimaging Figure 1- Cranial MRI of the patient 145 Received: 16.08.2020, Accepted: 04.12.2020, Available Online Date: 05.10.2021 1MD., Antalya Kepez State Hospital, Department of Psychiatry, Antalya, 2MD., Ordu University Training and Research Hospital, Department of Psychiatry, Ordu, Turkey e-mail: bosbora@yahoo.com https://doi.org/10.5080/u25957 studies indicate apathy to be a reflect of impaired frontal-subcortical circuits and the functional disorder of the connections between the ventromedial prefrontal cortex and the basal ganglia (Chase 2011). Comparison of 45 individuals with depression due to aging and 43 healthy individuals showed apathy to be associated with fronto-limbic gray and white matter abnormalities which continued after antidepressant treatment. The structural anomalies of the posterior subgenual cingulate gyrus and the uncinate fasciculus were discussed (Yuen 2014). The case discussed here is presented to emphasize the importance of brain imaging methods and detailed investigation of atypical symptoms for diagnostic approaches to psychiatric disorders. Especially, complaints at young age of depression with psychomotor retardation, reduced fluency of speech and sudden onset withdrawal without stressors should be a warning of secondary depression. Yours sincerely... Şerif Bora Nazlı1 , Muhammet Sevindik2 REFERENCES Chase TN (2011) Apathy in Neuropsychiatric Disease: Diagnosis, Pathophysiology, and Treatment. Neurotox Res 19:266-78. Chirchiglia D (2018) Pseudodepression as an Anticipatory Symptom of Frontal Lobe Brain Tumors. Int J Depress Anxiety 1:007. Huang J, Zeng C, Xiao J et al (2017) Association between depression and brain tumor: a systematic review and meta-analysis. Oncotarget 8:94932-43. Litofsky NS, Farace E, Anderson F et al (2004) Depression in patients with high-grade glioma: Results of the glioma outcomes project. Neurosurgery 54:358-67. Madhusoodanan S, Ting MB, Farah T et al (2015) Pyschiatric aspects of brain tumors: A review. World J Psychiatry 5:273-85. Moise D, Madhusoodanan S (2006) Psychiatric symptoms associated with brain tumors: a clinical enigma. CNS Spectr 2006;11:28-31. Oğuz N, Ilnem C, Yener F (2005) Psychiatric symptoms in brain tumors: Case reports. Bulletin of Clinical Psychopharmacology 15:18-21. Hocaoğlu Ç, Okumuş B (2018) Psychiatric manifestations and brain tumor: A case report and brief review. The Medical Journal of Mustafa Kemal University 9:42-9. Oreskovic NM, Strother CG, Zibners LM (2007) An unusual case of a central nervous system tumor presenting as a chief complaint of depression. Pediatric Emergency Care 23:486-8. Rooney A, Carson A, Grant R (2011) Depression in cerebral glioma patients: a systematic review of observational studies. J Natl Cancer Inst103:61-76. Rouchell AM, Pounds R, Tierney JG (2002) Depression Textbook of Consultation-Liaison Psychiatry, 2nd Edition, Volume 1. MG Wise, JR Rundell (Ed), Washington DC American Psychiatric Publishing, Inc, p.307-38. Özen SÖ, Hayriye ME (2004) Bedensel Hastalıklarda Depresyon. Klinik Psikiyatri Ek 2:63-9. Sözeri Varma G , Bingöl C , Topak O et al (2019) Relationship of apathy with depressive symptom severity and cognitive functions in geriatric depression. Arch Neuropsychiatry 56:133-8. Yuen GS, Gunning FM, Woods E et al (2014) Neuroanatomical correlates of apathy in late-life depression and antidepressant treatment response. J Affect Disord 166:179-86.\nHere is the question:\nNEUROLOGY: A 75-year-old woman brought for consultation by her family because they have been finding her depressed and with memory lapses for months. They are concerned that she may have Alzheimer's disease. The patient refers that she does not think anything is wrong with her and that she is as usual. In what order do the following symptoms generally occur in the progression of Alzheimer's disease:\nHere are the potential choices:\n1. Mood changes, behavioral symptoms, cognitive deficits.\n2. Behavioral symptoms, motor symptoms, decline of functional independence.\n3. Mood changes, cognitive deficit, decline of functional independence.\n4. Behavioral symptoms, mood changes, motor symptoms.\nThe correct answer is: 3. Mood changes, cognitive deficit, decline of functional independence."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n To assess the time to treatment for emergency department (ED) patients with critical hyperkalemia and to determine whether the timing of treatment was associated with clinical characteristics or electrocardiographic abnormalities. The authors performed a retrospective chart review of ED patients with the laboratory diagnosis of hyperkalemia (potassium level &gt; 6.0 mmol/L). Patients presenting in cardiac arrest or who were referred for hyperkalemia or dialysis were excluded. Patient charts were reviewed to find whether patients received specific treatment for hyperkalemia and, if so, what clinical attributes were associated with the time to initiation of treatment. Of 175 ED visits that occurred over a 1-year time period, 168 (96%) received specific treatment for hyperkalemia. The median time from triage to initiation of treatment was 117 minutes (interquartile range [IQR] = 59 to 196 minutes). The 7 cases in which hyperkalemia was not treated include 4 cases in which the patient was discharged home, with a missed diagnosis of hyperkalemia. Despite initiation of specific therapy for hyperkalemia in 168 cases, 2 patients died of cardiac arrhythmias. Among the patients who received treatment, 15% had a documented systolic blood pressure (sBP) &lt; 90 mmHg, and 30% of treated patients were admitted to intensive care units. The median potassium value was 6.5 mmol/L (IQR = 6.3 to 7.1 mmol/L). The predominant complaints were dyspnea (20%) and weakness (19%). Thirty-six percent of patients were taking angiotensin-converting enzyme (ACE) inhibitors. Initial electrocardiograms (ECGs) were abnormal in 83% of patient visits, including 24% of ECGs with nonspecific ST abnormalities. Findings of peaked T-wave morphology (34%), first-degree atrioventricular block (17%), and interventricular conduction delay (12%) did not lead to early treatment. Vital sign abnormalities, including hypotension (sBP &lt; 90 mmHg), were not associated with early treatment. The chief complaint of \"unresponsive\" was most likely to lead to early treatment; treatment delays occurred in patients not transported by ambulance, those with a chief complaint of syncope and those with a history of hypertension. Recognition of patients with severe hyperkalemia is challenging, and the initiation of appropriate therapy for this disorder is frequently delayed. Electrolyte disorders can alter cardiac ionic currents kinetics and depending on the changes can promote proarrhythmic or antiarrhythmic effects. The present report reviews the mechanisms, electrophysiolgical (EP), electrocardiographic (ECG), and clinical consequences of electrolyte disorders. Potassium (K⁺) is the most abundent intracellular cation and hypokalemia is the most commont electrolyte abnormality encountered in clinical practice. The most significant ECG manifestation of hypokalemia is a prominent U wave. Several cardiac and non cardiac drugs are known to suppress the HERG K⁺ channel and hence the I(K), and especially in the presence of hypokalemia, can result in prolonged action potential duration and QT interval, QTU alternans, early afterdepolarizations, and torsade de pointes ventricular tachyarrythmia (TdP VT). Hyperkalemia affects up to 8% of hospitalized patients mainly in the setting of compromised renal function. The ECG manifestation of hyperkalemia depends on serum K⁺ level. At 5.5-7.0 mmol/L K⁺, tall peaked, narrow-based T waves are seen. At &gt; 10.0 mmol/L K⁺, sinus arrest, marked intraventricular conduction delay, ventricular techycardia, and ventricular fibrillation can develop. Isolated abnormalities of extracellular calcium (Ca⁺⁺) produce clinically significant EP effects only when they are extreme in either direction. Hypocalcemia, frequently seen in the setting of chronic renal insufficiency, results in prolonged ST segment and QT interval while hypercalcemia, usually seen with hyperparathyroidism, results in shortening of both intervals. Although magnesium is the second most abudent intracellular cation, the significance of magnesium disorders are controversial partly because of the frequent association of other electrolyte abnormalities. However, IV magnesium by blocking the L-type Ca(⁺⁺) current can successfully terminate TdP VT without affecting the prolonged QT interval. Finally, despite the frequency of sodium abnormalities, particularly hyponatremia, its EP effects are rarely clinically significant. Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasionally when severe it can cause palpitations, muscle pain, muscle weakness, or numbness. Hyperkalemia can cause an abnormal heart rhythm which can result in cardiac arrest and death. Common causes of hyperkalemia include kidney failure, hypoaldosteronism, and rhabdomyolysis. A number of medications can also cause high blood potassium including spironolactone, NSAIDs, and angiotensin converting enzyme inhibitors. The severity is divided into mild (5.5–5.9mmol/L), moderate (6.0–6.4mmol/L), and severe (>6.5mmol/L). High levels can be detected on an electrocardiogram (ECG). Pseudohyperkalemia, due to breakdown of cells during or after taking the blood sample, should be ruled out. Excessive intake of licorice may cause pseudohyperaldosteronism which, in turn, may lead to hypertension and hypokalemia. Severe hypokalemia may lead to electrocardiogram (ECG) changes including long QT interval potentially progressing into malignant arrhythmias. Here we present a 43-year-old woman admitted to the hospital with chest pain and a stinging sensation in the upper extremities. Her peak blood pressure was 177/98 mmHg and the blood test revealed low plasma potassium of 1.9 mmol/L. The ECG revealed flattened T-waves and long QT interval. Prior to admission, the patient had increased licorice ingestion to a total of some 70 g daily. The licorice intake was stopped and potassium was administrated orally and intravenously. Plasma potassium normalized and the ECG changes remitted. To our knowledge a few other cases of licorice-induced pseudohyperaldosteronism and long QT interval have previously been reported. This underlines the importance of quantifying licorice intake in younger people with unexplained high blood pressure and low potassium. Even small amounts of licorice daily may increase the risk of developing hypertension; therefore, licorice should be asked for specifically. Even though licorice intake is very easy to cover in the patient's history, it is often missed. Excessive licorice intake may course severe hypokalemia causing long QT interval in the ECG recording, potentially progressing into arrhythmias and even cardiac arrest/sudden death. Hypokalemia &lt;3 mmol/L and present ECG changes should be treated with potassium intravenously. Licorice-induced hypertension may be associated with syndrome of apparent mineralocorticoid excess (SAME). Plasma renin and aldosterone are both low at diagnosis and normalize when licorice is stopped. The surface electrocardiogram (ECG) has been used as a useful method for detection of metabolic disturbances for a long time. However, it may be difficult to distinguish the exact disturbance when more than one metabolic abnormality exists in a patient simultaneously. Although, \"classic\" ECG characterizations of common electrolyte disturbances are well described, multiple concurrent electrolyte disturbances may lead to ECG abnormalities that may not be easily detectable. This ECG concerns a 60-year-old male presented with general fatigue, weakness, epigastric pain, anorexia, nausea and extreme hypercalcemia (serum total and ionized calcium levels 20.5 mg/dL and 12.02 mg/dl, respectively), hypokalemia and hypomagnesemia associated with elevated parathyroid hormone (1160 pg/ml) and normal serum vitamin D level (97 ng/ml) . This rare manifestation of primary hyperparathyroidism has been named hyperparathyroid crisis in the literature. Hyperparathyroid crisis is an emergency form of multiple electrolyte abnormalities that manifest as a life-threatening hypercalcemia and simultaneous hypokalemia and hypomagnesemia; these two later are believed to be caused by diuretic effect of calcium on the renal tubules. The unique pattern of ECG in our patient first was misdiagnosed as prominent T waves with prolongation of the QT corrected (QTc) interval, which has been reported several times in patients with hyperparathyroidism crisis, compatible with our patient. But more investigation revealed that, the QTc interval not only is not prolonged, it is shortened as it is expected from the effect of hypercalcemia on electrocardiogram. The exact pattern of the patient`s ECG (figure 1) can be interpreted as it follows: (1) Flattening of the T wave, (2) a prominent U wave, (3) prolongation of the descending limb of the T wave such that it overlapped with the next U wave (4) virtual absence of ST segment and (5) shortening of the QT corrected interval. In conclusion, it should be emphasized when the T and U waves are separated by a very short segment they can mimic the appearance of a prolonged QT interval. However, more investigation can demonstrate the exact electrocardiographic pattern especially in multiple electrolyte disturbances, when \"classic\" ECG patterns are not expectable. Case summaryA 10-year-old boy presented with severe progressive generalised weakness on a background of 3 days of diarrhoea and vomiting. Vital signs were normal. Peripheral neurological examination revealed grade 1-2 power in all limbs, hypotonia and hyporeflexia. Sensation was fully intact. Cranial nerve examination and speech were normal. The ECG (figure 1) and initial venous blood gas (figure 2) are shown.edpract;107/1/21/F1F1F1Figure 1ECG.edpract;107/1/21/F2F2F2Figure 2Venous blood gas. QUESTION 1: What abnormalities are present on the ECG?Peaked T waves, prolonged PR segment and loss of P waves?Shortening of the QT interval and Osborn waves (J waves)?T wave flattening/inversion, prominent U waves and long QU interval?Prolonged QT interval with multiple atrial and ventricular ectopics? QUESTION 2: How would you manage this patient's hypokalaemia? QUESTION 3: What is the likely diagnosis?Conversion disorder.Myasthenia gravis.Periodic paralysis.Guillain-Barré syndrome.Botulism. QUESTION 4: What interventions can be considered for long-term treatment of this condition? <iAnswers can be found on page 2</i. Diagnosis Hypokalemia (low blood potassium levels) commonly occurs during attacks; levels below 3.0 mmol/l are typically encountered. Magnesium and phosphate levels are often found to be decreased. Creatine kinase levels are elevated in two thirds of cases, usually due to a degree of muscle injury; severe elevations suggestive of rhabdomyolysis (muscle tissue destruction) are rare. Electrocardiography (ECG/EKG) may show tachycardia (a fast heart rate) due to the thyroid disease, abnormalities due to cardiac arrhythmia (atrial fibrillation, ventricular tachycardia), and conduction changes associated with hypokalemia (U waves, QRS widening, QT prolongation, and T wave flattening). Electromyography shows changes similar to those encountered in myopathies (muscle diseases), with a reduced amplitude of the compound muscle action potentials (CMAPs); they resolve when treatment has commenced. A course of the disease of a 68-year-old female who had been taking medigoxin, furosemide, verapamil and an unknown amount of spironolactone and potassium salt due to congestive heart failure is presented. She was admitted to emergency department of the University Hospital Rebro after an episode of syncopal attack because of arrhythmia due to hyperkalemia (8.9 nmol/L). She has had a fast idioventricular rhythm, followed by atrial tachycardia after that and with fast ventricular rhythm, S-T segment depression and a tall and peaked T-wave. In the following electrocardiograms left anterior hemiblock appeared, a tall R-wave of the anterolateral location, supraventricular and ventricular premature beats and atrioventricular block of the first degree. The patient had signs of non-oliguric form of acute renal failure at the admission which was a partly explanation for the development of hyperkalemia, together with the use of spironolactone and potassium salt. After the treatment she had normal serum creatinine values. She suffered from combined mitral valve disease: stenosis with a predominant regurgitation of the II/III degree. She was discharged from the hospital in a compensated state with normal serum potassium values. Elevated potassium level is a common and reversible peri-arrest condition. Diagnosis and management of hyperkalemia in a short time is critical, where electrocardiogram (ECG) alterations might be helpful. We aimed to investigate the role of clinical features and ECGs in early diagnosing and treating hyperkalemia. Prospectively, adult patients who presented to the emergency department (ED) from July 2019 to March 2020 with hyperkalemia (serum potassium ≥5.5mmol/L) were included. History was obtained, and laboratory investigations and ECGs were performed at the presentation and before initiating hyperkalemia therapy. Hyperkalemia severity was divided into mild (5.5-5.9mmol/L), moderate (6.0-6.4mmol/L), and severe (≥6.5mmol/L). A cardiologist and emergency physician blinded to laboratory values, study design, and patients' diagnoses interpreted ECGs and presenting symptoms independently to predict hyperkalemia. Sixty-seven hyperkalemic patients with a mean (±SD) serum potassium level of 6.5±0.7mmol/L were included in this study. The mean age was 63.9±15.1, and 58.2% were females. Hyperkalemia was mild in 10.4%, moderate in 40.3%, and severe in 49.3%. Almost two thirds of patients (71.6%) had hypertension, 67.2% diabetes, and 64.2% chronic kidney disease. About one-quarter of patients (22.4%) were asymptomatic, while fatigue (46.3%), dyspnea (28.4%), and nausea/vomiting (20.9%) were the most common presenting symptoms. Normal ECGs were observed in 25.4% of patients, while alterations in 74.6%. Atrial fibrillation (13.4%), peaked T wave (11.9%), widened QRS (11.9%), prolonged PR interval (10.5%), and flattening P wave (10.5%) were the most common. Peaked T wave was significantly more common in severe hyperkalemia (87.5%) than in mild and moderate hyperkalemia (12.5%, 0.0%, respectively) (p=0.041). The physicians' sensitivities for predicting hyperkalemia were 35.8% and 28.4%, improved to 51.5% and 42.4%, respectively, when limiting the analyses to severe hyperkalemia. The mean (±SD) time to initial hyperkalemia treatment was 63.8±31.5 min. Potassium levels were positively correlated with PR interval (r=0.283, p=0.038), QRS duration (r=0.361, p=0.003), peaked T wave (r=0.242, p=0.041), and serum levels of creatinine (r=0.347, p=0.004), BUN (r=0.312, p=0.008), and CK (r=0.373, p=0.039). The physicians' abilities to predict hyperkalemia based on ECG and symptoms were poor. ECG could not be solely relied on, and serum potassium tests should be conducted for accurate diagnosis. A 60-year-old woman with a 6-year history of numbness in her hands was admitted to hospital with dyspnea. Laboratory findings showed the elevation of creatine kinase (creatine kinase MB isoenzyme was less than 4 IU/l). Chest X-ray revealed cardiomegaly and pulmonary edema. Electrocardiogram showed a T wave inversion in V<sub2-5</sub and a prolonged QT interval. Echocardiography demonstrated reduced left ventricular ejection fraction (LVEF) and massive pericardial effusion. The patient was diagnosed with heart failure. Further testing found hypocalcemia and idiopathic hypoparathyroidism. In addition to diuretics, calcium replacement therapy for hypocalcemia improved the LVEF and reduced pericardial effusion. Hypocalcemia rarely leads to heart failure and pericardial effusion. In our case, heart failure and the massive pericardial effusion were secondary to hypocalcemia due to idiopathic hypoparathyroidism. &lt;<bLearning objective:</b Hypocalcemia should be considered in patients with heart failure, reduced ejection fraction, and massive pericardial effusion. Supportive findings for diagnosis of heart failure caused by hypocalcemia are numbness, elevation of creatine kinase, T wave inversion, and prolonged QT interval.&gt;. FIguRE 269e-24 Prominent U waves (II, III, and V4–V6) with ventricular repolarization prolongation in a patient with severe hypokalemia. CHAPTER 269e Atlas of Electrocardiography FIguRE 269e-25 Abbreviated ST segment such that the T wave looks like it takes off directly from QRS in some leads (I, V4, aVL, and V5) in a patient with severe hypercalcemia. Note also high takeoff of ST segment in V2/V3 simulating acute ischemia. PART 10 Disorders of the Cardiovascular System FIguRE 269e-26 SR with LVH, left atrial abnormality, and tall peaked T waves in the precordial leads with inferolateral ST depressions (II, III, aVF, and V6); left anterior fascicular block and borderline prolonged QT interval in a patient with renal failure, hypertension, and hyperkalemia; prolonged QT is secondary to associated hypocalcemia. The physiological actions of magnesium within the cardiac conduction system and myocytes have yet to be fully elucidated. Because concurrent hypocalcemia or hypokalemia were also present in previous human reports, specific electrocardiographic effects of isolated hypomagnesemia have not been clearly delineated. We report a case in which dynamic electrocardiogram (ECG) changes were demonstrated in isolated hypomagnesemia. A 37-year-old man with history of heavy alcohol use was admitted for syncope. The ECG showed global T-wave inversions with prolonged corrected QT (QTc) duration on ECG. Extensive work-up including cardiac catheterization was unremarkable. His serum magnesium was noted to be low at 1.1 mg/dL, and his serum calcium and potassium were within normal limits. The patient received magnesium infusion with subsequent ECGs showing resolution of his global T-wave inversions and prolonged QTc. This case is unique because it reports dynamic ECG changes in a patient with isolated hypomagnesemia. Although isolated hypomagnesemia is commonly believed to result in dysrhythmia, we were unaware of any previous cases of ECG abnormalities in humans. Clinically, we advise checking serum magnesium and correcting hypomagnesemia when prolonged QTc duration and global T-wave inversions are seen on ECG. Electrolytes disturbances and intoxication: Digitalis intoxication Calcium: hypocalcemia and hypercalcemia Potassium: hypokalemia and hyperkalemia Serotonin Toxicity Ischemia and infarction: Wellens' syndrome (LAD occlusion) de Winter T waves (LAD occlusion) ST elevation and ST depression High Frequency QRS changes Myocardial infarction (heart attack) Non-Q wave myocardial infarction NSTEMI STEMI Sgarbossa's criteria for ischemia with a LBBB Structural: Acute pericarditis Right and left ventricular hypertrophy Right ventricular strain or S1Q3T3 (can be seen in pulmonary embolism) History Since SPS is not selective for potassium ions, other electrolyte imbalances may occur while using SPS in hyperkalemic patients. Patients should be monitored carefully for the signs and symptoms of other electrolyte abnormalities such as hypokalemia,  hypomagnesemia, and hypocalcemia. Hypokalemia may be associated with cardiac arrhythmias and severe muscle weakness. Hypokalemia may be evident as prolongation of the QT interval, T-wave inversions, prominent U waves (an extra upward wave after the T-wave) in Electrocardiogram (ECG). Some patients may present with significant symptoms of rebound hyperkalemia, which may be evident in ECG as a tall peaked T wave. Hypomagnesemia can present with muscle weakness and potentiate hypokalemia. Hypocalcemia presents with tremors, muscle weakness, tetany, and rarely, seizures. A 47-year-old man presented to our emergency department (ED) with limbs weakness for 2 h. His heart rate was 127 beats per minute and blood pressure was 95/49 mm Hg. He found weakness of limbs after 4-h sleep. Physical examinations revealed that the muscle strength of upper limbs is 3/5, and lower limbs are 2/5. Electrocardiogram (ECG) revealed wide QRS complex, monomorphic ventricular tachycardia (VT) with ST-segment depression and long QT interval. Serum potassium level was extremely low as 1.0 mEq/L. This led to periodic hypokalemic paralysis. Due to severe hypokalemia with possible atrioventricular block, the patient was admitted to the intensive care unit. During hospitalization, his potassium level returned to 5.1 mEq/L on the first day. He had a low level of thyroid stimulating hormone (TSH) of &lt;0.03 micro-IU/mL (normal range: 0.25-4.00) and a high free thyroxine (T4) level of 2.43 ng/dL (normal range: 0.89-1.79 ng/dL). Therefore, hyperthyroidism was diagnosed, and 5 mg of methimazole was administered twice a day. The patient was discharged on the seventh day after admission. The final diagnosis is thyrotoxic periodic paralysis (TPP), also as known as nocturnal paralysis or night palsy. Hypokalemia, defined as a plasma potassium concentration &lt;3.5 mmol/l, is the most common electrolyte abnormality encountered in our clinical practice. Unfortunately, in many cases, the etiologies were unclear and resulted in a wrong treatment. Indeed, the true etiology could be such a 'rare' one and could be found by doing a comprehensive work up. One of this is Gitelman's syndrome, a rare genetic disorder characterized by hypokalemic alkalosis, hypomagnesemia, hypocalciuria, and secondary aldosteronism without hypertension. Since this disorder is found in 1% Caucasian populations, this is one of the most frequently inherited renal tubular disorders. A 27 year old man came to emergency room with weakness and generalised muscle cramps. He was investigated three months before for a similar electrolyte disturbance which was found to be inconclusive. The routine laboratory data in emergency room revealed a potassium concentration of 2.3 mmol/l. He had never used diuretics or hormonal therapy nor had history of vomiting or diarrhea. He had normal blood pressure and the blood gas analysis revealed metabolic alkalosis. On his ECG (electrocardiography), we found the prominent U wave. Despite his low concentration of serum potassium and cloride, the concentration of these electrolytes in urine were extremely high. We also found hipomagnesemia. The calcium concentration in serum was normal with slightly hypocalciuria. Even with aggressive oral and intravenous potassium suplementation, the patient remained hypokalemic. In cases when the etiology of hypokalemia is unclear, we should perform some investigations to confirm the diagnosis and give the proper treatment. In Gitelman's syndrome, where the defect in the distal tubule cannot be corrected, the treatment must be a life-long. Most patients require oral potassium and magnesium supplementation, since drug therapy is usually incompletely effective. Hyperkalemia is defined as a serum potassium level >5.5 mmol/L (>5.5 meq/L) and can neurologically present as muscle weakness with or without paresthesias. Hyperkalemia becomes life threatening when it produces electrocardiographic abnormalities such as peaked T waves or a widened QRS complex. In these cases, prompt treatment is essential and consists of strategies that protect the heart against arrhythmias (calcium gluconate administration); promote potassium redistribution into cells (with glucose, insulin, and β2-agonist medications); and increase potassium removal (through sodium polystyrene sulfonate, loop diuretics, or hemodialysis). Hypercalcemia usually occurs in the setting of either hyperparathyroidism or systemic malignancy. Neurologic manifestations include encephalopathy as well as muscle weakness due to reduced neuromuscular excitability. Seizures can occur but are more common in states of low calcium. Diagnosis Numerous diagnoses and findings can be made based upon electrocardiography, and many are discussed above. Overall, the diagnoses are made based on the patterns. For example, an \"irregularly irregular\" QRS complex without P waves is the hallmark of atrial fibrillation; however, other findings can be present as well, such as a bundle branch block that alters the shape of the QRS complexes. ECGs can be interpreted in isolation but should be applied – like all diagnostic tests – in the context of the patient. For example, an observation of peaked T waves is not sufficient to diagnose hyperkalemia; such a diagnosis should be verified by measuring the blood potassium level. Conversely, a discovery of hyperkalemia should be followed by an ECG for manifestations such as peaked T waves, widened QRS complexes, and loss of P waves. The following is an organized list of possible ECG-based diagnoses. Hypokalemia can result in a variety of cardiac dysrhythmias. Although cardiac dysrhythmias or ECG changes are more likely to be associated with moderate to severe hypokalemia, there is a high degree of individual variability and can occur with even mild decreases in serum levels. This variability is dependent on concomitant factors such as magnesium depletion, digitalis therapy, among others. Moreover, characteristic ECG changes do not manifest in all patients. The ECG changes that occur are T-wave flattening initially, followed by ST depression and the appearance of a U wave that can be difficult to distinguish from the T wave. The U wave is often seen in the lateral precordial leads of V4 to V6. Prolongation of the PR and QT interval can also occur. Risk of arrhythmias is highest in older patients, those with heart disease and those receiving digoxin or antiarrhythmic drugs. Administration of anesthesia in the setting of hypokalemia is also a risk for dysrhythmias and impaired cardiac contractility but more so with acute rather than chronic hypokalemia. The first test that should be ordered in a patient with suspected hyperkalemia is an ECG since the most lethal complication of hyperkalemia is cardiac condition abnormalities which can lead to dysrhythmias and death. Elevated potassium causes ECG changes in a dose-dependent manner: K = 5.5 to 6.5 mEq/L ECG will show tall, peaked t-waves K = 6.5 to 7.5 mEq/L ECG will show loss of p-waves K = 7 to 8 ECG mEq/L will show widening of the QRS complex K = 8 to 10 mEq/L will produce cardiac arrhythmias, sine wave pattern, and asystole\nHere is the question:\nNEPHROLOGY: An 80-year-old patient with a history of hypertension and on treatment with enalapril and spironolactone comes to the hospital with asthenia and severe muscle weakness. Blood pressure is 110/70 mmHg. In the ECG, there are sharp and elevated T waves, ventricular extrasystoles and short QT. What is the most likely diagnosis?\nHere are the potential choices:\n1. Hypercalcemia.\n2. Hyperkalemia.\n3. Hypomagnesemia.\n4. Hypocalcemia.\n5. Hypernatremia.\nThe correct answer is: ",
        "gold_answer": "2 Hyperkalemia.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n To assess the time to treatment for emergency department (ED) patients with critical hyperkalemia and to determine whether the timing of treatment was associated with clinical characteristics or electrocardiographic abnormalities. The authors performed a retrospective chart review of ED patients with the laboratory diagnosis of hyperkalemia (potassium level &gt; 6.0 mmol/L). Patients presenting in cardiac arrest or who were referred for hyperkalemia or dialysis were excluded. Patient charts were reviewed to find whether patients received specific treatment for hyperkalemia and, if so, what clinical attributes were associated with the time to initiation of treatment. Of 175 ED visits that occurred over a 1-year time period, 168 (96%) received specific treatment for hyperkalemia. The median time from triage to initiation of treatment was 117 minutes (interquartile range [IQR] = 59 to 196 minutes). The 7 cases in which hyperkalemia was not treated include 4 cases in which the patient was discharged home, with a missed diagnosis of hyperkalemia. Despite initiation of specific therapy for hyperkalemia in 168 cases, 2 patients died of cardiac arrhythmias. Among the patients who received treatment, 15% had a documented systolic blood pressure (sBP) &lt; 90 mmHg, and 30% of treated patients were admitted to intensive care units. The median potassium value was 6.5 mmol/L (IQR = 6.3 to 7.1 mmol/L). The predominant complaints were dyspnea (20%) and weakness (19%). Thirty-six percent of patients were taking angiotensin-converting enzyme (ACE) inhibitors. Initial electrocardiograms (ECGs) were abnormal in 83% of patient visits, including 24% of ECGs with nonspecific ST abnormalities. Findings of peaked T-wave morphology (34%), first-degree atrioventricular block (17%), and interventricular conduction delay (12%) did not lead to early treatment. Vital sign abnormalities, including hypotension (sBP &lt; 90 mmHg), were not associated with early treatment. The chief complaint of \"unresponsive\" was most likely to lead to early treatment; treatment delays occurred in patients not transported by ambulance, those with a chief complaint of syncope and those with a history of hypertension. Recognition of patients with severe hyperkalemia is challenging, and the initiation of appropriate therapy for this disorder is frequently delayed. Electrolyte disorders can alter cardiac ionic currents kinetics and depending on the changes can promote proarrhythmic or antiarrhythmic effects. The present report reviews the mechanisms, electrophysiolgical (EP), electrocardiographic (ECG), and clinical consequences of electrolyte disorders. Potassium (K⁺) is the most abundent intracellular cation and hypokalemia is the most commont electrolyte abnormality encountered in clinical practice. The most significant ECG manifestation of hypokalemia is a prominent U wave. Several cardiac and non cardiac drugs are known to suppress the HERG K⁺ channel and hence the I(K), and especially in the presence of hypokalemia, can result in prolonged action potential duration and QT interval, QTU alternans, early afterdepolarizations, and torsade de pointes ventricular tachyarrythmia (TdP VT). Hyperkalemia affects up to 8% of hospitalized patients mainly in the setting of compromised renal function. The ECG manifestation of hyperkalemia depends on serum K⁺ level. At 5.5-7.0 mmol/L K⁺, tall peaked, narrow-based T waves are seen. At &gt; 10.0 mmol/L K⁺, sinus arrest, marked intraventricular conduction delay, ventricular techycardia, and ventricular fibrillation can develop. Isolated abnormalities of extracellular calcium (Ca⁺⁺) produce clinically significant EP effects only when they are extreme in either direction. Hypocalcemia, frequently seen in the setting of chronic renal insufficiency, results in prolonged ST segment and QT interval while hypercalcemia, usually seen with hyperparathyroidism, results in shortening of both intervals. Although magnesium is the second most abudent intracellular cation, the significance of magnesium disorders are controversial partly because of the frequent association of other electrolyte abnormalities. However, IV magnesium by blocking the L-type Ca(⁺⁺) current can successfully terminate TdP VT without affecting the prolonged QT interval. Finally, despite the frequency of sodium abnormalities, particularly hyponatremia, its EP effects are rarely clinically significant. Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasionally when severe it can cause palpitations, muscle pain, muscle weakness, or numbness. Hyperkalemia can cause an abnormal heart rhythm which can result in cardiac arrest and death. Common causes of hyperkalemia include kidney failure, hypoaldosteronism, and rhabdomyolysis. A number of medications can also cause high blood potassium including spironolactone, NSAIDs, and angiotensin converting enzyme inhibitors. The severity is divided into mild (5.5–5.9mmol/L), moderate (6.0–6.4mmol/L), and severe (>6.5mmol/L). High levels can be detected on an electrocardiogram (ECG). Pseudohyperkalemia, due to breakdown of cells during or after taking the blood sample, should be ruled out. Excessive intake of licorice may cause pseudohyperaldosteronism which, in turn, may lead to hypertension and hypokalemia. Severe hypokalemia may lead to electrocardiogram (ECG) changes including long QT interval potentially progressing into malignant arrhythmias. Here we present a 43-year-old woman admitted to the hospital with chest pain and a stinging sensation in the upper extremities. Her peak blood pressure was 177/98 mmHg and the blood test revealed low plasma potassium of 1.9 mmol/L. The ECG revealed flattened T-waves and long QT interval. Prior to admission, the patient had increased licorice ingestion to a total of some 70 g daily. The licorice intake was stopped and potassium was administrated orally and intravenously. Plasma potassium normalized and the ECG changes remitted. To our knowledge a few other cases of licorice-induced pseudohyperaldosteronism and long QT interval have previously been reported. This underlines the importance of quantifying licorice intake in younger people with unexplained high blood pressure and low potassium. Even small amounts of licorice daily may increase the risk of developing hypertension; therefore, licorice should be asked for specifically. Even though licorice intake is very easy to cover in the patient's history, it is often missed. Excessive licorice intake may course severe hypokalemia causing long QT interval in the ECG recording, potentially progressing into arrhythmias and even cardiac arrest/sudden death. Hypokalemia &lt;3 mmol/L and present ECG changes should be treated with potassium intravenously. Licorice-induced hypertension may be associated with syndrome of apparent mineralocorticoid excess (SAME). Plasma renin and aldosterone are both low at diagnosis and normalize when licorice is stopped. The surface electrocardiogram (ECG) has been used as a useful method for detection of metabolic disturbances for a long time. However, it may be difficult to distinguish the exact disturbance when more than one metabolic abnormality exists in a patient simultaneously. Although, \"classic\" ECG characterizations of common electrolyte disturbances are well described, multiple concurrent electrolyte disturbances may lead to ECG abnormalities that may not be easily detectable. This ECG concerns a 60-year-old male presented with general fatigue, weakness, epigastric pain, anorexia, nausea and extreme hypercalcemia (serum total and ionized calcium levels 20.5 mg/dL and 12.02 mg/dl, respectively), hypokalemia and hypomagnesemia associated with elevated parathyroid hormone (1160 pg/ml) and normal serum vitamin D level (97 ng/ml) . This rare manifestation of primary hyperparathyroidism has been named hyperparathyroid crisis in the literature. Hyperparathyroid crisis is an emergency form of multiple electrolyte abnormalities that manifest as a life-threatening hypercalcemia and simultaneous hypokalemia and hypomagnesemia; these two later are believed to be caused by diuretic effect of calcium on the renal tubules. The unique pattern of ECG in our patient first was misdiagnosed as prominent T waves with prolongation of the QT corrected (QTc) interval, which has been reported several times in patients with hyperparathyroidism crisis, compatible with our patient. But more investigation revealed that, the QTc interval not only is not prolonged, it is shortened as it is expected from the effect of hypercalcemia on electrocardiogram. The exact pattern of the patient`s ECG (figure 1) can be interpreted as it follows: (1) Flattening of the T wave, (2) a prominent U wave, (3) prolongation of the descending limb of the T wave such that it overlapped with the next U wave (4) virtual absence of ST segment and (5) shortening of the QT corrected interval. In conclusion, it should be emphasized when the T and U waves are separated by a very short segment they can mimic the appearance of a prolonged QT interval. However, more investigation can demonstrate the exact electrocardiographic pattern especially in multiple electrolyte disturbances, when \"classic\" ECG patterns are not expectable. Case summaryA 10-year-old boy presented with severe progressive generalised weakness on a background of 3 days of diarrhoea and vomiting. Vital signs were normal. Peripheral neurological examination revealed grade 1-2 power in all limbs, hypotonia and hyporeflexia. Sensation was fully intact. Cranial nerve examination and speech were normal. The ECG (figure 1) and initial venous blood gas (figure 2) are shown.edpract;107/1/21/F1F1F1Figure 1ECG.edpract;107/1/21/F2F2F2Figure 2Venous blood gas. QUESTION 1: What abnormalities are present on the ECG?Peaked T waves, prolonged PR segment and loss of P waves?Shortening of the QT interval and Osborn waves (J waves)?T wave flattening/inversion, prominent U waves and long QU interval?Prolonged QT interval with multiple atrial and ventricular ectopics? QUESTION 2: How would you manage this patient's hypokalaemia? QUESTION 3: What is the likely diagnosis?Conversion disorder.Myasthenia gravis.Periodic paralysis.Guillain-Barré syndrome.Botulism. QUESTION 4: What interventions can be considered for long-term treatment of this condition? <iAnswers can be found on page 2</i. Diagnosis Hypokalemia (low blood potassium levels) commonly occurs during attacks; levels below 3.0 mmol/l are typically encountered. Magnesium and phosphate levels are often found to be decreased. Creatine kinase levels are elevated in two thirds of cases, usually due to a degree of muscle injury; severe elevations suggestive of rhabdomyolysis (muscle tissue destruction) are rare. Electrocardiography (ECG/EKG) may show tachycardia (a fast heart rate) due to the thyroid disease, abnormalities due to cardiac arrhythmia (atrial fibrillation, ventricular tachycardia), and conduction changes associated with hypokalemia (U waves, QRS widening, QT prolongation, and T wave flattening). Electromyography shows changes similar to those encountered in myopathies (muscle diseases), with a reduced amplitude of the compound muscle action potentials (CMAPs); they resolve when treatment has commenced. A course of the disease of a 68-year-old female who had been taking medigoxin, furosemide, verapamil and an unknown amount of spironolactone and potassium salt due to congestive heart failure is presented. She was admitted to emergency department of the University Hospital Rebro after an episode of syncopal attack because of arrhythmia due to hyperkalemia (8.9 nmol/L). She has had a fast idioventricular rhythm, followed by atrial tachycardia after that and with fast ventricular rhythm, S-T segment depression and a tall and peaked T-wave. In the following electrocardiograms left anterior hemiblock appeared, a tall R-wave of the anterolateral location, supraventricular and ventricular premature beats and atrioventricular block of the first degree. The patient had signs of non-oliguric form of acute renal failure at the admission which was a partly explanation for the development of hyperkalemia, together with the use of spironolactone and potassium salt. After the treatment she had normal serum creatinine values. She suffered from combined mitral valve disease: stenosis with a predominant regurgitation of the II/III degree. She was discharged from the hospital in a compensated state with normal serum potassium values. Elevated potassium level is a common and reversible peri-arrest condition. Diagnosis and management of hyperkalemia in a short time is critical, where electrocardiogram (ECG) alterations might be helpful. We aimed to investigate the role of clinical features and ECGs in early diagnosing and treating hyperkalemia. Prospectively, adult patients who presented to the emergency department (ED) from July 2019 to March 2020 with hyperkalemia (serum potassium ≥5.5mmol/L) were included. History was obtained, and laboratory investigations and ECGs were performed at the presentation and before initiating hyperkalemia therapy. Hyperkalemia severity was divided into mild (5.5-5.9mmol/L), moderate (6.0-6.4mmol/L), and severe (≥6.5mmol/L). A cardiologist and emergency physician blinded to laboratory values, study design, and patients' diagnoses interpreted ECGs and presenting symptoms independently to predict hyperkalemia. Sixty-seven hyperkalemic patients with a mean (±SD) serum potassium level of 6.5±0.7mmol/L were included in this study. The mean age was 63.9±15.1, and 58.2% were females. Hyperkalemia was mild in 10.4%, moderate in 40.3%, and severe in 49.3%. Almost two thirds of patients (71.6%) had hypertension, 67.2% diabetes, and 64.2% chronic kidney disease. About one-quarter of patients (22.4%) were asymptomatic, while fatigue (46.3%), dyspnea (28.4%), and nausea/vomiting (20.9%) were the most common presenting symptoms. Normal ECGs were observed in 25.4% of patients, while alterations in 74.6%. Atrial fibrillation (13.4%), peaked T wave (11.9%), widened QRS (11.9%), prolonged PR interval (10.5%), and flattening P wave (10.5%) were the most common. Peaked T wave was significantly more common in severe hyperkalemia (87.5%) than in mild and moderate hyperkalemia (12.5%, 0.0%, respectively) (p=0.041). The physicians' sensitivities for predicting hyperkalemia were 35.8% and 28.4%, improved to 51.5% and 42.4%, respectively, when limiting the analyses to severe hyperkalemia. The mean (±SD) time to initial hyperkalemia treatment was 63.8±31.5 min. Potassium levels were positively correlated with PR interval (r=0.283, p=0.038), QRS duration (r=0.361, p=0.003), peaked T wave (r=0.242, p=0.041), and serum levels of creatinine (r=0.347, p=0.004), BUN (r=0.312, p=0.008), and CK (r=0.373, p=0.039). The physicians' abilities to predict hyperkalemia based on ECG and symptoms were poor. ECG could not be solely relied on, and serum potassium tests should be conducted for accurate diagnosis. A 60-year-old woman with a 6-year history of numbness in her hands was admitted to hospital with dyspnea. Laboratory findings showed the elevation of creatine kinase (creatine kinase MB isoenzyme was less than 4 IU/l). Chest X-ray revealed cardiomegaly and pulmonary edema. Electrocardiogram showed a T wave inversion in V<sub2-5</sub and a prolonged QT interval. Echocardiography demonstrated reduced left ventricular ejection fraction (LVEF) and massive pericardial effusion. The patient was diagnosed with heart failure. Further testing found hypocalcemia and idiopathic hypoparathyroidism. In addition to diuretics, calcium replacement therapy for hypocalcemia improved the LVEF and reduced pericardial effusion. Hypocalcemia rarely leads to heart failure and pericardial effusion. In our case, heart failure and the massive pericardial effusion were secondary to hypocalcemia due to idiopathic hypoparathyroidism. &lt;<bLearning objective:</b Hypocalcemia should be considered in patients with heart failure, reduced ejection fraction, and massive pericardial effusion. Supportive findings for diagnosis of heart failure caused by hypocalcemia are numbness, elevation of creatine kinase, T wave inversion, and prolonged QT interval.&gt;. FIguRE 269e-24 Prominent U waves (II, III, and V4–V6) with ventricular repolarization prolongation in a patient with severe hypokalemia. CHAPTER 269e Atlas of Electrocardiography FIguRE 269e-25 Abbreviated ST segment such that the T wave looks like it takes off directly from QRS in some leads (I, V4, aVL, and V5) in a patient with severe hypercalcemia. Note also high takeoff of ST segment in V2/V3 simulating acute ischemia. PART 10 Disorders of the Cardiovascular System FIguRE 269e-26 SR with LVH, left atrial abnormality, and tall peaked T waves in the precordial leads with inferolateral ST depressions (II, III, aVF, and V6); left anterior fascicular block and borderline prolonged QT interval in a patient with renal failure, hypertension, and hyperkalemia; prolonged QT is secondary to associated hypocalcemia. The physiological actions of magnesium within the cardiac conduction system and myocytes have yet to be fully elucidated. Because concurrent hypocalcemia or hypokalemia were also present in previous human reports, specific electrocardiographic effects of isolated hypomagnesemia have not been clearly delineated. We report a case in which dynamic electrocardiogram (ECG) changes were demonstrated in isolated hypomagnesemia. A 37-year-old man with history of heavy alcohol use was admitted for syncope. The ECG showed global T-wave inversions with prolonged corrected QT (QTc) duration on ECG. Extensive work-up including cardiac catheterization was unremarkable. His serum magnesium was noted to be low at 1.1 mg/dL, and his serum calcium and potassium were within normal limits. The patient received magnesium infusion with subsequent ECGs showing resolution of his global T-wave inversions and prolonged QTc. This case is unique because it reports dynamic ECG changes in a patient with isolated hypomagnesemia. Although isolated hypomagnesemia is commonly believed to result in dysrhythmia, we were unaware of any previous cases of ECG abnormalities in humans. Clinically, we advise checking serum magnesium and correcting hypomagnesemia when prolonged QTc duration and global T-wave inversions are seen on ECG. Electrolytes disturbances and intoxication: Digitalis intoxication Calcium: hypocalcemia and hypercalcemia Potassium: hypokalemia and hyperkalemia Serotonin Toxicity Ischemia and infarction: Wellens' syndrome (LAD occlusion) de Winter T waves (LAD occlusion) ST elevation and ST depression High Frequency QRS changes Myocardial infarction (heart attack) Non-Q wave myocardial infarction NSTEMI STEMI Sgarbossa's criteria for ischemia with a LBBB Structural: Acute pericarditis Right and left ventricular hypertrophy Right ventricular strain or S1Q3T3 (can be seen in pulmonary embolism) History Since SPS is not selective for potassium ions, other electrolyte imbalances may occur while using SPS in hyperkalemic patients. Patients should be monitored carefully for the signs and symptoms of other electrolyte abnormalities such as hypokalemia,  hypomagnesemia, and hypocalcemia. Hypokalemia may be associated with cardiac arrhythmias and severe muscle weakness. Hypokalemia may be evident as prolongation of the QT interval, T-wave inversions, prominent U waves (an extra upward wave after the T-wave) in Electrocardiogram (ECG). Some patients may present with significant symptoms of rebound hyperkalemia, which may be evident in ECG as a tall peaked T wave. Hypomagnesemia can present with muscle weakness and potentiate hypokalemia. Hypocalcemia presents with tremors, muscle weakness, tetany, and rarely, seizures. A 47-year-old man presented to our emergency department (ED) with limbs weakness for 2 h. His heart rate was 127 beats per minute and blood pressure was 95/49 mm Hg. He found weakness of limbs after 4-h sleep. Physical examinations revealed that the muscle strength of upper limbs is 3/5, and lower limbs are 2/5. Electrocardiogram (ECG) revealed wide QRS complex, monomorphic ventricular tachycardia (VT) with ST-segment depression and long QT interval. Serum potassium level was extremely low as 1.0 mEq/L. This led to periodic hypokalemic paralysis. Due to severe hypokalemia with possible atrioventricular block, the patient was admitted to the intensive care unit. During hospitalization, his potassium level returned to 5.1 mEq/L on the first day. He had a low level of thyroid stimulating hormone (TSH) of &lt;0.03 micro-IU/mL (normal range: 0.25-4.00) and a high free thyroxine (T4) level of 2.43 ng/dL (normal range: 0.89-1.79 ng/dL). Therefore, hyperthyroidism was diagnosed, and 5 mg of methimazole was administered twice a day. The patient was discharged on the seventh day after admission. The final diagnosis is thyrotoxic periodic paralysis (TPP), also as known as nocturnal paralysis or night palsy. Hypokalemia, defined as a plasma potassium concentration &lt;3.5 mmol/l, is the most common electrolyte abnormality encountered in our clinical practice. Unfortunately, in many cases, the etiologies were unclear and resulted in a wrong treatment. Indeed, the true etiology could be such a 'rare' one and could be found by doing a comprehensive work up. One of this is Gitelman's syndrome, a rare genetic disorder characterized by hypokalemic alkalosis, hypomagnesemia, hypocalciuria, and secondary aldosteronism without hypertension. Since this disorder is found in 1% Caucasian populations, this is one of the most frequently inherited renal tubular disorders. A 27 year old man came to emergency room with weakness and generalised muscle cramps. He was investigated three months before for a similar electrolyte disturbance which was found to be inconclusive. The routine laboratory data in emergency room revealed a potassium concentration of 2.3 mmol/l. He had never used diuretics or hormonal therapy nor had history of vomiting or diarrhea. He had normal blood pressure and the blood gas analysis revealed metabolic alkalosis. On his ECG (electrocardiography), we found the prominent U wave. Despite his low concentration of serum potassium and cloride, the concentration of these electrolytes in urine were extremely high. We also found hipomagnesemia. The calcium concentration in serum was normal with slightly hypocalciuria. Even with aggressive oral and intravenous potassium suplementation, the patient remained hypokalemic. In cases when the etiology of hypokalemia is unclear, we should perform some investigations to confirm the diagnosis and give the proper treatment. In Gitelman's syndrome, where the defect in the distal tubule cannot be corrected, the treatment must be a life-long. Most patients require oral potassium and magnesium supplementation, since drug therapy is usually incompletely effective. Hyperkalemia is defined as a serum potassium level >5.5 mmol/L (>5.5 meq/L) and can neurologically present as muscle weakness with or without paresthesias. Hyperkalemia becomes life threatening when it produces electrocardiographic abnormalities such as peaked T waves or a widened QRS complex. In these cases, prompt treatment is essential and consists of strategies that protect the heart against arrhythmias (calcium gluconate administration); promote potassium redistribution into cells (with glucose, insulin, and β2-agonist medications); and increase potassium removal (through sodium polystyrene sulfonate, loop diuretics, or hemodialysis). Hypercalcemia usually occurs in the setting of either hyperparathyroidism or systemic malignancy. Neurologic manifestations include encephalopathy as well as muscle weakness due to reduced neuromuscular excitability. Seizures can occur but are more common in states of low calcium. Diagnosis Numerous diagnoses and findings can be made based upon electrocardiography, and many are discussed above. Overall, the diagnoses are made based on the patterns. For example, an \"irregularly irregular\" QRS complex without P waves is the hallmark of atrial fibrillation; however, other findings can be present as well, such as a bundle branch block that alters the shape of the QRS complexes. ECGs can be interpreted in isolation but should be applied – like all diagnostic tests – in the context of the patient. For example, an observation of peaked T waves is not sufficient to diagnose hyperkalemia; such a diagnosis should be verified by measuring the blood potassium level. Conversely, a discovery of hyperkalemia should be followed by an ECG for manifestations such as peaked T waves, widened QRS complexes, and loss of P waves. The following is an organized list of possible ECG-based diagnoses. Hypokalemia can result in a variety of cardiac dysrhythmias. Although cardiac dysrhythmias or ECG changes are more likely to be associated with moderate to severe hypokalemia, there is a high degree of individual variability and can occur with even mild decreases in serum levels. This variability is dependent on concomitant factors such as magnesium depletion, digitalis therapy, among others. Moreover, characteristic ECG changes do not manifest in all patients. The ECG changes that occur are T-wave flattening initially, followed by ST depression and the appearance of a U wave that can be difficult to distinguish from the T wave. The U wave is often seen in the lateral precordial leads of V4 to V6. Prolongation of the PR and QT interval can also occur. Risk of arrhythmias is highest in older patients, those with heart disease and those receiving digoxin or antiarrhythmic drugs. Administration of anesthesia in the setting of hypokalemia is also a risk for dysrhythmias and impaired cardiac contractility but more so with acute rather than chronic hypokalemia. The first test that should be ordered in a patient with suspected hyperkalemia is an ECG since the most lethal complication of hyperkalemia is cardiac condition abnormalities which can lead to dysrhythmias and death. Elevated potassium causes ECG changes in a dose-dependent manner: K = 5.5 to 6.5 mEq/L ECG will show tall, peaked t-waves K = 6.5 to 7.5 mEq/L ECG will show loss of p-waves K = 7 to 8 ECG mEq/L will show widening of the QRS complex K = 8 to 10 mEq/L will produce cardiac arrhythmias, sine wave pattern, and asystole\nHere is the question:\nNEPHROLOGY: An 80-year-old patient with a history of hypertension and on treatment with enalapril and spironolactone comes to the hospital with asthenia and severe muscle weakness. Blood pressure is 110/70 mmHg. In the ECG, there are sharp and elevated T waves, ventricular extrasystoles and short QT. What is the most likely diagnosis?\nHere are the potential choices:\n1. Hypercalcemia.\n2. Hyperkalemia.\n3. Hypomagnesemia.\n4. Hypocalcemia.\n5. Hypernatremia.\nThe correct answer is: 2. Hyperkalemia."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Fetal heart rate (FHR) patterns from 746 consecutive, documented vaginal deliveries within a 1 year period were reported on using the Hammacher Score. Characteristic FHR patterns were described and the frequency of acidosis calculated. FHR score, the single FHR parameters, baseline (BL), floatingline (FL) and oscillation type (OT) and the acid-base balance of the neonate were submitted to a correlation analysis according to Spearman. FHR patterns reported as ominous (FHR score &gt; or = 5) were observed in 25.9% and were associated with a frequency of acidosis (pHUA &lt; or = 7.20) of 38.1% Suspicious fetal heart rate patterns (FHR score 3-4) were seen in 60%, here the frequency of acidosis was 8.5%. With the inclusion of decelerations by the parameter FL an increased frequency of acidosis of 29% was registered only when 4 points were allocated. Total FHR score and the score parameter baseline (BL) correlated closest with the pH changes at the end of birth. Tachycardic FHR patterns showed the highest frequency of acidosis (55%) and ominous tracings (83%). The commonest FHR pattern, normocardia with decelerations (48%) exhibited only a low frequency of acidosis (8%) and ominous tracings (15%) with an average pH value of 7.27 +/- 0.08. To prevent an unnecessary operative delivery in the presence of an ominous FHR finding, whether in the late first stage or early second stage when birth is not imminent, a fetal blood analysis should be carried out. With a suspiciously assessed fetal heart rate pattern the fetal blood analysis will only rarely reveal a severe acidosis (pHUA &lt; or = 7.10). The objective of this study is to establish the reference values range of the fetal oxygen saturation during the first and the second period of labor and their dispersal according to the extent of cervical dillatation in cases with normal FHR--absence of fetal hypoxia and asphyxia of the newborn. This is a prospective study which involves 94 women with normal FHR. All of the newborns are with umbilical artery pH values greater than 7.15 and 5 min Apgar score greater than 7; there was no necessity for any reanimation procedures, assisted ventilation or intensive care treatment. The fetal oxygen saturation (SpO2) is monitored by fetal pulseoxymeter Nellcor N 400, fetal sensors FS - 14. Cardiotocographic monitoring is carried out simultaneously. Blood is obtained from the fetal scalp during labor for blood gas and pH analysis, and umbilical artery pH as well as the Apgar score of the newborn are determined. The average monitoring time during the first period of labor is 107.19+/-29.49 min. with reliability of the recordings 86.54+/-6.10%. The average monitoring time for the second period of labor is 36.72+/-8.31 min. with reliability of the recordings 75.42 +/-9.61%. The mean SpO2 values are 48.71+/-5.52% during the first period and 47.30+/-4.62% during the second period of labor. The reference SpO2 values ranging between the 25-th and 75-th percentile in fetuses with normal FHR are 46-52 % for the first and 44-50 % for the second period. The results for fetal SpO2 during the different stages of cervical dillatation are as follows: for 4-5 cm - 49.49+/-5.12%, for 6-7 cm - 48.76+/-5.42%, for 8-9 cm - 48.39+/-5.49%. The fetal SpO2 dispersal during cervical dillatation of 4-5, 6-7 and 8-9cm accordingly demonstrates a nonsignificant decrease of SpO2 for the different groups (p&gt;0.05). The fetal SpO2 dispersal between the first and the second period of labor also demonstrates decrease of SpO2 values and shows a minor statistically significant difference (p &lt; 0.05 - Repeated measures ANOVA), which is considered to be within the normal range and does not reflect on the newborn's well-being. FHR monitoring and microanalysis of fetal blood are mutually complementary procedures, and optimal knowledge of the fetal state is achieved by making use of both, the former for the preliminary screening of all cases at risk and the latter for the purpose of deciding on obstetric management where pathological changes are evident in the FHR. The major difficulty in obtaining a precise value for the fetal acid-base balance lies in the occurence of \"falsely abnormal\" cases, i.e. cases in which the fetal pH falls during labor but the clinical condition at birth is good (APGAR greater than or equal to 7). In our own series the incidence of such cases among fetuses at risk was 11.2% (Tab. I). In the majority of these cases the fetal acidosis is thought to be a result of increased metabolic acidosis in the mother (maternogenic fetal metabolic acidosis). The importance of the maternogenic fetal acidosis during labor lies in the fact that unless it is recognised, rapid extraction of the fetus will appear necessary on clinical grounds, although it is in fact unnecessary, since this form of acidosis has no adverse effect on the fetus. Various parameters have been proposed for the differential diagnosis of the maternogenic fetal acidosis. These include the feto-maternal difference in base deficit (F/M deltaBD), the materno-fetal differences in pHqu 40 (M/F deltapHqu 40) the materno-fetal difference actual pH (M/F actual deltapH), and the materno-fetal difference in base deficit of the extra-cellular fluid (M/F deltaBDHb5). A critical analysis of these parameters has been carried out on the results of microtests performed during a 5 year period (1968-1972) at the First Clinic of Obstetrics and Gynecology of Milan University. The cases comprised 59 regarded as normal (normal course of pregnancy, spontaneous commencement of labor at term, clear amniotic fluid, regular FHR, spontaneous birth, APGAR at 90 sec between 8 and 10, weight at birth greater than 2500 g), and 335 considered to be at risk (maternal disease, presence of meconium stained amniotic fluid and/or abnormal changes in FHR). In all of these cases the FHR was recorded by cardiotokography, and the tracings were interpreted according to HON. Microsamples of blood were taken from both mother and fetus during labor and the following determinations were carried out: actual pH, pHqu 40, Hb concentration, hemoglobin oxygen saturation, base deficit Hb5 (BDHb5). The maternofetal differences were then calculated. The same determinations were carried out on samples of maternal blood and of arterial and venous cord blood taken immediately after delivery. The clinical condition of the infant was evaluated by the APGAR score at 90 seconds after birth. To determine the best way of fetal monitoring during the active second stage of labor. Articles were searched using PubMed and Cochrane library. Active phase of labor begins with the onset of maternal pushing. It is characterised by frequent and prolonged uterine contractions as well as maternal bearing down efforts. Altogether those mechanical forces lead to an intrauterine pressure increase up to 250 mm Hg and to a marked reduction in placental perfusion. A prolonged period of expulsion will lead to an impairment of fetal oxygenation as well as a rise in carbon dioxide level. Melchior's FHR classification is specific of the active second stage of labor and described five fetal heart rate patterns: from type 0 to type 4. A reduction in pH and a rise in lactate and P(CO2) values occurred as one progresses from type 0 to type 4 (NP4). During the active phase of labor every method has a significant rate of signal loss. Loss of sensor contact occurred in up to 64% of time with oximetry, 35 to 48% of recordings obtained via external Doppler sensors have more than 20% of signal loss. Even 8 to 11% of recordings obtained via scalp sensors have more than 20% of signal loss. Fetal scalp blood sampling does not allow a continuous recording of fetal well-being and is difficult to perform during this stage. No method has a 100% sensitivity to detect metabolic acidosis. Normal FHR of 1.3% are coupled with an acidosis. Even ST analysis exhibited a small but real false negative rate (NP4). Active second phase of labor is at high risk of fetal acidosis, and required a close follow-up of the FHR. The length of maternal bearing down efforts should be matched to the fetal heart rhythm Melchior's classification pattern. Optimal length of bearing down efforts could be 30 min for type 0, 20 min for type 1 and 10 min for type 2, 3 or 4 (NP4). After theoretical education on the development of fetal acidosis and the fetal blood sampling technique, 12 midwives in a training program carried out or assisted in 40 fetal blood sampling procedures. Sampling was possible at a cervical dilatation of 1.5 cm. 11/12 midwives were successful in their first sampling attempt. The instrument used for analysis was an automated microprocessor device with a minimum sampling volume of 15 microliter of blood. There was a statistically highly significant correlation between the results obtained with the instrument tested and the reference device (r = 0.9; n = 36). 82% of the measurements fell within +/- 0.04 pH units of the reference device. With the instrument placed in the labor room, and using the current technique with very small blood samples, it is possible to obtain a fetal pH value within 10 minutes after the development of a pathological fetal heart rate pattern. The aim of this study was to clarify the association between fetal heart rate (FHR) tracing interpretation levels in the second stage of labor and poor fetal acid-base balance. The database at one tertiary hospital in Nagoya, Japan, was retrospectively reviewed for women with singleton fetuses in cephalic presentation and vaginal labor at ≥37 + 0 gestational weeks between 1 June 2011 and 30 April 2012. Continuous FHR tracings in the second stage of labor were subdivided into 15-min intervals, each of which we called a window, from the beginning of labor through delivery, and were assessed according to the five-tier classification proposed by the Japan Society of Obstetrics and Gynecology, in which level 1 is normal, level 2 is subnormal, and levels 3-5 are abnormal patterns. In total, 777 parturient women were eligible for the study protocol. The numbers of women with maximal levels of 1, 2, 3, 4, and 5 were 3, 77, 341, 349, and 7, respectively. No cases of severe fetal acidosis (pH &lt; 7.0 or base excess &lt;-12 mmol/L) were recorded when the maximal levels were below 3. Both the pH and base excess of the umbilical artery decreased with higher levels of FHR tracings interpretation (P &lt; 0.001). Both the summations of level-4 windows and level-3 and level-4 windows were significantly higher in women with severe fetal acidosis than in women without (P &lt; 0.001), indicating that the duration of abnormal levels is associated with severe fetal acidosis. Both the degree and duration of FHR tracing abnormalities correlate with severe fetal acidosis. Although several investigators have attempted to define the normal values of umbilical cord blood pH and gases, there is considerable controversy about the optimal cutoff values to diagnosis intrauterine asphyxia. A possible reason for this might be that several studies have included data from fetuses born after different duration of labor. To determine the effect of labor and the duration of second stage on labor on umbilical arterial acid-base status at birth in healthy term infants. Umbilical artery acid-base status was determined in patients (n = 356) who met the following criteria: 1) singleton term pregnancy with no significant medical, obstetric, or neonatal complications; 2) vertex presentation if delivered vaginally; 3) neither regional nor general anesthesia applied if delivered vaginally; 4) no use of oxytocin; 5) normal fetal heart rate patterns; 6) clear amniotic fluid; 7) Apgar scores at 1 and 5 min &gt; or = 7; 8) appropriate fetal weight for gestational age. Patients were divided into three groups. A-patients delivered by cesarean section (CS) in the absence of labor (n = 135); B-patients delivered by CS during first stage of labor (n = 62); C-patients with vaginal birth (n = 159). A Kruskal-Wallis ANOVA with post-hoc procedures and stepwise multiple regression analysis were performed. 1) There were significant differences in cord arterial acid-base values between study groups (pH: no labor CS, 7.27 +/- 0.05 vs labor CS, 7.26 +/- 0.05 vs vaginal birth, 7.24 +/- 0.07, p &lt; 0.00001). 2) There was a significant fall in cord arterial pH and bicarbonate concentrations with increased duration of second stage of labor in newborns born vaginally (pH: duration of second stage, 1-30 min, 7.25 +/- 0.07 vs 31-60 min, 7.22 +/- 0.06 vs &gt; 61 min, 7.21 +/- 0.07, p &lt; 0.05). 3) Analysis of confounding variables which could influence the cord pH such as parity, use of vacuum, gestational age, maternal age, and birth weight by stepwise multiple regression analysis indicated that only the duration of second stage of labor pain had a significant relationship with cord blood pH. There is a significant fall in umbilical artery pH and bicarbonate with the presence of labor and increased duration of second stage of labor in healthy term neonates. This should be taken into consideration in evaluating neonatal well-being by cord blood pH and acid-base measurements. The objective of this study was the evaluation of intrapartum pulse oximetry as an indicator of fetal distress and the condition of the newborn during clinical routine surveillance in an University Perinatal Center. Between 1998 and 1999 pulse oximetry (SpO2) was used additionally to routine fetal monitoring by electronic fetal heart rate tracing (CTG) and fetal blood sampling (FBA) in 128 cases with nonreassuring heart rate pattern. Cut off values were FIGO Score &lt; 8 for the heart rate pattern and for fetal blood sampling during labor results of &lt; 7.25 (preacidosis). The condition of the newborn was defined by the APGAR score with the cut off &lt; 7 at 1 minute, while the biochemical status was evaluated by means of arterial blood sampling of the umbilical artery directly after birth using a pH of &lt; 7.20 to verify acidosis. Predictive values of critically low SpO2 values (&lt; 30%) for at least 10 minutes as well as corresponding sensitivities and specificities were calculated together with 95% confidence intervals to identify fetal distress or a depressed condition of the newborns. Of 128 fetuses included in this study 66 (52%) were born spontaneously, 23 (18%) were born by operative vaginal delivery and 39 (31%) by means of cesarean section. The high rate of cesarean section was due to cephalopelvic disproportion in 29 cases. Fetal outcome was evaluated with a clinical score: mean APGAR score value 8.5 SD +/- 1. The mean value of the pH in the umbilical artery was 7.23 +/- 0.04. During a SpO2 monitoring period of 18,381 minutes we analyzed a contact time of 63%. Comparing SpO2 values of &lt; 30% with preacidosis in the fetal blood sampling, we found a positive predictive value of merely 0.17 (95% CI: 0.00-0.64). Of 9 preacidotic cases during delivery only 1 was indicated by a saturation value below 30% (sensitivity 0.11, 95% CI: 0.00-0.48). The specificity and negative predictive value were calculated as 0.83 (95% CI: 0.65-0.94) and 0.76 (95% CI: 0.58-0.89) respectively. Of eleven cases with acidosis in the blood of the umbilical cord artery, pH &lt; 7.20, only 2 were indicated by a SpO2 values below 30%. Which is equivalent to a sensitivity of 0.18 (95% CI: 0.03-0.52). Results of a receiver operator curve analysis showed no substantial deviation from the diagonal. The area under the curve was 0.62, the 95% CI (0.47-0.76) indicating no significant discrimination. Three of 49 fetuses with SpO2 recording during the last 10 minutes were born in clinical depressed status (APGAR &lt; 7). None was indicated by a SpO2 value below 30%. Fetal distress and impaired condition of the newborn are not identified or predicted during routine application of SpO2 monitoring in the fetus during labor with adequate safety. Cardiotocography (CTG) is the main method of intrapartum fetal surveillance. In 2015 a new guideline was introduced by the International Federation of Gynecology and Obstetrics (FIGO), FIGO-15. In Sweden it was adjusted to SWE-17, replacing the previous national template, SWE-09. This study, conducted at one university hospital and one regional hospital in southern Sweden, evaluated the diagnostic validity of these three templates to detect fetal acidosis during the first stage of labor. A total of 73 neonates with pH &lt;7.1 in umbilical cord artery or vein at cesarean delivery during the first stage of labor were identified retrospectively. For each acidotic neonate, three non-acidemic neonates, with a pH ≥7.2 in cord artery and vein, and Apgar scores ≥9 at five and ten minutes, in all 219 neonates, were selected. The CTG tracings before birth in acidemic neonates, and tracings at the same cervical dilatation in the non-acidemic neonates, were independently assessed by three professionals from the obstetric staff, blinded to group and clinical data. Based on their categorizations of the included variables (baseline, variability, accelerations, decelerations and contraction rate), each CTG tracing was systematically classified according to the three templates. The sensitivity and specificity to identify acidemia by the classification pathological were determined for each template. Interobserver agreement in the assessments of tracings as pathological or not was analyzed, using free-marginal Kappa index. The sensitivity for patterns classified as pathological to identify acidemia was similar for FIGO-15 (71%) and SWE-17 (77%, <ip</i = .13), and the specificity was 97% for both. SWE-09 had a significantly higher sensitivity (95%, <ip</i &lt; .001) albeit with a lower specificity (90%, <ip</i &lt; .001) than the other two templates. Among acidemic neonates, the fraction of tracings classified as normal was higher with SWE-17 (9.6%) than with SWE-09 (0%; <ip</i = .01) and FIGO-15 (1.4%; <ip</i = .06). For tracings from neonates with acidemia, agreement for three independent assessors was strong (κ 0.85) with SWE-09, and weak for FIGO-15 (κ 0.47), and SWE-17 (κ 0.51). For tracings from neonates without acidemia, the agreement was almost perfect for FIGO-15 (κ 0.91), strong withSWE-17 (κ 0.90) and moderate with SWE-09 (κ 0.78). The ability of FIGO-15 and SWE-17 to identify fetal acidosis is considered insufficient. The combination of a high sensitivity and a high specificity makes SWE-09 the most discriminatory template during the first stage of labor. In 871 deliveries out of a total of 3980 effected during 1980-1982 at the Winterthur Gynaecological Hospital, we found it necessary to perform one or several microanalyses of blood (blood gas analyses) sub partu. Among these, we found retrospectively that in 22 cases the microanalysis of the blood gas had prevented us from performing caesarean section which would have seemed necessary if we had relied on the cardiotocographical findings alone. Micro-analysis of blood gas made it possible to exclude the presence of pre-acidosis or acidosis which would have made Caesarean section imperative; in all these cases, normal delivery via the vagina was achieved, and in no case did this result in severe acidosis. All newborn had a 5-minute Apgar score of 7 and higher. We can conclude from these results, therefore, that the indication for an immediate termination of delivery via Caesarean section should not depend solely on a pathological cardiotocogram; the final decision should be arrived at only after micro-analyses of blood gas have confirmed the presence of foetal pre-acidosis or acidosis. The use of pH and base excess (FSSPHBE) from fetal scalp sampling (FSS) was abandoned when cardiotocography (CTG) was believed to be sufficiently accurate to direct patient management. We sought to understand the fetus' tolerance to stress in the 1st stage of labor and to develop a better and earlier screening test for its risk for developing acidosis. To do so, we investigated sequential changes in fetal pH and BE obtained from FSS in the 1st stage of labor as part of a research protocol from the 1970s. We then examined the utility of multiple of the median (MoM's) conversion of BE and pH values, and the capacity of Fetal Reserve Index (FRI) scores to be a proxy for such changes. We then sought to examine the predictive capacity of 1st stage FRI and its change over the course of the first stage of labor for the subsequent development of acidosis risk in the 2nd stage of labor. Using a retrospective research database evaluation, we evaluated FSSPHBE data from 475 high-risk parturients monitored in labor and their neonates for 1 h postpartum.We categorized specimens according to cervical dilatation (CxD) at the time of FSSPHBE and developed non-parametric, multiples of the median (MOMs) assessments. FRI scores and their change over time were used as predictors of FSSPHBE. Our main outcome measures were the changes in BE and pH at different cervical dilatations (CxD) and acidosis risk in the early 2nd stage of labor. FSSPHBE worsens over the course of the 1st stage. The implications of any given BE are very different depending upon CxD. At 9 cm, -8 Mmol/L is 1.1 MOM; at 3 cm, it would be 2.0 MOM. The FRI level and its trajectory provide a 1st stage screening tool for acidosis risk in the second stage. Fetal acid-base balance (\"reserve\") deteriorates beginning early in the 1st stage of labor, irrespective of whether the fetus reaches a critical threshold of concern for actual acidosis. The use of MoM's logic improves appreciation of such information. The FRI and its trajectory reasonably approximate the trajectory of the FSSPHBE and appears to be a suitable screening test for early deterioration and for earlier interventions to keep the fetus out of trouble rather than wait until high risk status develops. Updated 2015 FIGO Intrapartum Fetal Monitoring Guidelines FIGO has recently modified the guidelines on intrapartum fetal monitoring, proposing the following interpretation: Normal: No hypoxia or acidosis; no intervention necessary to improve fetal oxygenation state. Baseline 110–160bpm Variability 5–25bpm No repetitive decelerations (decelerations are defined as repetitive when associated with >50% contractions) Suspicious: Low probability of hypoxia/acidosis, warrants action to correct reversible causes if identified, close monitoring or adjunctive methods. Lacking at least one characteristic of normality, but with no pathological features. Pathological: High probability of hypoxia/acidosis, requires immediate action to correct reversible causes, adjunctive methods, or if this is not possible expedite delivery. In acute situations, delivery should happen immediately. Baseline <100bpm Reduced or increased variability or sinusoidal pattern Signs and symptoms Generally it is preferable to describe specific signs in lieu of declaring fetal distress that include: Decreased movement felt by the mother Meconium in the amniotic fluid (\"meconium stained fluid\") Non-reassuring patterns seen on cardiotocography: increased or decreased fetal heart rate (tachycardia and bradycardia), especially during and after a contraction decreased variability in the fetal heart rate late decelerations Biochemical signs, assessed by collecting a small sample of baby's blood from a scalp prick through the open cervix in labor fetal metabolic acidosis elevated fetal blood lactate levels (from fetal scalp blood testing) indicating the baby has a lactic acidosis Some of these signs are more reliable predictors of fetal compromise than others. For example, cardiotocography can give high false positive rates, even when interpreted by highly experienced medical personnel. Metabolic acidosis is a more reliable predictor, but is not always available. Cardiotocography has become the standard for fetal monitoring in labor. False-positive findings during electronic fetal heart rate monitoring may were not associated with neonatal acidemia. Because of the poor specificity of fetal heart rate monitoring in predicting fetal distress, new methods are being investigated as a way to improve the accuracy of assessing the infant's condition during labor. The aim of this study was to determinate the efficiency of fetal blood oxygen saturation (FSpO2) and computer analysis of the fetal heart rate (Co-CTG) in the late 1-st stage of labor as a prognostic factor of newborn acidemia. Total 62 subjects were studied. During labors and deliveries fetal oxygen saturation was continuously recorded, with use of Nellecor N-400 fetal pulse oximeter and continous CTG were performed by Hewlett Packard 50A. Transdermal fetal oxygen saturation measurements and CTG results obtained during the labors was analyzed using MONAKO system (ITAM Zabrze). The results were compared with the values of pH and base deficit in the umbilical artery measured just after delivery. The sensitivity, specificity, negative, positive predictive values and Youden factor based on FHR and FSpO2, for prognosis of neonatal acidosis were: 65%, 80%, 16%, 97.5% 60% and 0.135 respectively FHR; and 100%, 60%, 100%, 96.8% and 0.968 respectively FSpO2. 1. The examination of fetal blood oxygen saturation in the labor is a useful prognostic factor of the newborn outcome. 2. The best predictive value for intrapartum fetal asphyxia with metabolic acidosis was found when fetal pulse oximetry is added to cardiotocography. In a study by Tarvonen et al. (2019), it was demonstrated that the occurrence of saltatory pattern (already with the minimum duration of 2 minutes) in CTG tracings during labor was associated with fetal hypoxia indicated by high umbilical vein (UV) blood erythropoietin (EPO) levels and umbilical artery (UA) blood acidosis at birth in human fetuses. As saltatory patterns preceded late decelerations of fetal heart rate (FHR) in the majority of cases, saltatory pattern seems to be an early sign of fetal hypoxia. According to the authors, awareness on this gives obstetricians and midwives time to intensify electronic fetal monitoring and to plan possible interventions before fetal asphyxia occurs. If repeat test >6, observe and repeat per protocol Repeat testing same day; if biophysical profile score :;6, deliver Deliver AFV = amnionic fluid volume; NST = nonstress test. Reproduced with permission from Manning FA, Morrison I, Harman CR, et al: Fetal assessment based on fetal biophysical profile scoring: experience in 19,221 referred high-risk pregnancies. II. An analysis of false-negative fetal deaths, Am J Obstet Gynecol. 1987 Oct;157(4 Pt 1 ):880-884. I. ):J0 downstream impedance (Chap. 10, p. 213). For growth 7.30 7.25 0E:J E:J= 7.20 7.10 7.05 FIGURE 17-9 Mean umbilical vein pH (±2 SD) obtained by cordocentesis in relation to fetal biophysical profile score category. (Data from Manning, 1993.) API determination for which �5 cm was considered abnormal (Chap. 11, p. 230). his abbreviated biophysical proile required approximately 10 minutes to perform, and they concluded that it was a superb antepartum surveillance method because there were no unexpected fetal deaths.\nHere is the question:\nGYNECOLOGY AND OBSTETRICS: Woman 40 weeks gestation in labor with 6 cm dilation. She presents a decelerative fetal pattern in cardiotocographic recordings, so it is decided to perform a fetal blood smear to assess fetal well-being. Result 7.22. The correct conduct is:\nHere are the potential choices:\n1. Severe acidosis. Urgent cesarean section.\n2. Pre-pathological value repeat microtome 15-20 minutes.\n3. Moderate acidosis. Repeat microtome in 1-2 hours.\n4. Value in normal limits, leave natural evolution of labor.\n5. Repeat at the time of possible error in obtaining the shot.\nThe correct answer is: ",
        "gold_answer": "2 Pre-pathological value repeat microtome 15-20 minutes.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Fetal heart rate (FHR) patterns from 746 consecutive, documented vaginal deliveries within a 1 year period were reported on using the Hammacher Score. Characteristic FHR patterns were described and the frequency of acidosis calculated. FHR score, the single FHR parameters, baseline (BL), floatingline (FL) and oscillation type (OT) and the acid-base balance of the neonate were submitted to a correlation analysis according to Spearman. FHR patterns reported as ominous (FHR score &gt; or = 5) were observed in 25.9% and were associated with a frequency of acidosis (pHUA &lt; or = 7.20) of 38.1% Suspicious fetal heart rate patterns (FHR score 3-4) were seen in 60%, here the frequency of acidosis was 8.5%. With the inclusion of decelerations by the parameter FL an increased frequency of acidosis of 29% was registered only when 4 points were allocated. Total FHR score and the score parameter baseline (BL) correlated closest with the pH changes at the end of birth. Tachycardic FHR patterns showed the highest frequency of acidosis (55%) and ominous tracings (83%). The commonest FHR pattern, normocardia with decelerations (48%) exhibited only a low frequency of acidosis (8%) and ominous tracings (15%) with an average pH value of 7.27 +/- 0.08. To prevent an unnecessary operative delivery in the presence of an ominous FHR finding, whether in the late first stage or early second stage when birth is not imminent, a fetal blood analysis should be carried out. With a suspiciously assessed fetal heart rate pattern the fetal blood analysis will only rarely reveal a severe acidosis (pHUA &lt; or = 7.10). The objective of this study is to establish the reference values range of the fetal oxygen saturation during the first and the second period of labor and their dispersal according to the extent of cervical dillatation in cases with normal FHR--absence of fetal hypoxia and asphyxia of the newborn. This is a prospective study which involves 94 women with normal FHR. All of the newborns are with umbilical artery pH values greater than 7.15 and 5 min Apgar score greater than 7; there was no necessity for any reanimation procedures, assisted ventilation or intensive care treatment. The fetal oxygen saturation (SpO2) is monitored by fetal pulseoxymeter Nellcor N 400, fetal sensors FS - 14. Cardiotocographic monitoring is carried out simultaneously. Blood is obtained from the fetal scalp during labor for blood gas and pH analysis, and umbilical artery pH as well as the Apgar score of the newborn are determined. The average monitoring time during the first period of labor is 107.19+/-29.49 min. with reliability of the recordings 86.54+/-6.10%. The average monitoring time for the second period of labor is 36.72+/-8.31 min. with reliability of the recordings 75.42 +/-9.61%. The mean SpO2 values are 48.71+/-5.52% during the first period and 47.30+/-4.62% during the second period of labor. The reference SpO2 values ranging between the 25-th and 75-th percentile in fetuses with normal FHR are 46-52 % for the first and 44-50 % for the second period. The results for fetal SpO2 during the different stages of cervical dillatation are as follows: for 4-5 cm - 49.49+/-5.12%, for 6-7 cm - 48.76+/-5.42%, for 8-9 cm - 48.39+/-5.49%. The fetal SpO2 dispersal during cervical dillatation of 4-5, 6-7 and 8-9cm accordingly demonstrates a nonsignificant decrease of SpO2 for the different groups (p&gt;0.05). The fetal SpO2 dispersal between the first and the second period of labor also demonstrates decrease of SpO2 values and shows a minor statistically significant difference (p &lt; 0.05 - Repeated measures ANOVA), which is considered to be within the normal range and does not reflect on the newborn's well-being. FHR monitoring and microanalysis of fetal blood are mutually complementary procedures, and optimal knowledge of the fetal state is achieved by making use of both, the former for the preliminary screening of all cases at risk and the latter for the purpose of deciding on obstetric management where pathological changes are evident in the FHR. The major difficulty in obtaining a precise value for the fetal acid-base balance lies in the occurence of \"falsely abnormal\" cases, i.e. cases in which the fetal pH falls during labor but the clinical condition at birth is good (APGAR greater than or equal to 7). In our own series the incidence of such cases among fetuses at risk was 11.2% (Tab. I). In the majority of these cases the fetal acidosis is thought to be a result of increased metabolic acidosis in the mother (maternogenic fetal metabolic acidosis). The importance of the maternogenic fetal acidosis during labor lies in the fact that unless it is recognised, rapid extraction of the fetus will appear necessary on clinical grounds, although it is in fact unnecessary, since this form of acidosis has no adverse effect on the fetus. Various parameters have been proposed for the differential diagnosis of the maternogenic fetal acidosis. These include the feto-maternal difference in base deficit (F/M deltaBD), the materno-fetal differences in pHqu 40 (M/F deltapHqu 40) the materno-fetal difference actual pH (M/F actual deltapH), and the materno-fetal difference in base deficit of the extra-cellular fluid (M/F deltaBDHb5). A critical analysis of these parameters has been carried out on the results of microtests performed during a 5 year period (1968-1972) at the First Clinic of Obstetrics and Gynecology of Milan University. The cases comprised 59 regarded as normal (normal course of pregnancy, spontaneous commencement of labor at term, clear amniotic fluid, regular FHR, spontaneous birth, APGAR at 90 sec between 8 and 10, weight at birth greater than 2500 g), and 335 considered to be at risk (maternal disease, presence of meconium stained amniotic fluid and/or abnormal changes in FHR). In all of these cases the FHR was recorded by cardiotokography, and the tracings were interpreted according to HON. Microsamples of blood were taken from both mother and fetus during labor and the following determinations were carried out: actual pH, pHqu 40, Hb concentration, hemoglobin oxygen saturation, base deficit Hb5 (BDHb5). The maternofetal differences were then calculated. The same determinations were carried out on samples of maternal blood and of arterial and venous cord blood taken immediately after delivery. The clinical condition of the infant was evaluated by the APGAR score at 90 seconds after birth. To determine the best way of fetal monitoring during the active second stage of labor. Articles were searched using PubMed and Cochrane library. Active phase of labor begins with the onset of maternal pushing. It is characterised by frequent and prolonged uterine contractions as well as maternal bearing down efforts. Altogether those mechanical forces lead to an intrauterine pressure increase up to 250 mm Hg and to a marked reduction in placental perfusion. A prolonged period of expulsion will lead to an impairment of fetal oxygenation as well as a rise in carbon dioxide level. Melchior's FHR classification is specific of the active second stage of labor and described five fetal heart rate patterns: from type 0 to type 4. A reduction in pH and a rise in lactate and P(CO2) values occurred as one progresses from type 0 to type 4 (NP4). During the active phase of labor every method has a significant rate of signal loss. Loss of sensor contact occurred in up to 64% of time with oximetry, 35 to 48% of recordings obtained via external Doppler sensors have more than 20% of signal loss. Even 8 to 11% of recordings obtained via scalp sensors have more than 20% of signal loss. Fetal scalp blood sampling does not allow a continuous recording of fetal well-being and is difficult to perform during this stage. No method has a 100% sensitivity to detect metabolic acidosis. Normal FHR of 1.3% are coupled with an acidosis. Even ST analysis exhibited a small but real false negative rate (NP4). Active second phase of labor is at high risk of fetal acidosis, and required a close follow-up of the FHR. The length of maternal bearing down efforts should be matched to the fetal heart rhythm Melchior's classification pattern. Optimal length of bearing down efforts could be 30 min for type 0, 20 min for type 1 and 10 min for type 2, 3 or 4 (NP4). After theoretical education on the development of fetal acidosis and the fetal blood sampling technique, 12 midwives in a training program carried out or assisted in 40 fetal blood sampling procedures. Sampling was possible at a cervical dilatation of 1.5 cm. 11/12 midwives were successful in their first sampling attempt. The instrument used for analysis was an automated microprocessor device with a minimum sampling volume of 15 microliter of blood. There was a statistically highly significant correlation between the results obtained with the instrument tested and the reference device (r = 0.9; n = 36). 82% of the measurements fell within +/- 0.04 pH units of the reference device. With the instrument placed in the labor room, and using the current technique with very small blood samples, it is possible to obtain a fetal pH value within 10 minutes after the development of a pathological fetal heart rate pattern. The aim of this study was to clarify the association between fetal heart rate (FHR) tracing interpretation levels in the second stage of labor and poor fetal acid-base balance. The database at one tertiary hospital in Nagoya, Japan, was retrospectively reviewed for women with singleton fetuses in cephalic presentation and vaginal labor at ≥37 + 0 gestational weeks between 1 June 2011 and 30 April 2012. Continuous FHR tracings in the second stage of labor were subdivided into 15-min intervals, each of which we called a window, from the beginning of labor through delivery, and were assessed according to the five-tier classification proposed by the Japan Society of Obstetrics and Gynecology, in which level 1 is normal, level 2 is subnormal, and levels 3-5 are abnormal patterns. In total, 777 parturient women were eligible for the study protocol. The numbers of women with maximal levels of 1, 2, 3, 4, and 5 were 3, 77, 341, 349, and 7, respectively. No cases of severe fetal acidosis (pH &lt; 7.0 or base excess &lt;-12 mmol/L) were recorded when the maximal levels were below 3. Both the pH and base excess of the umbilical artery decreased with higher levels of FHR tracings interpretation (P &lt; 0.001). Both the summations of level-4 windows and level-3 and level-4 windows were significantly higher in women with severe fetal acidosis than in women without (P &lt; 0.001), indicating that the duration of abnormal levels is associated with severe fetal acidosis. Both the degree and duration of FHR tracing abnormalities correlate with severe fetal acidosis. Although several investigators have attempted to define the normal values of umbilical cord blood pH and gases, there is considerable controversy about the optimal cutoff values to diagnosis intrauterine asphyxia. A possible reason for this might be that several studies have included data from fetuses born after different duration of labor. To determine the effect of labor and the duration of second stage on labor on umbilical arterial acid-base status at birth in healthy term infants. Umbilical artery acid-base status was determined in patients (n = 356) who met the following criteria: 1) singleton term pregnancy with no significant medical, obstetric, or neonatal complications; 2) vertex presentation if delivered vaginally; 3) neither regional nor general anesthesia applied if delivered vaginally; 4) no use of oxytocin; 5) normal fetal heart rate patterns; 6) clear amniotic fluid; 7) Apgar scores at 1 and 5 min &gt; or = 7; 8) appropriate fetal weight for gestational age. Patients were divided into three groups. A-patients delivered by cesarean section (CS) in the absence of labor (n = 135); B-patients delivered by CS during first stage of labor (n = 62); C-patients with vaginal birth (n = 159). A Kruskal-Wallis ANOVA with post-hoc procedures and stepwise multiple regression analysis were performed. 1) There were significant differences in cord arterial acid-base values between study groups (pH: no labor CS, 7.27 +/- 0.05 vs labor CS, 7.26 +/- 0.05 vs vaginal birth, 7.24 +/- 0.07, p &lt; 0.00001). 2) There was a significant fall in cord arterial pH and bicarbonate concentrations with increased duration of second stage of labor in newborns born vaginally (pH: duration of second stage, 1-30 min, 7.25 +/- 0.07 vs 31-60 min, 7.22 +/- 0.06 vs &gt; 61 min, 7.21 +/- 0.07, p &lt; 0.05). 3) Analysis of confounding variables which could influence the cord pH such as parity, use of vacuum, gestational age, maternal age, and birth weight by stepwise multiple regression analysis indicated that only the duration of second stage of labor pain had a significant relationship with cord blood pH. There is a significant fall in umbilical artery pH and bicarbonate with the presence of labor and increased duration of second stage of labor in healthy term neonates. This should be taken into consideration in evaluating neonatal well-being by cord blood pH and acid-base measurements. The objective of this study was the evaluation of intrapartum pulse oximetry as an indicator of fetal distress and the condition of the newborn during clinical routine surveillance in an University Perinatal Center. Between 1998 and 1999 pulse oximetry (SpO2) was used additionally to routine fetal monitoring by electronic fetal heart rate tracing (CTG) and fetal blood sampling (FBA) in 128 cases with nonreassuring heart rate pattern. Cut off values were FIGO Score &lt; 8 for the heart rate pattern and for fetal blood sampling during labor results of &lt; 7.25 (preacidosis). The condition of the newborn was defined by the APGAR score with the cut off &lt; 7 at 1 minute, while the biochemical status was evaluated by means of arterial blood sampling of the umbilical artery directly after birth using a pH of &lt; 7.20 to verify acidosis. Predictive values of critically low SpO2 values (&lt; 30%) for at least 10 minutes as well as corresponding sensitivities and specificities were calculated together with 95% confidence intervals to identify fetal distress or a depressed condition of the newborns. Of 128 fetuses included in this study 66 (52%) were born spontaneously, 23 (18%) were born by operative vaginal delivery and 39 (31%) by means of cesarean section. The high rate of cesarean section was due to cephalopelvic disproportion in 29 cases. Fetal outcome was evaluated with a clinical score: mean APGAR score value 8.5 SD +/- 1. The mean value of the pH in the umbilical artery was 7.23 +/- 0.04. During a SpO2 monitoring period of 18,381 minutes we analyzed a contact time of 63%. Comparing SpO2 values of &lt; 30% with preacidosis in the fetal blood sampling, we found a positive predictive value of merely 0.17 (95% CI: 0.00-0.64). Of 9 preacidotic cases during delivery only 1 was indicated by a saturation value below 30% (sensitivity 0.11, 95% CI: 0.00-0.48). The specificity and negative predictive value were calculated as 0.83 (95% CI: 0.65-0.94) and 0.76 (95% CI: 0.58-0.89) respectively. Of eleven cases with acidosis in the blood of the umbilical cord artery, pH &lt; 7.20, only 2 were indicated by a SpO2 values below 30%. Which is equivalent to a sensitivity of 0.18 (95% CI: 0.03-0.52). Results of a receiver operator curve analysis showed no substantial deviation from the diagonal. The area under the curve was 0.62, the 95% CI (0.47-0.76) indicating no significant discrimination. Three of 49 fetuses with SpO2 recording during the last 10 minutes were born in clinical depressed status (APGAR &lt; 7). None was indicated by a SpO2 value below 30%. Fetal distress and impaired condition of the newborn are not identified or predicted during routine application of SpO2 monitoring in the fetus during labor with adequate safety. Cardiotocography (CTG) is the main method of intrapartum fetal surveillance. In 2015 a new guideline was introduced by the International Federation of Gynecology and Obstetrics (FIGO), FIGO-15. In Sweden it was adjusted to SWE-17, replacing the previous national template, SWE-09. This study, conducted at one university hospital and one regional hospital in southern Sweden, evaluated the diagnostic validity of these three templates to detect fetal acidosis during the first stage of labor. A total of 73 neonates with pH &lt;7.1 in umbilical cord artery or vein at cesarean delivery during the first stage of labor were identified retrospectively. For each acidotic neonate, three non-acidemic neonates, with a pH ≥7.2 in cord artery and vein, and Apgar scores ≥9 at five and ten minutes, in all 219 neonates, were selected. The CTG tracings before birth in acidemic neonates, and tracings at the same cervical dilatation in the non-acidemic neonates, were independently assessed by three professionals from the obstetric staff, blinded to group and clinical data. Based on their categorizations of the included variables (baseline, variability, accelerations, decelerations and contraction rate), each CTG tracing was systematically classified according to the three templates. The sensitivity and specificity to identify acidemia by the classification pathological were determined for each template. Interobserver agreement in the assessments of tracings as pathological or not was analyzed, using free-marginal Kappa index. The sensitivity for patterns classified as pathological to identify acidemia was similar for FIGO-15 (71%) and SWE-17 (77%, <ip</i = .13), and the specificity was 97% for both. SWE-09 had a significantly higher sensitivity (95%, <ip</i &lt; .001) albeit with a lower specificity (90%, <ip</i &lt; .001) than the other two templates. Among acidemic neonates, the fraction of tracings classified as normal was higher with SWE-17 (9.6%) than with SWE-09 (0%; <ip</i = .01) and FIGO-15 (1.4%; <ip</i = .06). For tracings from neonates with acidemia, agreement for three independent assessors was strong (κ 0.85) with SWE-09, and weak for FIGO-15 (κ 0.47), and SWE-17 (κ 0.51). For tracings from neonates without acidemia, the agreement was almost perfect for FIGO-15 (κ 0.91), strong withSWE-17 (κ 0.90) and moderate with SWE-09 (κ 0.78). The ability of FIGO-15 and SWE-17 to identify fetal acidosis is considered insufficient. The combination of a high sensitivity and a high specificity makes SWE-09 the most discriminatory template during the first stage of labor. In 871 deliveries out of a total of 3980 effected during 1980-1982 at the Winterthur Gynaecological Hospital, we found it necessary to perform one or several microanalyses of blood (blood gas analyses) sub partu. Among these, we found retrospectively that in 22 cases the microanalysis of the blood gas had prevented us from performing caesarean section which would have seemed necessary if we had relied on the cardiotocographical findings alone. Micro-analysis of blood gas made it possible to exclude the presence of pre-acidosis or acidosis which would have made Caesarean section imperative; in all these cases, normal delivery via the vagina was achieved, and in no case did this result in severe acidosis. All newborn had a 5-minute Apgar score of 7 and higher. We can conclude from these results, therefore, that the indication for an immediate termination of delivery via Caesarean section should not depend solely on a pathological cardiotocogram; the final decision should be arrived at only after micro-analyses of blood gas have confirmed the presence of foetal pre-acidosis or acidosis. The use of pH and base excess (FSSPHBE) from fetal scalp sampling (FSS) was abandoned when cardiotocography (CTG) was believed to be sufficiently accurate to direct patient management. We sought to understand the fetus' tolerance to stress in the 1st stage of labor and to develop a better and earlier screening test for its risk for developing acidosis. To do so, we investigated sequential changes in fetal pH and BE obtained from FSS in the 1st stage of labor as part of a research protocol from the 1970s. We then examined the utility of multiple of the median (MoM's) conversion of BE and pH values, and the capacity of Fetal Reserve Index (FRI) scores to be a proxy for such changes. We then sought to examine the predictive capacity of 1st stage FRI and its change over the course of the first stage of labor for the subsequent development of acidosis risk in the 2nd stage of labor. Using a retrospective research database evaluation, we evaluated FSSPHBE data from 475 high-risk parturients monitored in labor and their neonates for 1 h postpartum.We categorized specimens according to cervical dilatation (CxD) at the time of FSSPHBE and developed non-parametric, multiples of the median (MOMs) assessments. FRI scores and their change over time were used as predictors of FSSPHBE. Our main outcome measures were the changes in BE and pH at different cervical dilatations (CxD) and acidosis risk in the early 2nd stage of labor. FSSPHBE worsens over the course of the 1st stage. The implications of any given BE are very different depending upon CxD. At 9 cm, -8 Mmol/L is 1.1 MOM; at 3 cm, it would be 2.0 MOM. The FRI level and its trajectory provide a 1st stage screening tool for acidosis risk in the second stage. Fetal acid-base balance (\"reserve\") deteriorates beginning early in the 1st stage of labor, irrespective of whether the fetus reaches a critical threshold of concern for actual acidosis. The use of MoM's logic improves appreciation of such information. The FRI and its trajectory reasonably approximate the trajectory of the FSSPHBE and appears to be a suitable screening test for early deterioration and for earlier interventions to keep the fetus out of trouble rather than wait until high risk status develops. Updated 2015 FIGO Intrapartum Fetal Monitoring Guidelines FIGO has recently modified the guidelines on intrapartum fetal monitoring, proposing the following interpretation: Normal: No hypoxia or acidosis; no intervention necessary to improve fetal oxygenation state. Baseline 110–160bpm Variability 5–25bpm No repetitive decelerations (decelerations are defined as repetitive when associated with >50% contractions) Suspicious: Low probability of hypoxia/acidosis, warrants action to correct reversible causes if identified, close monitoring or adjunctive methods. Lacking at least one characteristic of normality, but with no pathological features. Pathological: High probability of hypoxia/acidosis, requires immediate action to correct reversible causes, adjunctive methods, or if this is not possible expedite delivery. In acute situations, delivery should happen immediately. Baseline <100bpm Reduced or increased variability or sinusoidal pattern Signs and symptoms Generally it is preferable to describe specific signs in lieu of declaring fetal distress that include: Decreased movement felt by the mother Meconium in the amniotic fluid (\"meconium stained fluid\") Non-reassuring patterns seen on cardiotocography: increased or decreased fetal heart rate (tachycardia and bradycardia), especially during and after a contraction decreased variability in the fetal heart rate late decelerations Biochemical signs, assessed by collecting a small sample of baby's blood from a scalp prick through the open cervix in labor fetal metabolic acidosis elevated fetal blood lactate levels (from fetal scalp blood testing) indicating the baby has a lactic acidosis Some of these signs are more reliable predictors of fetal compromise than others. For example, cardiotocography can give high false positive rates, even when interpreted by highly experienced medical personnel. Metabolic acidosis is a more reliable predictor, but is not always available. Cardiotocography has become the standard for fetal monitoring in labor. False-positive findings during electronic fetal heart rate monitoring may were not associated with neonatal acidemia. Because of the poor specificity of fetal heart rate monitoring in predicting fetal distress, new methods are being investigated as a way to improve the accuracy of assessing the infant's condition during labor. The aim of this study was to determinate the efficiency of fetal blood oxygen saturation (FSpO2) and computer analysis of the fetal heart rate (Co-CTG) in the late 1-st stage of labor as a prognostic factor of newborn acidemia. Total 62 subjects were studied. During labors and deliveries fetal oxygen saturation was continuously recorded, with use of Nellecor N-400 fetal pulse oximeter and continous CTG were performed by Hewlett Packard 50A. Transdermal fetal oxygen saturation measurements and CTG results obtained during the labors was analyzed using MONAKO system (ITAM Zabrze). The results were compared with the values of pH and base deficit in the umbilical artery measured just after delivery. The sensitivity, specificity, negative, positive predictive values and Youden factor based on FHR and FSpO2, for prognosis of neonatal acidosis were: 65%, 80%, 16%, 97.5% 60% and 0.135 respectively FHR; and 100%, 60%, 100%, 96.8% and 0.968 respectively FSpO2. 1. The examination of fetal blood oxygen saturation in the labor is a useful prognostic factor of the newborn outcome. 2. The best predictive value for intrapartum fetal asphyxia with metabolic acidosis was found when fetal pulse oximetry is added to cardiotocography. In a study by Tarvonen et al. (2019), it was demonstrated that the occurrence of saltatory pattern (already with the minimum duration of 2 minutes) in CTG tracings during labor was associated with fetal hypoxia indicated by high umbilical vein (UV) blood erythropoietin (EPO) levels and umbilical artery (UA) blood acidosis at birth in human fetuses. As saltatory patterns preceded late decelerations of fetal heart rate (FHR) in the majority of cases, saltatory pattern seems to be an early sign of fetal hypoxia. According to the authors, awareness on this gives obstetricians and midwives time to intensify electronic fetal monitoring and to plan possible interventions before fetal asphyxia occurs. If repeat test >6, observe and repeat per protocol Repeat testing same day; if biophysical profile score :;6, deliver Deliver AFV = amnionic fluid volume; NST = nonstress test. Reproduced with permission from Manning FA, Morrison I, Harman CR, et al: Fetal assessment based on fetal biophysical profile scoring: experience in 19,221 referred high-risk pregnancies. II. An analysis of false-negative fetal deaths, Am J Obstet Gynecol. 1987 Oct;157(4 Pt 1 ):880-884. I. ):J0 downstream impedance (Chap. 10, p. 213). For growth 7.30 7.25 0E:J E:J= 7.20 7.10 7.05 FIGURE 17-9 Mean umbilical vein pH (±2 SD) obtained by cordocentesis in relation to fetal biophysical profile score category. (Data from Manning, 1993.) API determination for which �5 cm was considered abnormal (Chap. 11, p. 230). his abbreviated biophysical proile required approximately 10 minutes to perform, and they concluded that it was a superb antepartum surveillance method because there were no unexpected fetal deaths.\nHere is the question:\nGYNECOLOGY AND OBSTETRICS: Woman 40 weeks gestation in labor with 6 cm dilation. She presents a decelerative fetal pattern in cardiotocographic recordings, so it is decided to perform a fetal blood smear to assess fetal well-being. Result 7.22. The correct conduct is:\nHere are the potential choices:\n1. Severe acidosis. Urgent cesarean section.\n2. Pre-pathological value repeat microtome 15-20 minutes.\n3. Moderate acidosis. Repeat microtome in 1-2 hours.\n4. Value in normal limits, leave natural evolution of labor.\n5. Repeat at the time of possible error in obtaining the shot.\nThe correct answer is: 2. Pre-pathological value repeat microtome 15-20 minutes."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 60-year-old man was admitted to our hospital because of fever, hemorrhagic tendency, anemia and neurological abnormality. A blood count revealed that the hemoglobin was 6.8 g/dl, the reticulocyte was 17.3 percent with 2 erythroblasts per 100 white cells, the white cell count was 7,100/microliters and the platelet count was 0.8 x 10(4)/microliters. Peripheral blood smear demonstrated marked fragmentation of red cells. Bone marrow examination disclosed the marked erythroid hyperplasia. Although the bleeding time was prolonged (14 minutes 30 seconds), the other hemostatic data were within normal limits. The serum bilirubin level was 1.57 mg/dl; LDH level, 1,437 U/l; creatinine level, 0.92 mg/dl; BUN level 14.7 mg/dl. Haptoglobin was below 10 mg/dl. Results of immunological tests were all negative except the result of PAIgG (576.6 ng/10(7) cells). The urinalysis showed proteinuria, microhematuria and trace granular and hyaline casts. A diagnosis of thrombotic thrombocytopenic purpura was made. The patient was initially treated with prednisolone (60 mg), aspirin (1,000 mg), dipyridamole (150 mg), gabexate mesilate (1.5 g), sodium oxagrel (80 mg) daily with little response. The thirty days after admission, infusion of gamma globulin (20 g, daily) was given for 3 days. The clinical state and laboratory findings became dramatically improved shortly after the administration of gamma globulin and the laboratory data came to be normalized after 1 month. After ten months of this treatment, the patient is remained asymptomatic and the hematological data are within normal range without using any drug. A trial seems justified to confirm the value of this mode of therapy. Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder that accounts for approximately 30 % of adult leukemias and 25 % of Non-Hodgkin lymphomas (NHL). It is the most common form of leukemia in the western world (incidence 3-5/100 000). Elderly people are mainly affected, median age at diagnosis is around 70 years and there is a slight predominance in men. The etiology of the disease is unknown. The initial symptoms are nonspecific. Cervical lymphadenopathy and splenomegaly followed by general fatigue are seen most commonly. Other possible symptoms include night sweats, fever, loss of weight (so-called B symptoms) and frequent infections. Several patients develop autoimmune complications as autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP). To confirm the diagnosis more than 5000 B-lymphocytes/µl need to be present. The expression of the typical surface markers CD5, CD19, and CD23 has to be confirmed by flow cytometry. Imaging studies as X-ray of the chest, ultrasound of the abdomen, or CT scan are used to assess the degree of lymphadenopathy or organomegaly. A bone marrow biopsy is not mandatory for the diagnosis. According to the European Binet staging system, CLL is divided into 3 stages (A, B and C). Patients in Binet stage A have 0 to 2 areas of node or organ enlargement with normal levels of hemoglobin and platelets. Binet stage B patients have 3 to 5 areas of node or organ enlargement and normal or slightly decreased levels of hemoglobin and platelets. Binet stage C patients have anemia (hemoglobin &lt; 10 g/dl) and/or thrombocytopenia (platelet counts &lt; 100 000/µl), with or without lymphadenopathy or organomegaly. As there is no survival benefit associated with early intervention, asymptomatic patients with early stage CLL (Binet stage A and B) are usually not treated but are followed on a \"watch and wait\" principle. Treatment indications include stage Binet C or signs of an active disease as rapidly progressive lymphadenopathy or organomegaly together with physical limitation, B symptoms that cannot be tolerated, rapidly deteriorating blood values, or rapidly increasing leukocyte counts. The patient's physical condition has major impact on the treatment decision. Currently immunochemotherapy with fludarabine, cyclophosphamide and the CD20-antibody rituximab (FCR) is the standard of care in previously untreated and physically fit CLL-patients. An alternative regimen is the combination of bendamustine and rituximab (BR). Physically compromised patients can be treated with the oral drug chlorambucil or with bendamustine with or without rituximab. Due to high morbidity and mortality, allogeneic stem cell transplantation is limited to a small group of patients and should be discussed in a high-risk situation, such as 17p deletion, lack of response to standard therapy or early relapse. PRESENTING FEATURES: An 18-year-old white man was admitted to the Osler Medical Service with the chief complaint of back pain. Two weeks prior to admission, the patient developed diffuse and aching upper back pain. Over the next couple of days, he also developed severe anterior chest pain that was somewhat pleuritic in nature but diffuse and extending bilaterally into the shoulders. One week prior to admission, he developed intermittent fevers and night sweats. The patient denied any lymphadenopathy, pharyngitis, sick contacts, shortness of breath, rash, or bleeding. He was seen by a physician and told that he had thrombocytopenia. There was no history of recent or remote unusual bleeding episodes. His medical history was unremarkable except for a childhood diagnosis of attention deficit/hyperactivity disorder. He was not taking any medications and had no history of tobacco, alcohol, or illicit drug use. He had no risk factors for human immunodeficiency virus infection. Physical examination showed that he was afebrile and had normal vital signs. He was a well-appearing man who was lying still because of pain. HEENT examination was unremarkable. There was no pharyngeal erythema or exudates. His lungs were clear. His neck was supple and without lymphadenopathy. Examination of his back and chest revealed no focal tenderness. There was no hepatosplenomegaly, and his skin was without petechiae or rashes. Examination of the patient's joints showed pain on passive and active movement of his shoulders bilaterally, but no frank arthritis. There was no rash, petechiae, or echymoses. Chest radiograph and electrocardiogram were unremarkable. On admission, the laboratory examination was notable for a hematocrit level of 32.5%, with a mean corpuscular volume of 79 fL, and white blood cell count of 2.8 x 10(3)/microL. Platelet count was 75 x 10(3)/microL. A white blood cell differential revealed 7% bands, 53% polys, 34% lymphs, 5% atypical lymphocytes, 2% nucleated red cells, and a few young unidentified cells. His chemistry studies were unremarkable. What is the diagnosis? To summarize the clinical characteristics, diagnosis and treatment of a case with autoimmune lymphoproliferative syndrome (ALPS) . The patient was diagnosed as autoimmune lymphoproliferactive syndrome (ALPS) after being admitted to the Department of Rheumatism and Immunology of Tianjin Children's Hospital in February 20, 2014. The clinical characteristics, physical examination, laboratory tests, gene tests, and treatment process were analyzed and related literature was reviewed. The patient was a 16-month- old boy.Since the first month of life, he started to have repeatedly fever, diarrhea, shortness of breath, lymphadenopathy, hepatosplenomegaly, anemia (HGBmin 50 g/L) and thrombocytopenia (min 35 × 10⁹/L) . But multiple exams showed a normal peripheral blood leukocyte count, hypergammaglobulinemia (IgG 19 800 mg/L, IgA 1 710 mg/L, IgM 2 590 mg/L) and significantly increased serum vitamin B12. Flow cytometric measures showed that CD3⁺ CD4⁻ CD8⁻ T lymphocytes significantly increased ( &gt; 10%) at four times. The count of CD3⁺ TCRαβ⁺ CD4⁻ CD8⁻T lymphocytes (double negative T cells; DNTs) &gt;3% twice. The genetic test showed that 309th FAS gene area showed heterozygous mutations, the boy was diagnosed as ALPS. Added examinations of lymphocytes apoptosis induced by FAS was positive. He was treated with prednisone 15 mg once daily and immunomodulator 150 mg three times a day, while in maintaining period with normal levels of hemoglobin and platelet, the dose of prednisone was reduced gradually. Till now, the patient has been treated and observed for 8 months. We retrieved the reports of ALPS in the databases at home and abroad published in recent 10 years, more than 400 cases reported from foreign countries, but there were only 5 domestic cases. Among those, 4 had onset in infancy and 1 at 6-years of age. All the cases presented servere lymphadenopathy and hepatosplenomegaly with anemia (4 of them with hemolytic anemia) and thrombocytopenia. Three cases had a history of frequent infection, one of them had glomerulonephritis. All patient with significant high level of serum immunoglobulin ( &gt; 1.5 times upper limit of normal range), in 3 of them serum vitamin B12 was &gt; 1.5 pg/L (the other 2 cases missed the exam). In 5 cases CD3⁺ CD4⁻ CD8⁻T cells &gt; 10%, and in 2 case DNTs were 8.9% and 15.7% respectively (the other 3 cases missed the exam). Three cases were clearly detected with FAS mutations. All patients were treated with corticosteroid, 2 of them were added with mycophenolate mofetil. The therapy presented effective result in early 1-3 months, but no long-term follow-up reports were available. ALPS is a disorder of disrupted lymphocyte homeostasis caused by defective Fas-mediated apoptosis, and it is one of the primary immunodeficiency diseases. The onset of the disease occurs during infancy mainly. Clinical lymphoid hyperplasia and autoimmune phenomena are outstanding signs, which can be associated with frequent infections and allergies. The level of serum vitamin B12 &gt; 1.5 pg/L and the count of CD3⁺ CD4⁻ CD8⁻ T cell show important significance. Exact diagnosis should depend on detecting DNTs and FAS gene. Tuberculosis is still one of the most prevalent and fatal infectious diseases in spite of considerable improvements in medical science. Splenic tuberculosis is a rare form of extrapulmonary tuberculosis. There are limited numbers of cases in which immune thrombocytopenia is associated with splenic tuberculosis. We report a case of immune thrombocytopenic purpura due to splenic tuberculosis. Our case was a 58-year-old female with headache, gum bleeding, redness in legs, and ecchymoses on the arms for 10 days. On admission to hospital, laboratory tests were as follows: platelet count 6.000/mmc (150 000-450 000), haemoglobin: 12 g/dl, WBC: 8000/mm3, erythrocyte sedimentation rate: 58 mm/h and C-reactive protein was in normal ranges. After standard laboratory tests, the patient was diagnosed with idiopathic thrombocytopenic purpura. The patient presented abdominal lymphadenopathies and spleen in normal size in radiological examinations. Diagnostic laparotomy and splenectomy and lymph node excision was performed and splenic tuberculosis was detected in pathologic and microbiologic examination. The patient was successfully treated with apheresis platelets suspension, intravenous immunoglobulin and antituberculous therapy. In conclusion, splenic tuberculosis should be suspected in patients who have fever, abdominal lymphadenopathies and immune thrombocytopenic purpura. Histopathological examination is still an ideal method to confirm the diagnosis, suitably aided by microbiological examination. A 73-year-old female with past medical history of essential hypertension, hyperlipidemia, seasonal allergies, and chronic back pain presented to the hospital with complaints of headaches, fevers, fatigue, generalized body aches, shortness of breath, and diarrhea. Initial complete blood count was remarkable for leukopenia with an absolute lymph count of 0.60 K/µL and severe thrombocytopenia (platelet count &lt; 3 K/µL). She was tested for COVID-19 via nasopharyngeal swab polymerase chain reaction (PCR) testing and found positive. Additional labs showed an elevated D-dimer, C-reactive protein, fibrinogen, and lactate dehydrogenase. Vitamin B12 and folate levels were obtained and found to be normal. Peripheral smear showed no schistocytes or additional hematologic abnormalities apart from thrombocytopenia. The patient was transfused one unit of platelets with no improvement in platelet count. Fibrinogen count was obtained and found in normal range at 458 mg/dL. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) were all found to be normal. Immune thrombocytopenia purpura (ITP) was suspected and intravenous immunoglobulin (IVIG) was administered at a dose of 1 g/kg/day for two doses. By day 4, the patient had marked response to treatment with platelet recovery to 105 K/µL and subsequently discharged by day 5 with complete resolution of symptoms and platelet count of 146 K/µL. Twenty-eight days after discharge, she presented to hematology clinic with platelet count of 8 K/µL. Repeat nasopharyngeal swab PCR COVID testing was negative and she was treated with IVIG and pulse dexamethasone with prompt response, confirming suspicion of underlying, undiagnosed ITP prior to COVID infection. Fever ˜38.3° C (101° F) and illness lasting ˜3 weeks and no known immunocompromised state History and physical examination Stop antibiotic treatment and glucocorticoids Obligatory investigations: ESR and CRP, hemoglobin, platelet count, leukocyte count and differential, electrolytes, creatinine, total protein, protein electrophoresis, alkaline phosphatase, AST, ALT, LDH, creatine kinase, antinuclear antibodies, rheumatoid factor, urinalysis, blood cultures (n=3), urine culture, chest x-ray, abdominal ultrasonography, and tuberculin skin test Chemistry tests include lactate dehydrogenase (LDH) levels, uric acid levels, erythrocyte sedimentation rate (ESR), kidney and liver function, total protein levels, and an albumin-to-globulin ratio. The ESR and uric acid level may be elevated. Creatinine is occasionally elevated and electrolytes are occasionally abnormal. A high blood calcium level is noted in approximately 4% of patients. The LDH level is frequently elevated, indicating the extent of Waldenström macroglobulinemia–related tissue involvement. Rheumatoid factor, cryoglobulins, direct antiglobulin test and cold agglutinin titre results can be positive. Beta-2 microglobulin and C-reactive protein test results are not specific for Waldenström macroglobulinemia. Beta-2 microglobulin is elevated in proportion to tumor mass. Coagulation abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies are optional. Serum Fever >38.3°C (101°F) on at least two occasions 2. Illness duration of ≥3 weeks 3. 4. Diagnosis that remains uncertain after a thorough history-taking, physical examination, and the following obligatory investigations: determination of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level; platelet count; leukocyte count and differential; measurement of levels of hemoglobin, electrolytes, creatinine, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, ferritin, antinuclear antibodies, and rheumatoid factor; protein electrophoresis; urinalysis; blood cultures (n = 3); urine culture; chest x-ray; abdominal ultrasonography; and tuberculin skin test (TST). The range of FUO etiologies has evolved over time as a result of changes in the spectrum of diseases causing FUO, the widespread Percentage of Cases Due to Indicated Cause BACKGROUND Immune thrombocytopenia (ITP) is rare in infants under 1 year old. Bleeding often occurs when the platelet count is &lt;20 000/uL. The disease can progress because of accompanying COVID-19 disease. CASE REPORT A 9-month-old boy, weighing 8.5 kg, came to the hospital with petechiae on the forehead, cheeks, mouth, and extremities. The patient had rhinorrhea for 3 days previously and was febrile, pale, weak, and could not drink. He had the measles-rubella vaccination 19 days prior. Physical examination showed no abnormalities of the eyes, ears, nose, throat, and mouth. Heart and lungs were within normal limits, with no organomegaly, lymphadenopathy, or congenital anomaly of the abdomen. Laboratory examination showed hemoglobin, 12.7 g/dL; leukocytes, 7420/uL; platelet count, 16 000/uL; and hematocrit, 37.9%. Erythrocyte sedimentation rate was 14 mm at 1 h and 21 mm at 2 h. Peripheral blood smear showed normal RBC morphology, normal leukocytes, and few platelets. IgG was reactive and IgM was nonreactive on rapid antibody test. RT-PCR was positive for SARS-COV-2. Chest-X-ray showed pneumonia. The diagnosis was newly diagnosed ITP with COVID-19. Patient was treated with 30 mg/kg body weight/day of IV methylprednisolone for 3 days (250 mg); then 20 mg/kg body weight/day (175 mg) orally for 4 days in 3 divided doses. Azithromycin 100 mg/day, zinc 20 mg/day, and vitamin C 50 mg/day orally were also given. CONCLUSIONS COVID-19 screening is highly recommended during this pandemic to identify it as a potential cause of childhood ITP. Megadose methylprednisolone had an excellent response in alleviating ITP with confirmed COVID-19 in an infant. This report illustrates the importance of a detailed history and physical exam and careful analysis of hematologic parameters when diagnosing ITP. This case demonstrates that even with subtle deviations from typical ITP findings one must promptly reevaluate the diagnosis. This case also highlights the importance of peripheral smear review by an expert in pediatric hematopathology. A previously healthy 10 year-old Asian boy presented with 2 months of easy bruising. Review of systems was negative for any constitutional symptoms. On examination, he appeared well but had numerous large ecchymoses. He had no appreciable lymphadenopathy or splenomegaly. The liver was palpable 1.5 cm below the costal margin. A complete blood count (CBC) showed: platelets = 17 × 109/L, hemoglobin = 128 g/L, white blood cell count = 5.43 × 109/L, and neutrophils = 1.63 × 109/L. A blood smear was reported as normal. Urate was 370 umol/L and lactate dehydrogenase (LDH) was 803 U/L. The child was admitted with a presumptive diagnosis of immune thrombocytopenic purpura (ITP) and treated with intravenous immunoglobulin. The following day, the blood smear was reviewed by a hematopathologist who identified blasts. A bone marrow aspiration (BMA) confirmed the diagnosis of precursor B-cell acute lymphoblastic leukemia. In children presenting with suspected ITP, leukemia should always be considered. A BMA was historically performed on all patients with presumed ITP to rule out leukemia. In 2011, the American Society of Hematology (ASH) stopped recommending routine BMA in patients suspected of having ITP. ASH advises in cases with unusual findings on history, physical examination or CBC, it is reasonable to perform a BMA. Our patient had mild hepatomegaly, which may have qualified him for a BMA. He also had an elevated LDH and urate, which are not listed as criteria for BMA by ASH but were considered atypical for ITP by the clinical team. A literature search did not reveal any primary data assessing these markers. While corticosteroids are a first line treatment in ITP, they must be reserved for when clinicians are confident that the patient does not have leukemia. Steroid administration prior to diagnosing leukemia results in delayed diagnosis and may increase the risk of complications and decrease survival. Signs and symptoms Thrombocytopenia usually has no symptoms and is picked up on a routine complete blood count. Some individuals with thrombocytopenia may experience external bleeding such as nosebleeds, or bleeding gums. Some women may have heavier or longer periods or breakthrough bleeding. Bruising, particularly purpura in the forearms and petechiae in the feet, legs, and mucous membranes, may be caused by spontaneous bleeding under the skin. Eliciting a full medical history is vital to ensure the low platelet count is not secondary to another disorder. Ensuring that the other blood cell types, such as red blood cells and white blood cells are not also suppressed, is also important. Painless, round, and pinpoint (1 to 3 mm in diameter) petechiae usually appear and fade, and sometimes group to form ecchymoses. Larger than petechiae, ecchymoses are purple, blue, or yellow-green areas of skin that vary in size and shape. They can occur anywhere on the body. To report a case of possible severe, life-threatening thrombocytopenia associated with trimethoprim/sulfamethoxazole (TMP/SMX) therapy. A 54-year-old white woman received a 10-day course of TMP/SMX for treatment of chronic sinusitis. One day after finishing the course of TMP/SMX therapy, the presented to the emergency department because of the development of scattered petechiae on both hands and blood blisters in her mouth. On admission, her complete blood cell count results revealed a severely low platelet count of 2 x 10(3)/mm3. Other laboratory test results were normal, except for elevated blood glucose (nonfasting blood glucose). TMP/SMX was believed to be the most likely cause of thrombocytopenia. She was treated successfully with a transfusion of 2 units of platelets and oral prednisone. Her platelet count increased to 110 x 10(3)/mm3 4 days after discontinuation of TMP/SMX. She was discharged on hospital day 5. On follow-up (2 wk after hospital discharge), her platelet count was normal (351 x 10(3)/mm3). TMP/SMX has been implicated as a cause of thrombocytopenia, which is defined as platelet count &lt; 150 x 10(3)/mm3. Although it is uncommon, spontaneous severe bleeding may occur when platelet count decreases to &lt; or = 10 x 10(3)/mm3. Thrombocytopenia associated with TMP/SMX appears to be an immune-mediated process resulting in platelet destruction by drug-dependent platelet antibodies. Treatment of thrombocytopenia associated with TMP/SMX therapy includes discontinuation of the offending drug and the use of corticosteroids. Platelet transfusion and intravenous immunoglobulin may be required in some patients. Thrombocytopenia associated with TMP/SMX therapy can be serious or life threatening because it may result in significant bleeding complications. This hematologic adverse effect of TMP/SMX may occur even with the usual recommended dosage and duration of therapy. Careful monitoring of complete blood cell count, including platelet count, before and during TMP/SMX therapy is suggested. A 66 years female, who was since last year under astenia, arthralgias, pimply lesions in spread plates and tests showing eritrosedimentation over 100 mm, anemi, leucocitosis with neutrofilia, policlonal hypergammaglobulinemia, slight proteinuria and IgE on 900. This patient was sporadically treated with corticoids. When made the medical consult had lost 34lb., was under anorexy, as well as dyspepsia. Hemoglobyn 6.9 gr/dl, leucocytes 20000/mm3, neutrofils at 90%, proteinogram the same as former, with hypoalbuminemia. She was taking prednisona, 16 mg/day. When examined showed depress of conscience, astenia, and dermic lesions already quoted. 4 cm nonpainful right axillary adenopaty adhered to deep planes. Medulogram with increased iron, hyperegenerative. Ganglionar biopsia: linfoid hyperplasic process linked to inmune response. Toracoabdominal tomography with adenomegalia in torax and retroperitoneo. Skin biopsia: neutrofilic vasculitis. The patient suspends the 16 mg of prednisona and fever as well as generalized adenopatias come up. After laying aside other ethiologies, and understanding as Castleman Multicentric disease, it is started to supply prednisona 1 mg/kg of weight with a clinical and biochemical fast and outstanding response. After 7 months it was progressively suspended the esteroids and 60 days later, the process fall back; for that, corticoids are restarted, with a good evolution. The illness of Castleman although it is not very frequent, it should be considered as differential diagnosis in those clinical cases that are accompanied with important general commitment, linphadenopaties and respons to steroid therapy. The International Prognostic Scoring System for Waldenström's Macroglobulinemia is a predictive model to characterise long-term outcomes. According to the model, factors predicting reduced survival are: Age > 65 years Hemoglobin ≤ 11.5 g/dL Platelet count ≤ 100×109/L B2-microglobulin > 3 mg/L Serum monoclonal protein concentration > 70 g/L The risk categories are: Low: ≤ 1 adverse variable except age Intermediate: 2 adverse characteristics or age > 65 years High: > 2 adverse characteristics Five-year survival rates for these categories are 87%, 68% and 36%, respectively. The corresponding median survival rates are 12, 8, and 3.5 years. The International Prognostic Scoring System for Waldenström's Macroglobulinemia has been shown to be reliable. It is also applicable to patients on a rituximab-based treatment regimen. An additional predictive factor is elevated serum lactate dehydrogenase (LDH).\nHere is the question:\nHEMATOLOGY: A 19-year-old girl with no medical history of interest, except for a self-limited case of influenza 3 weeks earlier, who comes to the emergency department with petechiae and ecchymosis of spontaneous onset. On physical examination the patient was in good general condition, afebrile, normotensive and oriented in time and space. There were petechiae scattered throughout the lower extremities and abdomen and small ecchymoses in decubitus areas. No lymphadenopathy or splenomegaly were palpated. Laboratory tests showed the following findings: Hb 12.6 g/dL, leukocytes 5,500/mm3, platelets 7000/mm3. The peripheral blood smear showed normal erythrocyte morphology, normal differential leukocyte count and the planetary count was concordant with the autoanalyzer figure without platelet aggregates. Biochemistry and proteinogram, beta 2 microglobulin and LDH are normal. Which of the following do you think is the most appropriate initial treatment?\nHere are the potential choices:\n1. Platelet transfusion.\n2. Weekly Rituximab.\n3. Cyclophosphamide in 4-day pulses every 21 days.\n4. Daily plasmapheresis.\n5. Prednisone at 1 mg/day for 2-3 weeks.\nThe correct answer is: ",
        "gold_answer": "1 Platelet transfusion.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 60-year-old man was admitted to our hospital because of fever, hemorrhagic tendency, anemia and neurological abnormality. A blood count revealed that the hemoglobin was 6.8 g/dl, the reticulocyte was 17.3 percent with 2 erythroblasts per 100 white cells, the white cell count was 7,100/microliters and the platelet count was 0.8 x 10(4)/microliters. Peripheral blood smear demonstrated marked fragmentation of red cells. Bone marrow examination disclosed the marked erythroid hyperplasia. Although the bleeding time was prolonged (14 minutes 30 seconds), the other hemostatic data were within normal limits. The serum bilirubin level was 1.57 mg/dl; LDH level, 1,437 U/l; creatinine level, 0.92 mg/dl; BUN level 14.7 mg/dl. Haptoglobin was below 10 mg/dl. Results of immunological tests were all negative except the result of PAIgG (576.6 ng/10(7) cells). The urinalysis showed proteinuria, microhematuria and trace granular and hyaline casts. A diagnosis of thrombotic thrombocytopenic purpura was made. The patient was initially treated with prednisolone (60 mg), aspirin (1,000 mg), dipyridamole (150 mg), gabexate mesilate (1.5 g), sodium oxagrel (80 mg) daily with little response. The thirty days after admission, infusion of gamma globulin (20 g, daily) was given for 3 days. The clinical state and laboratory findings became dramatically improved shortly after the administration of gamma globulin and the laboratory data came to be normalized after 1 month. After ten months of this treatment, the patient is remained asymptomatic and the hematological data are within normal range without using any drug. A trial seems justified to confirm the value of this mode of therapy. Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder that accounts for approximately 30 % of adult leukemias and 25 % of Non-Hodgkin lymphomas (NHL). It is the most common form of leukemia in the western world (incidence 3-5/100 000). Elderly people are mainly affected, median age at diagnosis is around 70 years and there is a slight predominance in men. The etiology of the disease is unknown. The initial symptoms are nonspecific. Cervical lymphadenopathy and splenomegaly followed by general fatigue are seen most commonly. Other possible symptoms include night sweats, fever, loss of weight (so-called B symptoms) and frequent infections. Several patients develop autoimmune complications as autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP). To confirm the diagnosis more than 5000 B-lymphocytes/µl need to be present. The expression of the typical surface markers CD5, CD19, and CD23 has to be confirmed by flow cytometry. Imaging studies as X-ray of the chest, ultrasound of the abdomen, or CT scan are used to assess the degree of lymphadenopathy or organomegaly. A bone marrow biopsy is not mandatory for the diagnosis. According to the European Binet staging system, CLL is divided into 3 stages (A, B and C). Patients in Binet stage A have 0 to 2 areas of node or organ enlargement with normal levels of hemoglobin and platelets. Binet stage B patients have 3 to 5 areas of node or organ enlargement and normal or slightly decreased levels of hemoglobin and platelets. Binet stage C patients have anemia (hemoglobin &lt; 10 g/dl) and/or thrombocytopenia (platelet counts &lt; 100 000/µl), with or without lymphadenopathy or organomegaly. As there is no survival benefit associated with early intervention, asymptomatic patients with early stage CLL (Binet stage A and B) are usually not treated but are followed on a \"watch and wait\" principle. Treatment indications include stage Binet C or signs of an active disease as rapidly progressive lymphadenopathy or organomegaly together with physical limitation, B symptoms that cannot be tolerated, rapidly deteriorating blood values, or rapidly increasing leukocyte counts. The patient's physical condition has major impact on the treatment decision. Currently immunochemotherapy with fludarabine, cyclophosphamide and the CD20-antibody rituximab (FCR) is the standard of care in previously untreated and physically fit CLL-patients. An alternative regimen is the combination of bendamustine and rituximab (BR). Physically compromised patients can be treated with the oral drug chlorambucil or with bendamustine with or without rituximab. Due to high morbidity and mortality, allogeneic stem cell transplantation is limited to a small group of patients and should be discussed in a high-risk situation, such as 17p deletion, lack of response to standard therapy or early relapse. PRESENTING FEATURES: An 18-year-old white man was admitted to the Osler Medical Service with the chief complaint of back pain. Two weeks prior to admission, the patient developed diffuse and aching upper back pain. Over the next couple of days, he also developed severe anterior chest pain that was somewhat pleuritic in nature but diffuse and extending bilaterally into the shoulders. One week prior to admission, he developed intermittent fevers and night sweats. The patient denied any lymphadenopathy, pharyngitis, sick contacts, shortness of breath, rash, or bleeding. He was seen by a physician and told that he had thrombocytopenia. There was no history of recent or remote unusual bleeding episodes. His medical history was unremarkable except for a childhood diagnosis of attention deficit/hyperactivity disorder. He was not taking any medications and had no history of tobacco, alcohol, or illicit drug use. He had no risk factors for human immunodeficiency virus infection. Physical examination showed that he was afebrile and had normal vital signs. He was a well-appearing man who was lying still because of pain. HEENT examination was unremarkable. There was no pharyngeal erythema or exudates. His lungs were clear. His neck was supple and without lymphadenopathy. Examination of his back and chest revealed no focal tenderness. There was no hepatosplenomegaly, and his skin was without petechiae or rashes. Examination of the patient's joints showed pain on passive and active movement of his shoulders bilaterally, but no frank arthritis. There was no rash, petechiae, or echymoses. Chest radiograph and electrocardiogram were unremarkable. On admission, the laboratory examination was notable for a hematocrit level of 32.5%, with a mean corpuscular volume of 79 fL, and white blood cell count of 2.8 x 10(3)/microL. Platelet count was 75 x 10(3)/microL. A white blood cell differential revealed 7% bands, 53% polys, 34% lymphs, 5% atypical lymphocytes, 2% nucleated red cells, and a few young unidentified cells. His chemistry studies were unremarkable. What is the diagnosis? To summarize the clinical characteristics, diagnosis and treatment of a case with autoimmune lymphoproliferative syndrome (ALPS) . The patient was diagnosed as autoimmune lymphoproliferactive syndrome (ALPS) after being admitted to the Department of Rheumatism and Immunology of Tianjin Children's Hospital in February 20, 2014. The clinical characteristics, physical examination, laboratory tests, gene tests, and treatment process were analyzed and related literature was reviewed. The patient was a 16-month- old boy.Since the first month of life, he started to have repeatedly fever, diarrhea, shortness of breath, lymphadenopathy, hepatosplenomegaly, anemia (HGBmin 50 g/L) and thrombocytopenia (min 35 × 10⁹/L) . But multiple exams showed a normal peripheral blood leukocyte count, hypergammaglobulinemia (IgG 19 800 mg/L, IgA 1 710 mg/L, IgM 2 590 mg/L) and significantly increased serum vitamin B12. Flow cytometric measures showed that CD3⁺ CD4⁻ CD8⁻ T lymphocytes significantly increased ( &gt; 10%) at four times. The count of CD3⁺ TCRαβ⁺ CD4⁻ CD8⁻T lymphocytes (double negative T cells; DNTs) &gt;3% twice. The genetic test showed that 309th FAS gene area showed heterozygous mutations, the boy was diagnosed as ALPS. Added examinations of lymphocytes apoptosis induced by FAS was positive. He was treated with prednisone 15 mg once daily and immunomodulator 150 mg three times a day, while in maintaining period with normal levels of hemoglobin and platelet, the dose of prednisone was reduced gradually. Till now, the patient has been treated and observed for 8 months. We retrieved the reports of ALPS in the databases at home and abroad published in recent 10 years, more than 400 cases reported from foreign countries, but there were only 5 domestic cases. Among those, 4 had onset in infancy and 1 at 6-years of age. All the cases presented servere lymphadenopathy and hepatosplenomegaly with anemia (4 of them with hemolytic anemia) and thrombocytopenia. Three cases had a history of frequent infection, one of them had glomerulonephritis. All patient with significant high level of serum immunoglobulin ( &gt; 1.5 times upper limit of normal range), in 3 of them serum vitamin B12 was &gt; 1.5 pg/L (the other 2 cases missed the exam). In 5 cases CD3⁺ CD4⁻ CD8⁻T cells &gt; 10%, and in 2 case DNTs were 8.9% and 15.7% respectively (the other 3 cases missed the exam). Three cases were clearly detected with FAS mutations. All patients were treated with corticosteroid, 2 of them were added with mycophenolate mofetil. The therapy presented effective result in early 1-3 months, but no long-term follow-up reports were available. ALPS is a disorder of disrupted lymphocyte homeostasis caused by defective Fas-mediated apoptosis, and it is one of the primary immunodeficiency diseases. The onset of the disease occurs during infancy mainly. Clinical lymphoid hyperplasia and autoimmune phenomena are outstanding signs, which can be associated with frequent infections and allergies. The level of serum vitamin B12 &gt; 1.5 pg/L and the count of CD3⁺ CD4⁻ CD8⁻ T cell show important significance. Exact diagnosis should depend on detecting DNTs and FAS gene. Tuberculosis is still one of the most prevalent and fatal infectious diseases in spite of considerable improvements in medical science. Splenic tuberculosis is a rare form of extrapulmonary tuberculosis. There are limited numbers of cases in which immune thrombocytopenia is associated with splenic tuberculosis. We report a case of immune thrombocytopenic purpura due to splenic tuberculosis. Our case was a 58-year-old female with headache, gum bleeding, redness in legs, and ecchymoses on the arms for 10 days. On admission to hospital, laboratory tests were as follows: platelet count 6.000/mmc (150 000-450 000), haemoglobin: 12 g/dl, WBC: 8000/mm3, erythrocyte sedimentation rate: 58 mm/h and C-reactive protein was in normal ranges. After standard laboratory tests, the patient was diagnosed with idiopathic thrombocytopenic purpura. The patient presented abdominal lymphadenopathies and spleen in normal size in radiological examinations. Diagnostic laparotomy and splenectomy and lymph node excision was performed and splenic tuberculosis was detected in pathologic and microbiologic examination. The patient was successfully treated with apheresis platelets suspension, intravenous immunoglobulin and antituberculous therapy. In conclusion, splenic tuberculosis should be suspected in patients who have fever, abdominal lymphadenopathies and immune thrombocytopenic purpura. Histopathological examination is still an ideal method to confirm the diagnosis, suitably aided by microbiological examination. A 73-year-old female with past medical history of essential hypertension, hyperlipidemia, seasonal allergies, and chronic back pain presented to the hospital with complaints of headaches, fevers, fatigue, generalized body aches, shortness of breath, and diarrhea. Initial complete blood count was remarkable for leukopenia with an absolute lymph count of 0.60 K/µL and severe thrombocytopenia (platelet count &lt; 3 K/µL). She was tested for COVID-19 via nasopharyngeal swab polymerase chain reaction (PCR) testing and found positive. Additional labs showed an elevated D-dimer, C-reactive protein, fibrinogen, and lactate dehydrogenase. Vitamin B12 and folate levels were obtained and found to be normal. Peripheral smear showed no schistocytes or additional hematologic abnormalities apart from thrombocytopenia. The patient was transfused one unit of platelets with no improvement in platelet count. Fibrinogen count was obtained and found in normal range at 458 mg/dL. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) were all found to be normal. Immune thrombocytopenia purpura (ITP) was suspected and intravenous immunoglobulin (IVIG) was administered at a dose of 1 g/kg/day for two doses. By day 4, the patient had marked response to treatment with platelet recovery to 105 K/µL and subsequently discharged by day 5 with complete resolution of symptoms and platelet count of 146 K/µL. Twenty-eight days after discharge, she presented to hematology clinic with platelet count of 8 K/µL. Repeat nasopharyngeal swab PCR COVID testing was negative and she was treated with IVIG and pulse dexamethasone with prompt response, confirming suspicion of underlying, undiagnosed ITP prior to COVID infection. Fever ˜38.3° C (101° F) and illness lasting ˜3 weeks and no known immunocompromised state History and physical examination Stop antibiotic treatment and glucocorticoids Obligatory investigations: ESR and CRP, hemoglobin, platelet count, leukocyte count and differential, electrolytes, creatinine, total protein, protein electrophoresis, alkaline phosphatase, AST, ALT, LDH, creatine kinase, antinuclear antibodies, rheumatoid factor, urinalysis, blood cultures (n=3), urine culture, chest x-ray, abdominal ultrasonography, and tuberculin skin test Chemistry tests include lactate dehydrogenase (LDH) levels, uric acid levels, erythrocyte sedimentation rate (ESR), kidney and liver function, total protein levels, and an albumin-to-globulin ratio. The ESR and uric acid level may be elevated. Creatinine is occasionally elevated and electrolytes are occasionally abnormal. A high blood calcium level is noted in approximately 4% of patients. The LDH level is frequently elevated, indicating the extent of Waldenström macroglobulinemia–related tissue involvement. Rheumatoid factor, cryoglobulins, direct antiglobulin test and cold agglutinin titre results can be positive. Beta-2 microglobulin and C-reactive protein test results are not specific for Waldenström macroglobulinemia. Beta-2 microglobulin is elevated in proportion to tumor mass. Coagulation abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies are optional. Serum Fever >38.3°C (101°F) on at least two occasions 2. Illness duration of ≥3 weeks 3. 4. Diagnosis that remains uncertain after a thorough history-taking, physical examination, and the following obligatory investigations: determination of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level; platelet count; leukocyte count and differential; measurement of levels of hemoglobin, electrolytes, creatinine, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, ferritin, antinuclear antibodies, and rheumatoid factor; protein electrophoresis; urinalysis; blood cultures (n = 3); urine culture; chest x-ray; abdominal ultrasonography; and tuberculin skin test (TST). The range of FUO etiologies has evolved over time as a result of changes in the spectrum of diseases causing FUO, the widespread Percentage of Cases Due to Indicated Cause BACKGROUND Immune thrombocytopenia (ITP) is rare in infants under 1 year old. Bleeding often occurs when the platelet count is &lt;20 000/uL. The disease can progress because of accompanying COVID-19 disease. CASE REPORT A 9-month-old boy, weighing 8.5 kg, came to the hospital with petechiae on the forehead, cheeks, mouth, and extremities. The patient had rhinorrhea for 3 days previously and was febrile, pale, weak, and could not drink. He had the measles-rubella vaccination 19 days prior. Physical examination showed no abnormalities of the eyes, ears, nose, throat, and mouth. Heart and lungs were within normal limits, with no organomegaly, lymphadenopathy, or congenital anomaly of the abdomen. Laboratory examination showed hemoglobin, 12.7 g/dL; leukocytes, 7420/uL; platelet count, 16 000/uL; and hematocrit, 37.9%. Erythrocyte sedimentation rate was 14 mm at 1 h and 21 mm at 2 h. Peripheral blood smear showed normal RBC morphology, normal leukocytes, and few platelets. IgG was reactive and IgM was nonreactive on rapid antibody test. RT-PCR was positive for SARS-COV-2. Chest-X-ray showed pneumonia. The diagnosis was newly diagnosed ITP with COVID-19. Patient was treated with 30 mg/kg body weight/day of IV methylprednisolone for 3 days (250 mg); then 20 mg/kg body weight/day (175 mg) orally for 4 days in 3 divided doses. Azithromycin 100 mg/day, zinc 20 mg/day, and vitamin C 50 mg/day orally were also given. CONCLUSIONS COVID-19 screening is highly recommended during this pandemic to identify it as a potential cause of childhood ITP. Megadose methylprednisolone had an excellent response in alleviating ITP with confirmed COVID-19 in an infant. This report illustrates the importance of a detailed history and physical exam and careful analysis of hematologic parameters when diagnosing ITP. This case demonstrates that even with subtle deviations from typical ITP findings one must promptly reevaluate the diagnosis. This case also highlights the importance of peripheral smear review by an expert in pediatric hematopathology. A previously healthy 10 year-old Asian boy presented with 2 months of easy bruising. Review of systems was negative for any constitutional symptoms. On examination, he appeared well but had numerous large ecchymoses. He had no appreciable lymphadenopathy or splenomegaly. The liver was palpable 1.5 cm below the costal margin. A complete blood count (CBC) showed: platelets = 17 × 109/L, hemoglobin = 128 g/L, white blood cell count = 5.43 × 109/L, and neutrophils = 1.63 × 109/L. A blood smear was reported as normal. Urate was 370 umol/L and lactate dehydrogenase (LDH) was 803 U/L. The child was admitted with a presumptive diagnosis of immune thrombocytopenic purpura (ITP) and treated with intravenous immunoglobulin. The following day, the blood smear was reviewed by a hematopathologist who identified blasts. A bone marrow aspiration (BMA) confirmed the diagnosis of precursor B-cell acute lymphoblastic leukemia. In children presenting with suspected ITP, leukemia should always be considered. A BMA was historically performed on all patients with presumed ITP to rule out leukemia. In 2011, the American Society of Hematology (ASH) stopped recommending routine BMA in patients suspected of having ITP. ASH advises in cases with unusual findings on history, physical examination or CBC, it is reasonable to perform a BMA. Our patient had mild hepatomegaly, which may have qualified him for a BMA. He also had an elevated LDH and urate, which are not listed as criteria for BMA by ASH but were considered atypical for ITP by the clinical team. A literature search did not reveal any primary data assessing these markers. While corticosteroids are a first line treatment in ITP, they must be reserved for when clinicians are confident that the patient does not have leukemia. Steroid administration prior to diagnosing leukemia results in delayed diagnosis and may increase the risk of complications and decrease survival. Signs and symptoms Thrombocytopenia usually has no symptoms and is picked up on a routine complete blood count. Some individuals with thrombocytopenia may experience external bleeding such as nosebleeds, or bleeding gums. Some women may have heavier or longer periods or breakthrough bleeding. Bruising, particularly purpura in the forearms and petechiae in the feet, legs, and mucous membranes, may be caused by spontaneous bleeding under the skin. Eliciting a full medical history is vital to ensure the low platelet count is not secondary to another disorder. Ensuring that the other blood cell types, such as red blood cells and white blood cells are not also suppressed, is also important. Painless, round, and pinpoint (1 to 3 mm in diameter) petechiae usually appear and fade, and sometimes group to form ecchymoses. Larger than petechiae, ecchymoses are purple, blue, or yellow-green areas of skin that vary in size and shape. They can occur anywhere on the body. To report a case of possible severe, life-threatening thrombocytopenia associated with trimethoprim/sulfamethoxazole (TMP/SMX) therapy. A 54-year-old white woman received a 10-day course of TMP/SMX for treatment of chronic sinusitis. One day after finishing the course of TMP/SMX therapy, the presented to the emergency department because of the development of scattered petechiae on both hands and blood blisters in her mouth. On admission, her complete blood cell count results revealed a severely low platelet count of 2 x 10(3)/mm3. Other laboratory test results were normal, except for elevated blood glucose (nonfasting blood glucose). TMP/SMX was believed to be the most likely cause of thrombocytopenia. She was treated successfully with a transfusion of 2 units of platelets and oral prednisone. Her platelet count increased to 110 x 10(3)/mm3 4 days after discontinuation of TMP/SMX. She was discharged on hospital day 5. On follow-up (2 wk after hospital discharge), her platelet count was normal (351 x 10(3)/mm3). TMP/SMX has been implicated as a cause of thrombocytopenia, which is defined as platelet count &lt; 150 x 10(3)/mm3. Although it is uncommon, spontaneous severe bleeding may occur when platelet count decreases to &lt; or = 10 x 10(3)/mm3. Thrombocytopenia associated with TMP/SMX appears to be an immune-mediated process resulting in platelet destruction by drug-dependent platelet antibodies. Treatment of thrombocytopenia associated with TMP/SMX therapy includes discontinuation of the offending drug and the use of corticosteroids. Platelet transfusion and intravenous immunoglobulin may be required in some patients. Thrombocytopenia associated with TMP/SMX therapy can be serious or life threatening because it may result in significant bleeding complications. This hematologic adverse effect of TMP/SMX may occur even with the usual recommended dosage and duration of therapy. Careful monitoring of complete blood cell count, including platelet count, before and during TMP/SMX therapy is suggested. A 66 years female, who was since last year under astenia, arthralgias, pimply lesions in spread plates and tests showing eritrosedimentation over 100 mm, anemi, leucocitosis with neutrofilia, policlonal hypergammaglobulinemia, slight proteinuria and IgE on 900. This patient was sporadically treated with corticoids. When made the medical consult had lost 34lb., was under anorexy, as well as dyspepsia. Hemoglobyn 6.9 gr/dl, leucocytes 20000/mm3, neutrofils at 90%, proteinogram the same as former, with hypoalbuminemia. She was taking prednisona, 16 mg/day. When examined showed depress of conscience, astenia, and dermic lesions already quoted. 4 cm nonpainful right axillary adenopaty adhered to deep planes. Medulogram with increased iron, hyperegenerative. Ganglionar biopsia: linfoid hyperplasic process linked to inmune response. Toracoabdominal tomography with adenomegalia in torax and retroperitoneo. Skin biopsia: neutrofilic vasculitis. The patient suspends the 16 mg of prednisona and fever as well as generalized adenopatias come up. After laying aside other ethiologies, and understanding as Castleman Multicentric disease, it is started to supply prednisona 1 mg/kg of weight with a clinical and biochemical fast and outstanding response. After 7 months it was progressively suspended the esteroids and 60 days later, the process fall back; for that, corticoids are restarted, with a good evolution. The illness of Castleman although it is not very frequent, it should be considered as differential diagnosis in those clinical cases that are accompanied with important general commitment, linphadenopaties and respons to steroid therapy. The International Prognostic Scoring System for Waldenström's Macroglobulinemia is a predictive model to characterise long-term outcomes. According to the model, factors predicting reduced survival are: Age > 65 years Hemoglobin ≤ 11.5 g/dL Platelet count ≤ 100×109/L B2-microglobulin > 3 mg/L Serum monoclonal protein concentration > 70 g/L The risk categories are: Low: ≤ 1 adverse variable except age Intermediate: 2 adverse characteristics or age > 65 years High: > 2 adverse characteristics Five-year survival rates for these categories are 87%, 68% and 36%, respectively. The corresponding median survival rates are 12, 8, and 3.5 years. The International Prognostic Scoring System for Waldenström's Macroglobulinemia has been shown to be reliable. It is also applicable to patients on a rituximab-based treatment regimen. An additional predictive factor is elevated serum lactate dehydrogenase (LDH).\nHere is the question:\nHEMATOLOGY: A 19-year-old girl with no medical history of interest, except for a self-limited case of influenza 3 weeks earlier, who comes to the emergency department with petechiae and ecchymosis of spontaneous onset. On physical examination the patient was in good general condition, afebrile, normotensive and oriented in time and space. There were petechiae scattered throughout the lower extremities and abdomen and small ecchymoses in decubitus areas. No lymphadenopathy or splenomegaly were palpated. Laboratory tests showed the following findings: Hb 12.6 g/dL, leukocytes 5,500/mm3, platelets 7000/mm3. The peripheral blood smear showed normal erythrocyte morphology, normal differential leukocyte count and the planetary count was concordant with the autoanalyzer figure without platelet aggregates. Biochemistry and proteinogram, beta 2 microglobulin and LDH are normal. Which of the following do you think is the most appropriate initial treatment?\nHere are the potential choices:\n1. Platelet transfusion.\n2. Weekly Rituximab.\n3. Cyclophosphamide in 4-day pulses every 21 days.\n4. Daily plasmapheresis.\n5. Prednisone at 1 mg/day for 2-3 weeks.\nThe correct answer is: 5. Prednisone at 1 mg/day for 2-3 weeks."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Third thoracic vertebra (T3) The thoracic spinal nerve 3 (T3) passes out underneath it. Fourth thoracic vertebra (T4) The fourth thoracic vertebra, together with the fifth, is at the same level as the sternal angle. The thoracic spinal nerve 4 (T4) passes out underneath it. Fifth thoracic vertebra (T5) The fifth thoracic vertebra, together with the fourth, is at the same level as the sternal angle. The human trachea divides into two main bronchi at the level of the 5th thoracic vertebra, but may also end higher or lower, depending on breathing. The thoracic spinal nerve 5 (T5) passes out underneath it. Sixth thoracic vertebra (T6) The thoracic spinal nerve 6 (T6) passes out underneath it. Seventh thoracic vertebra (T7) The thoracic spinal nerve 7 (T7) passes out underneath it. Eighth thoracic vertebra (T8) The eighth thoracic vertebra is, together with the ninth thoracic vertebra, at the same level as the xiphisternum. The cervical spinal nerve 5 (C5) is a spinal nerve of the cervical segment. It originates from the spinal column from above the cervical vertebra 5 (C5). It contributes to the phrenic nerve, long thoracic nerve, and dorsal scapular nerve before joining cervical spinal nerve 6 to form the upper trunk, a trunk of the brachial plexus, which then forms the lateral cord, and finally the musculocutaneous nerve. Additional Images References Spinal nerves We studied the variations in the ventral rami of 152 brachial plexuses in 77 Korean adults. Brachial plexus were composed mostly of the fifth, sixth, seventh and eighth cervical nerves and the first thoracic nerve (77.0%). In 21.7% of the cases examined, the fourth, fifth, sixth, seventh and eighth cervical and the first thoracic nerves contributed to the plexus. A plexus composed of the fourth, fifth, sixth, seventh and eighth cervical and the first and second thoracic nerves, and a plexus composed of the fifth, sixth, seventh eighth cervical nerves were also observed. The plexuses were classified into three groups according to cephalic limitation, and the plexus of group 2 in which the whole fifth cervical nerve enters the plexus, were observed the most frequent. The average diameter of the sixth and the seventh cervical ventral rami of the plexus was greatest and that of the fifth cervical was smallest. The largest nerve entering the plexus was the sixth or the seventh cervical nerve in about 79% of cases. The dorsal scapular nerve originated from the fifth cervical ventral ramus in 110 cases (75.8%). The long thoracic nerve was formed by joining of roots from the fifth, sixth, and seventh cervical nerves in 76.0% of cases. Also, a branch to the phrenic nerve, the suprascapular nerve, a nerve to the pectoralis major muscle and a nerve to the subscapular muscle arising from the ventral rami of the plexus were observed. The cervical nerves innervate the sternohyoid, sternothyroid and omohyoid muscles. A loop of nerves called ansa cervicalis is part of the cervical plexus. Thoracic nerves The thoracic nerves are the twelve spinal nerves emerging from the thoracic vertebrae. Each thoracic nerve T1 -T12 originates from below each corresponding thoracic vertebra. Branches also exit the spine and go directly to the paravertebral ganglia of the autonomic nervous system where they are involved in the functions of organs and glands in the head, neck, thorax and abdomen. Anterior divisions: The intercostal nerves come from thoracic nerves T1-T11, and run between the ribs. At T2 and T3, further branches form the intercostobrachial nerve. The subcostal nerve comes from nerve T12, and runs below the twelfth rib. The inferior cervical ganglion is situated between the base of the transverse process of the last cervical vertebra and the neck of the first rib, on the medial side of the costocervical artery. Its form is irregular; it is larger in size than the middle cervical ganglion, and is frequently fused with the first thoracic ganglion, under which circumstances it is then called the \"stellate ganglion.\" Structure It is connected to the middle cervical ganglion by two or more cords, one of which forms a loop around the subclavian artery and supplies offsets to it. This loop is named the ansa subclavia (Vieussenii). The ganglion sends gray rami communicantes to the seventh and eighth cervical nerves. Twenty-four adult cadavers (48 sides) were used to investigate the incidence of a branch arising from the ventral ramus of the fourth cervical nerve (C4) with the phrenic nerve and subsequently joining the brachial plexus. Six brachial plexuses with spinal cords and phrenic nerves were dissected under a surgical microscope to investigate localization of fibers contained in the C4 branch to the brachial plexus. The incidence of the C4 branch was 23% (11/48 sides). Branches from C4 to the brachial plexus divided into anterior and posterior divisions on four sides (4/6 sides). On two sides, the branch did not divide but consisted entirely of an anterior division (2/6 sides). In the brachial plexus, anterior division fibers of the C4 branch were intertwined with fibers from the anterior divisions of the ventral rami of the fifth and sixth cervical nerves. They then passed to the suprascapular nerve and the anterior division of the superior trunk (6/6 sides). On the other hand, posterior division fibers of the C4 branch were intertwined with fibers from the posterior divisions of the ventral rami of the fifth and sixth cervical nerves. They then passed to the suprascapular nerve (2/6 sides) and the posterior division of the superior trunk (4/6 sides). The anterior division of the C4 branch received fibers from the ventral rootlets of the entire fourth cervical segment, whereas the posterior division received fibers from the ventral rootlets of the caudal half of the fourth cervical segment only. The fact that the suprascapular nerve received fibers from both the anterior and posterior divisions of the C4 branch was considered to support our claim that the human suprascapular nerve belongs to both the anterior and posterior divisions of the brachial plexus. The cervicoaxillary canal is the passageway that extends between the neck and the upper extremities through which the long thoracic nerve and other structures pass. Its structure is defined by being posteriorly bordered by the scapula, anteriorly by the clavicle, and medially by the first rib. The long thoracic nerve traverses this passageway in addition to axillary blood vessels and the brachial plexus. This complex nerve network arises in the neck from the fifth, sixth, seventh and eighth cervical roots, C5, C6, C7 and C8, together with the first thoracic root, T1. It then enters the canal in the axilla. References Skeletal system Upper limb anatomy Shoulder Nerves The cervical enlargement corresponds with the attachments of the large nerves which supply the upper limbs. Located just above the brachial plexus, it extends from about the fifth cervical to the first thoracic vertebra, its maximum circumference (about 38 mm.) being on a level with the attachment of the sixth pair of cervical nerves. The reason behind the enlargement of the cervical region is because of the increased neural input and output to the upper limbs. An analogous region in the lower limbs occurs at the lumbar enlargement. References External links - \"Vertebral Canal and Spinal Cord: Regions of the Spinal Cord\" - \"Spinal Cord, Fetus, Posterior View\" Nerves of the upper limb Intermediate nerve Greater petrosal nerve Chorda tympani (also in trigeminal? redundancy?) Vestibulocochlear nerve Vestibular nerve Cochlear nerve Glossopharyngeal nerve Tympanic nerve Tympanic plexus Lesser petrosal nerve Vagus nerve Superior laryngeal nerve Recurrent laryngeal nerve Accessory nerve Hypoglossal nerve Spinal nerves Cervical nerves Suboccipital nerve Greater occipital nerve Third occipital nerve Cervical plexus Ansa cervicalis Lesser occipital nerve Great auricular nerve Transverse cervical nerve Supraclavicular nerves Phrenic nerve Brachial plexus Supraclavicular part Dorsal scapular nerve Long thoracic nerve Subclavian nerve Suprascapular nerve Subscapular nerves Lower subscapular nerve Upper subscapular nerve Thoracodorsal nerve Medial pectoral nerve Lateral pectoral nerve Infraclavicular part Musculocutaneous nerve Medial cutaneous nerve of arm Medial cutaneous nerve of forearm Median nerve Ulnar nerve Radial nerve Axillary nerve Thoracic nerves Lumbar nerves Several dissections were performed to determine the level of spinal cord termination and the vertebral level at which the dorsal and ventral roots of spinal nerves C1-S4 emerged from the spinal cord in the rat. These levels of emergence were then compared to the level of exit from the vertebral canal. The dissections demonstrated that the effect of differential growth between spinal cord and vertebral column begins in the lower cervical region and becomes progressively more pronounced throughout thoracic and lumbar levels. The disparity between the vertebral level of emergence of spinal roots from the spinal cord and their level of exit via intervertebral foramina was found to be considerably larger than was previously reported by Greene ('68). It was further noted that the spinal cord terminated at the level of the intervertebral disc between the third and fourth lumbar vertebrae, not between the fourth and fifth lumbar vertebrae as reported by Greene ('68). The posterior thoracic nucleus, (Clarke's column, column of Clarke, dorsal nucleus, nucleus dorsalis of Clarke) is a group of interneurons found in the medial part of lamina VII, also known as the intermediate zone, of the spinal cord. It is mainly located from the cervical vertebra C7 to lumbar L3-L4 levels and is an important structure for proprioception of the lower limb. Anatomy It occupies the medial part of the base of the posterior grey column and appears on the transverse section as a well-defined oval area. It begins caudally at the level of the second or third lumbar nerve, and reaches its maximum size opposite the twelfth thoracic nerve. Above the level of the eight thoracic nerve its size diminishes, and the column ends opposite the last cervical or first thoracic nerve. There are seven pairs of these muscles, the first pair being between the atlas and axis, and the last pair between the seventh cervical and first thoracic vertebræ. Thoracic In the thoracic region they are present between the transverse processes of the lower three thoracic vertebrae, and between the transverse processes of the last thoracic and the first lumbar. These are called the thoracic intertransversarii and are supplied by the posterior rami of the spinal nerves. Lumbar In the lumbar region they are arranged in pairs, on either side of the vertebral column, one set occupying the entire interspace between the transverse processes of the lumbar vertebrae, are the lateral lumbar intertransversarii. the other set, the medial lumbar intertransversarii, passing from the accessory process of one vertebra to the mammillary of the vertebra below. Nomenclature of spinal nerves There are approximately 31 pairs of spinal nerves (Fig. 2.62), named according to their position with respect to associated vertebrae: eight cervical nerves—C1 to C8, twelve thoracic nerves—T1 to T12, five lumbar nerves—L1 to L5, five sacral nerves—S1 to S5, one coccygeal nerve—Co. The first cervical nerve (C1) emerges from the vertebral canal between the skull and vertebra CI (Fig. 2.63). Therefore cervical nerves C2 to C7 also emerge from the vertebral canal above their respective vertebrae. Because there are only seven cervical vertebrae, C8 emerges between vertebrae CVII and TI. As a consequence, all remaining spinal nerves, beginning with T1, emerge from the vertebral canal below their respective vertebrae. This study was conducted to identify anatomical variations of the spinal accessory nerve (SAN) in the upper neck, the landmark of the anterior and inferior border of level IIb, and to evaluate the nerve's effect on the border and the number of lymph nodes (LNs) in level IIb. Case series with planned data collection. A total of 181 neck dissections (NDs) were prospectively enrolled in this study. The relation between the SAN and adjacent structures (internal jugular vein [IJV], sternocleidomastoid muscle [SCM], cervical plexus) and the number of LNs in level IIb was investigated. The SAN crossed the IJV ventrally in 72 cases (39.8%) and dorsally in 104 cases (57.4%), and passed through the IJV in five cases (2.8%). The SAN ran along the inner surface of the SCM and sent branches to the SCM without penetration of the muscle in 83 cases (45.9%), whereas in 98 cases (54.1%) the nerve sent branches to the SCM by penetration. Cervical plexus contribution to the SAN was seen from C2 in 96 cases (53.1%), C2 and C3 in 69 cases (38.1%), and C3 in 16 cases (8.8%). The mean number of LNs of level IIa and level IIb was 6.5 and 8.2 in cases in which the SAN crossed the IJV ventrally, and 6.8 and 5.4 in dorsally crossing cases. LNs included in the neck level IIb in ventrally crossing SAN cases were significantly larger than the dorsally crossing cases (P &lt; 0.05). Our results may help to minimize the incidence of injuring the SAN in the upper neck during ND. Neck level IIb would contain more LNs if the course of the nerve leans toward the ventral side. It is broad in the middle, narrow and pointed at either end, and consists of three portions, a superior oblique, an inferior oblique, and a vertical. The superior oblique portion arises from the anterior tubercles of the transverse processes of the third, fourth, and fifth cervical vertebrae and, ascending obliquely with a medial inclination, is inserted by a narrow tendon into the tubercle on the anterior arch of the atlas. The inferior oblique portion, the smallest part of the muscle, arises from the front of the bodies of the first two or three thoracic vertebrae; and, ascending obliquely in a lateral direction, is inserted into the anterior tubercles of the transverse processes of the fifth and sixth cervical vertebrae. The vertical portion arises, below, from the front of the bodies of the upper three thoracic and lower three cervical vertebrae, and is inserted into the front of the bodies of the second, third, and fourth cervical vertebrae. Neck dissection (ND) is an important technique for the treatment of cervical lymph node metastasis in patients with head and neck cancer. Since the introduction of functional ND (FND), various modifications have been made to reduce the adverse effects of radical ND. Recently, many investigators have documented cases of FND with preservation of the spinal accessory nerve (SAN) and/or the sternocleidomastoid muscle, which have contributed to improve the quality of life following ND. For this type of ND, special attention must be paid to identify the SAN and the internal jugular vein (IJV). We performed 123 NDs over 2 years at the Department of Otolaryngology, Head and Neck Surgery, Kobe University Hospital. We collected data of all patients who underwent NDs by retrospectively reviewing the relevant hospital medical records and operative notes. In 4 out of 123 NDs (3.3%), an anomaly of the SAN passing through the fenestrated IJV was observed. Although this anomaly is rare, head and neck surgeons should be aware of this anomalous relationship between the SAN and the IJV in order to avoid accidental injury to these structures during ND. The vertebral artery may be divided into four parts: The first (preforaminal) part runs upward and backward between the Longus colli and the Scalenus anterior. In front of it are the internal jugular and vertebral veins, and it is crossed by the inferior thyroid artery; the left vertebral is crossed by the thoracic duct also. Behind it are the transverse process of the seventh cervical vertebra, the sympathetic trunk and its inferior cervical ganglion The second (foraminal) part runs upward through the transverse foramina of the C6 to C2 vertebrae, and is surrounded by branches from the inferior cervical sympathetic ganglion and by a plexus of veins which unite to form the vertebral vein at the lower part of the neck. It is situated in front of the trunks of the cervical nerves, and pursues an almost vertical course as far as the transverse process of the axis. Lateral surfaces The sides of the vertebral column are separated from the posterior surface by the articular processes in the cervical and thoracic regions and by the transverse processes in the lumbar region. In the thoracic region, the sides of the bodies of the vertebrae are marked in the back by the facets for articulation with the heads of the ribs. More posteriorly are the intervertebral foramina, formed by the juxtaposition of the vertebral notches, oval in shape, smallest in the cervical and upper part of the thoracic regions and gradually increasing in size to the last lumbar. They transmit the special spinal nerves and are situated between the transverse processes in the cervical region and in front of them, in the thoracic and lumbar regions. The phrenic nerve can be found deep to the posterior triangle within the prevertebral fascia as it runs along the anterior surface of the anterior scalene muscle. The spinal nerves of the fifth cervical vertebra through the first thoracic vertebra form the roots and trunks of the brachial plexus, which can also appear within the prevertebral fascia between the anterior and middle scale muscles. [11] The semispinalis cervicis (or semispinalis colli), arises by a series of tendinous and fleshy fibers from the transverse processes of the upper five or six thoracic vertebrae, and is inserted into the cervical spinous processes, from the axis to the fifth cervical vertebrae inclusive. The semispinalis cervicis is thicker than the semispinalis thoracis. The fasciculus connected with the axis is the largest, and is chiefly muscular in structure. The semispinalis thoracis (or semispinalis dorsi) muscle consists of thin, narrow, fleshy fasciculi, interposed between tendons of considerable length. It arises by a series of small tendons from the transverse processes of the sixth to the tenth thoracic vertebrae, and is inserted, by tendons, into the spinous processes of the upper four thoracic and lower two cervical vertebrae. The semispinalis muscles are innervated by the dorsal rami of the cervical spinal nerves. See also List of muscles of the human body Additional images The superficial branches of the cervical plexus that supply cutaneous sensation to the skin overlying the cervical region emerge from the posterior aspect of the sternocleidomastoid muscle near its midpoint, at a site known as the nerve point of the neck. The anterior rami of the spinal nerves pierce the investing fascia and split to form four cutaneous nerves that run deep to the platysma. The lesser occipital nerve forms from the second cervical spinal nerve and ascends posterior to the sternocleidomastoid to innervate the skin of the scalp and neck posterior to the ear. The greater auricular nerve forms from the second and third cervical spinal nerves and ascends on the anterior surface of the sternocleidomastoid to innervate the skin over the mastoid and parotid region inferior to the ear. The transverse cervical nerve forms from the second and third cervical spinal nerves and crosses horizontally over the sternocleidomastoid to innervate the anterior aspect of the neck. The supraclavicular nerve forms from the third and fourth cervical spinal nerves and descends across the surface of the investing fascia over the posterior triangle as it branches widely to innervate the skin over the clavicle and first two ribs. [10] Middle cervical ganglion. A second ganglion inferior to the superior cervical ganglion along the course of the sympathetic trunk (the middle cervical ganglion) is encountered at about the level of cervical vertebra CVI (Figs. 8.193 and 8.194). Branches from this ganglion pass to: cervical spinal nerves C5 and C6 through gray rami communicantes, and the heart as middle cardiac nerves. Inferior cervical ganglion. At the lower end of the cervical part of the sympathetic trunk is another ganglion (the inferior cervical ganglion), which becomes very large when it combines with the first thoracic ganglion and forms the cervicothoracic ganglion (stellate ganglion). The inferior cervical ganglion (Figs. 8.193 and 8.194) is anterior to the neck of rib I and the transverse process of cervical vertebra CVII, and posterior to the first part of the subclavian artery and the origin of the vertebral artery. Vertebra prominens The vertebra prominens, or C7, has a distinctive long and prominent spinous process, which is palpable from the skin surface. Sometimes, the seventh cervical vertebra is associated with an abnormal extra rib, known as a cervical rib, which develops from the anterior root of the transverse process. These ribs are usually small, but may occasionally compress blood vessels (such as the subclavian artery or subclavian vein) or nerves in the brachial plexus, causing pain, numbness, tingling, and weakness in the upper limb, a condition known as thoracic outlet syndrome. Very rarely, this rib occurs in a pair. The long spinous process of C7 is thick and nearly horizontal in direction. It is not bifurcated, and ends in a tubercle that the ligamentum nuchae attaches to. This process is not always the most prominent of the spinous processes, being found only about 70% of the time, C6 or T1 can sometimes be the most prominent. The interspinales are short muscle fascicles, found in pairs between the spinous processes of the contiguous vertebrae, one on either side of the interspinal ligament. In the cervical region the cervical interspinales are most distinct, and consist of six pairs, the first being situated between the axis and third vertebra, and the last between the seventh cervical and the first thoracic. They are small narrow bundles, attached, above and below, to the apices of the spinous processes. In the thoracic region the thoracic interspinales are found between the first and second vertebrae, and sometimes between the second and third, and between the eleventh and twelfth. In the lumbar region there are four pairs of lumbar interspinales in the intervals between the five lumbar vertebrae. There is also occasionally one between the last thoracic and first lumbar, and one between the fifth lumbar and the sacrum. the neck, third cervical; the epaulet area, fourth cervical; the deltoid area, fifth cervical; the radial forearm and thumb, sixth cervical; the index and middle fingers, seventh cervical; the little finger and ulnar border of hand and forearm, eighth cervical–first thoracic; the nipple, fourth to fifth thoracic; the umbilicus, tenth thoracic; the groin, first lumbar; the medial side of the knee, third lumbar; the medial malleolus, the fourth lumbar; the great toe, fifth lumbar; the little toe, first sacral; the back of the thigh and lateral foot, second sacral; and the genitoanal zones, third, fourth, and fifth sacral segments. The cervical ganglia are paravertebral ganglia of the sympathetic nervous system. Preganglionic nerves from the thoracic spinal cord enter into the cervical ganglions and synapse with its postganglionic fibers or nerves. The cervical ganglion has three paravertebral ganglia: superior cervical ganglion (largest) - adjacent to C2 & C3; postganglionic axon projects to target: (heart, head, neck) via \"hitchhiking\" on the carotid arteries middle cervical ganglion (smallest) - adjacent to C6; target: heart, neck inferior cervical ganglion. The inferior ganglion may be fused with the first thoracic ganglion to form a single structure, the stellate ganglion. - adjacent to C7; target: heart, lower neck, arm, posterior cranial arteries Nerves emerging from cervical sympathetic ganglia contribute to the cardiac plexus, among other things. Unlike all other ganglia, the medial branches of the cervical ganglia are 95% postganglionic axons. Additional images References The spinous process on C7 is distinctively long and gives the name vertebra prominens to this vertebra. Also a cervical rib can develop from C7 as an anatomical variation. The term cervicothoracic is often used to refer to the cervical and thoracic vertebrae together, and sometimes also their surrounding areas. Thoracic vertebrae The twelve thoracic vertebrae and their transverse processes have surfaces that articulate with the ribs. Some rotation can occur between the thoracic vertebrae, but their connection with the rib cage prevents much flexion or other movement. They may also be known as \"dorsal vertebrae\" in the human context. The vertebral bodies are roughly heart-shaped and are about as wide anterio-posteriorly as they are in the transverse dimension. Vertebral foramina are roughly circular in shape. The top surface of the first thoracic vertebra has a hook-shaped uncinate process, just like the cervical vertebrae. The cervical spinal nerve 3 (C3) is a spinal nerve of the cervical segment. It originates from the spinal column from above the cervical vertebra 3 (C3). References Spinal nerves Within the Central Nervous System (CNS), nerve cell bodies are generally organized into functional clusters, called nuclei. Axons within the CNS are grouped into tracts. There are 31 spinal cord nerve segments in a human spinal cord: 8 cervical segments forming 8 pairs of cervical nerves (C1 spinal nerves exit the spinal column between the foramen magnum and the C1 vertebra; C2 nerves exit between the posterior arch of the C1 vertebra and the lamina of C2; C3–C8 spinal nerves pass through the IVF above their corresponding cervical vertebrae, with the exception of the C8 pair which exit between the C7 and T1 vertebrae) 12 thoracic segments forming 12 pairs of thoracic nerves 5 lumbar segments forming 5 pairs of lumbar nerves 5 sacral segments forming 5 pairs of sacral nerves 1 coccygeal segment Spinal Cord Anatomy Spinal segments are the part of the spinal cord, from which ventral and dorsal roots exit to form a specific pair of spinal nerves. The spinal chord is not segmented itself, it is only made into segments by the spinal nerves as they leave. 31 deferent segments exists in a human spinal cord: 8 cervical segments Cervical nerves exit above C1 segment and below C1-C7. Note that this creates 8 nerves and segments corresponding to only 7 cervical vertebra. 12 thoracic segments Nerves exit below T1-T12. 5 lumbar segments Nerves exit below L1-L5. 5 sacral segments Nerves exit below S1-S5. 1 coccygeal segment Originally, during development there are two segments S1 and S2 which fuse. The nerves in this case exit at the coccyx. In more detail Individual thoracic vertebrae First thoracic vertebra (T1) The first thoracic vertebra has, on either side of the body, an entire articular facet for the head of the first rib, and a demi-facet for the upper half of the head of the second rib. The body is like that of a cervical vertebra, being broad, concave, and lipped on either side. The superior articular surfaces are directed upward and backward; the spinous process is thick, long, and almost horizontal. The transverse processes are long, and the upper vertebral notches are deeper than those of the other thoracic vertebrae. The thoracic spinal nerve 1 (T1) passes out underneath it. Second thoracic vertebra (T2) The thoracic spinal nerve 2 (T2) passes out underneath it. The second thoracic vertebra is larger than the first thoracic vertebra Third thoracic vertebra (T3) The thoracic spinal nerve 3 (T3) passes out underneath it.\nHere is the question:\nANATOMY: A 42-year-old woman with breast cancer has metastases at the level of the intervertebral foramina between the 4th and 5th cervical vertebrae and between the 4th and 5th thoracic vertebrae. Which spinal nerves will be injured?\nHere are the potential choices:\n1. Fourth cervical and fourth thoracic nerves.\n2. Fifth cervical and fifth thoracic nerves.\n3. Fourth cervical and fifth thoracic nerves.\n4. Fifth cervical and fourth thoracic nerve.\n5. Third cervical and fourth thoracic nerve.\nThe correct answer is: ",
        "gold_answer": "4 Fifth cervical and fourth thoracic nerve.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Third thoracic vertebra (T3) The thoracic spinal nerve 3 (T3) passes out underneath it. Fourth thoracic vertebra (T4) The fourth thoracic vertebra, together with the fifth, is at the same level as the sternal angle. The thoracic spinal nerve 4 (T4) passes out underneath it. Fifth thoracic vertebra (T5) The fifth thoracic vertebra, together with the fourth, is at the same level as the sternal angle. The human trachea divides into two main bronchi at the level of the 5th thoracic vertebra, but may also end higher or lower, depending on breathing. The thoracic spinal nerve 5 (T5) passes out underneath it. Sixth thoracic vertebra (T6) The thoracic spinal nerve 6 (T6) passes out underneath it. Seventh thoracic vertebra (T7) The thoracic spinal nerve 7 (T7) passes out underneath it. Eighth thoracic vertebra (T8) The eighth thoracic vertebra is, together with the ninth thoracic vertebra, at the same level as the xiphisternum. The cervical spinal nerve 5 (C5) is a spinal nerve of the cervical segment. It originates from the spinal column from above the cervical vertebra 5 (C5). It contributes to the phrenic nerve, long thoracic nerve, and dorsal scapular nerve before joining cervical spinal nerve 6 to form the upper trunk, a trunk of the brachial plexus, which then forms the lateral cord, and finally the musculocutaneous nerve. Additional Images References Spinal nerves We studied the variations in the ventral rami of 152 brachial plexuses in 77 Korean adults. Brachial plexus were composed mostly of the fifth, sixth, seventh and eighth cervical nerves and the first thoracic nerve (77.0%). In 21.7% of the cases examined, the fourth, fifth, sixth, seventh and eighth cervical and the first thoracic nerves contributed to the plexus. A plexus composed of the fourth, fifth, sixth, seventh and eighth cervical and the first and second thoracic nerves, and a plexus composed of the fifth, sixth, seventh eighth cervical nerves were also observed. The plexuses were classified into three groups according to cephalic limitation, and the plexus of group 2 in which the whole fifth cervical nerve enters the plexus, were observed the most frequent. The average diameter of the sixth and the seventh cervical ventral rami of the plexus was greatest and that of the fifth cervical was smallest. The largest nerve entering the plexus was the sixth or the seventh cervical nerve in about 79% of cases. The dorsal scapular nerve originated from the fifth cervical ventral ramus in 110 cases (75.8%). The long thoracic nerve was formed by joining of roots from the fifth, sixth, and seventh cervical nerves in 76.0% of cases. Also, a branch to the phrenic nerve, the suprascapular nerve, a nerve to the pectoralis major muscle and a nerve to the subscapular muscle arising from the ventral rami of the plexus were observed. The cervical nerves innervate the sternohyoid, sternothyroid and omohyoid muscles. A loop of nerves called ansa cervicalis is part of the cervical plexus. Thoracic nerves The thoracic nerves are the twelve spinal nerves emerging from the thoracic vertebrae. Each thoracic nerve T1 -T12 originates from below each corresponding thoracic vertebra. Branches also exit the spine and go directly to the paravertebral ganglia of the autonomic nervous system where they are involved in the functions of organs and glands in the head, neck, thorax and abdomen. Anterior divisions: The intercostal nerves come from thoracic nerves T1-T11, and run between the ribs. At T2 and T3, further branches form the intercostobrachial nerve. The subcostal nerve comes from nerve T12, and runs below the twelfth rib. The inferior cervical ganglion is situated between the base of the transverse process of the last cervical vertebra and the neck of the first rib, on the medial side of the costocervical artery. Its form is irregular; it is larger in size than the middle cervical ganglion, and is frequently fused with the first thoracic ganglion, under which circumstances it is then called the \"stellate ganglion.\" Structure It is connected to the middle cervical ganglion by two or more cords, one of which forms a loop around the subclavian artery and supplies offsets to it. This loop is named the ansa subclavia (Vieussenii). The ganglion sends gray rami communicantes to the seventh and eighth cervical nerves. Twenty-four adult cadavers (48 sides) were used to investigate the incidence of a branch arising from the ventral ramus of the fourth cervical nerve (C4) with the phrenic nerve and subsequently joining the brachial plexus. Six brachial plexuses with spinal cords and phrenic nerves were dissected under a surgical microscope to investigate localization of fibers contained in the C4 branch to the brachial plexus. The incidence of the C4 branch was 23% (11/48 sides). Branches from C4 to the brachial plexus divided into anterior and posterior divisions on four sides (4/6 sides). On two sides, the branch did not divide but consisted entirely of an anterior division (2/6 sides). In the brachial plexus, anterior division fibers of the C4 branch were intertwined with fibers from the anterior divisions of the ventral rami of the fifth and sixth cervical nerves. They then passed to the suprascapular nerve and the anterior division of the superior trunk (6/6 sides). On the other hand, posterior division fibers of the C4 branch were intertwined with fibers from the posterior divisions of the ventral rami of the fifth and sixth cervical nerves. They then passed to the suprascapular nerve (2/6 sides) and the posterior division of the superior trunk (4/6 sides). The anterior division of the C4 branch received fibers from the ventral rootlets of the entire fourth cervical segment, whereas the posterior division received fibers from the ventral rootlets of the caudal half of the fourth cervical segment only. The fact that the suprascapular nerve received fibers from both the anterior and posterior divisions of the C4 branch was considered to support our claim that the human suprascapular nerve belongs to both the anterior and posterior divisions of the brachial plexus. The cervicoaxillary canal is the passageway that extends between the neck and the upper extremities through which the long thoracic nerve and other structures pass. Its structure is defined by being posteriorly bordered by the scapula, anteriorly by the clavicle, and medially by the first rib. The long thoracic nerve traverses this passageway in addition to axillary blood vessels and the brachial plexus. This complex nerve network arises in the neck from the fifth, sixth, seventh and eighth cervical roots, C5, C6, C7 and C8, together with the first thoracic root, T1. It then enters the canal in the axilla. References Skeletal system Upper limb anatomy Shoulder Nerves The cervical enlargement corresponds with the attachments of the large nerves which supply the upper limbs. Located just above the brachial plexus, it extends from about the fifth cervical to the first thoracic vertebra, its maximum circumference (about 38 mm.) being on a level with the attachment of the sixth pair of cervical nerves. The reason behind the enlargement of the cervical region is because of the increased neural input and output to the upper limbs. An analogous region in the lower limbs occurs at the lumbar enlargement. References External links - \"Vertebral Canal and Spinal Cord: Regions of the Spinal Cord\" - \"Spinal Cord, Fetus, Posterior View\" Nerves of the upper limb Intermediate nerve Greater petrosal nerve Chorda tympani (also in trigeminal? redundancy?) Vestibulocochlear nerve Vestibular nerve Cochlear nerve Glossopharyngeal nerve Tympanic nerve Tympanic plexus Lesser petrosal nerve Vagus nerve Superior laryngeal nerve Recurrent laryngeal nerve Accessory nerve Hypoglossal nerve Spinal nerves Cervical nerves Suboccipital nerve Greater occipital nerve Third occipital nerve Cervical plexus Ansa cervicalis Lesser occipital nerve Great auricular nerve Transverse cervical nerve Supraclavicular nerves Phrenic nerve Brachial plexus Supraclavicular part Dorsal scapular nerve Long thoracic nerve Subclavian nerve Suprascapular nerve Subscapular nerves Lower subscapular nerve Upper subscapular nerve Thoracodorsal nerve Medial pectoral nerve Lateral pectoral nerve Infraclavicular part Musculocutaneous nerve Medial cutaneous nerve of arm Medial cutaneous nerve of forearm Median nerve Ulnar nerve Radial nerve Axillary nerve Thoracic nerves Lumbar nerves Several dissections were performed to determine the level of spinal cord termination and the vertebral level at which the dorsal and ventral roots of spinal nerves C1-S4 emerged from the spinal cord in the rat. These levels of emergence were then compared to the level of exit from the vertebral canal. The dissections demonstrated that the effect of differential growth between spinal cord and vertebral column begins in the lower cervical region and becomes progressively more pronounced throughout thoracic and lumbar levels. The disparity between the vertebral level of emergence of spinal roots from the spinal cord and their level of exit via intervertebral foramina was found to be considerably larger than was previously reported by Greene ('68). It was further noted that the spinal cord terminated at the level of the intervertebral disc between the third and fourth lumbar vertebrae, not between the fourth and fifth lumbar vertebrae as reported by Greene ('68). The posterior thoracic nucleus, (Clarke's column, column of Clarke, dorsal nucleus, nucleus dorsalis of Clarke) is a group of interneurons found in the medial part of lamina VII, also known as the intermediate zone, of the spinal cord. It is mainly located from the cervical vertebra C7 to lumbar L3-L4 levels and is an important structure for proprioception of the lower limb. Anatomy It occupies the medial part of the base of the posterior grey column and appears on the transverse section as a well-defined oval area. It begins caudally at the level of the second or third lumbar nerve, and reaches its maximum size opposite the twelfth thoracic nerve. Above the level of the eight thoracic nerve its size diminishes, and the column ends opposite the last cervical or first thoracic nerve. There are seven pairs of these muscles, the first pair being between the atlas and axis, and the last pair between the seventh cervical and first thoracic vertebræ. Thoracic In the thoracic region they are present between the transverse processes of the lower three thoracic vertebrae, and between the transverse processes of the last thoracic and the first lumbar. These are called the thoracic intertransversarii and are supplied by the posterior rami of the spinal nerves. Lumbar In the lumbar region they are arranged in pairs, on either side of the vertebral column, one set occupying the entire interspace between the transverse processes of the lumbar vertebrae, are the lateral lumbar intertransversarii. the other set, the medial lumbar intertransversarii, passing from the accessory process of one vertebra to the mammillary of the vertebra below. Nomenclature of spinal nerves There are approximately 31 pairs of spinal nerves (Fig. 2.62), named according to their position with respect to associated vertebrae: eight cervical nerves—C1 to C8, twelve thoracic nerves—T1 to T12, five lumbar nerves—L1 to L5, five sacral nerves—S1 to S5, one coccygeal nerve—Co. The first cervical nerve (C1) emerges from the vertebral canal between the skull and vertebra CI (Fig. 2.63). Therefore cervical nerves C2 to C7 also emerge from the vertebral canal above their respective vertebrae. Because there are only seven cervical vertebrae, C8 emerges between vertebrae CVII and TI. As a consequence, all remaining spinal nerves, beginning with T1, emerge from the vertebral canal below their respective vertebrae. This study was conducted to identify anatomical variations of the spinal accessory nerve (SAN) in the upper neck, the landmark of the anterior and inferior border of level IIb, and to evaluate the nerve's effect on the border and the number of lymph nodes (LNs) in level IIb. Case series with planned data collection. A total of 181 neck dissections (NDs) were prospectively enrolled in this study. The relation between the SAN and adjacent structures (internal jugular vein [IJV], sternocleidomastoid muscle [SCM], cervical plexus) and the number of LNs in level IIb was investigated. The SAN crossed the IJV ventrally in 72 cases (39.8%) and dorsally in 104 cases (57.4%), and passed through the IJV in five cases (2.8%). The SAN ran along the inner surface of the SCM and sent branches to the SCM without penetration of the muscle in 83 cases (45.9%), whereas in 98 cases (54.1%) the nerve sent branches to the SCM by penetration. Cervical plexus contribution to the SAN was seen from C2 in 96 cases (53.1%), C2 and C3 in 69 cases (38.1%), and C3 in 16 cases (8.8%). The mean number of LNs of level IIa and level IIb was 6.5 and 8.2 in cases in which the SAN crossed the IJV ventrally, and 6.8 and 5.4 in dorsally crossing cases. LNs included in the neck level IIb in ventrally crossing SAN cases were significantly larger than the dorsally crossing cases (P &lt; 0.05). Our results may help to minimize the incidence of injuring the SAN in the upper neck during ND. Neck level IIb would contain more LNs if the course of the nerve leans toward the ventral side. It is broad in the middle, narrow and pointed at either end, and consists of three portions, a superior oblique, an inferior oblique, and a vertical. The superior oblique portion arises from the anterior tubercles of the transverse processes of the third, fourth, and fifth cervical vertebrae and, ascending obliquely with a medial inclination, is inserted by a narrow tendon into the tubercle on the anterior arch of the atlas. The inferior oblique portion, the smallest part of the muscle, arises from the front of the bodies of the first two or three thoracic vertebrae; and, ascending obliquely in a lateral direction, is inserted into the anterior tubercles of the transverse processes of the fifth and sixth cervical vertebrae. The vertical portion arises, below, from the front of the bodies of the upper three thoracic and lower three cervical vertebrae, and is inserted into the front of the bodies of the second, third, and fourth cervical vertebrae. Neck dissection (ND) is an important technique for the treatment of cervical lymph node metastasis in patients with head and neck cancer. Since the introduction of functional ND (FND), various modifications have been made to reduce the adverse effects of radical ND. Recently, many investigators have documented cases of FND with preservation of the spinal accessory nerve (SAN) and/or the sternocleidomastoid muscle, which have contributed to improve the quality of life following ND. For this type of ND, special attention must be paid to identify the SAN and the internal jugular vein (IJV). We performed 123 NDs over 2 years at the Department of Otolaryngology, Head and Neck Surgery, Kobe University Hospital. We collected data of all patients who underwent NDs by retrospectively reviewing the relevant hospital medical records and operative notes. In 4 out of 123 NDs (3.3%), an anomaly of the SAN passing through the fenestrated IJV was observed. Although this anomaly is rare, head and neck surgeons should be aware of this anomalous relationship between the SAN and the IJV in order to avoid accidental injury to these structures during ND. The vertebral artery may be divided into four parts: The first (preforaminal) part runs upward and backward between the Longus colli and the Scalenus anterior. In front of it are the internal jugular and vertebral veins, and it is crossed by the inferior thyroid artery; the left vertebral is crossed by the thoracic duct also. Behind it are the transverse process of the seventh cervical vertebra, the sympathetic trunk and its inferior cervical ganglion The second (foraminal) part runs upward through the transverse foramina of the C6 to C2 vertebrae, and is surrounded by branches from the inferior cervical sympathetic ganglion and by a plexus of veins which unite to form the vertebral vein at the lower part of the neck. It is situated in front of the trunks of the cervical nerves, and pursues an almost vertical course as far as the transverse process of the axis. Lateral surfaces The sides of the vertebral column are separated from the posterior surface by the articular processes in the cervical and thoracic regions and by the transverse processes in the lumbar region. In the thoracic region, the sides of the bodies of the vertebrae are marked in the back by the facets for articulation with the heads of the ribs. More posteriorly are the intervertebral foramina, formed by the juxtaposition of the vertebral notches, oval in shape, smallest in the cervical and upper part of the thoracic regions and gradually increasing in size to the last lumbar. They transmit the special spinal nerves and are situated between the transverse processes in the cervical region and in front of them, in the thoracic and lumbar regions. The phrenic nerve can be found deep to the posterior triangle within the prevertebral fascia as it runs along the anterior surface of the anterior scalene muscle. The spinal nerves of the fifth cervical vertebra through the first thoracic vertebra form the roots and trunks of the brachial plexus, which can also appear within the prevertebral fascia between the anterior and middle scale muscles. [11] The semispinalis cervicis (or semispinalis colli), arises by a series of tendinous and fleshy fibers from the transverse processes of the upper five or six thoracic vertebrae, and is inserted into the cervical spinous processes, from the axis to the fifth cervical vertebrae inclusive. The semispinalis cervicis is thicker than the semispinalis thoracis. The fasciculus connected with the axis is the largest, and is chiefly muscular in structure. The semispinalis thoracis (or semispinalis dorsi) muscle consists of thin, narrow, fleshy fasciculi, interposed between tendons of considerable length. It arises by a series of small tendons from the transverse processes of the sixth to the tenth thoracic vertebrae, and is inserted, by tendons, into the spinous processes of the upper four thoracic and lower two cervical vertebrae. The semispinalis muscles are innervated by the dorsal rami of the cervical spinal nerves. See also List of muscles of the human body Additional images The superficial branches of the cervical plexus that supply cutaneous sensation to the skin overlying the cervical region emerge from the posterior aspect of the sternocleidomastoid muscle near its midpoint, at a site known as the nerve point of the neck. The anterior rami of the spinal nerves pierce the investing fascia and split to form four cutaneous nerves that run deep to the platysma. The lesser occipital nerve forms from the second cervical spinal nerve and ascends posterior to the sternocleidomastoid to innervate the skin of the scalp and neck posterior to the ear. The greater auricular nerve forms from the second and third cervical spinal nerves and ascends on the anterior surface of the sternocleidomastoid to innervate the skin over the mastoid and parotid region inferior to the ear. The transverse cervical nerve forms from the second and third cervical spinal nerves and crosses horizontally over the sternocleidomastoid to innervate the anterior aspect of the neck. The supraclavicular nerve forms from the third and fourth cervical spinal nerves and descends across the surface of the investing fascia over the posterior triangle as it branches widely to innervate the skin over the clavicle and first two ribs. [10] Middle cervical ganglion. A second ganglion inferior to the superior cervical ganglion along the course of the sympathetic trunk (the middle cervical ganglion) is encountered at about the level of cervical vertebra CVI (Figs. 8.193 and 8.194). Branches from this ganglion pass to: cervical spinal nerves C5 and C6 through gray rami communicantes, and the heart as middle cardiac nerves. Inferior cervical ganglion. At the lower end of the cervical part of the sympathetic trunk is another ganglion (the inferior cervical ganglion), which becomes very large when it combines with the first thoracic ganglion and forms the cervicothoracic ganglion (stellate ganglion). The inferior cervical ganglion (Figs. 8.193 and 8.194) is anterior to the neck of rib I and the transverse process of cervical vertebra CVII, and posterior to the first part of the subclavian artery and the origin of the vertebral artery. Vertebra prominens The vertebra prominens, or C7, has a distinctive long and prominent spinous process, which is palpable from the skin surface. Sometimes, the seventh cervical vertebra is associated with an abnormal extra rib, known as a cervical rib, which develops from the anterior root of the transverse process. These ribs are usually small, but may occasionally compress blood vessels (such as the subclavian artery or subclavian vein) or nerves in the brachial plexus, causing pain, numbness, tingling, and weakness in the upper limb, a condition known as thoracic outlet syndrome. Very rarely, this rib occurs in a pair. The long spinous process of C7 is thick and nearly horizontal in direction. It is not bifurcated, and ends in a tubercle that the ligamentum nuchae attaches to. This process is not always the most prominent of the spinous processes, being found only about 70% of the time, C6 or T1 can sometimes be the most prominent. The interspinales are short muscle fascicles, found in pairs between the spinous processes of the contiguous vertebrae, one on either side of the interspinal ligament. In the cervical region the cervical interspinales are most distinct, and consist of six pairs, the first being situated between the axis and third vertebra, and the last between the seventh cervical and the first thoracic. They are small narrow bundles, attached, above and below, to the apices of the spinous processes. In the thoracic region the thoracic interspinales are found between the first and second vertebrae, and sometimes between the second and third, and between the eleventh and twelfth. In the lumbar region there are four pairs of lumbar interspinales in the intervals between the five lumbar vertebrae. There is also occasionally one between the last thoracic and first lumbar, and one between the fifth lumbar and the sacrum. the neck, third cervical; the epaulet area, fourth cervical; the deltoid area, fifth cervical; the radial forearm and thumb, sixth cervical; the index and middle fingers, seventh cervical; the little finger and ulnar border of hand and forearm, eighth cervical–first thoracic; the nipple, fourth to fifth thoracic; the umbilicus, tenth thoracic; the groin, first lumbar; the medial side of the knee, third lumbar; the medial malleolus, the fourth lumbar; the great toe, fifth lumbar; the little toe, first sacral; the back of the thigh and lateral foot, second sacral; and the genitoanal zones, third, fourth, and fifth sacral segments. The cervical ganglia are paravertebral ganglia of the sympathetic nervous system. Preganglionic nerves from the thoracic spinal cord enter into the cervical ganglions and synapse with its postganglionic fibers or nerves. The cervical ganglion has three paravertebral ganglia: superior cervical ganglion (largest) - adjacent to C2 & C3; postganglionic axon projects to target: (heart, head, neck) via \"hitchhiking\" on the carotid arteries middle cervical ganglion (smallest) - adjacent to C6; target: heart, neck inferior cervical ganglion. The inferior ganglion may be fused with the first thoracic ganglion to form a single structure, the stellate ganglion. - adjacent to C7; target: heart, lower neck, arm, posterior cranial arteries Nerves emerging from cervical sympathetic ganglia contribute to the cardiac plexus, among other things. Unlike all other ganglia, the medial branches of the cervical ganglia are 95% postganglionic axons. Additional images References The spinous process on C7 is distinctively long and gives the name vertebra prominens to this vertebra. Also a cervical rib can develop from C7 as an anatomical variation. The term cervicothoracic is often used to refer to the cervical and thoracic vertebrae together, and sometimes also their surrounding areas. Thoracic vertebrae The twelve thoracic vertebrae and their transverse processes have surfaces that articulate with the ribs. Some rotation can occur between the thoracic vertebrae, but their connection with the rib cage prevents much flexion or other movement. They may also be known as \"dorsal vertebrae\" in the human context. The vertebral bodies are roughly heart-shaped and are about as wide anterio-posteriorly as they are in the transverse dimension. Vertebral foramina are roughly circular in shape. The top surface of the first thoracic vertebra has a hook-shaped uncinate process, just like the cervical vertebrae. The cervical spinal nerve 3 (C3) is a spinal nerve of the cervical segment. It originates from the spinal column from above the cervical vertebra 3 (C3). References Spinal nerves Within the Central Nervous System (CNS), nerve cell bodies are generally organized into functional clusters, called nuclei. Axons within the CNS are grouped into tracts. There are 31 spinal cord nerve segments in a human spinal cord: 8 cervical segments forming 8 pairs of cervical nerves (C1 spinal nerves exit the spinal column between the foramen magnum and the C1 vertebra; C2 nerves exit between the posterior arch of the C1 vertebra and the lamina of C2; C3–C8 spinal nerves pass through the IVF above their corresponding cervical vertebrae, with the exception of the C8 pair which exit between the C7 and T1 vertebrae) 12 thoracic segments forming 12 pairs of thoracic nerves 5 lumbar segments forming 5 pairs of lumbar nerves 5 sacral segments forming 5 pairs of sacral nerves 1 coccygeal segment Spinal Cord Anatomy Spinal segments are the part of the spinal cord, from which ventral and dorsal roots exit to form a specific pair of spinal nerves. The spinal chord is not segmented itself, it is only made into segments by the spinal nerves as they leave. 31 deferent segments exists in a human spinal cord: 8 cervical segments Cervical nerves exit above C1 segment and below C1-C7. Note that this creates 8 nerves and segments corresponding to only 7 cervical vertebra. 12 thoracic segments Nerves exit below T1-T12. 5 lumbar segments Nerves exit below L1-L5. 5 sacral segments Nerves exit below S1-S5. 1 coccygeal segment Originally, during development there are two segments S1 and S2 which fuse. The nerves in this case exit at the coccyx. In more detail Individual thoracic vertebrae First thoracic vertebra (T1) The first thoracic vertebra has, on either side of the body, an entire articular facet for the head of the first rib, and a demi-facet for the upper half of the head of the second rib. The body is like that of a cervical vertebra, being broad, concave, and lipped on either side. The superior articular surfaces are directed upward and backward; the spinous process is thick, long, and almost horizontal. The transverse processes are long, and the upper vertebral notches are deeper than those of the other thoracic vertebrae. The thoracic spinal nerve 1 (T1) passes out underneath it. Second thoracic vertebra (T2) The thoracic spinal nerve 2 (T2) passes out underneath it. The second thoracic vertebra is larger than the first thoracic vertebra Third thoracic vertebra (T3) The thoracic spinal nerve 3 (T3) passes out underneath it.\nHere is the question:\nANATOMY: A 42-year-old woman with breast cancer has metastases at the level of the intervertebral foramina between the 4th and 5th cervical vertebrae and between the 4th and 5th thoracic vertebrae. Which spinal nerves will be injured?\nHere are the potential choices:\n1. Fourth cervical and fourth thoracic nerves.\n2. Fifth cervical and fifth thoracic nerves.\n3. Fourth cervical and fifth thoracic nerves.\n4. Fifth cervical and fourth thoracic nerve.\n5. Third cervical and fourth thoracic nerve.\nThe correct answer is: 3. Fourth cervical and fifth thoracic nerves."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n There are controversies about taking routine mucosal biopsy when the gross colonoscopic finding is normal. This study was conducted to determine the frequency of clinically important histological abnormalities, prospectively, in chronic diarrhea patients with grossly normal or nonspecific colonoscopic findings. One hundred and eighteen patients suffering from nonbloody diarrhea with average frequency of more than two times a day for more than 4 weeks were included. Multiple biopsies (cecum, ascending colon, mid-transverse colon, descending colon, sigmoid colon and rectum) were taken during colonoscopic examinations and each biopsy specimen was reviewed by one pathologist after H&amp;E and Masson-trichrome staining. Clinically significant abnormalities (2 collagenous colitis, 1 lymphocytic colitis, 1 eosinophilic enterocolitis, 1 ulcerative colitis and 4 melanosis coli) were observed in 9 patients (7.6%). Sixteen cases (13.6%) of borderline histological abnormalities were observed (8 cases of possible collagenous colitis and 8 cases showing some features of lymphocytic colitis). Ninety two cases (78.8%) showed nonspecific inflammation only. Clinically important histological lesions can exist in significant percentage in spite of normal or nonspecific colonoscopic findings, which can justify routine mucosal biopsy in the evaluation of chronic diarrhea patients. The clinical significance of borderline histological abnormalities needs to be determined by careful follow-up studies. Diagnosis Colonoscopic appearances are normal or near normal. As the changes are often patchy, an examination limited to the rectum may miss cases of microscopic colitis, and so a full colonoscopy is necessary. Multiple colonic biopsies are taken in order to make the diagnosis. Histological features of colonic biopsies indicating microscopic colitis are: greater than 20 intraepithelial lymphocytes per 100 epithelial cells and, additionally, 10-20 μm of a thickened subepithelial collagen band in collagenous colitis. Inflammation of the lamina propria, with mainly mononuclear cells, may be observed in collagenous colitis. Collagenous colitis and lymphocytic colitis are the two major conditions characterized by chronic watery diarrhoea, without endoscopic or radiological lesions, but with histological abnormalities and therefore considered as \"microscopic colitis\". The histology of colonic biopsies shows inflammation of the mucosa, and either thickening of the subepithelial collagen band or an increase of lymphocytes in the surface epithelium. Different variant forms have been reported under separate names. These are probably not specific entities. The incidence of microscopic colitis is slightly less than the incidence of chronic idiopathic inflammatory bowel diseases (IBD). Microscopic colitis and IBD are clearly different entities. The relation between both entities is weak but double. Biopsy samples from patients with IBD may mimic the features of lymphocytic or collagenous colitis, both in the initial onset and during follow-up. In the large majority of these cases, endoscopy shows or has shown mucosal lesions. In rare cases, however, a double diagnosis was made. Certain patients, usually of older age, presented first with a microscopic, usually collagenous colitis and developed subsequently genuine ulcerative colitis. Microscopic colitis (MC) is an encompassing term for two diseases; collagenous colitis and lymphocytic colitis. The colon appears normal by colonoscopy and a diagnosis is only obtained with a biopsy. The histopathology of collagenous colitis is mainly characterized by a thickening of the subepithelial basement membrane of the colonic mucosa with a band of collagen. Lymphocytic colitis is mainly characterized by an intraepithelial lymphocytosis without the collagen thickening. Even though the two diseases have a distinctive pathology their clinical symptoms are characterized by chronic watery diarrhea without bleeding. Microscopic colitis is thought to cause about 4-13% of all chronic diarrhea but their relative frequency is much higher among older people. The mean annual incidence for collagenous and lymphocytic colitis has been increasing. Steroids are the most effective treatment for microscopic colitis and budesonide is the most studied and effective therapy for MC. The aim of this paper is to give a review of two relatively new diseases which are among the most common cause of chronic diarrhea, especially among older people. A typical symptom of microscopic colitis (MC) is chronic watery diarrhea with normal endoscopic findings and characteristic inflammatory changes in histopathology. Treatment of the disease is mainly empiric. MC has two main subtypes: lymphocytic colitis and collagenous colitis. There are also untypical histopathological forms of MC: MC with giant cells, MC not otherwise specified (NOS) and cryptal lymphocytic coloproctitis. Some other histopathological changes in MC have been observed, especially Paneth cell hyperplasia or epithelial degeneration. Eosinophilic colitis, acute colitis, amyloidosis, ulcerative colitis and Crohn's disease should be taken into consideration in differential diagnosis. The most reliable biopsy material for histopathological examination are samples obtained from transverse colon. Some studies proved that treatment of MC makes it possible to reduce not only clinical, but also histopathological, manifestations. Pathology Microscopic colitis is characterized by an increase in inflammatory cells, particularly lymphocytes, in colonic biopsies with an otherwise normal appearance and architecture of the colon. Inflammatory cells are increased both in the surface epithelium (\"intraepithelial lymphocytes\") and in the lamina propria. The key feature is more than 20 intra-epithelial lymphocytes per 100 epithelial cells. These are the principal features of lymphocytic colitis. An additional distinguishing feature of collagenous colitis is a thickened subepithelial collagen layer, which may be up to 30 micrometres thick, that occurs in addition to the features found in lymphocytic colitis. The fact that the two types of microscopic colitis share many features including epidemiology, risk factors and, response to therapy has led to the suggestion that they are actually subtypes of the same disease. Microscopic colitis (MC) is a chronic inflammatory process observed in colon biopsies of patients with chronic aqueous diarrhea. It is called microscopic because diagnosis is determined by histological studies since the microscopic characteristics of the colon endoscopy are normal. Two patterns exist: Lymphocytic Microscopic Colitis and Collagenous Microscopic Colitis. Etiology is unknown, and the proposed pathogenic mechanisms indicate an immunological phenomenon. Based on this, the authors of this study hypothesize that lymphocytic infiltration of the lamina propria could be related to cytotoxic lymphocytes CD8 as causative agents of colon tissue damage. Prove hypothesis of immunological pathogenesis of MC. APPARATUS AND METHODS: Thirty eight (38) patients with diagnosed MC were recruited for the last four years in the Pathology Laboratory at Ricardo Palma University. Twenty two (22) colon biopsies with the most severe histological lesions were selected. These biopsies were obtained from 17 patients: 5 patients had 2 biopsies in 2 colonoscopy sessions. Biopsies were fixed in neutral formaldehyde, processed through the paraffin inclusion method, and stained with hematoxiline-eosine and Masson trichromic to distinguish collagenous tissue. Immunohistochemistry was conducted in 4- or 5-micron-thick histological sections processed through the immunoperoxidase method. Nineteen (19) biopsies corresponded to Lymphocytic MC and 3 to Collagenous MC. Lymphocytic MC showed intraepithelial lymphocytosis, dystrophic epithelial damage in the areas of lymphocytic infiltration, lamina propria inflammation with lymphocytes and plasma cells, and normal basement membrane. Collagenous MC showed thickened basement membrane due to the presence of a collagenous band, mild to moderate intraepithelial lymphocytosis, vacuolization,and frequent detachment of protective epithelium. Twenty two (22) biopsies were positive in the immunohistochemical studies. The simple clinical colitis activity index was created in 1998 and is used to assess the severity of symptoms. Endoscopic The best test for diagnosis of ulcerative colitis remains endoscopy, which is examination of the internal surface of the bowel using a flexible camera. Initially, a flexible sigmoidoscopy may be completed to establish the diagnosis. The physician may elect to limit the extent of the initial exam if severe colitis is encountered to minimize the risk of perforation of the colon. However, a complete colonoscopy with entry into the terminal ileum should be performed to rule out Crohn's disease, and assess extent and severity of disease. Endoscopic findings in ulcerative colitis include: erythema (redness of the mucosa), friability of the mucosa, superficial ulceration, and loss of the vascular appearance of the colon. When present, ulcerations may be confluent. Pseudopolyps may be observed. The literature review gives the present-day views of the definition, etiology, pathogenesis, diagnosis, and treatment of microscopic colitis (MC). In the present view, MC is an inflammatory bowel disease of unknown etiology, which is characterized by chronic watery diarrhea, no macroscopic signs of large bowel involvement in the presence of specific pathomorphological changes. There are two major forms of MC, which are similar in its clinical picture, yet, heterogeneous in histological criteria: collagenous colitis (CC) and lymphocytic colitis (LC). As of now, the prevalence of MC is about 100 cases per 100,000 population, which is similar with that in other inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. MC generally prevails in women aged over 50 years. The etiology and pathogenesis of MC have not fully investigated. Watery diarrhea is as a predominant pathognomonic symptom in all the patients with MC. The major histological criterion for the diagnosis of CC is subepithelial collagen lining thickening (more than 10 pm) and that for LC is higher intraepithelial lymphocyte counts (more than 20 intraepithelial lymphocytes/100 epitheliocytes). The topical glucocorticosteroid budesonide is currently the only agent, the efficacy of which has been proven in both inducing and maintaining remission in patients with MC in many clinical trials. Collagenous colitis and lymphocytic colitis are defined by a clinicopathologic syndrome with chronic watery diarrhea, microscopic lesions of colonic biopsies, and normal barium enema and colonoscopy. A histopathological study was performed on multiple colorectal biopsies to compare 12 cases of collagenous colitis (defined by a subepithelial collagen thicker than 10 microns) and 7 cases of lymphocytic colitis (defined by a number of intraepithelial lymphocytes more than 20 per 100 epithelial cells at least in one biopsied site). The study included a semiquantitative analysis of inflammatory infiltrate in the lamina propria, crypts distortion and epithelial detachment. The number of intraepithelial lymphocytes per 100 epithelial cells was determined in surface epithelium and crypts. The subepithelial collagen thickening was studied by computerised morphometry. The intraepithelial lymphocytes, villous atrophy and thickness of the subepithelial collagen were also determined in gastric and duodenal biopsies. In collagenous colitis, the subepithelial collagenous thickness ranged from 10 to 40 microns in the colon (median 20.99 microns). In 4 cases of collagenous colitis, no thickening of the collagen plate was seen in the rectum. We found constant epithelial detachment and mucosal distortion. In lymphocytic colitis, the thickness of the subepithelial collagen ranged from 6 to 10 microns in 4 cases and was less than 6 microns in 3 cases (median 6.24 microns). The median number of intraepithelial lymphocytes in surface epithelium was 22.35 (range 18.2 to 40) in lymphocytic colitis versus 12.22 (range 4.6 to 24.4) in collagenous colitis. In conclusion, we observed an overlap of both the collagenous plate thickness and the number of intraepithelial lymphocytes in collagenous colitis and lymphocytic colitis. This result favours a unified histogenesis for these two entities. Lymphocytic colitis is a subtype of microscopic colitis, a condition characterized by chronic non-bloody watery diarrhea. Causes No definite cause has been determined. The peak incidence of lymphocytic colitis is in persons over age 50; the disease affects women and men equally. Some reports have implicated long-term usage of NSAIDs, proton pump inhibitors, and selective serotonin reuptake inhibitors, and other drugs. Associations with other autoimmune disorders suggests that overactive immune responses occur. Diagnosis The colonoscopy is normal but histology of the mucosal biopsy reveals an accumulation of lymphocytes in the colonic epithelium and connective tissue (lamina propria). Collagenous colitis shares this feature but additionally shows a distinctive thickening of the subepithelial collagen table. Microscopic colitis is a clinicopathological entity which, in addition to typical symptoms such as watery diarrhea, is characterized by its specific histopathology. Since colonoscopy yields normal findings, microscopic colitis belongs in a histological domain. The term encompasses two forms: lymphocytic and collagenous colitis. Histologically, lymphocytic colitis shows an increase in intraepithelial lymphocytes of more than 20 lymphocytes per 100 surface colonocytes, while collagenous colitis is characterized by a thickened subepithelial collagen layer of more than 10 µm. Specific stains help in the quantification of both. Since microscopic colitis does not always affect the entire colon and the number of intraepithelial lymphocytes varies physiologically, obtaining stepwise biopsies of the colon (with information on location where possible) is recommended. A thickened collagen layer is relatively specific for collagenous colitis, whereas intraepithelial lymphocytosis is also found in other diseases. Therefore, to make a correct diagnosis, it is important to correlate histological findings with clinical symptoms, including the main symptom of watery diarrhea. An important investigation in the assessment of colitis is biopsy. A very small piece of tissue (usually about 2mm) is removed from the bowel mucosa during endoscopy and examined under the microscope by a histopathologist. It can provide important information regarding the cause of the disease and the extent of bowel damage. Types There are many types of colitis. They are usually classified by the cause. Types of colitis include: Autoimmune Inflammatory bowel disease (IBD) – a group of chronic colitides. Ulcerative colitis (UC) – a chronic colitis that affects the large intestine. Crohn's disease (CD) – another type of IBD that often leads to colitis. Unknown Microscopic colitis – a colitis diagnosed by microscopic examination of colonic tissue; macroscopically (\"to the eye\") it appears normal. Lymphocytic colitis Collagenous colitis Treatment-caused Diversion colitis Chemical colitis Chemotherapy-induced colitis Radiation colitis Checkpoint inhibitor induced colitis Types There are four types of SCAD, based on endoscopic appearance. Pattern A is characterized by involvement of crescentic folds and is the most common type of SCAD (52%). Pattern B has an appearance similar to mild-to moderate ulcerative colitis (30.40%), whereas pattern C appears similar to Crohn's disease (10.90%). Pattern D is the least common, and appears similar to severe ulcerative colitis (6.50%). Diagnosis SCAD is diagnosed via colonoscopy, often incidentally during examination for unrelated concerns. Colonoscopy shows erythema of the colonic mucosa, which may be characterized by friability and exudate. The descending and sigmoid colon are typically involved. Biopsies of the affected area and the unaffected rectum confirm the diagnosis. Biopsies of SCAD show evidence of chronic inflammation. Rectal biopsies show normal mucosa. Ulcerative colitis is usually continuous from the rectum, with the rectum almost universally being involved. Perianal disease is rare. The degree of involvement endoscopically ranges from proctitis (rectal inflammation) to left sided colitis (extending to descending colon), to extensive colitis (extending proximal to descending colon). Histologic Biopsies of the mucosa are taken during endoscopy to confirm the diagnosis of UC and differentiate it from Crohn's disease, which is managed differently clinically. Histologic findings in ulcerative colitis includes: distortion of crypt architecture, crypt abscesses, and inflammatory cells in the mucosa (lymphocytes, plasma cells, and granulocytes). Unlike the transmural inflammation seen in Crohn's disease, the inflammation of ulcerative colitis is limited to the mucosa. Microscopic colitis refers to two related medical conditions which cause diarrhea: collagenous colitis and lymphocytic colitis. Both conditions are characterized by the presence of chronic non-bloody watery diarrhea, normal appearances on colonoscopy and characteristic histopathology findings of inflammatory cells. Signs and symptoms The main symptom is persistent non-bloody watery diarrhea, which may be profuse. People may also experience abdominal pain, fecal incontinence, and unintentional weight loss. Microscopic colitis is the diagnosis in around 10% of cases investigated for chronic non-bloody diarrhea. Microscopic colitis has emerged as a major cause of chronic watery non-bloody diarrhoea, particularly in elderly females. The term is used as an umbrella term to categorize a subgroup of colitides with distinct clinicopathological phenotypes and no significant endoscopic abnormalities. Lymphocytic colitis is defined by an increased number of surface intraepithelial lymphocytes, and collagenous colitis by a thickened collagen band underneath the surface epithelium. There is increased inflammation in the lamina propria, but only little or no crypt architectural distortion. Incomplete and variant forms showing less characteristic features have been reported under different names. The differential diagnosis mainly includes resolving infectious colitis and changes related to the intake of drugs such as non-steroidal anti-inflammatory drugs. Substantial clinical and histological overlap between lymphocytic and collagenous colitis has been described, raising the suspicion that the conditions are two histological manifestations of the same entity, possibly representing different manifestations during the disease course or different stages of disease development. In this review, we provide a practical approach for pathologists, with a focus on diagnostic criteria and differential diagnosis, and discuss recent insights into the pathogenesis of disease and the relationship with classic chronic inflammatory bowel disease, i.e. Crohn's disease and ulcerative colitis.  collagenous colitis (CC) and lymphocytic colitis (LC) are two entities of unknown cause, characterized by chronic watery diarrhea, grossly normal-appearing colonic mucosa and abnormal histopathological findings in colonic biopsies. The clinical features of the disease are based mainly on case reports or small uncontrolled series. Although normal colonoscopic findings are, as a rule, part of the diagnosis of CC, several cases of macroscopic colitis associated with CC have been reported, and the spectrum of endoscopic mucosal changes has not been described in large series. we present a retrospective study of all patients who underwent total colonoscopy and mucosal biopsy in our Endoscopy Unit between 1991 and 1997. Clinical and endoscopic findings in patients diagnosed as having CC or LC were recorded. of 676 patients studied, 398 suffered from chronic diarrhea. Collagenous colitis was diagnosed in 22 patients and LC in 10. Eleven per cent of the patients with CC and 20% of those with LC did not have diarrhea. Macroscopic colitis was observed in 6 out of 22 patients with CC (27%) and in 4 out of 10 with LC (40%). Macroscopic lesions included edema, erythema, abnormal vascular pattern, superficial erosions or ulcerations and hemorrhagic lacerations. In this series 7.03% of the patients with chronic diarrhea were diagnosed as having CC or LC. collagenous colitis and LC are two entities that should be considered in the differential diagnosis of chronic diarrhea. Total colonoscopy with multiple biopsies that include the right colon are mandatory. The presence of macroscopic lesions on endoscopy does not rule out a diagnosis of either entity. We identified patients who fulfilled the histopathological criteria for CC or LC but who did not have diarrhea. No disease specific markers are currently known in the blood, enabling the reliable separation of Crohn's disease and ulcerative colitis patients. The way doctors can tell the difference between Crohn's disease and UC is the location and nature of the inflammatory changes. Crohn's can affect any part of the gastrointestinal tract, from mouth to anus (skip lesions), although a majority of the cases start in the terminal ileum. Ulcerative colitis, in contrast, is restricted to the colon and the rectum. Microscopically, ulcerative colitis is restricted to the mucosa (epithelial lining of the gut), while Crohn's disease affects the full thickness of the bowel wall (\"transmural lesions\"). Lastly, Crohn's disease and ulcerative colitis present with extra-intestinal manifestations (such as liver problems, arthritis, skin manifestations and eye problems) in different proportions. The clinical presentation of ulcerative colitis depends on the extent of the disease process. Up to 15% of individuals may have severe disease upon initial onset of symptoms. A substantial proportion (up to 45%) of people with a history of UC without any ongoing symptoms (clinical remission) have objective evidence of ongoing inflammation. Ulcerative colitis is associated with a generalized inflammatory process that can affect many parts of the body. Sometimes, these associated extra-intestinal symptoms are the initial signs of the disease. Extent of involvement In contrast to Crohn's disease, which can affect areas of the gastrointestinal tract outside of the colon, ulcerative colitis is usually confined to the colon. Inflammation in ulcerative colitis is usually continuous, typically involving the rectum, with involvement extending proximally (to sigmoid colon, ascending colon, etc). In contrast, inflammation with Crohn's disease is often patchy, with so-called \"skip lesions.\" Lymphocytic colitis (LC) and collagenous colitis (CC), both known as microscopic colitis (MC), are uncommon entities with increasing incidence as more clinicians take biopsies from macroscopically normal colons and as pathologists use more rigorous diagnostic criteria to be confident of the diagnosis. Information on the incidence of this type of colitis is limited and based on reported cases. The purpose of this work is to estimate the incidence of LC and CC in reviewed routine colonoscopies. We reviewed 2815 colonoscopies performed at a tertiary referral center with an open-access service using restricted histological criteria in order to establish the frequency rate of LC and CC in routine colonoscopic biopsy material. Cases suspicious for MC were stained with Masson's trichrome or Congo red stain and immunohistochemically for lymphocytes, where appropriate. Review of routine colonoscopic biopsies showed that MC is underreported in our colonoscopic material. Incidence rates of LC and CC (0.9 and 0.4, respectively) were based on morphological assessment of colonoscopic biopsies using stringent criteria together with clinical data and after differentiation with other lesions which can mimic MC. The 10.2% rate of this type of colitis in patients with chronic watery diarrhea indicates the necessity to consider these lesions in older individuals with diarrhea and normal endoscopical colonic mucosa. To investigate the prevalence of microscopic colitis among patients presenting with chronic watery diarrhea. Colonic biopsies from 400 patients presenting with chronic watery diarrhea and other symptoms pertaining to lower gastrointestinal tract were studied. After a detailed clinical history and thorough physical examination full length colonoscopy was done using flexible colonoscope. Colonic biopsies were taken from abnormal and normal areas. Three to five micron thick sections were cut and stained with hematoxylin and eosin and Masson's trichrome stain to highlight sub epithelial collagen. Fifteen out of 400 (3.7%) colonic biopsies from patients presenting with chronic diarrhea had evidence of microscopic colitis. Five out of fifteen biopsies (33%) were diagnosed as collagenous colitis, 10 biopsies (67%) had evidence of lymphocytic colitis; 14/400(3.5%) histologically normal biopsies were taken as controls to compare various demographic and risk factors. Ten out of 15 patients (67%) were clinically diagnosed as irritable bowel syndrome. In the remaining five an infective etiology was suspected. On colonoscopy12/15 (80%) had no abnormality and 3/15 (20%) had mild hyperemia. A possibility of microscopic colitis should be considered while examining colonoscopic biopsy of a patient with chronic watery diarrhea and normal colonoscopy to avoid the misdiagnosis that may affect the treatment of patients. Microscopic colitis (MC) is a clinical syndrome of severe watery diarrhea with few or no endoscopic abnormalities. The incidence of MC is reported similar to that of other inflammatory bowel diseases. The need for histological confirmation of MC frequently guides reimbursement health policies. With the advent of high-definition (HD) coloscopes, the incidence of reporting distinct endoscopic findings in MC has risen. This has the potential to improve timely diagnosis and cost-effective MC management and diminish the workload and costs of busy modern endoscopy units. Publications on distinct endoscopic findings in MC available until March 31st, 2017 were searched systematically (electronic and manual) in PubMed database. The following search terms/descriptors were used: collagenous colitis (CC) OR lymphocytic colitis (LC) AND endoscopy, colonoscopy, findings, macroscopic, erythema, mucosa, vasculature, scars, lacerations, fractures. An additional search for MC AND perforation was made. Eighty (n=80) articles, predominantly single case reports (n=49), were found. Overall, 1582 (1159F; 61.6±14.1 years) patients (pts) with MC and endoscopic findings were reported. The majority of articles (n=62) were on CC (pts 756; 77.5% females). We identified 16 papers comprising 779 pts (69.2% females) with LC and 7 articles describing 47 pts (72.3% females) diagnosed as MC. The youngest patient was 10 and the oldest a 97-year-old. Aside diarrhea, symptoms included abdominal pain, weight loss, bloating, flatulence, edema and others. In the study group we found 615 (38.8%) persons with macroscopic lesions in gut. Isolated linear ulcerations were identified in 7 pts (1.1%) while non-ulcerous lesions i.e. pseudomembranes, a variable degree of vasculature pruning &amp; dwindling, mucosal lacerations and abnormalities such as erythema/edema/nodularity, or surface textural alteration in 608 pts (98.1%). The location of endoscopic findings was not reported in 27 articles. The distinct endoscopic findings were described in the left (descending, sigmoid, rectum - 10/21/11 studies), right (cecum, ascending - 7/7 studies), transverse colon (n=12), as well as duodenum (n=4), and terminal ileum (n=2). In 17 (1.1%) pts colonic perforation occurred. Endoscopic findings are recognized with increased frequency in pts with MC. This could improve MC diagnosis by prompting a more extensive biopsy protocol in such cases and an earlier initiation of treatment. Procedure-related perforation has been reported in this group; therefore, cautious air insufflation is advisable when endoscopic findings are recognised. Collagenous colitis is an inflammatory bowel disease affecting the colon specifically with peak incidence in the 5th decade of life, affecting women more than men. Its clinical presentation involves watery diarrhea in the absence of rectal bleeding. It is often classified under the umbrella entity microscopic colitis, that it shares with a related condition, lymphocytic colitis. Signs and symptoms Microscopic colitis causes chronic watery diarrhea with greater than 10 bowel movements per day. Some patients report nocturnal diarrhea, abdominal pain, urgency, fecal incontinence, fatigue, dehydration and weight loss. Patients report a significantly diminished quality of life. Causes The cause of collagenous colitis is unknown.\nHere is the question:\nPATHOLOGICAL ANATOMY: A 59-year-old woman presents with chronic watery diarrhea of 4 months' duration. On endoscopy, the mucosa showed no relevant features. In particular, no ulcers or friable areas were observed. A biopsy of the transverse colon was performed. Histopathology revealed a thickened area below the superficial lining epithelium, which was more evident by Masson's trichrome technique and involved epithelial atrophy and denudation. There was also a clear increase in intraepithelial lymphocyte density. The diagnosis of the intestinal lesion is?\nHere are the potential choices:\n1. Chronic ulcerative colitis.\n2. Pseudomembranous colitis.\n3. Collagenous colitis.\n4. Fibrosing Crohn's disease.\nThe correct answer is: ",
        "gold_answer": "3 Collagenous colitis.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n There are controversies about taking routine mucosal biopsy when the gross colonoscopic finding is normal. This study was conducted to determine the frequency of clinically important histological abnormalities, prospectively, in chronic diarrhea patients with grossly normal or nonspecific colonoscopic findings. One hundred and eighteen patients suffering from nonbloody diarrhea with average frequency of more than two times a day for more than 4 weeks were included. Multiple biopsies (cecum, ascending colon, mid-transverse colon, descending colon, sigmoid colon and rectum) were taken during colonoscopic examinations and each biopsy specimen was reviewed by one pathologist after H&amp;E and Masson-trichrome staining. Clinically significant abnormalities (2 collagenous colitis, 1 lymphocytic colitis, 1 eosinophilic enterocolitis, 1 ulcerative colitis and 4 melanosis coli) were observed in 9 patients (7.6%). Sixteen cases (13.6%) of borderline histological abnormalities were observed (8 cases of possible collagenous colitis and 8 cases showing some features of lymphocytic colitis). Ninety two cases (78.8%) showed nonspecific inflammation only. Clinically important histological lesions can exist in significant percentage in spite of normal or nonspecific colonoscopic findings, which can justify routine mucosal biopsy in the evaluation of chronic diarrhea patients. The clinical significance of borderline histological abnormalities needs to be determined by careful follow-up studies. Diagnosis Colonoscopic appearances are normal or near normal. As the changes are often patchy, an examination limited to the rectum may miss cases of microscopic colitis, and so a full colonoscopy is necessary. Multiple colonic biopsies are taken in order to make the diagnosis. Histological features of colonic biopsies indicating microscopic colitis are: greater than 20 intraepithelial lymphocytes per 100 epithelial cells and, additionally, 10-20 μm of a thickened subepithelial collagen band in collagenous colitis. Inflammation of the lamina propria, with mainly mononuclear cells, may be observed in collagenous colitis. Collagenous colitis and lymphocytic colitis are the two major conditions characterized by chronic watery diarrhoea, without endoscopic or radiological lesions, but with histological abnormalities and therefore considered as \"microscopic colitis\". The histology of colonic biopsies shows inflammation of the mucosa, and either thickening of the subepithelial collagen band or an increase of lymphocytes in the surface epithelium. Different variant forms have been reported under separate names. These are probably not specific entities. The incidence of microscopic colitis is slightly less than the incidence of chronic idiopathic inflammatory bowel diseases (IBD). Microscopic colitis and IBD are clearly different entities. The relation between both entities is weak but double. Biopsy samples from patients with IBD may mimic the features of lymphocytic or collagenous colitis, both in the initial onset and during follow-up. In the large majority of these cases, endoscopy shows or has shown mucosal lesions. In rare cases, however, a double diagnosis was made. Certain patients, usually of older age, presented first with a microscopic, usually collagenous colitis and developed subsequently genuine ulcerative colitis. Microscopic colitis (MC) is an encompassing term for two diseases; collagenous colitis and lymphocytic colitis. The colon appears normal by colonoscopy and a diagnosis is only obtained with a biopsy. The histopathology of collagenous colitis is mainly characterized by a thickening of the subepithelial basement membrane of the colonic mucosa with a band of collagen. Lymphocytic colitis is mainly characterized by an intraepithelial lymphocytosis without the collagen thickening. Even though the two diseases have a distinctive pathology their clinical symptoms are characterized by chronic watery diarrhea without bleeding. Microscopic colitis is thought to cause about 4-13% of all chronic diarrhea but their relative frequency is much higher among older people. The mean annual incidence for collagenous and lymphocytic colitis has been increasing. Steroids are the most effective treatment for microscopic colitis and budesonide is the most studied and effective therapy for MC. The aim of this paper is to give a review of two relatively new diseases which are among the most common cause of chronic diarrhea, especially among older people. A typical symptom of microscopic colitis (MC) is chronic watery diarrhea with normal endoscopic findings and characteristic inflammatory changes in histopathology. Treatment of the disease is mainly empiric. MC has two main subtypes: lymphocytic colitis and collagenous colitis. There are also untypical histopathological forms of MC: MC with giant cells, MC not otherwise specified (NOS) and cryptal lymphocytic coloproctitis. Some other histopathological changes in MC have been observed, especially Paneth cell hyperplasia or epithelial degeneration. Eosinophilic colitis, acute colitis, amyloidosis, ulcerative colitis and Crohn's disease should be taken into consideration in differential diagnosis. The most reliable biopsy material for histopathological examination are samples obtained from transverse colon. Some studies proved that treatment of MC makes it possible to reduce not only clinical, but also histopathological, manifestations. Pathology Microscopic colitis is characterized by an increase in inflammatory cells, particularly lymphocytes, in colonic biopsies with an otherwise normal appearance and architecture of the colon. Inflammatory cells are increased both in the surface epithelium (\"intraepithelial lymphocytes\") and in the lamina propria. The key feature is more than 20 intra-epithelial lymphocytes per 100 epithelial cells. These are the principal features of lymphocytic colitis. An additional distinguishing feature of collagenous colitis is a thickened subepithelial collagen layer, which may be up to 30 micrometres thick, that occurs in addition to the features found in lymphocytic colitis. The fact that the two types of microscopic colitis share many features including epidemiology, risk factors and, response to therapy has led to the suggestion that they are actually subtypes of the same disease. Microscopic colitis (MC) is a chronic inflammatory process observed in colon biopsies of patients with chronic aqueous diarrhea. It is called microscopic because diagnosis is determined by histological studies since the microscopic characteristics of the colon endoscopy are normal. Two patterns exist: Lymphocytic Microscopic Colitis and Collagenous Microscopic Colitis. Etiology is unknown, and the proposed pathogenic mechanisms indicate an immunological phenomenon. Based on this, the authors of this study hypothesize that lymphocytic infiltration of the lamina propria could be related to cytotoxic lymphocytes CD8 as causative agents of colon tissue damage. Prove hypothesis of immunological pathogenesis of MC. APPARATUS AND METHODS: Thirty eight (38) patients with diagnosed MC were recruited for the last four years in the Pathology Laboratory at Ricardo Palma University. Twenty two (22) colon biopsies with the most severe histological lesions were selected. These biopsies were obtained from 17 patients: 5 patients had 2 biopsies in 2 colonoscopy sessions. Biopsies were fixed in neutral formaldehyde, processed through the paraffin inclusion method, and stained with hematoxiline-eosine and Masson trichromic to distinguish collagenous tissue. Immunohistochemistry was conducted in 4- or 5-micron-thick histological sections processed through the immunoperoxidase method. Nineteen (19) biopsies corresponded to Lymphocytic MC and 3 to Collagenous MC. Lymphocytic MC showed intraepithelial lymphocytosis, dystrophic epithelial damage in the areas of lymphocytic infiltration, lamina propria inflammation with lymphocytes and plasma cells, and normal basement membrane. Collagenous MC showed thickened basement membrane due to the presence of a collagenous band, mild to moderate intraepithelial lymphocytosis, vacuolization,and frequent detachment of protective epithelium. Twenty two (22) biopsies were positive in the immunohistochemical studies. The simple clinical colitis activity index was created in 1998 and is used to assess the severity of symptoms. Endoscopic The best test for diagnosis of ulcerative colitis remains endoscopy, which is examination of the internal surface of the bowel using a flexible camera. Initially, a flexible sigmoidoscopy may be completed to establish the diagnosis. The physician may elect to limit the extent of the initial exam if severe colitis is encountered to minimize the risk of perforation of the colon. However, a complete colonoscopy with entry into the terminal ileum should be performed to rule out Crohn's disease, and assess extent and severity of disease. Endoscopic findings in ulcerative colitis include: erythema (redness of the mucosa), friability of the mucosa, superficial ulceration, and loss of the vascular appearance of the colon. When present, ulcerations may be confluent. Pseudopolyps may be observed. The literature review gives the present-day views of the definition, etiology, pathogenesis, diagnosis, and treatment of microscopic colitis (MC). In the present view, MC is an inflammatory bowel disease of unknown etiology, which is characterized by chronic watery diarrhea, no macroscopic signs of large bowel involvement in the presence of specific pathomorphological changes. There are two major forms of MC, which are similar in its clinical picture, yet, heterogeneous in histological criteria: collagenous colitis (CC) and lymphocytic colitis (LC). As of now, the prevalence of MC is about 100 cases per 100,000 population, which is similar with that in other inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. MC generally prevails in women aged over 50 years. The etiology and pathogenesis of MC have not fully investigated. Watery diarrhea is as a predominant pathognomonic symptom in all the patients with MC. The major histological criterion for the diagnosis of CC is subepithelial collagen lining thickening (more than 10 pm) and that for LC is higher intraepithelial lymphocyte counts (more than 20 intraepithelial lymphocytes/100 epitheliocytes). The topical glucocorticosteroid budesonide is currently the only agent, the efficacy of which has been proven in both inducing and maintaining remission in patients with MC in many clinical trials. Collagenous colitis and lymphocytic colitis are defined by a clinicopathologic syndrome with chronic watery diarrhea, microscopic lesions of colonic biopsies, and normal barium enema and colonoscopy. A histopathological study was performed on multiple colorectal biopsies to compare 12 cases of collagenous colitis (defined by a subepithelial collagen thicker than 10 microns) and 7 cases of lymphocytic colitis (defined by a number of intraepithelial lymphocytes more than 20 per 100 epithelial cells at least in one biopsied site). The study included a semiquantitative analysis of inflammatory infiltrate in the lamina propria, crypts distortion and epithelial detachment. The number of intraepithelial lymphocytes per 100 epithelial cells was determined in surface epithelium and crypts. The subepithelial collagen thickening was studied by computerised morphometry. The intraepithelial lymphocytes, villous atrophy and thickness of the subepithelial collagen were also determined in gastric and duodenal biopsies. In collagenous colitis, the subepithelial collagenous thickness ranged from 10 to 40 microns in the colon (median 20.99 microns). In 4 cases of collagenous colitis, no thickening of the collagen plate was seen in the rectum. We found constant epithelial detachment and mucosal distortion. In lymphocytic colitis, the thickness of the subepithelial collagen ranged from 6 to 10 microns in 4 cases and was less than 6 microns in 3 cases (median 6.24 microns). The median number of intraepithelial lymphocytes in surface epithelium was 22.35 (range 18.2 to 40) in lymphocytic colitis versus 12.22 (range 4.6 to 24.4) in collagenous colitis. In conclusion, we observed an overlap of both the collagenous plate thickness and the number of intraepithelial lymphocytes in collagenous colitis and lymphocytic colitis. This result favours a unified histogenesis for these two entities. Lymphocytic colitis is a subtype of microscopic colitis, a condition characterized by chronic non-bloody watery diarrhea. Causes No definite cause has been determined. The peak incidence of lymphocytic colitis is in persons over age 50; the disease affects women and men equally. Some reports have implicated long-term usage of NSAIDs, proton pump inhibitors, and selective serotonin reuptake inhibitors, and other drugs. Associations with other autoimmune disorders suggests that overactive immune responses occur. Diagnosis The colonoscopy is normal but histology of the mucosal biopsy reveals an accumulation of lymphocytes in the colonic epithelium and connective tissue (lamina propria). Collagenous colitis shares this feature but additionally shows a distinctive thickening of the subepithelial collagen table. Microscopic colitis is a clinicopathological entity which, in addition to typical symptoms such as watery diarrhea, is characterized by its specific histopathology. Since colonoscopy yields normal findings, microscopic colitis belongs in a histological domain. The term encompasses two forms: lymphocytic and collagenous colitis. Histologically, lymphocytic colitis shows an increase in intraepithelial lymphocytes of more than 20 lymphocytes per 100 surface colonocytes, while collagenous colitis is characterized by a thickened subepithelial collagen layer of more than 10 µm. Specific stains help in the quantification of both. Since microscopic colitis does not always affect the entire colon and the number of intraepithelial lymphocytes varies physiologically, obtaining stepwise biopsies of the colon (with information on location where possible) is recommended. A thickened collagen layer is relatively specific for collagenous colitis, whereas intraepithelial lymphocytosis is also found in other diseases. Therefore, to make a correct diagnosis, it is important to correlate histological findings with clinical symptoms, including the main symptom of watery diarrhea. An important investigation in the assessment of colitis is biopsy. A very small piece of tissue (usually about 2mm) is removed from the bowel mucosa during endoscopy and examined under the microscope by a histopathologist. It can provide important information regarding the cause of the disease and the extent of bowel damage. Types There are many types of colitis. They are usually classified by the cause. Types of colitis include: Autoimmune Inflammatory bowel disease (IBD) – a group of chronic colitides. Ulcerative colitis (UC) – a chronic colitis that affects the large intestine. Crohn's disease (CD) – another type of IBD that often leads to colitis. Unknown Microscopic colitis – a colitis diagnosed by microscopic examination of colonic tissue; macroscopically (\"to the eye\") it appears normal. Lymphocytic colitis Collagenous colitis Treatment-caused Diversion colitis Chemical colitis Chemotherapy-induced colitis Radiation colitis Checkpoint inhibitor induced colitis Types There are four types of SCAD, based on endoscopic appearance. Pattern A is characterized by involvement of crescentic folds and is the most common type of SCAD (52%). Pattern B has an appearance similar to mild-to moderate ulcerative colitis (30.40%), whereas pattern C appears similar to Crohn's disease (10.90%). Pattern D is the least common, and appears similar to severe ulcerative colitis (6.50%). Diagnosis SCAD is diagnosed via colonoscopy, often incidentally during examination for unrelated concerns. Colonoscopy shows erythema of the colonic mucosa, which may be characterized by friability and exudate. The descending and sigmoid colon are typically involved. Biopsies of the affected area and the unaffected rectum confirm the diagnosis. Biopsies of SCAD show evidence of chronic inflammation. Rectal biopsies show normal mucosa. Ulcerative colitis is usually continuous from the rectum, with the rectum almost universally being involved. Perianal disease is rare. The degree of involvement endoscopically ranges from proctitis (rectal inflammation) to left sided colitis (extending to descending colon), to extensive colitis (extending proximal to descending colon). Histologic Biopsies of the mucosa are taken during endoscopy to confirm the diagnosis of UC and differentiate it from Crohn's disease, which is managed differently clinically. Histologic findings in ulcerative colitis includes: distortion of crypt architecture, crypt abscesses, and inflammatory cells in the mucosa (lymphocytes, plasma cells, and granulocytes). Unlike the transmural inflammation seen in Crohn's disease, the inflammation of ulcerative colitis is limited to the mucosa. Microscopic colitis refers to two related medical conditions which cause diarrhea: collagenous colitis and lymphocytic colitis. Both conditions are characterized by the presence of chronic non-bloody watery diarrhea, normal appearances on colonoscopy and characteristic histopathology findings of inflammatory cells. Signs and symptoms The main symptom is persistent non-bloody watery diarrhea, which may be profuse. People may also experience abdominal pain, fecal incontinence, and unintentional weight loss. Microscopic colitis is the diagnosis in around 10% of cases investigated for chronic non-bloody diarrhea. Microscopic colitis has emerged as a major cause of chronic watery non-bloody diarrhoea, particularly in elderly females. The term is used as an umbrella term to categorize a subgroup of colitides with distinct clinicopathological phenotypes and no significant endoscopic abnormalities. Lymphocytic colitis is defined by an increased number of surface intraepithelial lymphocytes, and collagenous colitis by a thickened collagen band underneath the surface epithelium. There is increased inflammation in the lamina propria, but only little or no crypt architectural distortion. Incomplete and variant forms showing less characteristic features have been reported under different names. The differential diagnosis mainly includes resolving infectious colitis and changes related to the intake of drugs such as non-steroidal anti-inflammatory drugs. Substantial clinical and histological overlap between lymphocytic and collagenous colitis has been described, raising the suspicion that the conditions are two histological manifestations of the same entity, possibly representing different manifestations during the disease course or different stages of disease development. In this review, we provide a practical approach for pathologists, with a focus on diagnostic criteria and differential diagnosis, and discuss recent insights into the pathogenesis of disease and the relationship with classic chronic inflammatory bowel disease, i.e. Crohn's disease and ulcerative colitis.  collagenous colitis (CC) and lymphocytic colitis (LC) are two entities of unknown cause, characterized by chronic watery diarrhea, grossly normal-appearing colonic mucosa and abnormal histopathological findings in colonic biopsies. The clinical features of the disease are based mainly on case reports or small uncontrolled series. Although normal colonoscopic findings are, as a rule, part of the diagnosis of CC, several cases of macroscopic colitis associated with CC have been reported, and the spectrum of endoscopic mucosal changes has not been described in large series. we present a retrospective study of all patients who underwent total colonoscopy and mucosal biopsy in our Endoscopy Unit between 1991 and 1997. Clinical and endoscopic findings in patients diagnosed as having CC or LC were recorded. of 676 patients studied, 398 suffered from chronic diarrhea. Collagenous colitis was diagnosed in 22 patients and LC in 10. Eleven per cent of the patients with CC and 20% of those with LC did not have diarrhea. Macroscopic colitis was observed in 6 out of 22 patients with CC (27%) and in 4 out of 10 with LC (40%). Macroscopic lesions included edema, erythema, abnormal vascular pattern, superficial erosions or ulcerations and hemorrhagic lacerations. In this series 7.03% of the patients with chronic diarrhea were diagnosed as having CC or LC. collagenous colitis and LC are two entities that should be considered in the differential diagnosis of chronic diarrhea. Total colonoscopy with multiple biopsies that include the right colon are mandatory. The presence of macroscopic lesions on endoscopy does not rule out a diagnosis of either entity. We identified patients who fulfilled the histopathological criteria for CC or LC but who did not have diarrhea. No disease specific markers are currently known in the blood, enabling the reliable separation of Crohn's disease and ulcerative colitis patients. The way doctors can tell the difference between Crohn's disease and UC is the location and nature of the inflammatory changes. Crohn's can affect any part of the gastrointestinal tract, from mouth to anus (skip lesions), although a majority of the cases start in the terminal ileum. Ulcerative colitis, in contrast, is restricted to the colon and the rectum. Microscopically, ulcerative colitis is restricted to the mucosa (epithelial lining of the gut), while Crohn's disease affects the full thickness of the bowel wall (\"transmural lesions\"). Lastly, Crohn's disease and ulcerative colitis present with extra-intestinal manifestations (such as liver problems, arthritis, skin manifestations and eye problems) in different proportions. The clinical presentation of ulcerative colitis depends on the extent of the disease process. Up to 15% of individuals may have severe disease upon initial onset of symptoms. A substantial proportion (up to 45%) of people with a history of UC without any ongoing symptoms (clinical remission) have objective evidence of ongoing inflammation. Ulcerative colitis is associated with a generalized inflammatory process that can affect many parts of the body. Sometimes, these associated extra-intestinal symptoms are the initial signs of the disease. Extent of involvement In contrast to Crohn's disease, which can affect areas of the gastrointestinal tract outside of the colon, ulcerative colitis is usually confined to the colon. Inflammation in ulcerative colitis is usually continuous, typically involving the rectum, with involvement extending proximally (to sigmoid colon, ascending colon, etc). In contrast, inflammation with Crohn's disease is often patchy, with so-called \"skip lesions.\" Lymphocytic colitis (LC) and collagenous colitis (CC), both known as microscopic colitis (MC), are uncommon entities with increasing incidence as more clinicians take biopsies from macroscopically normal colons and as pathologists use more rigorous diagnostic criteria to be confident of the diagnosis. Information on the incidence of this type of colitis is limited and based on reported cases. The purpose of this work is to estimate the incidence of LC and CC in reviewed routine colonoscopies. We reviewed 2815 colonoscopies performed at a tertiary referral center with an open-access service using restricted histological criteria in order to establish the frequency rate of LC and CC in routine colonoscopic biopsy material. Cases suspicious for MC were stained with Masson's trichrome or Congo red stain and immunohistochemically for lymphocytes, where appropriate. Review of routine colonoscopic biopsies showed that MC is underreported in our colonoscopic material. Incidence rates of LC and CC (0.9 and 0.4, respectively) were based on morphological assessment of colonoscopic biopsies using stringent criteria together with clinical data and after differentiation with other lesions which can mimic MC. The 10.2% rate of this type of colitis in patients with chronic watery diarrhea indicates the necessity to consider these lesions in older individuals with diarrhea and normal endoscopical colonic mucosa. To investigate the prevalence of microscopic colitis among patients presenting with chronic watery diarrhea. Colonic biopsies from 400 patients presenting with chronic watery diarrhea and other symptoms pertaining to lower gastrointestinal tract were studied. After a detailed clinical history and thorough physical examination full length colonoscopy was done using flexible colonoscope. Colonic biopsies were taken from abnormal and normal areas. Three to five micron thick sections were cut and stained with hematoxylin and eosin and Masson's trichrome stain to highlight sub epithelial collagen. Fifteen out of 400 (3.7%) colonic biopsies from patients presenting with chronic diarrhea had evidence of microscopic colitis. Five out of fifteen biopsies (33%) were diagnosed as collagenous colitis, 10 biopsies (67%) had evidence of lymphocytic colitis; 14/400(3.5%) histologically normal biopsies were taken as controls to compare various demographic and risk factors. Ten out of 15 patients (67%) were clinically diagnosed as irritable bowel syndrome. In the remaining five an infective etiology was suspected. On colonoscopy12/15 (80%) had no abnormality and 3/15 (20%) had mild hyperemia. A possibility of microscopic colitis should be considered while examining colonoscopic biopsy of a patient with chronic watery diarrhea and normal colonoscopy to avoid the misdiagnosis that may affect the treatment of patients. Microscopic colitis (MC) is a clinical syndrome of severe watery diarrhea with few or no endoscopic abnormalities. The incidence of MC is reported similar to that of other inflammatory bowel diseases. The need for histological confirmation of MC frequently guides reimbursement health policies. With the advent of high-definition (HD) coloscopes, the incidence of reporting distinct endoscopic findings in MC has risen. This has the potential to improve timely diagnosis and cost-effective MC management and diminish the workload and costs of busy modern endoscopy units. Publications on distinct endoscopic findings in MC available until March 31st, 2017 were searched systematically (electronic and manual) in PubMed database. The following search terms/descriptors were used: collagenous colitis (CC) OR lymphocytic colitis (LC) AND endoscopy, colonoscopy, findings, macroscopic, erythema, mucosa, vasculature, scars, lacerations, fractures. An additional search for MC AND perforation was made. Eighty (n=80) articles, predominantly single case reports (n=49), were found. Overall, 1582 (1159F; 61.6±14.1 years) patients (pts) with MC and endoscopic findings were reported. The majority of articles (n=62) were on CC (pts 756; 77.5% females). We identified 16 papers comprising 779 pts (69.2% females) with LC and 7 articles describing 47 pts (72.3% females) diagnosed as MC. The youngest patient was 10 and the oldest a 97-year-old. Aside diarrhea, symptoms included abdominal pain, weight loss, bloating, flatulence, edema and others. In the study group we found 615 (38.8%) persons with macroscopic lesions in gut. Isolated linear ulcerations were identified in 7 pts (1.1%) while non-ulcerous lesions i.e. pseudomembranes, a variable degree of vasculature pruning &amp; dwindling, mucosal lacerations and abnormalities such as erythema/edema/nodularity, or surface textural alteration in 608 pts (98.1%). The location of endoscopic findings was not reported in 27 articles. The distinct endoscopic findings were described in the left (descending, sigmoid, rectum - 10/21/11 studies), right (cecum, ascending - 7/7 studies), transverse colon (n=12), as well as duodenum (n=4), and terminal ileum (n=2). In 17 (1.1%) pts colonic perforation occurred. Endoscopic findings are recognized with increased frequency in pts with MC. This could improve MC diagnosis by prompting a more extensive biopsy protocol in such cases and an earlier initiation of treatment. Procedure-related perforation has been reported in this group; therefore, cautious air insufflation is advisable when endoscopic findings are recognised. Collagenous colitis is an inflammatory bowel disease affecting the colon specifically with peak incidence in the 5th decade of life, affecting women more than men. Its clinical presentation involves watery diarrhea in the absence of rectal bleeding. It is often classified under the umbrella entity microscopic colitis, that it shares with a related condition, lymphocytic colitis. Signs and symptoms Microscopic colitis causes chronic watery diarrhea with greater than 10 bowel movements per day. Some patients report nocturnal diarrhea, abdominal pain, urgency, fecal incontinence, fatigue, dehydration and weight loss. Patients report a significantly diminished quality of life. Causes The cause of collagenous colitis is unknown.\nHere is the question:\nPATHOLOGICAL ANATOMY: A 59-year-old woman presents with chronic watery diarrhea of 4 months' duration. On endoscopy, the mucosa showed no relevant features. In particular, no ulcers or friable areas were observed. A biopsy of the transverse colon was performed. Histopathology revealed a thickened area below the superficial lining epithelium, which was more evident by Masson's trichrome technique and involved epithelial atrophy and denudation. There was also a clear increase in intraepithelial lymphocyte density. The diagnosis of the intestinal lesion is?\nHere are the potential choices:\n1. Chronic ulcerative colitis.\n2. Pseudomembranous colitis.\n3. Collagenous colitis.\n4. Fibrosing Crohn's disease.\nThe correct answer is: 3. Collagenous colitis."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A Japanese man who died at age 85 had been followed since the age of 59, when he first presented. He had hypertension of 162/102 mmHg and a loud systolic murmur on his first visit. He had had an active daily life without any medication for the next 10 years. At the age of 72 he complained of mild chest discomfort on exercise. Although electrocardiography showed no abnormalities, echocardiogram showed calcified bicuspid aortic valve with mild stenosis. At the age of 81 the dyspnea and chest oppression were exacerbated, associated with marked ST depression on exercise electrocardiogram and restriction of aortic valve opening on echocardiograms. In the following years a gradual increase in QRS voltage and ST depression with T wave inversion were recorded on resting electrocardiograms and sharp increases in both left ventricular end-diastolic diameter and flow velocity at the aortic root were observed on echocardiograms. At the age of 85 he died of intractable heart failure with massive pleural effusion. Autopsy revealed marked hypertrophy and moderate dilatation of the heart (weight: 580 g). The bicuspid aortic valve had anterior-posterior cusps with a raphe on the anterior cusp. The mobility of the cusps was almost lost because of severe calcification and thickening. Severe stenosis was found near the orifice of the right coronary artery, but there were no significant ischemic myocardial lesions. PRESENTING FEATURES: A 70-year-old African American man was admitted with a history of fever, chills, and malaise of several days' duration. His past medical history was notable for end-stage renal disease requiring hemodialysis, coronary artery disease, and aortic stenosis requiring a bioprosthetic aortic valve replacement. On the day of admission, the patient was noted to have a shaking chill while undergoing dialysis through his catheter and was admitted to the hospital. He complained of pain at the catheter insertion site, shortness of breath, and dyspnea on exertion, but denied chest pain. On physical examination, the patient had a temperature of 100.4 degrees F, with a heart rate of 64 beats per minute, blood pressure of 127/72 mm Hg, and an oxygen saturation of 97% on room air. He was a mildly obese man in no apparent distress. He had shotty cervical lymphadenopathy and a right subclavian dialysis catheter in place, with erythema and pus at the entry site. His jugular venous pressure was 10 cm H(2)O. Lung examination showed bibasilar rales. Heart sounds were normal, with no rub or gallop. He had a 2/6 systolic ejection murmur best heart at the left sternal border as well as a 3/6 holosystolic murmur at the apex that radiated to his left axilla. Examination of the abdomen and extremities was unremarkable. The patient's neurological examination was unremarkable, and he was alert and oriented to person, place, and time. Laboratory studies showed an elevated white blood cell count of 16,700 cells/microL. His blood urea nitrogen level was 43 mg/dL and his serum creatinine level was 4.9 mg/dL. Multiple blood cultures grew methicillin-resistant Staphylococcus aureus. An admission, chest radiograph showed no infiltrate. An admission electrocardiogram showed normal sinus rhythm with first degree atrioventricular block, left anterior fascicular block, and left ventricular hypertrophy. shows rhythm strips from lead II electrocardiograms 5 months before admission (top), on admission (middle) and 5 days after admission (bottom). What is the diagnosis? A 53-year-old woman with no previous medical history complained of easy fatigue over the last 6 months. She had a positive family history for coronary artery disease but no other risk factors. On physical examination, a 3/6 pansystolic murmur was heard over the apex, and the lung auscultation was unremarkable. Her ECG showed a left anterior fascicular block, with poor R wave progression in the anterior leads (see online supplementary image A). A subsequent echocardiogram revealed a slightly dilated for the patient's body surface area (BSA) (1.73 m<sup2</sup) left ventricle (55/35 mm), with preserved systolic function and a moderate functional mitral regurgitation. The estimated pulmonary artery pressure was 45 mm Hg. During treadmill radionuclide scintigraphy, her exercise tolerance was normal, with good inotropic response, and 96% oxygen saturation at rest and at peak exercise. A 2 mm ST segment depression was noted at peak effort, which persisted well into recovery (see online supplementary image B). The scintigraphy scan showed extensive reversible anteroapical wall ischaemia (see online supplementary image C). At this point she was referred to us for right and left heart catheterisation. Intracardiac pressures and saturations were: right atrium (RA)RA=3 mm Hg, right ventricle (RV)=26/3 mm Hg, Pulmonary artery (PA)=26/10/mean 16 mm Hg, pulmonary capillary wedge pressure (PCWP)=11 mm Hg, left ventricle (LV)=110/10 mm Hg, Aorta (Ao)=110/60/mean 80 mm Hg, Superior vena cava saturation (SVCsat)=62%, RAsat=62%, PAsat=78%, Aosat=96% and estimated pulmonary to systematic flow ratio (Qp/Qs)=1.8. Her coronary angiography and CT angiography are shown in figure 1A,B.DC1SP110.1136/heartjnl-2017-311256.supp1Supplementary material 1 DC2SP210.1136/heartjnl-2017-311256.supp2Supplementary material 2 DC3SP310.1136/heartjnl-2017-311256.supp3Supplementary material 3 heartjnl;103/17/1390/F1F1F1Figure 1Coronary and CT angiograms. What is the most likely diagnosis?Right coronary fistula to right ventricleKawasaki disease with fistulaAnomalous origin of the left coronary artery from the pulmonary arteryPersistent truncus arteriosus. Medical signs of aortic stenosis include pulsus parvus et tardus, that is, diminished and delayed carotid pulse, fourth heart sound, decreased A2 sound, sustained apex beat, precordial thrill. Auscultation may reveal a systolic murmur of a harsh crescendo-decrescendo type, heard in 2nd right intercostal space and radiating to the carotid arteries. Aortic regurgitation Patients with aortic regurgitation may experience heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, and angina pectoris. In acute cases patients may experience cyanosis and circulatory shock. Medical signs of aortic regurgitation include increased pulse pressure by increased systolic and decreased diastolic blood pressure, but these findings may not be significant if acute. The patient may have a diastolic decrescendo murmur best heard at left sternal border, water hammer pulse, Austin Flint murmur, and a displaced apex beat down and to the left. A third heart sound may be present Mitral stenosis Patients with mitral stenosis may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, chest pain, hemoptysis, thromboembolism, or ascites and edema (if right-sided heart failure develops). Symptoms of mitral stenosis increase with exercise and pregnancy A 66-year-old male patient was admitted to our clinic because of shortness of breath and chest pain. A grade 4/6 diastolic murmur was heard on auscultation. Physical examination revealed signs of congestive heart failure and poor peripheral perfusion. There was a diagnosis of type II ascending aortic dissection in the history of the patient. He had refused emergency surgical intervention three years earlier. Computed tomography revealed that the ascending aorta was dilated to about 10 cm in diameter, and there was a chronic aortic type II dissection. The patient had second- to third-degree aortic insufficiency and he had a calcified bicuspid aortic valve on echocardiography. Two-vessel disease and a 90-mmHg aortic gradient were detected on angiography. Graft replacement of the ascending aorta, serape aortic valve replacement with a mechanical valve, and coronary arterial bypass grafting were performed successfully under cardiopulmonary bypass with an open aortic technique. The patient was discharged on the 10th postoperative day with no problems.  Aortic regurgitation when acute and/or severe can be suspected when the patient has a wide pulse pressure, and a low pitched early diastolic murmur is auscultated again over the right sternal border at the second intercostal space. Accentuated P2 may also be noticed due to elevated pressures in the pulmonary vasculature. Chronic aortic regurgitation may illicit a blowing diastolic decrescendo murmur with a positive correlation between the duration of murmur and the severity of the disease. Often auscultation of a laterally and inferiorly displaced apical impulse is present and sustained. Often there is the phenomenon of Corrigan pulse (water hammer), a bounding and forceful pulse that rapidly increases and collapses. Other less common physical exam findings include the de Musset sign, which is subtle head bobbing with a pulse, as well as the Quincke sign and Muller sign (pulsations on the fingernails and uvula, respectively). Similar physical exam findings to aortic stenosis can also be seen late in disease progression. Acute aortic regurgitation will present differently depending on the etiology. If a patient presents with tearing severe chest pain along with physical exam findings such as variation in blood pressure between the right and left extremities, consider aortic dissection as a cause. If the patient presented with a history of streptococcal infection along with fevers, swollen and tender joints, skin nodules, new onset of rash, then rheumatic heart disease would be high on the differential. The patient, MSM, a 69-year-old man, sought medical care due to left dorsal and right lower limb pain. The chest x-ray showed mediastinal enlargement. He was undergoing examination when he lost consciousness and went into shock. Subcutaneous emphysema was observed in the left hemithorax, as well as abolition of breath sounds at auscultation. Tracheal intubation was performed with draining of blood-tinged fluid from the left hemithorax. Echocardiography showed left ventricle with 44/29 mm; septum, 12 mm; posterior wall, 13 mm; mild aortic root dilation, dissection of the lamina and periaortic hematoma. The valves and pericardium were normal. The patient was transferred to Instituto do Coraçao - InCor. Physical examination (21 Oct 2004: 10:45) showed that the patient was sedated with tracheal intubation, pale, heart rate at 90 bpm, blood pressure 130 x 80 mmHg, bloody drainage in the chest tube. Electrocardiogram - frequency 90 bpm, sinus rhythm, low voltage in the frontal plane and decreased voltage in left leads (Fig. 1). Computed tomography showed bilateral subcutaneous emphysema, thoracic aorta with inaccurate borders in its descending portion (from the subclavian artery to the middle portion), collapsed left lung and extensive collection of hematic characteristics in same hemithorax and middle and posterior mediastinum. Small right pneumothorax; small right pleural effusion with underlying parenchymal alterations. The analysis of the heart was impaired by the presence of hemothorax. While undergoing computed tomography, the patient showed no pulse, mydriasis, with asystole unresponsive to resuscitation and died (21 Oct 2011; 15:00 h). If there is increased stroke volume of the left ventricle due to volume overload, an ejection systolic 'flow' murmur may also be present when auscultating the same aortic area. Unless there is concomitant aortic valve stenosis, the murmur should not start with an ejection click. There may also be an Austin Flint murmur, a soft mid-diastolic rumble heard at the apical area; it appears when a regurgitant jet of blood from severe aortic regurgitation partially closes the anterior mitral leaflet. Peripheral physical signs of aortic regurgitation are related to the high pulse pressure and the rapid decrease in blood pressure during diastole due to blood returning to the heart from the aorta through the incompetent aortic valve, although the usefulness of some of the eponymous signs has been questioned: Phonocardiograms detect AI by having electric voltage mimic the sounds the heart makes. Characteristics- indicative of aortic regurgitation are as follow: Cocaine use: This condition is suspected when a person with few or no risk of arteriosclerosis presented with non-traumatic chest pain. Ingestion of cocaine can cause vasoconstriction of coronary arteries, thus producing chest pain similar to heart attack. Symptoms can appear within one hour of cocaine use. Aortic stenosis: This condition happens when the person has underlying congenital bicuspid valve, aortic sclerosis, or history of rheumatic fever. Chest pain usually happens during physical activity. Syncope is a late symptom. Signs and symptoms of heart failure may also present. On auscultation, loud ejection systolic murmur can be best heard at the right second intercostal space and radiates to the carotid artery in the neck. Splitting of second heart sound is heard in severe stenosis. The Austin Flint murmur is a rumbling diastolic murmur best heard at the apex of the heart that is associated with severe aortic regurgitation and is usually heard best in the fifth intercostal space at the midclavicular line. Younger patients are more likely to have a history of a bicuspid aortic valve or rheumatic heart disease, while older patients are more likely to suffer from calcific valvular disease. A blood pressure reading on the patient will show an increased pulse pressure due to the backflow of blood through the aortic valve during diastole. An astute clinician may be able to palpate a \"water hammer\" pulse, which is also known as \"Corrigan's pulse.\" This finding demonstrates arterial swelling followed by a brisk diastolic fall. Patients may endorse a history of syncope or lightheadedness associated with an inability to maintain forward flow through the aortic valve and the significant difference between systolic and diastolic pressure. Decreasing exercise tolerance and the inability to perform activities of daily living should prompt screening for this condition. The acquired aortic stenosis manifests with exertional dyspnea, syncope, angina, and, ultimately, heart failure. [17] [18] Typically, symptoms begin at the age of 50 to 70 years in patients with the bicuspid aortic valve and in greater than 70 years in patients with tri-leaflet valve calcific stenosis. Patients progressively experience a gradual decrease in exercise tolerance, dyspnea on exertion, and fatigue. Severe exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, and pulmonary edema show various degrees of pulmonary venous hypertension. Angina results from the combination of the need for increased oxygen in hypertrophied myocardium and reduction of oxygen delivery secondary to the excessive compression of coronary vessels. Syncope is caused by the decrease in cerebral perfusion occurring during exertion when the arterial pressure declines due to systemic vasodilation and an inadequate increase in cardiac output related to stenosis. It is also due to the malfunction of the baroreceptor mechanism in severe aortic stenosis. Non-cardiac symptoms include gastrointestinal (GI) bleeding and cerebral emboli. GI bleeding is observed in patients with severe aortic stenosis and is often associated with angiodysplasia or other vascular malformations. It manifests from shear stress-induced platelet aggregation and reduction in the von Willebrand factor. [19] Cerebral emboli occur due to microthrombi formation on thickened bicuspid valves. There is also an observed increase in the risk of infective endocarditis in patients with aortic valve disease, especially with a bicuspid valve. On examination, carotid upstroke can be observed on palpation. A slow-rising, late-peaking, and a low-amplitude carotid impulse, pulsus parvus et tardus, is an expected finding in severe aortic stenosis and, when present, is specific to aortic stenosis. On auscultation, the second heart sound may lack a split and can be heard as a single sound during inspiration. It can also become paradoxical when the closure of the aortic valve gets delayed than the pulmonic valve. A mid-systolic ejection murmur, heard best over the right second intercostal space, with radiation into the right neck. However, high-frequency components may radiate to the apex in calcified aortic valves, and this phenomenon is called the Gallavardin phenomenon. The murmur becomes softer in LV failure and when there is a fall of stroke volume. A 23-year-old woman followed at another medical centre for congenital heart disease (CHD) presented to our emergency clinic with 3 weeks of bilateral pleuritic chest pain. She returned from holiday in Greece 6 weeks earlier where a tattoo and nasal piercing had been performed. There was no history of night sweats or fever.Her temperature was 37.5°C, heart rate 120 beats/min, oxygen saturations 94% on room air and blood pressure 110/74. Her chest was clear and there was systolic murmur on auscultation. The chest radiograph showed peripheral bilateral lower zone atelectasis. The ECG demonstrated sinus tachycardia. The haemoglobin was 11.2 g/dL, white cell count 10.18×10<sup9</sup/L, C-reactive protein 67 mg/L (normal &lt;5 mg/L) and D dimer=430 ng/mL (normal &lt;230 ng/mL).A pulmonary embolus was suspected and a CT pulmonary angiogram was performed (figure 1). Based on the CT findings, what is the most likely underlying congenital heart lesion in this patient?Bicuspid aortic valveCoarctation of the aortaFontan circulationParachute mitral valveVentricular septal defect heartjnl;105/6/464/F1F1F1Figure 1CT pulmonary angiogram (coronal views). Finally the sacrum and ankles are checked for pitting edema which is caused by right ventricular failure in isolation or as part of congestive cardiac failure. Auscultation One should comment on S1 and S2 – if the splitting is abnormal or louder than usual. S3 – the emphasis and timing of the syllables in the word Kentucky is similar to the pattern of sounds in a precordial S3. S4 – the emphasis and timing of the syllables in the word Tennessee is similar to the pattern of sounds in a precordial S4. If S4 S1 S2 S3 Also known as a gallop rhythm. diastolic murmurs (e.g. aortic regurgitation, mitral stenosis) systolic murmurs (e.g. aortic stenosis, mitral regurgitation) pericardial rub (suggestive of pericarditis) The base of the lungs should be auscultated for signs of pulmonary oedema due to a cardiac cause such as bilateral basal crepitations. Death in patients with severe AS occurs most commonly in the seventh and eighth decades. Based on data obtained at postmortem examination in patients before surgical treatment became widely available, the average time to death after the onset of various symptoms was as follows: angina pectoris, 3 years; syncope, 3 years; dyspnea, 2 years; congestive heart failure, 1.5–2 years. Moreover, in >80% of patients who died with AS, symptoms had existed for <4 years. Among adults dying with valvular AS, sudden death, which presumably resulted from an arrhythmia, occurred in 10–20%; however, most sudden deaths occurred in patients who had previously been symptomatic. Sudden death as the first manifestation of severe AS is very uncommon (<1% per year) in asymptomatic adult patients. Calcific AS is a progressive disease, with an annual reduction in valve area averaging 0.1 cm2 and annual increases in the peak jet velocity and mean valve gradient averaging 0.3 meters/s and 7 mmHg, respectively The authors report 6 cases of severe and silent aortic insufficiency having simulated in all aspects the picture of a dilated cardiomyopathy at the stage of cardiac insufficiency with primary manifestations. They insist on signs leading to the diagnosis of this clinical entity: past history of rheumatism, signs of electrical left ventricular hypertrophy in the absence of arterial hypertension, aortic calcifications and mostly presence of a discrete mitral diastolic fluttering during echocardiographic examination. Supra-sigmoid aortic angiography confirms the diagnosis of severe aortic regurgitation. In order to explain the non-perception of the murmur, they invoke the alteration of the transmission secondary to an air cushion (3 cases the association of another valvulopathy with murmur (1 case) and mainly the decrease of the leakage by increase of the left ventricular telediastolic pressure and the decrease of the diastolic aortic pressure, with diminution of the turbulences. The advantage of knowing this entity rests on the possibility of valve replacement, even at the stage of myocardial failure, since the satisfactory long-term post-operative evolution in 4 patients stands in contrast with the dangerous nature of a spontaneous evolution. For aortic stenosis, a systolic ejection murmur can often be heard best over the right sternal border at the second intercostal space. This murmur will peak early during systole when the disease is mild, and as severity increases will peak later, it also tends to radiate to the carotid arteries along with a slowly rising carotid upstroke. Auscultation often reveals a sustained apical impulse as well. In severe disease states, a thrill can sometimes be palpated over the carotid arteries and aortic area. Additional physical exam findings due to complications and sequelae of aortic stenosis include those associated with heart failure and left ventricle remodeling, such as third and fourth heart sounds, pulmonary crackles, jugular venous distention, and pedal edema. Auscultation of the heart (eg, physiologic murmur) Aortic valve sclerosis Where to listen: APT M 111234567777777 Left sternal border: Aortic regurgitation Pulmonic regurgitation cardiomyopathy PA M T Aortic area: Systolic murmur Pulmonic area: Tricuspid area: Mitral area (apex): Crescendo-decrescendo systolic ejection murmur and soft S2 (ejection click may be present). LV >> aortic pressure during systole. Loudest at heart base; radiates to carotids. “Pulsus parvus et tardus”—pulses are weak with a delayed peak. Can lead to Syncope, Angina, and Dyspnea on exertion (SAD). Most commonly due to age-related calcification in older patients (> 60 years old) or in younger patients with early-onset calcification of bicuspid aortic valve. Palpation may reveal cardiac enlargement and abnormal contraction of the cardiac impulse (left ventricular dyskinesia). Auscultation can uncover arterial bruits, a third and/or fourth heart sound, and, if acute ischemia or previous infarction has impaired papillary muscle function, an apical systolic murmur due to mitral regurgitation. These auscultatory signs are best appreciated with the patient in the left lateral decubitus position. Aortic stenosis, aortic regurgitation (Chap. 283), pulmonary hypertension (Chap. 304), and hypertrophic cardiomyopathy (Chap. 287) must be excluded, since these disorders may cause angina in the absence of coronary atherosclerosis. Examination during an anginal attack is useful, since ischemia can cause transient left ventricular failure with the appearance of a third 1582 and/or fourth heart sound, a dyskinetic cardiac apex, mitral regurgitation, and even pulmonary edema. Tenderness of the chest wall, localization of the discomfort with a single A 28-year-old woman with a history of critical pulmonic stenosis, status postsurgical valvotomy and subsequent pulmonary valve replacement, presented to the cardiology clinic with 1 year of progressive exertional dyspnoea. She has a heart rate of 75 bpm and blood pressure of 110/55 mm Hg. Cardiac auscultation reveals a 1/6 systolic ejection murmur along the left sternum and an early 3/6 diastolic decrescendo murmur. A transthoracic echocardiogram is obtained (figure 1). Which of the following would be most likely found during right heart catheterisation?Ratio of pulmonary to systemic blood flow (Qp:Qs) &gt;1.5Pulmonary vascular resistance &gt;3 Wood unitsRight atrial pressure &gt;10mm HgPulmonary artery systolic pressure &gt;45mm Hg E. Pulmonary artery diastolic pressure &lt;10mm Hg. A 49-year-old man visiting New Orleans from Chile comes to the hospital complaining of exertional dyspnea for 2 months with the more recent onset of ankle edema. He is a slender man with a blood pressure of 91/60 mmHg, crackles at both lung bases, and markedly distended neck veins. His cardiac rhythm is irregular. A soft murmur of mitral regurgitation and a soft S-3 are heard at the left ventricular apex. All four pedal pulses are easily palpable. Epigastric tenderness is noted on palpation; although the patient has a history of peptic ulcer disease, the tenderness is probably due to an enlarged left lobe of his liver, the result of hepatic congestion from his heart failure. A chest radiograph shows generalized cardiomegaly with an especially large left ventricle. Pulmonary congestion and small bilateral pleural effusions also are noted. The Figure shows the electrocardiogram recorded on admission. AR is associated with widened pulse pressure as a result of systolic hypertension and decreased diastolic pressure. The apical LV impulse is hyperdynamic and displaced laterally and inferiorly. A prominent systolic thrill may be palpable at the base of the heart or suprasternal notch and over the carotid arteries. It is caused by the large forward stroke volumes and low aortic diastolic pressure. S1 is normal, but S2 is increased (with a dilated aortic root) or decreased (when the aortic leaflets are thickened). A high frequency, blowing, decrescendo, diastolic murmur is heard best third intercostal space along the left sternal border. It is easier to appreciate the murmur of AR at the end of expiration while the patient is leaning forward.  The murmur increases with squatting or isometric exercise and decreases with maneuvers that decrease blood pressure. This murmur is early diastolic with mild AR and becomes holodiastolic with severe AR. Cardiovascular Findings Tachycardia and hypotension may be present along with jugular venous distention. Auscultation of the heart helps to differentiate between the various causes of valvular lesions causing pulmonary edema. Auscultation typically reveals an S3 gallop in volume overload states, which may be associated with accentuation of the pulmonic component of S2. Several different types of murmurs can be heard depending on the cause of the valvular lesion. Mitral stenosis produces a low-pitched, rumbling diastolic murmur associated with an opening snap at the apex, which becomes accentuated on expiration and produces loud S1. Mitral regurgitation produces a blowing, high-pitched pan-systolic murmur best heard at the apex, radiating to the left axilla and accentuating on expiration, producing soft S1. Aortic stenosis produces a harsh crescendo-decrescendo ejection systolic murmur at the aortic area, increasing on expiration, usually radiating towards the right side of the neck. Aortic regurgitation produces a high-pitched blowing early diastolic murmur best heard in the aortic area, greatest during expiration. Pathophysiology Supravalvular aortic stenosis is due to diffuse or discrete narrowing of ascending aorta. The murmur associated with it is systolic murmur and is similar in character to valvular aortic stenosis murmur but commonly present at 1st Intercostal space (ICS) on the right. Individuals with this anomaly may have unequal carotid pulses, differential blood pressure in upper extremities and a palpable thrill in Suprasternal notch. Individuals with significant supravalvular AS chronically may develop left ventricular hypertrophy and also are at risk of developing coronary artery stenosis. With increased metabolic demands (e.g. exercise) such individuals may develop subendocardial or myocardial ischemia due to increased myocardial oxygen demand and seek medical help with symptoms of exercise induced angina. Diagnosis Treatment References Diseases of the aorta\nHere is the question:\nCARDIOLOGY: A 78-year-old patient with no past history who consults for asthenia and dyspnea of 3 months of evolution, which has progressed to rest in the last few days. In the previous days he also refers chest pain with anginal characteristics with small efforts. On examination, blood pressure of 110/80 mmHg, heart rate of 85 bpm and auscultation with a rough systolic murmur in the right second intercostal space and crackles in both lung bases. Which of the following is the most likely diagnosis?\nHere are the potential choices:\n1. Mitral insufficiency.\n2. Aortic stenosis.\n3. Aortic insufficiency.\n4. Dilated cardiomyopathy of ischemic origin.\nThe correct answer is: ",
        "gold_answer": "2 Aortic stenosis.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A Japanese man who died at age 85 had been followed since the age of 59, when he first presented. He had hypertension of 162/102 mmHg and a loud systolic murmur on his first visit. He had had an active daily life without any medication for the next 10 years. At the age of 72 he complained of mild chest discomfort on exercise. Although electrocardiography showed no abnormalities, echocardiogram showed calcified bicuspid aortic valve with mild stenosis. At the age of 81 the dyspnea and chest oppression were exacerbated, associated with marked ST depression on exercise electrocardiogram and restriction of aortic valve opening on echocardiograms. In the following years a gradual increase in QRS voltage and ST depression with T wave inversion were recorded on resting electrocardiograms and sharp increases in both left ventricular end-diastolic diameter and flow velocity at the aortic root were observed on echocardiograms. At the age of 85 he died of intractable heart failure with massive pleural effusion. Autopsy revealed marked hypertrophy and moderate dilatation of the heart (weight: 580 g). The bicuspid aortic valve had anterior-posterior cusps with a raphe on the anterior cusp. The mobility of the cusps was almost lost because of severe calcification and thickening. Severe stenosis was found near the orifice of the right coronary artery, but there were no significant ischemic myocardial lesions. PRESENTING FEATURES: A 70-year-old African American man was admitted with a history of fever, chills, and malaise of several days' duration. His past medical history was notable for end-stage renal disease requiring hemodialysis, coronary artery disease, and aortic stenosis requiring a bioprosthetic aortic valve replacement. On the day of admission, the patient was noted to have a shaking chill while undergoing dialysis through his catheter and was admitted to the hospital. He complained of pain at the catheter insertion site, shortness of breath, and dyspnea on exertion, but denied chest pain. On physical examination, the patient had a temperature of 100.4 degrees F, with a heart rate of 64 beats per minute, blood pressure of 127/72 mm Hg, and an oxygen saturation of 97% on room air. He was a mildly obese man in no apparent distress. He had shotty cervical lymphadenopathy and a right subclavian dialysis catheter in place, with erythema and pus at the entry site. His jugular venous pressure was 10 cm H(2)O. Lung examination showed bibasilar rales. Heart sounds were normal, with no rub or gallop. He had a 2/6 systolic ejection murmur best heart at the left sternal border as well as a 3/6 holosystolic murmur at the apex that radiated to his left axilla. Examination of the abdomen and extremities was unremarkable. The patient's neurological examination was unremarkable, and he was alert and oriented to person, place, and time. Laboratory studies showed an elevated white blood cell count of 16,700 cells/microL. His blood urea nitrogen level was 43 mg/dL and his serum creatinine level was 4.9 mg/dL. Multiple blood cultures grew methicillin-resistant Staphylococcus aureus. An admission, chest radiograph showed no infiltrate. An admission electrocardiogram showed normal sinus rhythm with first degree atrioventricular block, left anterior fascicular block, and left ventricular hypertrophy. shows rhythm strips from lead II electrocardiograms 5 months before admission (top), on admission (middle) and 5 days after admission (bottom). What is the diagnosis? A 53-year-old woman with no previous medical history complained of easy fatigue over the last 6 months. She had a positive family history for coronary artery disease but no other risk factors. On physical examination, a 3/6 pansystolic murmur was heard over the apex, and the lung auscultation was unremarkable. Her ECG showed a left anterior fascicular block, with poor R wave progression in the anterior leads (see online supplementary image A). A subsequent echocardiogram revealed a slightly dilated for the patient's body surface area (BSA) (1.73 m<sup2</sup) left ventricle (55/35 mm), with preserved systolic function and a moderate functional mitral regurgitation. The estimated pulmonary artery pressure was 45 mm Hg. During treadmill radionuclide scintigraphy, her exercise tolerance was normal, with good inotropic response, and 96% oxygen saturation at rest and at peak exercise. A 2 mm ST segment depression was noted at peak effort, which persisted well into recovery (see online supplementary image B). The scintigraphy scan showed extensive reversible anteroapical wall ischaemia (see online supplementary image C). At this point she was referred to us for right and left heart catheterisation. Intracardiac pressures and saturations were: right atrium (RA)RA=3 mm Hg, right ventricle (RV)=26/3 mm Hg, Pulmonary artery (PA)=26/10/mean 16 mm Hg, pulmonary capillary wedge pressure (PCWP)=11 mm Hg, left ventricle (LV)=110/10 mm Hg, Aorta (Ao)=110/60/mean 80 mm Hg, Superior vena cava saturation (SVCsat)=62%, RAsat=62%, PAsat=78%, Aosat=96% and estimated pulmonary to systematic flow ratio (Qp/Qs)=1.8. Her coronary angiography and CT angiography are shown in figure 1A,B.DC1SP110.1136/heartjnl-2017-311256.supp1Supplementary material 1 DC2SP210.1136/heartjnl-2017-311256.supp2Supplementary material 2 DC3SP310.1136/heartjnl-2017-311256.supp3Supplementary material 3 heartjnl;103/17/1390/F1F1F1Figure 1Coronary and CT angiograms. What is the most likely diagnosis?Right coronary fistula to right ventricleKawasaki disease with fistulaAnomalous origin of the left coronary artery from the pulmonary arteryPersistent truncus arteriosus. Medical signs of aortic stenosis include pulsus parvus et tardus, that is, diminished and delayed carotid pulse, fourth heart sound, decreased A2 sound, sustained apex beat, precordial thrill. Auscultation may reveal a systolic murmur of a harsh crescendo-decrescendo type, heard in 2nd right intercostal space and radiating to the carotid arteries. Aortic regurgitation Patients with aortic regurgitation may experience heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, and angina pectoris. In acute cases patients may experience cyanosis and circulatory shock. Medical signs of aortic regurgitation include increased pulse pressure by increased systolic and decreased diastolic blood pressure, but these findings may not be significant if acute. The patient may have a diastolic decrescendo murmur best heard at left sternal border, water hammer pulse, Austin Flint murmur, and a displaced apex beat down and to the left. A third heart sound may be present Mitral stenosis Patients with mitral stenosis may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, chest pain, hemoptysis, thromboembolism, or ascites and edema (if right-sided heart failure develops). Symptoms of mitral stenosis increase with exercise and pregnancy A 66-year-old male patient was admitted to our clinic because of shortness of breath and chest pain. A grade 4/6 diastolic murmur was heard on auscultation. Physical examination revealed signs of congestive heart failure and poor peripheral perfusion. There was a diagnosis of type II ascending aortic dissection in the history of the patient. He had refused emergency surgical intervention three years earlier. Computed tomography revealed that the ascending aorta was dilated to about 10 cm in diameter, and there was a chronic aortic type II dissection. The patient had second- to third-degree aortic insufficiency and he had a calcified bicuspid aortic valve on echocardiography. Two-vessel disease and a 90-mmHg aortic gradient were detected on angiography. Graft replacement of the ascending aorta, serape aortic valve replacement with a mechanical valve, and coronary arterial bypass grafting were performed successfully under cardiopulmonary bypass with an open aortic technique. The patient was discharged on the 10th postoperative day with no problems.  Aortic regurgitation when acute and/or severe can be suspected when the patient has a wide pulse pressure, and a low pitched early diastolic murmur is auscultated again over the right sternal border at the second intercostal space. Accentuated P2 may also be noticed due to elevated pressures in the pulmonary vasculature. Chronic aortic regurgitation may illicit a blowing diastolic decrescendo murmur with a positive correlation between the duration of murmur and the severity of the disease. Often auscultation of a laterally and inferiorly displaced apical impulse is present and sustained. Often there is the phenomenon of Corrigan pulse (water hammer), a bounding and forceful pulse that rapidly increases and collapses. Other less common physical exam findings include the de Musset sign, which is subtle head bobbing with a pulse, as well as the Quincke sign and Muller sign (pulsations on the fingernails and uvula, respectively). Similar physical exam findings to aortic stenosis can also be seen late in disease progression. Acute aortic regurgitation will present differently depending on the etiology. If a patient presents with tearing severe chest pain along with physical exam findings such as variation in blood pressure between the right and left extremities, consider aortic dissection as a cause. If the patient presented with a history of streptococcal infection along with fevers, swollen and tender joints, skin nodules, new onset of rash, then rheumatic heart disease would be high on the differential. The patient, MSM, a 69-year-old man, sought medical care due to left dorsal and right lower limb pain. The chest x-ray showed mediastinal enlargement. He was undergoing examination when he lost consciousness and went into shock. Subcutaneous emphysema was observed in the left hemithorax, as well as abolition of breath sounds at auscultation. Tracheal intubation was performed with draining of blood-tinged fluid from the left hemithorax. Echocardiography showed left ventricle with 44/29 mm; septum, 12 mm; posterior wall, 13 mm; mild aortic root dilation, dissection of the lamina and periaortic hematoma. The valves and pericardium were normal. The patient was transferred to Instituto do Coraçao - InCor. Physical examination (21 Oct 2004: 10:45) showed that the patient was sedated with tracheal intubation, pale, heart rate at 90 bpm, blood pressure 130 x 80 mmHg, bloody drainage in the chest tube. Electrocardiogram - frequency 90 bpm, sinus rhythm, low voltage in the frontal plane and decreased voltage in left leads (Fig. 1). Computed tomography showed bilateral subcutaneous emphysema, thoracic aorta with inaccurate borders in its descending portion (from the subclavian artery to the middle portion), collapsed left lung and extensive collection of hematic characteristics in same hemithorax and middle and posterior mediastinum. Small right pneumothorax; small right pleural effusion with underlying parenchymal alterations. The analysis of the heart was impaired by the presence of hemothorax. While undergoing computed tomography, the patient showed no pulse, mydriasis, with asystole unresponsive to resuscitation and died (21 Oct 2011; 15:00 h). If there is increased stroke volume of the left ventricle due to volume overload, an ejection systolic 'flow' murmur may also be present when auscultating the same aortic area. Unless there is concomitant aortic valve stenosis, the murmur should not start with an ejection click. There may also be an Austin Flint murmur, a soft mid-diastolic rumble heard at the apical area; it appears when a regurgitant jet of blood from severe aortic regurgitation partially closes the anterior mitral leaflet. Peripheral physical signs of aortic regurgitation are related to the high pulse pressure and the rapid decrease in blood pressure during diastole due to blood returning to the heart from the aorta through the incompetent aortic valve, although the usefulness of some of the eponymous signs has been questioned: Phonocardiograms detect AI by having electric voltage mimic the sounds the heart makes. Characteristics- indicative of aortic regurgitation are as follow: Cocaine use: This condition is suspected when a person with few or no risk of arteriosclerosis presented with non-traumatic chest pain. Ingestion of cocaine can cause vasoconstriction of coronary arteries, thus producing chest pain similar to heart attack. Symptoms can appear within one hour of cocaine use. Aortic stenosis: This condition happens when the person has underlying congenital bicuspid valve, aortic sclerosis, or history of rheumatic fever. Chest pain usually happens during physical activity. Syncope is a late symptom. Signs and symptoms of heart failure may also present. On auscultation, loud ejection systolic murmur can be best heard at the right second intercostal space and radiates to the carotid artery in the neck. Splitting of second heart sound is heard in severe stenosis. The Austin Flint murmur is a rumbling diastolic murmur best heard at the apex of the heart that is associated with severe aortic regurgitation and is usually heard best in the fifth intercostal space at the midclavicular line. Younger patients are more likely to have a history of a bicuspid aortic valve or rheumatic heart disease, while older patients are more likely to suffer from calcific valvular disease. A blood pressure reading on the patient will show an increased pulse pressure due to the backflow of blood through the aortic valve during diastole. An astute clinician may be able to palpate a \"water hammer\" pulse, which is also known as \"Corrigan's pulse.\" This finding demonstrates arterial swelling followed by a brisk diastolic fall. Patients may endorse a history of syncope or lightheadedness associated with an inability to maintain forward flow through the aortic valve and the significant difference between systolic and diastolic pressure. Decreasing exercise tolerance and the inability to perform activities of daily living should prompt screening for this condition. The acquired aortic stenosis manifests with exertional dyspnea, syncope, angina, and, ultimately, heart failure. [17] [18] Typically, symptoms begin at the age of 50 to 70 years in patients with the bicuspid aortic valve and in greater than 70 years in patients with tri-leaflet valve calcific stenosis. Patients progressively experience a gradual decrease in exercise tolerance, dyspnea on exertion, and fatigue. Severe exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, and pulmonary edema show various degrees of pulmonary venous hypertension. Angina results from the combination of the need for increased oxygen in hypertrophied myocardium and reduction of oxygen delivery secondary to the excessive compression of coronary vessels. Syncope is caused by the decrease in cerebral perfusion occurring during exertion when the arterial pressure declines due to systemic vasodilation and an inadequate increase in cardiac output related to stenosis. It is also due to the malfunction of the baroreceptor mechanism in severe aortic stenosis. Non-cardiac symptoms include gastrointestinal (GI) bleeding and cerebral emboli. GI bleeding is observed in patients with severe aortic stenosis and is often associated with angiodysplasia or other vascular malformations. It manifests from shear stress-induced platelet aggregation and reduction in the von Willebrand factor. [19] Cerebral emboli occur due to microthrombi formation on thickened bicuspid valves. There is also an observed increase in the risk of infective endocarditis in patients with aortic valve disease, especially with a bicuspid valve. On examination, carotid upstroke can be observed on palpation. A slow-rising, late-peaking, and a low-amplitude carotid impulse, pulsus parvus et tardus, is an expected finding in severe aortic stenosis and, when present, is specific to aortic stenosis. On auscultation, the second heart sound may lack a split and can be heard as a single sound during inspiration. It can also become paradoxical when the closure of the aortic valve gets delayed than the pulmonic valve. A mid-systolic ejection murmur, heard best over the right second intercostal space, with radiation into the right neck. However, high-frequency components may radiate to the apex in calcified aortic valves, and this phenomenon is called the Gallavardin phenomenon. The murmur becomes softer in LV failure and when there is a fall of stroke volume. A 23-year-old woman followed at another medical centre for congenital heart disease (CHD) presented to our emergency clinic with 3 weeks of bilateral pleuritic chest pain. She returned from holiday in Greece 6 weeks earlier where a tattoo and nasal piercing had been performed. There was no history of night sweats or fever.Her temperature was 37.5°C, heart rate 120 beats/min, oxygen saturations 94% on room air and blood pressure 110/74. Her chest was clear and there was systolic murmur on auscultation. The chest radiograph showed peripheral bilateral lower zone atelectasis. The ECG demonstrated sinus tachycardia. The haemoglobin was 11.2 g/dL, white cell count 10.18×10<sup9</sup/L, C-reactive protein 67 mg/L (normal &lt;5 mg/L) and D dimer=430 ng/mL (normal &lt;230 ng/mL).A pulmonary embolus was suspected and a CT pulmonary angiogram was performed (figure 1). Based on the CT findings, what is the most likely underlying congenital heart lesion in this patient?Bicuspid aortic valveCoarctation of the aortaFontan circulationParachute mitral valveVentricular septal defect heartjnl;105/6/464/F1F1F1Figure 1CT pulmonary angiogram (coronal views). Finally the sacrum and ankles are checked for pitting edema which is caused by right ventricular failure in isolation or as part of congestive cardiac failure. Auscultation One should comment on S1 and S2 – if the splitting is abnormal or louder than usual. S3 – the emphasis and timing of the syllables in the word Kentucky is similar to the pattern of sounds in a precordial S3. S4 – the emphasis and timing of the syllables in the word Tennessee is similar to the pattern of sounds in a precordial S4. If S4 S1 S2 S3 Also known as a gallop rhythm. diastolic murmurs (e.g. aortic regurgitation, mitral stenosis) systolic murmurs (e.g. aortic stenosis, mitral regurgitation) pericardial rub (suggestive of pericarditis) The base of the lungs should be auscultated for signs of pulmonary oedema due to a cardiac cause such as bilateral basal crepitations. Death in patients with severe AS occurs most commonly in the seventh and eighth decades. Based on data obtained at postmortem examination in patients before surgical treatment became widely available, the average time to death after the onset of various symptoms was as follows: angina pectoris, 3 years; syncope, 3 years; dyspnea, 2 years; congestive heart failure, 1.5–2 years. Moreover, in >80% of patients who died with AS, symptoms had existed for <4 years. Among adults dying with valvular AS, sudden death, which presumably resulted from an arrhythmia, occurred in 10–20%; however, most sudden deaths occurred in patients who had previously been symptomatic. Sudden death as the first manifestation of severe AS is very uncommon (<1% per year) in asymptomatic adult patients. Calcific AS is a progressive disease, with an annual reduction in valve area averaging 0.1 cm2 and annual increases in the peak jet velocity and mean valve gradient averaging 0.3 meters/s and 7 mmHg, respectively The authors report 6 cases of severe and silent aortic insufficiency having simulated in all aspects the picture of a dilated cardiomyopathy at the stage of cardiac insufficiency with primary manifestations. They insist on signs leading to the diagnosis of this clinical entity: past history of rheumatism, signs of electrical left ventricular hypertrophy in the absence of arterial hypertension, aortic calcifications and mostly presence of a discrete mitral diastolic fluttering during echocardiographic examination. Supra-sigmoid aortic angiography confirms the diagnosis of severe aortic regurgitation. In order to explain the non-perception of the murmur, they invoke the alteration of the transmission secondary to an air cushion (3 cases the association of another valvulopathy with murmur (1 case) and mainly the decrease of the leakage by increase of the left ventricular telediastolic pressure and the decrease of the diastolic aortic pressure, with diminution of the turbulences. The advantage of knowing this entity rests on the possibility of valve replacement, even at the stage of myocardial failure, since the satisfactory long-term post-operative evolution in 4 patients stands in contrast with the dangerous nature of a spontaneous evolution. For aortic stenosis, a systolic ejection murmur can often be heard best over the right sternal border at the second intercostal space. This murmur will peak early during systole when the disease is mild, and as severity increases will peak later, it also tends to radiate to the carotid arteries along with a slowly rising carotid upstroke. Auscultation often reveals a sustained apical impulse as well. In severe disease states, a thrill can sometimes be palpated over the carotid arteries and aortic area. Additional physical exam findings due to complications and sequelae of aortic stenosis include those associated with heart failure and left ventricle remodeling, such as third and fourth heart sounds, pulmonary crackles, jugular venous distention, and pedal edema. Auscultation of the heart (eg, physiologic murmur) Aortic valve sclerosis Where to listen: APT M 111234567777777 Left sternal border: Aortic regurgitation Pulmonic regurgitation cardiomyopathy PA M T Aortic area: Systolic murmur Pulmonic area: Tricuspid area: Mitral area (apex): Crescendo-decrescendo systolic ejection murmur and soft S2 (ejection click may be present). LV >> aortic pressure during systole. Loudest at heart base; radiates to carotids. “Pulsus parvus et tardus”—pulses are weak with a delayed peak. Can lead to Syncope, Angina, and Dyspnea on exertion (SAD). Most commonly due to age-related calcification in older patients (> 60 years old) or in younger patients with early-onset calcification of bicuspid aortic valve. Palpation may reveal cardiac enlargement and abnormal contraction of the cardiac impulse (left ventricular dyskinesia). Auscultation can uncover arterial bruits, a third and/or fourth heart sound, and, if acute ischemia or previous infarction has impaired papillary muscle function, an apical systolic murmur due to mitral regurgitation. These auscultatory signs are best appreciated with the patient in the left lateral decubitus position. Aortic stenosis, aortic regurgitation (Chap. 283), pulmonary hypertension (Chap. 304), and hypertrophic cardiomyopathy (Chap. 287) must be excluded, since these disorders may cause angina in the absence of coronary atherosclerosis. Examination during an anginal attack is useful, since ischemia can cause transient left ventricular failure with the appearance of a third 1582 and/or fourth heart sound, a dyskinetic cardiac apex, mitral regurgitation, and even pulmonary edema. Tenderness of the chest wall, localization of the discomfort with a single A 28-year-old woman with a history of critical pulmonic stenosis, status postsurgical valvotomy and subsequent pulmonary valve replacement, presented to the cardiology clinic with 1 year of progressive exertional dyspnoea. She has a heart rate of 75 bpm and blood pressure of 110/55 mm Hg. Cardiac auscultation reveals a 1/6 systolic ejection murmur along the left sternum and an early 3/6 diastolic decrescendo murmur. A transthoracic echocardiogram is obtained (figure 1). Which of the following would be most likely found during right heart catheterisation?Ratio of pulmonary to systemic blood flow (Qp:Qs) &gt;1.5Pulmonary vascular resistance &gt;3 Wood unitsRight atrial pressure &gt;10mm HgPulmonary artery systolic pressure &gt;45mm Hg E. Pulmonary artery diastolic pressure &lt;10mm Hg. A 49-year-old man visiting New Orleans from Chile comes to the hospital complaining of exertional dyspnea for 2 months with the more recent onset of ankle edema. He is a slender man with a blood pressure of 91/60 mmHg, crackles at both lung bases, and markedly distended neck veins. His cardiac rhythm is irregular. A soft murmur of mitral regurgitation and a soft S-3 are heard at the left ventricular apex. All four pedal pulses are easily palpable. Epigastric tenderness is noted on palpation; although the patient has a history of peptic ulcer disease, the tenderness is probably due to an enlarged left lobe of his liver, the result of hepatic congestion from his heart failure. A chest radiograph shows generalized cardiomegaly with an especially large left ventricle. Pulmonary congestion and small bilateral pleural effusions also are noted. The Figure shows the electrocardiogram recorded on admission. AR is associated with widened pulse pressure as a result of systolic hypertension and decreased diastolic pressure. The apical LV impulse is hyperdynamic and displaced laterally and inferiorly. A prominent systolic thrill may be palpable at the base of the heart or suprasternal notch and over the carotid arteries. It is caused by the large forward stroke volumes and low aortic diastolic pressure. S1 is normal, but S2 is increased (with a dilated aortic root) or decreased (when the aortic leaflets are thickened). A high frequency, blowing, decrescendo, diastolic murmur is heard best third intercostal space along the left sternal border. It is easier to appreciate the murmur of AR at the end of expiration while the patient is leaning forward.  The murmur increases with squatting or isometric exercise and decreases with maneuvers that decrease blood pressure. This murmur is early diastolic with mild AR and becomes holodiastolic with severe AR. Cardiovascular Findings Tachycardia and hypotension may be present along with jugular venous distention. Auscultation of the heart helps to differentiate between the various causes of valvular lesions causing pulmonary edema. Auscultation typically reveals an S3 gallop in volume overload states, which may be associated with accentuation of the pulmonic component of S2. Several different types of murmurs can be heard depending on the cause of the valvular lesion. Mitral stenosis produces a low-pitched, rumbling diastolic murmur associated with an opening snap at the apex, which becomes accentuated on expiration and produces loud S1. Mitral regurgitation produces a blowing, high-pitched pan-systolic murmur best heard at the apex, radiating to the left axilla and accentuating on expiration, producing soft S1. Aortic stenosis produces a harsh crescendo-decrescendo ejection systolic murmur at the aortic area, increasing on expiration, usually radiating towards the right side of the neck. Aortic regurgitation produces a high-pitched blowing early diastolic murmur best heard in the aortic area, greatest during expiration. Pathophysiology Supravalvular aortic stenosis is due to diffuse or discrete narrowing of ascending aorta. The murmur associated with it is systolic murmur and is similar in character to valvular aortic stenosis murmur but commonly present at 1st Intercostal space (ICS) on the right. Individuals with this anomaly may have unequal carotid pulses, differential blood pressure in upper extremities and a palpable thrill in Suprasternal notch. Individuals with significant supravalvular AS chronically may develop left ventricular hypertrophy and also are at risk of developing coronary artery stenosis. With increased metabolic demands (e.g. exercise) such individuals may develop subendocardial or myocardial ischemia due to increased myocardial oxygen demand and seek medical help with symptoms of exercise induced angina. Diagnosis Treatment References Diseases of the aorta\nHere is the question:\nCARDIOLOGY: A 78-year-old patient with no past history who consults for asthenia and dyspnea of 3 months of evolution, which has progressed to rest in the last few days. In the previous days he also refers chest pain with anginal characteristics with small efforts. On examination, blood pressure of 110/80 mmHg, heart rate of 85 bpm and auscultation with a rough systolic murmur in the right second intercostal space and crackles in both lung bases. Which of the following is the most likely diagnosis?\nHere are the potential choices:\n1. Mitral insufficiency.\n2. Aortic stenosis.\n3. Aortic insufficiency.\n4. Dilated cardiomyopathy of ischemic origin.\nThe correct answer is: 2. Aortic stenosis."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n This study was designed to follow the evolution of serum 1,25(OH)2D after surgery for primary hyperparathyroidism. Ten patients were studied before and for up to 85 d after removal of a single parathyroid adenoma. Blood and 24 h urine were obtained at various time points, for the measurement of serum or urinary phosphate and calcium indices. Before surgery, serum calcium (2.91 +/- 0.06 mmol/l; mean +/- SEM), parathyroid hormone (354 +/- 47 pg/ml) and 1,25(OH)2D (61.2 +/- 7.8 pg/ml) were elevated while serum phosphate (1.01 +/- 0.07 mmol/l) tended to be low. Relative hypoparathyroidism was evident for up to 5 d after surgery with the lowest value for serum parathyroid hormone (41 +/- 16 pg/ml) on day 1, serum calcium (2.12 +/- 0.06 mmol/l) on day 3 and highest value for serum phosphate (1.41 +/- 0.13 mmol/l) on day 5. As expected, serum 1,25(OH)2D levels decreased to 35.9 +/- 4.2 pg/ml 24 h after surgery. Stabilization of serum and urinary parameters to normal values was seen between day 5 and day 27; the only exception was serum 1,25(OH)2D, which increased again at day 27 to 57.6 +/- 5.0 pg/ml, a value as high as that before surgery. It was still elevated at day 50 (58.3 +/- 4.3 pg/ml), but returned towards normal values in three out of four patients (44 +/- 3.9 pg/ml) by day 80. No variation in 25(OH)D or 24,25(OH)2D was seen throughout the study. 1,25(OH)2D values could be related to serum parathyroid hormone values before surgery (r = 0.659, P less than 0.05) but not after. The secondary increase in serum 1,25(OH)2D could not be related to variations in serum calcium, phosphate, parathyroid hormone or diet. Further studies will be required to explain this phenomenon. Diagnosis As most cases of FHH are asymptomatic and benign, the diagnosis of FHH is less likely to be made. Typically, diagnosis is made in the pursuit of uncovering the etiology of hypercalcemia. Calcium levels are often in the high normal range or slightly elevated. Commonly, the parathyroid hormone level is checked and may be slightly elevated or also on the high normal end. Normally, high calcium should cause low PTH and so this level of PTH is inappropriately high due to the decreased sensitivity of the parathyroid to calcium. This may be mistaken for primary hyperparathyroidism. However, evaluation of urine calcium level will reveal a low level of urine calcium. This too is inappropriate as high serum calcium should result in high urine calcium. If urine calcium is not checked, this may lead to parathyroidectomy for presumed primary hyperparathyroidism. Additionally as the name implies, there may be a family history of benign hypercalcemia. Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant inherited disorder that is sometimes easily confused with primary hyperparathyroidism. It is characterized by hypercalcemia, hypocalciuria, and high-normal to mildly increased parathyroid hormone secretion. [88] [112] Familial hypocalciuric hypercalcemia is caused by a mutation in the calcium-sensing receptor of the chief cells of the parathyroid gland. Histologically, the parathyroid glands appear normal. There is usually a known family history of the disorder. There are no clinical symptoms, and it requires no treatment. The diagnosis is usually made by history or the calcium/creatinine excretion ratio, although 24-hour urine testing showing severe hypocalciuria of <100 mg/24 hours is highly suggestive. The calcium/creatinine excretion ratio [(urinary calcium x serum creatinine) / (serum calcium x urinary creatinine)] in the urine of patients with familial hypocalciuric hypercalcemia is very low, typically <0.01 in 80% of cases, and FHH is more likely if hypercalcemia is detected before age 40. [88] Other causes of hypocalciuric hypercalcemia should be ruled out (vitamin D deficiency, severely calcium-deficient diet, mild renal failure, use of thiazide or lithium). A calcium infusion test can also help distinguish FHH from primary hyperparathyroidism. A calcium load will increase urinary calcium excretion in primary hyperparathyroidism but not familial hypocalciuric hypercalcemia. [88] A definitive diagnosis can be made in questionable cases by genetic testing. [88] To investigate the changes in the 1 alpha,25-dihydroxyvitamin D [1,25(OH)2D] level and the role of parathyroid hormone (PTH) and calcitonin (CT) during the early neonatal periods, we measured 1,25(OH)2D, 25-hydroxyvitamin D [25(OH)D], PTH specific for mid-regions (mPTH) and urinary cAMP (UcAMP) to evaluate the renal tubular responsiveness to intrinsic PTH and CT, as well as serum Ca and P in 28 mothers at term delivery and in their babies at birth and 5 days of age. Cord serum 1,25(OH)2D levels were low (28.8 +/- 9.2 pg/ml, mean +/- SD), while maternal serum 1,25(OH)2D levels were high (62.2 +/- 22.6 pg/ml). The low 1,25(OH)2D value increased 2.5 times (62.2 +/- 22.6 pg/ml) in 5-day-old infants, reaching a high normal adult value, concomitant with the increases in mPTH and urinary cAMP/creatinine ratio (UcAMP/Cr). The correlations between 1,25(OH)2D and UcAMP/Cr, and 1,25(OH)2D and mPTH in all paired samples of babies at birth and at 5 days of age were r = 0.456, n = 50, P less than 0.01 and r = 0.341, n = 50, P less than 0.05, respectively. These data suggest that the parathyroid activation after birth is a major factor in the rapid 1,25(OH)2D increment at that time. CT levels were high in all paired samples and in 5-day-old infants. CT vs 1,25(OH)2D showed a significant correlation (r = 0.473, P less than 0.05, n = 24) as well as the relative increase of 1,25(OH)2D (delta pg/ml) after birth vs CT at age 5 days (r = 0.537, P less than 0.01, n = 24).(ABSTRACT TRUNCATED AT 250 WORDS) The diagnosis of FHH can be easy to make in an asymptomatic hypercalcemic patient with a family his­tory of hypercalcemia, a personal or family history of failed neck exploration, or normal serum PTH [1] [2] . More than 99% of the filtered calcium gets reabsorbed despite the presence of hypercalcemia. The 24 hours urinary calcium excretion is less than 100 mg/24 hours. The Ca/Cr excretion ratio is very low. It is calculated as follows: [UCa × SCr] / [SCa × UCr], where UCa is the urinary calcium con­centration, SCr is the serum creatinine, SCa is the serum calcium concentration, and UCr is the urinary creati­nine concentration, all in mg/dl. The Ca/Cr clearance ratio is less than 0.01 in 80% of cases. All patients with calcium/creatinine clearance ratio of 0.020 or less should be tested for mutations in the CaSR gene. Serum Magnesium is in the upper-normal range or mildly elevated; whereas, serum magnesium tends to be nor­mal or low in primary hyperparathyroidism. Once true hypercalcemia is established, the second most important laboratory test in the diagnostic evaluation is a PTH level using a two-site assay for the intact hormone. Increases in PTH are often accompanied by hypophosphatemia. In addition, serum creatinine should be measured to assess renal function; hypercalcemia may impair renal function, and renal clearance of PTH may be altered depending on the fragments detected by the assay. If the PTH level is increased (or “inappropriately normal”) in the setting of elevated calcium and low phosphorus, the diagnosis is almost always primary hyperparathyroidism. Because individuals with FHH may also present with mildly elevated PTH levels and hypercalcemia, this diagnosis should be considered and excluded because parathyroid surgery is ineffective in this condition. A calcium/creatinine clearance ratio (calculated as urine calcium/ serum calcium divided by urine creatinine/serum creatinine) of <0.01 is suggestive of FHH, particularly when Metabolic acidoses are diseases causing many diagnostic and therapeutic problems. Compensated metabolic acidosis can be unrecognised for a long time. This refers especially to isolated renal tubular acidosis (RTA). Unrecognised RTA causes calcium and phosphorus balance disturbances with clinical signs of improper bone mineralization. It happens that some patients with mentioned problems are \"treated\" as rachitic and take high doses of vitamin D. As a result, serum calcium and phosphates as well as urine calcium increase, without the satisfied influence on bone mineralization. We present a case of a 3.5 months old baby, who was \"treated\" as ricket in vitamin D deficiency. This baby was \"cured\" with high doses of cholecalciferol (0.0875 mg/24h for 2 weeks, then 0.175 mg/24h for 3 weeks) because of craniotabes. This treatment was carried on without any metabolic tests and caused the following disturbances: 25(OH)D serum level - 102.7 ng/ml (normal 11-54), 1,25(OH)2D serum level - 39.5 pg/ml (normal 15-70), calcaemia 2.7-2.85 mmol/l, phosphataemia 2.1 mmol/l. In this time the considerable hipercalciuria (second morning urine sample Ca/cr ratio 2.06 mmol/mmol) occurred. The other laboratory test showed as follows: serum albumins 4.5 g/dl, alkaline phosphatase 188 U/l, acid phosphatase 10.7 U l, Cl- 114.9 mmol/l, Na 146 mmol/l, K 4.8 mmol/l, HCO3a 16.6-20.1 mmol/l and pCO2 3.63-3.85 kPa, serum anion gap 11 mEq/l; pH of morning urine 6.5-7. These results suggested the presence of distal RTA aside from symptoms of vitamin D overdosage. The high serum levels of calcium and phosphates, craniotabes, rather low serum alkaline phosphatase activity and presence of metabolic acidosis the symptoms after the normalisation of calcium and phosphorus balance suggested that the distal RTA had been prior to calcium disturbances. Hypercalcemia can be hazardous during pregnancy, most cases being due to primary hyperparathyroidism. We report a case of hypercalcemia with suppressed PTH levels necessitating treatment with bisphosphonates during pregnancy. A 38-year-old woman at the 26th week gestation was admitted because of symptomatic hypercalcemia. She did not take any medication that could influence her calcium levels. Physical examination was unremarkable. Laboratory tests on admission were: calcium 12.7 mg/dL (8.5-10.5 mg/dL), phosphorus 1.8 mg/dL (2.5-4.5 mg/dL) and PTH on 3 consecutive tests 1.2, 1.3 and 1.2 pg/mL (15-65 pg/mL). Her 24h urine calcium was 900 mg, 25-OH-D 40 ng/mL (30-58 ng/mL) and 1,25-OH-D 99 pg/mL (80-146 for women in the third trimester). Abdominal ultrasound revealed multiple hypervascular liver lesions consistent with hemangiomas by MRI. Breast and neck ultrasound were normal, and chest CT revealed few non-significant 0.3-0.7 cm pulmonary nodules with no change after an interval of 3 months. She was treated with isotonic saline, loop diuretics and calcitonin. Despite this treatment, calcium levels remained high (14.1 mg/dL), and pamidronate was initiated. On 35th week gestation, she underwent a cesarean section complicated by hypocalcemia of the newborn. Eight weeks after delivery, her calcium levels are 9.4 mg/dL and PTH 18 mg/dL. According to the extensive workup and the post-partum normalization of PTH and calcium levels, we conclude that excessive secretion of placental PTHrP was the cause of hypercalcemia in this patient. No significant adverse effect of bisphosphonate on the mother or baby were seen at the short term follow up. Three patients (a grandmother, her daughter and her grandson) belonging to a 23-number-kindred of five generations suffered from adult-onset, X-linked, familiar hypophosphataemic osteomalacia. According to the familiar anecdotes the great-grandmother also had the same disease. The clinical diagnosis was documented by X-ray pictures, scintigraphic and bone histological results, the laboratory diagnosis was proven by blood and urine analyses examined after phosphate loading. The youngest, 24-year-old patient was treated with daily 3 g phosphate and high doses of calcitriol for 2 years. As a new feature of our therapy, per os treatment with 1.25 micrograms calcitriol was supplemented by daily 2-4 micrograms iv. bolus calcitriol for one week every month. The osteomalacia, causing serious symptoms and complaints, healed. Our treatment seemed to be safe, as renal functions, serum total and ionized calcium and PTH levels (including midnight values) remained in normal range. On the basis of our results this disease can be treated by administration of high doses of phosphate, provided that development of hyperparathyroidism is prevented by the coadministration of high doses of calcitriol. We studied the effects of glucocorticoid excess on calcium and phosphorus homeostasis in relation to vitamin D metabolites and parathyroid hormone (PTH) in seven patients with spontaneous ACTH-dependent Cushing's syndrome. Remission of hypercortisolism resulted in a significant increase in tubular reabsorption of phosphate [from 76 +/- 4% to 89 +/- 2% (mean +/- SEM); P less than 0.01] and serum phosphorus (from 3.1 +/- 0.1 to 4.2 +/- 0.2 mg/dl; P less than 0.005). Serum calcium did not change, although there was a reduction in daily urinary calcium excretion from 0.23 +/- 0.02 to 0.107 +/- 0.02 mg calcium/mg creatinine. Serum immunoreactive PTH (iPTH) levels were normal during Cushing's syndrome (34 +/- 5 microleq/ml), but fell significantly after remission to 22 +/- 2 microleq/ml (P less than 0.05). This small decrease in iPTH did not correlate with the improvement of phosphate homeostasis. Plasma 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D [1,25-(OH2)D] concentrations in Cushing's syndrome did not differ from measurements in 97 normal subjects. After treatment, 25OHD did not change, but 1,25-(OH)2D fell in each patient from a mean of 44 to 22 pg/ml (P less than 0.02). 1,25-(OH)2D was inversely correlated with serum phosphorus (r = 0.59; P less than 0.01), but did not correlate with iPTH. The known impairment of intestinal calcium absorption in Cushing's syndrome cannot be attributed to a decrease in the circulating levels of 1,25-(OH)2D. Endogenous hypercortisolism decreases tubular phosphate reabsorption and serum phosphorus, increase tubular phosphate reabsorption and serum phosphorus, increases iPTH, and results in an increase in 1,25-(OH)2D. These events may contribute to the severe loss of bone mass in such patients and may account for the calciuria and phosphaturia of Cushing's syndrome. Familial hypocalciuric hypercalcemia is a rare disease with autosomal dominant transmission. Its basic defect is unknown and it requires no treatment. A 4 month-old girl was admitted for unexplained crying. She was found to have hypercalcemia (2.8 mmol/l) and later values of blood calcium were 3, 3.1 and 3 mmol/l. The serum free ionic calcium level was also elevated. The serum concentrations of protein, phosphorus, magnesium and the alkaline phosphatase activity were all normal. Serum concentrations of 25-(OH)-D3, 1.25-(OH)-2-D3 and PTH were also normal. The urinary calcium/creatinine ratio was normal and the urinary calcium excretion was 1.08 mg/kg/d. Screening of family members showed hypercalcemia in the father (2.8 mmol/l) and a brother aged 7 years (2.9 mmol/l). Short-term treatment with disodium etidronate lowered the serum calcium level to normal, but hypercalcemia reappeared once the treatment was discontinued. This asymptomatic familial hypercalcemia has the characteristics of familial hypocalciuric hypercalcemia. There was no associated endocrine disorder. Screening of family members is worthwhile. Growth hormone excess has been associated with hypercalciuria and nephrolithiasis. Hypercalcemia in acromegaly is rare and usually due to coexistent primary hyperparathyroidism. To report two cases of 1,25-dihydroxyvitamin D (1,25 (OH)(2) D)-dependent hypercalcemia in cromegaly. A 50 year-old female with 2 years history of hypercalcemia presented with features of acromegaly. Serum calcium (Ca) was 10.9 mg/dl (8.6-10.2), parathyroid hormone (PTH) 20 pg/ml (10-65), PTH-related peptide undetectable, and 1,25 (OH)(2) D 119 pg/ml (15-75). Insulin-like growth factor 1 (IGF1) was 911 ng/ml (49-292) and growth hormone (GH) 14.5 ng/ml (0.03-10). MRI showed a 1.7 cm pituitary tumor. Transsphenoidal adenectomy (TSA) resulted in normalization of IGF1, GH, Ca, and 1,25 (OH)(2) D (50 pg/ml) and complete tumor resection. A 52-year-old female was diagnosed with visual field deficits on routine exam. MRI showed a 3 cm invasive pituitary macroadenoma. IGF1 was 416 ng/ml (87-238) and GH 75.8 (0-6.0) ng/ml. Incidentally, she was found with high Ca of 10.8 mg/dl (8.9-10.3) associated with PTH 19 pg/ml and 1,25 (OH)(2) D66 pg/ml. Postoperatively, IGF1 and GH remained abnormal (440 and 12.8 ng/ml, respectively), while MRI showed parasellar tumor residue. Ca remained high (10.1-11.1 mg/dl), along with elevated 1,25 (OH)(2) D level (81.3 pg/ml). In both cases, other causes of hypercalcemia were ruled out. We present 2 cases of 1,25 (OH)(2) D-dependent hypercalcemia associated with growth hormone excess. Complete resection of tumor produced biochemical remission of acromegaly and normalization of calcium and 1,25 (OH)(2) D levels, while incomplete resection was associated with persistent 1,25 (OH)(2) D-dependent hypercalcemia. Acromegaly should be considered a cause of 1,25 (OH)(2) D-dependent hypercalcemia. In order to better understand the difference between familial hypocalciuric hypercalcemia (FHH) and primary hyperparathyroidism (PHP), 4 adults with this disease (FHH(+], from the same kindred, and spanning 2 generations, were compared with 6 patients with PHP, 10 normal controls (N) and 3 unaffected members of the same kindred (FHH(-]. Clinically speaking, the FHH(+) patients were asymptomatic while those with PHP had recurring renal stones. Various phosphocalcic balance elements were measured in blood and urine, in a fasting state, following oral loading of 1 g calcium, as well as in 24-hour urine specimens. Serum calcium levels were slightly higher (11.90 +/- .14 vs 11.37 +/- .24 mg/dl; p less than .05), in patients with FHH(+), but serum phosphorus (2.47 +/- .38 vs 2.88 +/- .40 mg/dl), serum parathyroid hormone (301 +/- 147 vs 291 +/- 224 pg/ml) and serum 1,25(OH)2D (52.8 +/- 6.7 vs 55.0 +/- 12.0 pg/ml) values were similar to those observed in patients with PHP. Urinary calcium present in FHH(+), while fasting (.064 +/- .043 mg/100 ml G.F.), after the calcium loading (.150 +/- .071) and in the 24-hour specimen (.089 +/- .016), was below the 95% confidence limit of values obtained in patients with PHP (.225 +/- .026, p less than .001; .413 +/- .066, p less than .001; 314 +/- .080, p less than .001), but similar to those obtained in N and FHH(-).(ABSTRACT TRUNCATED AT 250 WORDS) Peritoneal dialysate containing 2.5 mEq/L of calcium has been used to prevent hypercalcemia when calcium-containing phosphate binders are given. However, worsening of hyperparathyroidism may result. Calcitriol used in conjunction with 2.5 mEq/L calcium dialysate is an attractive alternative, but has not been examined in a controlled trial. Eighteen patients were randomly assigned to either a control group (3.5 mEq/L calcium dialysate without calcitriol) or a study group (conversion to 2.5 mEq/L calcium dialysate with oral calcitriol, median dose 0.25 microgram/day). The initial mean serum calcium (9.9 vs 9.6 mg/dL), phosphate (5.4 vs 5.6 mg/dL), median n-terminal parathyroid hormone (PTH) levels (71 vs 55 pg/mL, normal &lt; 25), and median 1,25 (OH)2 vitamin D levels (4 vs 5 pg/mL, normal 15-60 pg/mL) were not different in the two groups. After 8 weeks the serum calcium and phosphate were unchanged from baseline in both groups. The 9 patients who converted to 2.5 mEq/L calcium dialysate had an insignificant fall in the PTH level, not different from the control group. The median 1,25 (OH)2 vitamin D level rose from 4 to 23 pg/mL (p = 0.003) on calcitriol, but remained unchanged in the control group (5 pg/mL). The median doses of oral calcium (0.9 vs 1.1 g/day) and the frequency of serum calcium levels greater than 11 mg/dL (4/9 vs 3/9 patients, 10% vs 8% of all values) were similar in the study and control groups. Aluminum hydroxide was required intermittently for serum phosphate control in 3 patients on 2.5 mEq/L calcium dialysate and 4 on 3.5 mEq/L calcium dialysate.(ABSTRACT TRUNCATED AT 250 WORDS) Biochemical tests related to calcium and phosphorus metabolism have traditionally been considered as a reliable tool to differentiate familial hypocalciuric hypercalcemia (FHH) from primary hyperparathyroidism (PHPT). However, diagnosis may sometimes be difficult even for experienced clinicians. Our objective was to assess the accuracy of diagnostic tests in FHH and the circumstances in which genetic studies are required. A descriptive study was conducted of two families with hypercalcemia and suspected atypical FHH. Urinary calcium excretion was measured in 24-hour urine using different tests (calcium excretion (CE), urinary calcium/creatinine clearance ratio (UCCR)), and serum PTH and 25-hydroxyvitamin D levels were tested. Index cases underwent genetic study. One patient from the first family showed overt, persistent hypercalciuria with values more consistent with PHPT than with FHH if we consider, as proposed by guidelines, a UCCR lower than 0.01 as diagnostic of FHH and a value higher than 0.02 as diagnostic of PHPT. The index case of the second family underwent surgery for a parathyroid adenoma. Both cases had a mutation c. 164C&gt;T (Pro55Leu) in exon 2 in heterozygosis. According to current clinical guidelines, definitive diagnosis of FHH requires genetic confirmation, which allowed in our case for detection of two families with FHH and atypical clinical presentations. We think that rational use of genetic tests may avoid unnecessary surgery and excess monitoring costs. an elevated chloride-to-phosphate ratio (>33). Urinary calcium levels need not be measured routinely, except in patients who have not had previ-ously documented normocalcemia or have a family history of hypercalcemia to rule out FHH. In patients with FHH, 24-hour urinary calcium excretion is characteristically low (<100 mg/d). Furthermore, the serum calcium-to-creatinine clearance ratio (24-hour urine calcium/plasma total calcium/24-hour urine creatinine/plasma creatinine) usually is <0.01 in patients with FHH, whereas it is typically >0.02 in patients with PHPT, although there are exceptions to this. Other biochemical features of PHPT are listed in Table 38-10. Elevated levels of alkaline phosphatase may be found in approximately 10% of patients with PHPT and are indicative of high-turnover bone disease. These patients are prone to developing postoperative hypocal-cemia due to bone hunger. Serum and urine protein electropho-resis may be necessary to exclude multiple\nHere is the question:\nENDOCRINOLOGY: In a 30-year-old female patient a calcium level of 11 mg/dl (normal less than 10.5 mg/dl) is found during a routine company examination. PTH determination was 45 pg/ml (VN 10-55 pg/ml). The history is unremarkable except for the fact that the mother and paternal grandfather were diagnosed with hyperparathyroidism and underwent surgery, although they remained hypercalcemic. Which test is most useful in confirming the diagnosis?\nHere are the potential choices:\n1. 25-OH D.\n2. 1,25-OH 2D.\n3. Urine calcium/creatinine ratio.\n4. Phosphate tubular reabsorption.\n5. PTHrP.\nThe correct answer is: ",
        "gold_answer": "3 Urine calcium/creatinine ratio.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n This study was designed to follow the evolution of serum 1,25(OH)2D after surgery for primary hyperparathyroidism. Ten patients were studied before and for up to 85 d after removal of a single parathyroid adenoma. Blood and 24 h urine were obtained at various time points, for the measurement of serum or urinary phosphate and calcium indices. Before surgery, serum calcium (2.91 +/- 0.06 mmol/l; mean +/- SEM), parathyroid hormone (354 +/- 47 pg/ml) and 1,25(OH)2D (61.2 +/- 7.8 pg/ml) were elevated while serum phosphate (1.01 +/- 0.07 mmol/l) tended to be low. Relative hypoparathyroidism was evident for up to 5 d after surgery with the lowest value for serum parathyroid hormone (41 +/- 16 pg/ml) on day 1, serum calcium (2.12 +/- 0.06 mmol/l) on day 3 and highest value for serum phosphate (1.41 +/- 0.13 mmol/l) on day 5. As expected, serum 1,25(OH)2D levels decreased to 35.9 +/- 4.2 pg/ml 24 h after surgery. Stabilization of serum and urinary parameters to normal values was seen between day 5 and day 27; the only exception was serum 1,25(OH)2D, which increased again at day 27 to 57.6 +/- 5.0 pg/ml, a value as high as that before surgery. It was still elevated at day 50 (58.3 +/- 4.3 pg/ml), but returned towards normal values in three out of four patients (44 +/- 3.9 pg/ml) by day 80. No variation in 25(OH)D or 24,25(OH)2D was seen throughout the study. 1,25(OH)2D values could be related to serum parathyroid hormone values before surgery (r = 0.659, P less than 0.05) but not after. The secondary increase in serum 1,25(OH)2D could not be related to variations in serum calcium, phosphate, parathyroid hormone or diet. Further studies will be required to explain this phenomenon. Diagnosis As most cases of FHH are asymptomatic and benign, the diagnosis of FHH is less likely to be made. Typically, diagnosis is made in the pursuit of uncovering the etiology of hypercalcemia. Calcium levels are often in the high normal range or slightly elevated. Commonly, the parathyroid hormone level is checked and may be slightly elevated or also on the high normal end. Normally, high calcium should cause low PTH and so this level of PTH is inappropriately high due to the decreased sensitivity of the parathyroid to calcium. This may be mistaken for primary hyperparathyroidism. However, evaluation of urine calcium level will reveal a low level of urine calcium. This too is inappropriate as high serum calcium should result in high urine calcium. If urine calcium is not checked, this may lead to parathyroidectomy for presumed primary hyperparathyroidism. Additionally as the name implies, there may be a family history of benign hypercalcemia. Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant inherited disorder that is sometimes easily confused with primary hyperparathyroidism. It is characterized by hypercalcemia, hypocalciuria, and high-normal to mildly increased parathyroid hormone secretion. [88] [112] Familial hypocalciuric hypercalcemia is caused by a mutation in the calcium-sensing receptor of the chief cells of the parathyroid gland. Histologically, the parathyroid glands appear normal. There is usually a known family history of the disorder. There are no clinical symptoms, and it requires no treatment. The diagnosis is usually made by history or the calcium/creatinine excretion ratio, although 24-hour urine testing showing severe hypocalciuria of <100 mg/24 hours is highly suggestive. The calcium/creatinine excretion ratio [(urinary calcium x serum creatinine) / (serum calcium x urinary creatinine)] in the urine of patients with familial hypocalciuric hypercalcemia is very low, typically <0.01 in 80% of cases, and FHH is more likely if hypercalcemia is detected before age 40. [88] Other causes of hypocalciuric hypercalcemia should be ruled out (vitamin D deficiency, severely calcium-deficient diet, mild renal failure, use of thiazide or lithium). A calcium infusion test can also help distinguish FHH from primary hyperparathyroidism. A calcium load will increase urinary calcium excretion in primary hyperparathyroidism but not familial hypocalciuric hypercalcemia. [88] A definitive diagnosis can be made in questionable cases by genetic testing. [88] To investigate the changes in the 1 alpha,25-dihydroxyvitamin D [1,25(OH)2D] level and the role of parathyroid hormone (PTH) and calcitonin (CT) during the early neonatal periods, we measured 1,25(OH)2D, 25-hydroxyvitamin D [25(OH)D], PTH specific for mid-regions (mPTH) and urinary cAMP (UcAMP) to evaluate the renal tubular responsiveness to intrinsic PTH and CT, as well as serum Ca and P in 28 mothers at term delivery and in their babies at birth and 5 days of age. Cord serum 1,25(OH)2D levels were low (28.8 +/- 9.2 pg/ml, mean +/- SD), while maternal serum 1,25(OH)2D levels were high (62.2 +/- 22.6 pg/ml). The low 1,25(OH)2D value increased 2.5 times (62.2 +/- 22.6 pg/ml) in 5-day-old infants, reaching a high normal adult value, concomitant with the increases in mPTH and urinary cAMP/creatinine ratio (UcAMP/Cr). The correlations between 1,25(OH)2D and UcAMP/Cr, and 1,25(OH)2D and mPTH in all paired samples of babies at birth and at 5 days of age were r = 0.456, n = 50, P less than 0.01 and r = 0.341, n = 50, P less than 0.05, respectively. These data suggest that the parathyroid activation after birth is a major factor in the rapid 1,25(OH)2D increment at that time. CT levels were high in all paired samples and in 5-day-old infants. CT vs 1,25(OH)2D showed a significant correlation (r = 0.473, P less than 0.05, n = 24) as well as the relative increase of 1,25(OH)2D (delta pg/ml) after birth vs CT at age 5 days (r = 0.537, P less than 0.01, n = 24).(ABSTRACT TRUNCATED AT 250 WORDS) The diagnosis of FHH can be easy to make in an asymptomatic hypercalcemic patient with a family his­tory of hypercalcemia, a personal or family history of failed neck exploration, or normal serum PTH [1] [2] . More than 99% of the filtered calcium gets reabsorbed despite the presence of hypercalcemia. The 24 hours urinary calcium excretion is less than 100 mg/24 hours. The Ca/Cr excretion ratio is very low. It is calculated as follows: [UCa × SCr] / [SCa × UCr], where UCa is the urinary calcium con­centration, SCr is the serum creatinine, SCa is the serum calcium concentration, and UCr is the urinary creati­nine concentration, all in mg/dl. The Ca/Cr clearance ratio is less than 0.01 in 80% of cases. All patients with calcium/creatinine clearance ratio of 0.020 or less should be tested for mutations in the CaSR gene. Serum Magnesium is in the upper-normal range or mildly elevated; whereas, serum magnesium tends to be nor­mal or low in primary hyperparathyroidism. Once true hypercalcemia is established, the second most important laboratory test in the diagnostic evaluation is a PTH level using a two-site assay for the intact hormone. Increases in PTH are often accompanied by hypophosphatemia. In addition, serum creatinine should be measured to assess renal function; hypercalcemia may impair renal function, and renal clearance of PTH may be altered depending on the fragments detected by the assay. If the PTH level is increased (or “inappropriately normal”) in the setting of elevated calcium and low phosphorus, the diagnosis is almost always primary hyperparathyroidism. Because individuals with FHH may also present with mildly elevated PTH levels and hypercalcemia, this diagnosis should be considered and excluded because parathyroid surgery is ineffective in this condition. A calcium/creatinine clearance ratio (calculated as urine calcium/ serum calcium divided by urine creatinine/serum creatinine) of <0.01 is suggestive of FHH, particularly when Metabolic acidoses are diseases causing many diagnostic and therapeutic problems. Compensated metabolic acidosis can be unrecognised for a long time. This refers especially to isolated renal tubular acidosis (RTA). Unrecognised RTA causes calcium and phosphorus balance disturbances with clinical signs of improper bone mineralization. It happens that some patients with mentioned problems are \"treated\" as rachitic and take high doses of vitamin D. As a result, serum calcium and phosphates as well as urine calcium increase, without the satisfied influence on bone mineralization. We present a case of a 3.5 months old baby, who was \"treated\" as ricket in vitamin D deficiency. This baby was \"cured\" with high doses of cholecalciferol (0.0875 mg/24h for 2 weeks, then 0.175 mg/24h for 3 weeks) because of craniotabes. This treatment was carried on without any metabolic tests and caused the following disturbances: 25(OH)D serum level - 102.7 ng/ml (normal 11-54), 1,25(OH)2D serum level - 39.5 pg/ml (normal 15-70), calcaemia 2.7-2.85 mmol/l, phosphataemia 2.1 mmol/l. In this time the considerable hipercalciuria (second morning urine sample Ca/cr ratio 2.06 mmol/mmol) occurred. The other laboratory test showed as follows: serum albumins 4.5 g/dl, alkaline phosphatase 188 U/l, acid phosphatase 10.7 U l, Cl- 114.9 mmol/l, Na 146 mmol/l, K 4.8 mmol/l, HCO3a 16.6-20.1 mmol/l and pCO2 3.63-3.85 kPa, serum anion gap 11 mEq/l; pH of morning urine 6.5-7. These results suggested the presence of distal RTA aside from symptoms of vitamin D overdosage. The high serum levels of calcium and phosphates, craniotabes, rather low serum alkaline phosphatase activity and presence of metabolic acidosis the symptoms after the normalisation of calcium and phosphorus balance suggested that the distal RTA had been prior to calcium disturbances. Hypercalcemia can be hazardous during pregnancy, most cases being due to primary hyperparathyroidism. We report a case of hypercalcemia with suppressed PTH levels necessitating treatment with bisphosphonates during pregnancy. A 38-year-old woman at the 26th week gestation was admitted because of symptomatic hypercalcemia. She did not take any medication that could influence her calcium levels. Physical examination was unremarkable. Laboratory tests on admission were: calcium 12.7 mg/dL (8.5-10.5 mg/dL), phosphorus 1.8 mg/dL (2.5-4.5 mg/dL) and PTH on 3 consecutive tests 1.2, 1.3 and 1.2 pg/mL (15-65 pg/mL). Her 24h urine calcium was 900 mg, 25-OH-D 40 ng/mL (30-58 ng/mL) and 1,25-OH-D 99 pg/mL (80-146 for women in the third trimester). Abdominal ultrasound revealed multiple hypervascular liver lesions consistent with hemangiomas by MRI. Breast and neck ultrasound were normal, and chest CT revealed few non-significant 0.3-0.7 cm pulmonary nodules with no change after an interval of 3 months. She was treated with isotonic saline, loop diuretics and calcitonin. Despite this treatment, calcium levels remained high (14.1 mg/dL), and pamidronate was initiated. On 35th week gestation, she underwent a cesarean section complicated by hypocalcemia of the newborn. Eight weeks after delivery, her calcium levels are 9.4 mg/dL and PTH 18 mg/dL. According to the extensive workup and the post-partum normalization of PTH and calcium levels, we conclude that excessive secretion of placental PTHrP was the cause of hypercalcemia in this patient. No significant adverse effect of bisphosphonate on the mother or baby were seen at the short term follow up. Three patients (a grandmother, her daughter and her grandson) belonging to a 23-number-kindred of five generations suffered from adult-onset, X-linked, familiar hypophosphataemic osteomalacia. According to the familiar anecdotes the great-grandmother also had the same disease. The clinical diagnosis was documented by X-ray pictures, scintigraphic and bone histological results, the laboratory diagnosis was proven by blood and urine analyses examined after phosphate loading. The youngest, 24-year-old patient was treated with daily 3 g phosphate and high doses of calcitriol for 2 years. As a new feature of our therapy, per os treatment with 1.25 micrograms calcitriol was supplemented by daily 2-4 micrograms iv. bolus calcitriol for one week every month. The osteomalacia, causing serious symptoms and complaints, healed. Our treatment seemed to be safe, as renal functions, serum total and ionized calcium and PTH levels (including midnight values) remained in normal range. On the basis of our results this disease can be treated by administration of high doses of phosphate, provided that development of hyperparathyroidism is prevented by the coadministration of high doses of calcitriol. We studied the effects of glucocorticoid excess on calcium and phosphorus homeostasis in relation to vitamin D metabolites and parathyroid hormone (PTH) in seven patients with spontaneous ACTH-dependent Cushing's syndrome. Remission of hypercortisolism resulted in a significant increase in tubular reabsorption of phosphate [from 76 +/- 4% to 89 +/- 2% (mean +/- SEM); P less than 0.01] and serum phosphorus (from 3.1 +/- 0.1 to 4.2 +/- 0.2 mg/dl; P less than 0.005). Serum calcium did not change, although there was a reduction in daily urinary calcium excretion from 0.23 +/- 0.02 to 0.107 +/- 0.02 mg calcium/mg creatinine. Serum immunoreactive PTH (iPTH) levels were normal during Cushing's syndrome (34 +/- 5 microleq/ml), but fell significantly after remission to 22 +/- 2 microleq/ml (P less than 0.05). This small decrease in iPTH did not correlate with the improvement of phosphate homeostasis. Plasma 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D [1,25-(OH2)D] concentrations in Cushing's syndrome did not differ from measurements in 97 normal subjects. After treatment, 25OHD did not change, but 1,25-(OH)2D fell in each patient from a mean of 44 to 22 pg/ml (P less than 0.02). 1,25-(OH)2D was inversely correlated with serum phosphorus (r = 0.59; P less than 0.01), but did not correlate with iPTH. The known impairment of intestinal calcium absorption in Cushing's syndrome cannot be attributed to a decrease in the circulating levels of 1,25-(OH)2D. Endogenous hypercortisolism decreases tubular phosphate reabsorption and serum phosphorus, increase tubular phosphate reabsorption and serum phosphorus, increases iPTH, and results in an increase in 1,25-(OH)2D. These events may contribute to the severe loss of bone mass in such patients and may account for the calciuria and phosphaturia of Cushing's syndrome. Familial hypocalciuric hypercalcemia is a rare disease with autosomal dominant transmission. Its basic defect is unknown and it requires no treatment. A 4 month-old girl was admitted for unexplained crying. She was found to have hypercalcemia (2.8 mmol/l) and later values of blood calcium were 3, 3.1 and 3 mmol/l. The serum free ionic calcium level was also elevated. The serum concentrations of protein, phosphorus, magnesium and the alkaline phosphatase activity were all normal. Serum concentrations of 25-(OH)-D3, 1.25-(OH)-2-D3 and PTH were also normal. The urinary calcium/creatinine ratio was normal and the urinary calcium excretion was 1.08 mg/kg/d. Screening of family members showed hypercalcemia in the father (2.8 mmol/l) and a brother aged 7 years (2.9 mmol/l). Short-term treatment with disodium etidronate lowered the serum calcium level to normal, but hypercalcemia reappeared once the treatment was discontinued. This asymptomatic familial hypercalcemia has the characteristics of familial hypocalciuric hypercalcemia. There was no associated endocrine disorder. Screening of family members is worthwhile. Growth hormone excess has been associated with hypercalciuria and nephrolithiasis. Hypercalcemia in acromegaly is rare and usually due to coexistent primary hyperparathyroidism. To report two cases of 1,25-dihydroxyvitamin D (1,25 (OH)(2) D)-dependent hypercalcemia in cromegaly. A 50 year-old female with 2 years history of hypercalcemia presented with features of acromegaly. Serum calcium (Ca) was 10.9 mg/dl (8.6-10.2), parathyroid hormone (PTH) 20 pg/ml (10-65), PTH-related peptide undetectable, and 1,25 (OH)(2) D 119 pg/ml (15-75). Insulin-like growth factor 1 (IGF1) was 911 ng/ml (49-292) and growth hormone (GH) 14.5 ng/ml (0.03-10). MRI showed a 1.7 cm pituitary tumor. Transsphenoidal adenectomy (TSA) resulted in normalization of IGF1, GH, Ca, and 1,25 (OH)(2) D (50 pg/ml) and complete tumor resection. A 52-year-old female was diagnosed with visual field deficits on routine exam. MRI showed a 3 cm invasive pituitary macroadenoma. IGF1 was 416 ng/ml (87-238) and GH 75.8 (0-6.0) ng/ml. Incidentally, she was found with high Ca of 10.8 mg/dl (8.9-10.3) associated with PTH 19 pg/ml and 1,25 (OH)(2) D66 pg/ml. Postoperatively, IGF1 and GH remained abnormal (440 and 12.8 ng/ml, respectively), while MRI showed parasellar tumor residue. Ca remained high (10.1-11.1 mg/dl), along with elevated 1,25 (OH)(2) D level (81.3 pg/ml). In both cases, other causes of hypercalcemia were ruled out. We present 2 cases of 1,25 (OH)(2) D-dependent hypercalcemia associated with growth hormone excess. Complete resection of tumor produced biochemical remission of acromegaly and normalization of calcium and 1,25 (OH)(2) D levels, while incomplete resection was associated with persistent 1,25 (OH)(2) D-dependent hypercalcemia. Acromegaly should be considered a cause of 1,25 (OH)(2) D-dependent hypercalcemia. In order to better understand the difference between familial hypocalciuric hypercalcemia (FHH) and primary hyperparathyroidism (PHP), 4 adults with this disease (FHH(+], from the same kindred, and spanning 2 generations, were compared with 6 patients with PHP, 10 normal controls (N) and 3 unaffected members of the same kindred (FHH(-]. Clinically speaking, the FHH(+) patients were asymptomatic while those with PHP had recurring renal stones. Various phosphocalcic balance elements were measured in blood and urine, in a fasting state, following oral loading of 1 g calcium, as well as in 24-hour urine specimens. Serum calcium levels were slightly higher (11.90 +/- .14 vs 11.37 +/- .24 mg/dl; p less than .05), in patients with FHH(+), but serum phosphorus (2.47 +/- .38 vs 2.88 +/- .40 mg/dl), serum parathyroid hormone (301 +/- 147 vs 291 +/- 224 pg/ml) and serum 1,25(OH)2D (52.8 +/- 6.7 vs 55.0 +/- 12.0 pg/ml) values were similar to those observed in patients with PHP. Urinary calcium present in FHH(+), while fasting (.064 +/- .043 mg/100 ml G.F.), after the calcium loading (.150 +/- .071) and in the 24-hour specimen (.089 +/- .016), was below the 95% confidence limit of values obtained in patients with PHP (.225 +/- .026, p less than .001; .413 +/- .066, p less than .001; 314 +/- .080, p less than .001), but similar to those obtained in N and FHH(-).(ABSTRACT TRUNCATED AT 250 WORDS) Peritoneal dialysate containing 2.5 mEq/L of calcium has been used to prevent hypercalcemia when calcium-containing phosphate binders are given. However, worsening of hyperparathyroidism may result. Calcitriol used in conjunction with 2.5 mEq/L calcium dialysate is an attractive alternative, but has not been examined in a controlled trial. Eighteen patients were randomly assigned to either a control group (3.5 mEq/L calcium dialysate without calcitriol) or a study group (conversion to 2.5 mEq/L calcium dialysate with oral calcitriol, median dose 0.25 microgram/day). The initial mean serum calcium (9.9 vs 9.6 mg/dL), phosphate (5.4 vs 5.6 mg/dL), median n-terminal parathyroid hormone (PTH) levels (71 vs 55 pg/mL, normal &lt; 25), and median 1,25 (OH)2 vitamin D levels (4 vs 5 pg/mL, normal 15-60 pg/mL) were not different in the two groups. After 8 weeks the serum calcium and phosphate were unchanged from baseline in both groups. The 9 patients who converted to 2.5 mEq/L calcium dialysate had an insignificant fall in the PTH level, not different from the control group. The median 1,25 (OH)2 vitamin D level rose from 4 to 23 pg/mL (p = 0.003) on calcitriol, but remained unchanged in the control group (5 pg/mL). The median doses of oral calcium (0.9 vs 1.1 g/day) and the frequency of serum calcium levels greater than 11 mg/dL (4/9 vs 3/9 patients, 10% vs 8% of all values) were similar in the study and control groups. Aluminum hydroxide was required intermittently for serum phosphate control in 3 patients on 2.5 mEq/L calcium dialysate and 4 on 3.5 mEq/L calcium dialysate.(ABSTRACT TRUNCATED AT 250 WORDS) Biochemical tests related to calcium and phosphorus metabolism have traditionally been considered as a reliable tool to differentiate familial hypocalciuric hypercalcemia (FHH) from primary hyperparathyroidism (PHPT). However, diagnosis may sometimes be difficult even for experienced clinicians. Our objective was to assess the accuracy of diagnostic tests in FHH and the circumstances in which genetic studies are required. A descriptive study was conducted of two families with hypercalcemia and suspected atypical FHH. Urinary calcium excretion was measured in 24-hour urine using different tests (calcium excretion (CE), urinary calcium/creatinine clearance ratio (UCCR)), and serum PTH and 25-hydroxyvitamin D levels were tested. Index cases underwent genetic study. One patient from the first family showed overt, persistent hypercalciuria with values more consistent with PHPT than with FHH if we consider, as proposed by guidelines, a UCCR lower than 0.01 as diagnostic of FHH and a value higher than 0.02 as diagnostic of PHPT. The index case of the second family underwent surgery for a parathyroid adenoma. Both cases had a mutation c. 164C&gt;T (Pro55Leu) in exon 2 in heterozygosis. According to current clinical guidelines, definitive diagnosis of FHH requires genetic confirmation, which allowed in our case for detection of two families with FHH and atypical clinical presentations. We think that rational use of genetic tests may avoid unnecessary surgery and excess monitoring costs. an elevated chloride-to-phosphate ratio (>33). Urinary calcium levels need not be measured routinely, except in patients who have not had previ-ously documented normocalcemia or have a family history of hypercalcemia to rule out FHH. In patients with FHH, 24-hour urinary calcium excretion is characteristically low (<100 mg/d). Furthermore, the serum calcium-to-creatinine clearance ratio (24-hour urine calcium/plasma total calcium/24-hour urine creatinine/plasma creatinine) usually is <0.01 in patients with FHH, whereas it is typically >0.02 in patients with PHPT, although there are exceptions to this. Other biochemical features of PHPT are listed in Table 38-10. Elevated levels of alkaline phosphatase may be found in approximately 10% of patients with PHPT and are indicative of high-turnover bone disease. These patients are prone to developing postoperative hypocal-cemia due to bone hunger. Serum and urine protein electropho-resis may be necessary to exclude multiple\nHere is the question:\nENDOCRINOLOGY: In a 30-year-old female patient a calcium level of 11 mg/dl (normal less than 10.5 mg/dl) is found during a routine company examination. PTH determination was 45 pg/ml (VN 10-55 pg/ml). The history is unremarkable except for the fact that the mother and paternal grandfather were diagnosed with hyperparathyroidism and underwent surgery, although they remained hypercalcemic. Which test is most useful in confirming the diagnosis?\nHere are the potential choices:\n1. 25-OH D.\n2. 1,25-OH 2D.\n3. Urine calcium/creatinine ratio.\n4. Phosphate tubular reabsorption.\n5. PTHrP.\nThe correct answer is: 3. Urine calcium/creatinine ratio."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Primary hyperaldosteronism is only rarely caused by unilateral adrenal hyperplasia. A 73-year-old hypertensive Greek man (on 10 mg amlodipine for the last ten years) presented in the emergency department with severe muscle weakness of all limbs. The initial physical and laboratory examination revealed normal blood pressure, muscle weakness, severe hypokalemia, sinus rhythm and U wave, rhabdomyolysis and metabolic alkalosis. The patient was immediately treated with intravenous administration of potassium-rich solutions, 25 mg spironolactone with progressive dose titration up to 100 mg. Because of high arterial blood pressure, irbesartan was added. On day 6, muscle weakness was completely restored with decrease of arterial blood pressure and further improvement of laboratory tests. The combination of hypokalemia with arterial hypertension raised the suspicion of primary hyperaldosteronism; therefore, we performed abdomen computed tomography scan, which revealed a nodular mass (15 mm in diameter) in the left adrenal gland. Plasma renin activity was in the lower normal range with a three-fold increase of plasma aldosterone concentration. We performed total resection of the left adrenal gland and the histopathological examination revealed hyperplasia of the left adrenal gland. This report presents a rare case of an elderly patient under antihypertensive treatment the last ten years for essential hypertension, who admitted to our emergency department with hypokalemia - induced myopathy as first manifestation of primary hyperaldosteronism due to unilateral adrenal hyperplasia. Based on two patients, we discuss the difficulties in diagnosing and managing primary aldosteronism in pregnancy, which derive from changes of the renin-angiotensin-aldosterone axis, from the uncertainty regarding blood pressure control along gestation and postpartum, and from the contraindication to the use of spironolactone. The first case is a 27 years old woman with a long standing refractory hypertension, a hemorrhagic stroke with left brachial hemiplegia and crural hemiparesia, two miscarriages, one stillbirth and one offspring with intrauterine growth retardation. Due to hypokalemia, a plasma aldosterone/renin activity ratio of 91, and a negative genetic screening for glucocorticoid remediable aldosteronism (GRA), a primary hyperaldosteronism with normal adrenals in CT scan was diagnosed, and good blood pressure control was attained with spironolactone. After two and a half years of normotension, a fifth pregnancy, managed with methyldopa evolved with satisfactory blood pressures, plasma potassium, fetal growth, uterine and umbilical arterial resistance indexes, and maternal endothelial function. At 37 1/2 weeks of pregnancy the patient delivered a healthy newborn weighing 2,960 g. Blood pressure rose during the 48 hours of postpartum in the absence of proteinuria and required i.v. hydralazine. The second patient is a 37 years old woman, with known refractory hypertension for 7 years, hypokalemia, plasma aldosterone/renin activity ratio greater than 40, normal adrenals in the CAT scan, and a negative genetic screening for GRA. She had normotensive pregnancies 5 and 3 years prior to the detection of hypertension, with hypertensive crisis in both postpartum periods, retrospectively considered as expressions of primary hyperaldosteronism. Primary aldosteronism (PA) is the most common form of secondary hypertension (HTN), with an estimated prevalence of 4% of hypertensive patients in primary care and around 10% of referred patients. Patients with PA have higher cardiovascular morbidity and mortality than age- and sex-matched patients with essential HTN and the same degree of blood pressure elevation. PA is characterized by an autonomous aldosterone production causing sodium retention, plasma renin supression, HTN, cardiovascular damage, and increased potassium excretion, leading to variable degrees of hypokalemia. Aldosterone-producing adenomas (APAs) account for around 40% and idiopathic hyperaldosteronism for around 60% of PA cases. The aldosterone-to-renin ratio is the most sensitive screening test for PA. There are several confirmatory tests and the current literature does not identify a \"gold standard\" confirmatory test for PA. In our institution, we recommend starting case confirmation with the furosemide test. After case confirmation, all patients with PA should undergo adrenal CT as the initial study in subtype testing to exclude adrenocortical carcinoma. Bilateral adrenal vein sampling (AVS) is the gold standard method to define the PA subtype, but it is not indicated in all cases. An experienced radiologist must perform AVS. Unilateral laparoscopic adrenalectomy is the preferential treatment for patients with APAs, and bilateral hyperplasia should be treated with mineralocorticoid antagonist (spironolactone or eplerenone). Cardiovascular morbidity caused by aldosterone excess can be decreased by either unilateral adrenalectomy or mineralocorticoid antagonist. In this review, we address the most relevant issues regarding PA screening, case confirmation, subtype classification, and treatment. Primary aldosteronism occurs in 1-10% of hypertensive patients and is classified in adenomas or bilateral adrenal hyperplasia. Computed tomography (CT) or magnetic resonance imaging can be used to discriminate these subtypes and in guiding treatment selection. This case report describes a 65-year-old man with hypertension and hypokalaemia during 25 years. Bilateral adrenal hyperplasia was diagnosed based on a CT, and an oral sodium-loading test with measurement of renin and aldosterone confirmed the diagnosis. Blood pressure and potassium in plasma was normalized during treatment with the mineralocorticoid receptor antagonist eplerenon.  We report a case of a renin secreting tumor, which is a very rare cause of secondary high blood pressure. A 22-year-old woman was hospitalised for exploration of high blood pressure (160/110 mmHg) with severe hypokaliemia (2,7 mmol/l) and secondary hyperaldosteronism. Physical examination was normal except the high blood pressure. Bioassays show increased kaliuresis (66 mmol/24h), plasma renin (89 pg/ml in clinostastism--108 pg/ml in orthostatism), pro-renin (1207 pg/ml in clinostastism--1412 pg/ml in orthostatism) and aldosterone (210 pg/ml in clinostastism--566 pg/ml in orthostatism). The rest of the endocrine tests were normal (cortisol and ACTH at 8:00 am, urinary free cortisol, overnight 1 mg dexamethasone suppression test). Doppler ultrasound method, performed by an experienced radiologist, did not show renal artery stenosis. Abdominal computerized tomography showed a nodular formation at the upper pole of the right kidney, isodense to renal medullary. The size tumor was 15 mm. The renal vein sampling shows high values of renin on both sides whereas, for the pro-renin, the values were higher on the tumor side. In spite of treatment with CEI (Converting Enzyme Inhibitors) and calcium antagonists, the blood pressure was not controlled. Hypokaliemia persisted (3 mmol/l) in spite of high daily potassium intake (64 mmol/l of potassium chloride). After tumor resection, reninoma was diagnosed by the pathology examination and blood pressure, plasma rennin, plasma aldosterone level returned to normal. To investigate the clinical characteristics, differential diagnosis, and surgery outcome of unilateral nodular adrenal hyperplasia (UNAH). The clinical data of 145 patients with primary aldosteronism, 67 males and 78 females, aged 37.9 (19-60), including 78 cases of aldosterone-producing adenoma (APA), 14 cases of UNAH, and 55 cases of idiopathic bilateral adrenal hyperplasia (BAH), were collected. Radioimmunoassay was used to examine the blood and urine aldosterone and plasma rennin activity. Automatic biochemical apparatus was used to examine the blood and urine electrolytes, renal functions, and urine microalbumin. Twelve-lead electrocardiography, echocardiography, and plain scanning of enhanced CT scanning of the bilateral adrenals were conducted. Adrenal venous sampling (AVS) was conducted in 62 patients to collect blood samples from vena cava and bilateral suprarenal veins to detect the levels of aldosterone and cortisol. All UNAH patients and 3 BAH patients underwent unilateral adrenalectomy and three APA patients underwent unilateral adrenalectomy or adenoma resection. Then the patients were followed up for 39.2 months. The incidence of UNAH is 9.7% in the primary aldosteronism patients. There were no significant differences in age, gender, duration of hypertension, blood pressure (SBP, DBP), and indexes indicating damages in target organs of hypertension (left ventricular hypertrophy rate, blood creatinine, urine microalbumin, etc) among these three groups. The level of serum potassium of the APA group was significantly lower than that of the BAH group (P &lt; 0.01), and the levels of plasma and urine aldosterone of the APA group were significantly higher than those of the BAH group (P &lt; 0.05 and P &lt; 0.01). The serum potassium of the UNAH group was higher than that of the APA group and lower than that of the BAH group, and the levels of plasma and urine aldosterone of the UNAH group were both higher than those of the APA group and lower than those of the BAH group, however all not significantly (all P &gt; 0.05). The coincidence rate of CT was 50% (7/14) in the UNAH group. The accuracy of AVS for diagnosis of UNAH was 85.7% (12/14). After operation, the serum potassium and plasma aldosterone concentrations returned normal in all the UNAH patients. Blood pressure returned to normal in 50% (7/14) of the UNAH patients, and was improved in the other 50% (7/14) patients. UNAH can be cured by adrenal surgery. The diagnostic values of clinical examination and adrenal CT are limited. AVS is essential in diagnosing UNAH patients. The prevalence of primary hyperaldosteronism is 5-10% of all hypertensive patients, and clearly above the estimated prevalence in the past. In nearly 30% of patients with therapy resistant hypertension, primary hyperaldosteronism is detected if they are investigated thoroughly. This will result in 1.5 to 2.5 million people in Germany suffering from primary hyperaldosteronism. Besides efficient diagnostic procedures, an effective treatment is of increasing importance. The aldosterone-producing adenoma (Conn's syndrome) is primarily cured by operation, in most cases performed endoscopically. Bilateral hyperplasia, which is found in two-thirds of primary hyperaldosteronism, is treated primarily by mineralocorticoid receptor antagonist: 12.5-50 mg/day spironolactone (in case of anti-androgenic side-effects alternatively by 50-100 mg/day eplerenone). If the blood pressure can not be lowered by this first-line treatment, an additional treatment with potassium-sparing diuretics, calcium-antagonists, ACE-inhibitors or angiotensin-2-antagonists is necessary. The start of medication should be closely monitored by serum electrolyte and creatinine controls. Diagnosis Other conditions such as Liddle's Syndrome can mimic the clinical features of AME, so diagnosis can be made by calculating the ratio of free urinary cortisol to free urinary cortisone. Since AME patients create less cortisone, the ratio will much be higher than non-affected patients. Alternatively, one could differentiate between the two syndromes by administering a potassium-sparing diuretic. Patients with Liddle's syndrome will only respond to a diuretic that binds the ENaC channel, whereas those with AME will respond to a diuretic that binds to ENaC or the mineralcorticoid receptor. Treatment The treatment for AME is based on the blood pressure control with Aldosterone antagonist like Spironolactone which also reverses the hypokalemic metabolic alkalosis and other anti-hypertensives. Renal transplant is found curative in almost all clinical cases.AME is exceedingly rare, with fewer than 100 cases recorded worldwide. We report one case of estimated glomerular filtration rate (eGFR) decline after taking unilateral adrenalectomy due to aldosterone adenoma. A 60-year-old male with 23-year history of hypertension was reported to the endocrinologist due to hypokalemia (serum potassium 3.01 mmol/L). Urine microalbumin/creatinine (ALB/CR) was 70.15 mg/g, serum creatinine was 82 μmol/L and eGFR was 89.79 mL/(min·1.73 m<sup2</sup). Random serum aldosterone was 172.2-203.5 ng/L, and random plasma rennin activity was 0-0.17 μg/(L·h). His captopril challenge test suggested that his aldosterone le-vels were suppressed by 8% (&lt; 30%) and the adrenal enhanced computed tomography scan revealed a left adrenal tumor. The patient was diagnosed with primary hyperaldosteronism (PA), aldosterone adenoma and underwent left laparoscopic adrenalectomy. Histological examination confirmed adrenal cortical adenoma. One week after the operation, his serum creatinine was increased to 127 μmol/L compared with preoperative level; eGFR was 32.34 mL/(min·1.73 m<sup2</sup). His systolic blood pressure (SBP) was 110 mmHg and diastolic blood pressure (DBP) was 60 mmHg (hypotensive drugs discontinued), and serum potassium level was 5.22 mmol/L. At the end of the 2-year follow up, the serum creatinine of this patient remained at 109-158 μmol/L and eGFR fluctuated from 63.28-40.12 mL/(min·1.73 m<sup2</sup). PA is one of the most common causes of secondary hypertension. Several studies have reported renal function deterioration of PA patients after unilateral adrenalectomy, like the patient in this article. Age, preoperative plasma aldosterone concentration, albuminuria and preoperative potassium level might be significant predictors of a decrease in the eGFR. Growing evidence suggests that aldosterone could contribute to structural kidney damage, arterial injury and hemodynamic disorder. At the same time, patients with PA exhibit glomerular hyperfiltration and glomerular vascular hypertension, leading to the misinterpretation of renal function in PA patients as subtle kidney damage may be masked by the glomerular hyperfiltration before treatment. After a unilateral adrenalectomy, glomerular hyperfiltration by aldosterone excess is resolved and renal damage can be unmasked. In conclusion, kidney function deterioration after adrenalectomy can be detected in some patients with PA. Thus, accurate evaluation of kidney function in patients with PA may be essential, especially for those with preoperative risk factors for postoperative renal impairment. After unilateral adrenalectomy, close monitoring of renal function and adequate management are required for PA patients. Primary hyperaldosteronism (PHA) represents less than 1 to 2% of all causes of hypertension (HT). We report 2 cases of primary hyperaldosteronism which emphasize the difficulty of distinguishing neoplastic PHA from idiopathic PHA, observed in a 60-year-old woman and a 42-year old woman, respectively. In both cases, the diagnosis of PHA was suggested by marked hypokalaemia with inappropriate potassium excretion and was confirmed by hyperaldosteronaemia and low and poorly stimulated renin activity. In the first case, computed tomography showed nodular hyperplasia of the 2 adrenal glands. The patient was treated with spironolactone and calcium channel blockers which controlled blood pressure and serum potassium. In the second case, computed tomography and magnetic resonance imaging revealed an adrenocortical adenoma confirmed by pathological examination after the operation. The diagnosis of primary hyperaldosteronism is based on three steps: detection, positive diagnosis and aetiological diagnosis. Detection is essentially based on demonstration of hypokalaemia. Positive diagnosis is based on demonstration of elevated aldosterone secretion with inhibited renin secretion. The aetiological diagnosis is dominated by the differentiation between Conn's adenoma and bilateral adrenal hyperplasia, which has therapeutic implications. Pseudohyperaldosteronism (also pseudoaldosteronism) is a medical condition which mimics the effects of elevated aldosterone (hyperaldosteronism) by presenting with high blood pressure (hypertension), low blood potassium levels (hypokalemia), metabolic alkalosis, and low levels of plasma renin activity (PRA). However, unlike hyperaldosteronism, this conditions exhibits low or normal levels of aldosterone in the blood. Causes include genetic disorders (e.g. Apparent mineralocorticoid excess syndrome, Liddle's syndrome, and types of Congenital adrenal hyperplasia), acquired conditions (e.g. Cushing's syndrome and mineralocorticoid-producing adrenal tumors), metabolic disorders, and dietary imbalances including excessive consumption of licorice. Confirmatory diagnosis depends on the specific root cause and may involve blood tests, urine tests, or genetic testing; however, all forms of this condition exhibit abnormally low concentrations of both plasma renin activity (PRA) and plasma We report the case of a 42-year-old male who was admitted to our hospital after an acute hypertensive crisis despite four-way anti-hypertensive therapy. The renal scintigraphy, the excretory urogram and the biochemical profile performed two years before were unremarkable, except for slightly elevated serum creatinine and plasma aldosterone, in presence of normal aldosterone/renin ratio. The renal arterial angiography that was performed despite a second unremarkable scintigraphy revealed high-grade bilateral arterial stenosis in the presence of multiple renal arteries. Following dilatation of the left stenosis, the aldosterone/renin ratio was pathologic. Recumbent and orthostatic aldosterone values were 830 pg/ml and 1824 pg/ml, respectively, and recumbent and orthostatic renin values were 0.82 and 1.21 ng angiotensin I/ml/h, respectively. The abdominal computed tomography performed to investigate a possible concomitant Conn's syndrome resulted in the detection of a left adrenal tumor. After resection of the lesion, plasma-aldosterone levels normalized and a pronounced rise in serum potassium levels was observed. Following angioplasty of the right renal artery stenosis, blood pressure could easily be managed with combined beta and calcium channel blocker therapy. Particularly in cases of bilateral (but also in the presence of unilateral) renal artery stenosis in association with Conn's syndrome, all the available screening methods for these disorders can fail. In cases of poor response to combination hypertensive therapies, renal arteriography and a fludrocortisone-suppression test should be performed in order to rule out both renal arterial stenosis and Conn's syndrome, even in the absence of clinical and biochemical findings suspicious for either disorder. Primary hyperaldosteronism (PHA) is characterized by an increased Aldosterone synthesis which is independent of the Renin-Angiotensin-Aldosterone-System (RAAS). The prevalence of PHA in patients who present in specialized hypertension centers is approx. 10 %. Besides patients with the classical symptoms known as \"Conn-Trias\" (hypertension, hypokalemia, metabolic alkalosis), the more frequent normokalemic patients with PHA also show a worse outcome compared to patients with essential hypertension. Identifying these patients is an important task in the evaluation of hypertension since targeted treatment options are available. Screening for PHA using the Aldosterone-Renin-Ratio (ARR) should be performed in patients with hypokalemic, severe or resistant hypertension. In addition, young patients with early onset of severe hypertension and/or positive family history should be screened. A positive screening result should be followed by a confirmatory test. The saline infusion test is the preferred clinical test for confirming a suspected PHA since it is accessible and time efficient. Other confirmatory tests are not used on a regular basis. After any confirmatory test, CT- or MRI-imaging and adrenal vein sampling (AVS) is used in order to differentiate between a unilateral adenoma, a bilateral hyperplasia or another cause of PHA. CT or MRI usually cannot discriminate smaller tumors form hyperplasia. Therefore AVS is used to detect lateralization of autonomous aldosterone production. Lateralization of aldosterone production indicates a unilateral adenoma. In these cases, laparoscopic adrenalectomy is the therapeutic option of choice with a hypertension cure rate of up to 60 %. If no lateralization is detectable, bilateral hyperplasia as the underlying cause of PHA is likely. Pharmacological inhibition of the mineralocorticoid receptor is the preferred treatment option in these cases. If Spironolactone is not well tolerated, Eplerenone and potassium-sparing diuretics should be prescribed. Often, however, in order to fully control hypertension, additional antihypertensive therapy is necessary. To show clinical, biochemical, and morphological data of 12 patients with primary hyperaldosteronism: eight with an aldosterone-producing adenoma and four with adrenal hyperplasia. To compare clinical and biochemical parameters of the patients with adenoma and hyperplasia. For those with adenoma, to verify clinical and biochemical modifications after adrenalectomy. In the 12 patients with hyperaldosteronism, retrospective analysis of clinical (age, sex, blood pressure), biochemical (plasmatic and urinary potassium, plasmatic aldosterone, plasma renin activity, and plasmatic aldosterone/renin activity ratio), and morphological (computed tomography, magnetic resonance, and norcholesterol scintigraphy) data was performed. 1--In the 12 patients with hyperaldosteronism (seven female), the age was 51.0 +/- 10.2 years (mean +/- standard deviation), the systolic pressure 200.9 +/- 34.5 mm Hg and the diastolic pressure 120.0 +/- 12.3 mm Hg. Hypertension was diagnosed 12.0 +/- 10.1 years before. As biochemical evidence, we found kalaemia of 3.06 +/- 0.28 and urinary potassium of 63.4 +/- 16.5 mEq/l, renin activity 0.98 +/- 1.02 ng/ml/h, plasmatic aldosterone of 49.4 +/- 36.0 ng/dl, aldosterone/renin activity &gt; 30 in 83% of the cases. As morphological evidence, computed tomography allowed diagnosis in nine patients, suggested it in two, being doubtful in one. Performed on four patients, resonance confirmed the tomography in three and was not contributive in one. The scintigraphy performed in four patients visualized two adenomas, was negative in one adenoma and in one hyperplasia. 2--In the eight patients with adenoma (six female), the youngest age and the highest diastolic pressure compared with patients with hyperplasia were statistically significant (p &lt; 0.01 and 0.05). In the adenomas, the biochemical changes were more pronounced, but not statistically significant. The plasmatic aldosterone/renin activity ratio was also higher in the adenoma cases. 3--After the adrenalectomy, blood pressure became normal in five patients and was more easily therapeutically controlled in three. The average systolic and diastolic pressures decreased and the biochemical parameters became normal in all patients. The pre/post surgical modification of these parameters had statistical significance (systolic pressure decrease, p &lt; 0.01; diastolic pressure decrease, p &lt; 0.01; kalaemia increase, p &lt; 0.001; renin activity increase, p &lt; 0.01; aldosterone decrease, p &lt; 0.02). The plasmatic aldosterone/renine activity ratio normalized in all patients. In diagnosing primary hyperaldosteronism, biochemical (kalaemia, urinary potassium, plasmatic aldosterone, renin activity, aldosterone plasmatic/renin activity) and tomography studies were important. On comparing the patients with hyperplasia with those with adenoma, we found that the latter are younger and exhibit higher diastolic pressure, both findings with statistical significance. After adenoma surgery, blood pressure became normal in five patients and improved in three, these findings, and the improvement of the kalaemia, plasmatic aldosterone, and renin activity parameters were statistically significant. A 36-year-old female case of normotensive normoreninemic primary aldosteronism with persistent hypokalemia and nephrocalcinosis is reported. She was referred to us for episodes of sudden muscle weakness during 8 years prior to admission. On the first day of admission, her blood pressure was 174/104 mmHg. On the second day of admission blood pressure normalized to 120/80 mmHg. Both of her parents were hypertensive. Arterial blood gas analysis showed metabolic alkalosis. Except an impaired urine concentration ability, renal functions were normal. Intravenous pyelogram showed numerous granular calcifications. Basal plasma renin activity was 1.0 approximately 1.5 ng/ml/hr and increased by sodium depletion. Plasma aldosterone concentration was 70 approximately 80 ng/dl and did not respond to various stimulations. Blood pressure was dependent on sodium balance. It fell on salt restriction and rose on salt loading. Blood pressure responses to vasoactive hormones were normal. Circulating plasma volume was within normal range. After removal of an adrenal adenoma, there was mild fall of blood pressure, serum potassium returned to normal level and plasma renin activity increased slightly. Histologically, there was renal tubular calcifications, and juxtaglomerular apparatus was normal. Blood pressure was elevated to 160/100 mmHg when patient was followed at out-patient clinic after discharge. We concluded that she had essential hypertension associated with primary aldosteronism. Although sodium loss and an increase in urinary kallikrein were found, they did not seem to be the cause of normoreninemic normotensive state of this patient, and the pathogenesis remains to be elucidated. Primary Primary aldosteronism (hyporeninemic hyperaldosteronism) was previously thought to be most commonly caused by an adrenal adenoma, termed Conn's syndrome. However, recent studies have shown that bilateral idiopathic adrenal hyperplasia is the cause in up to 70% of cases. Differentiating between the two is important, as this determines treatment. Also, see congenital adrenal hyperplasia. Adrenal carcinoma is an extremely rare cause of primary hyperaldosteronism. Two familial forms have been identified: type I (dexamethasone suppressible), and type II, which has been linked to the 7p22 gene. Features Hypertension Hypokalemia (e.g., may cause muscle weakness) Alkalosis Investigations High serum aldosterone Low serum renin High-resolution CT abdomen Management Adrenal adenoma: surgery Bilateral adrenocortical hyperplasia: aldosterone antagonist, e.g., spironolactone In patients with normal adrenal morphology and family history of early-onset, severe hypertension, a diagnosis of GRA should be Disorders of the Adrenal Cortex Clinical suspicion of mineralocorticoid excess Patients with hypertension and Severe hypertension (>3 BP drugs, drug-resistant) or Family history of early-onset hypertension or cerebrovascular events at < 40 years of age Measurement of aldosterone-renin ratio (ARR) on current blood pressure medication (stop spironolactone for 4 wks) and with hypokalemia corrected (ARR screen positive if ARR >750 pmol/L: ng/ml/h and aldosterone >450 pmol/L) (consider repeat off ˜-blockers for 2 wks if results are equivocal) Negative E.g., saline infusion test (2 liters physiologic saline over 4 h IV), oral sodium loading, fludrocortisone suppression Confirmation of diagnosis Rare: Both renin and Aldo suppressed Primary hyperaldosteronism has a number of causes. About 33% of cases are due to an adrenal adenoma that produces aldosterone, and 66% of cases are due to an enlargement of both adrenal glands. Other uncommon causes include adrenal cancer and an inherited disorder called familial hyperaldosteronism. Some recommend screening people with high blood pressure who are at increased risk, while others recommend screening all people with high blood pressure for the disease. Screening is usually done by measuring the aldosterone-to-renin ratio in the blood (ARR) whilst off interfering medications and a serum potassium over 4, with further testing used to confirm positive results. While low blood potassium is classically described in primary hyperaldosteronism, this is only present in about a quarter of people. To determine the underlying cause, medical imaging is carried out.\nHere is the question:\nCARDIOLOGY: A 58-year-old male with a history of arterial hypertension of 6 years of evolution, who consults for poor control of blood pressure figures despite receiving treatment with an angiotensin-converting enzyme inhibitor, a diuretic and a calcium antagonist. On consultation she presented with blood pressure of 149/100 mmHg. Laboratory tests: creatinine 1.2 mg/dl, potassium 2.2 mEq/l and compensated metabolic alkalosis; the rest of the biochemical study, blood count, coagulation and urinary sediment were normal. Mark the correct statement:\nHere are the potential choices:\n1. The origin of hypertension in this case is excessive aldosterone secretion caused by autonomic hyperfunction of the adrenal medulla.\n2. In most cases the anatomical substrate is bilateral hyperplasia of the adrenal cortex.\n3. CT scan is part of the diagnostic study in case of biochemical confirmation.\n4. Spironolactone is contraindicated in the management of this pathology.\nThe correct answer is: ",
        "gold_answer": "3 CT scan is part of the diagnostic study in case of biochemical confirmation.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Primary hyperaldosteronism is only rarely caused by unilateral adrenal hyperplasia. A 73-year-old hypertensive Greek man (on 10 mg amlodipine for the last ten years) presented in the emergency department with severe muscle weakness of all limbs. The initial physical and laboratory examination revealed normal blood pressure, muscle weakness, severe hypokalemia, sinus rhythm and U wave, rhabdomyolysis and metabolic alkalosis. The patient was immediately treated with intravenous administration of potassium-rich solutions, 25 mg spironolactone with progressive dose titration up to 100 mg. Because of high arterial blood pressure, irbesartan was added. On day 6, muscle weakness was completely restored with decrease of arterial blood pressure and further improvement of laboratory tests. The combination of hypokalemia with arterial hypertension raised the suspicion of primary hyperaldosteronism; therefore, we performed abdomen computed tomography scan, which revealed a nodular mass (15 mm in diameter) in the left adrenal gland. Plasma renin activity was in the lower normal range with a three-fold increase of plasma aldosterone concentration. We performed total resection of the left adrenal gland and the histopathological examination revealed hyperplasia of the left adrenal gland. This report presents a rare case of an elderly patient under antihypertensive treatment the last ten years for essential hypertension, who admitted to our emergency department with hypokalemia - induced myopathy as first manifestation of primary hyperaldosteronism due to unilateral adrenal hyperplasia. Based on two patients, we discuss the difficulties in diagnosing and managing primary aldosteronism in pregnancy, which derive from changes of the renin-angiotensin-aldosterone axis, from the uncertainty regarding blood pressure control along gestation and postpartum, and from the contraindication to the use of spironolactone. The first case is a 27 years old woman with a long standing refractory hypertension, a hemorrhagic stroke with left brachial hemiplegia and crural hemiparesia, two miscarriages, one stillbirth and one offspring with intrauterine growth retardation. Due to hypokalemia, a plasma aldosterone/renin activity ratio of 91, and a negative genetic screening for glucocorticoid remediable aldosteronism (GRA), a primary hyperaldosteronism with normal adrenals in CT scan was diagnosed, and good blood pressure control was attained with spironolactone. After two and a half years of normotension, a fifth pregnancy, managed with methyldopa evolved with satisfactory blood pressures, plasma potassium, fetal growth, uterine and umbilical arterial resistance indexes, and maternal endothelial function. At 37 1/2 weeks of pregnancy the patient delivered a healthy newborn weighing 2,960 g. Blood pressure rose during the 48 hours of postpartum in the absence of proteinuria and required i.v. hydralazine. The second patient is a 37 years old woman, with known refractory hypertension for 7 years, hypokalemia, plasma aldosterone/renin activity ratio greater than 40, normal adrenals in the CAT scan, and a negative genetic screening for GRA. She had normotensive pregnancies 5 and 3 years prior to the detection of hypertension, with hypertensive crisis in both postpartum periods, retrospectively considered as expressions of primary hyperaldosteronism. Primary aldosteronism (PA) is the most common form of secondary hypertension (HTN), with an estimated prevalence of 4% of hypertensive patients in primary care and around 10% of referred patients. Patients with PA have higher cardiovascular morbidity and mortality than age- and sex-matched patients with essential HTN and the same degree of blood pressure elevation. PA is characterized by an autonomous aldosterone production causing sodium retention, plasma renin supression, HTN, cardiovascular damage, and increased potassium excretion, leading to variable degrees of hypokalemia. Aldosterone-producing adenomas (APAs) account for around 40% and idiopathic hyperaldosteronism for around 60% of PA cases. The aldosterone-to-renin ratio is the most sensitive screening test for PA. There are several confirmatory tests and the current literature does not identify a \"gold standard\" confirmatory test for PA. In our institution, we recommend starting case confirmation with the furosemide test. After case confirmation, all patients with PA should undergo adrenal CT as the initial study in subtype testing to exclude adrenocortical carcinoma. Bilateral adrenal vein sampling (AVS) is the gold standard method to define the PA subtype, but it is not indicated in all cases. An experienced radiologist must perform AVS. Unilateral laparoscopic adrenalectomy is the preferential treatment for patients with APAs, and bilateral hyperplasia should be treated with mineralocorticoid antagonist (spironolactone or eplerenone). Cardiovascular morbidity caused by aldosterone excess can be decreased by either unilateral adrenalectomy or mineralocorticoid antagonist. In this review, we address the most relevant issues regarding PA screening, case confirmation, subtype classification, and treatment. Primary aldosteronism occurs in 1-10% of hypertensive patients and is classified in adenomas or bilateral adrenal hyperplasia. Computed tomography (CT) or magnetic resonance imaging can be used to discriminate these subtypes and in guiding treatment selection. This case report describes a 65-year-old man with hypertension and hypokalaemia during 25 years. Bilateral adrenal hyperplasia was diagnosed based on a CT, and an oral sodium-loading test with measurement of renin and aldosterone confirmed the diagnosis. Blood pressure and potassium in plasma was normalized during treatment with the mineralocorticoid receptor antagonist eplerenon.  We report a case of a renin secreting tumor, which is a very rare cause of secondary high blood pressure. A 22-year-old woman was hospitalised for exploration of high blood pressure (160/110 mmHg) with severe hypokaliemia (2,7 mmol/l) and secondary hyperaldosteronism. Physical examination was normal except the high blood pressure. Bioassays show increased kaliuresis (66 mmol/24h), plasma renin (89 pg/ml in clinostastism--108 pg/ml in orthostatism), pro-renin (1207 pg/ml in clinostastism--1412 pg/ml in orthostatism) and aldosterone (210 pg/ml in clinostastism--566 pg/ml in orthostatism). The rest of the endocrine tests were normal (cortisol and ACTH at 8:00 am, urinary free cortisol, overnight 1 mg dexamethasone suppression test). Doppler ultrasound method, performed by an experienced radiologist, did not show renal artery stenosis. Abdominal computerized tomography showed a nodular formation at the upper pole of the right kidney, isodense to renal medullary. The size tumor was 15 mm. The renal vein sampling shows high values of renin on both sides whereas, for the pro-renin, the values were higher on the tumor side. In spite of treatment with CEI (Converting Enzyme Inhibitors) and calcium antagonists, the blood pressure was not controlled. Hypokaliemia persisted (3 mmol/l) in spite of high daily potassium intake (64 mmol/l of potassium chloride). After tumor resection, reninoma was diagnosed by the pathology examination and blood pressure, plasma rennin, plasma aldosterone level returned to normal. To investigate the clinical characteristics, differential diagnosis, and surgery outcome of unilateral nodular adrenal hyperplasia (UNAH). The clinical data of 145 patients with primary aldosteronism, 67 males and 78 females, aged 37.9 (19-60), including 78 cases of aldosterone-producing adenoma (APA), 14 cases of UNAH, and 55 cases of idiopathic bilateral adrenal hyperplasia (BAH), were collected. Radioimmunoassay was used to examine the blood and urine aldosterone and plasma rennin activity. Automatic biochemical apparatus was used to examine the blood and urine electrolytes, renal functions, and urine microalbumin. Twelve-lead electrocardiography, echocardiography, and plain scanning of enhanced CT scanning of the bilateral adrenals were conducted. Adrenal venous sampling (AVS) was conducted in 62 patients to collect blood samples from vena cava and bilateral suprarenal veins to detect the levels of aldosterone and cortisol. All UNAH patients and 3 BAH patients underwent unilateral adrenalectomy and three APA patients underwent unilateral adrenalectomy or adenoma resection. Then the patients were followed up for 39.2 months. The incidence of UNAH is 9.7% in the primary aldosteronism patients. There were no significant differences in age, gender, duration of hypertension, blood pressure (SBP, DBP), and indexes indicating damages in target organs of hypertension (left ventricular hypertrophy rate, blood creatinine, urine microalbumin, etc) among these three groups. The level of serum potassium of the APA group was significantly lower than that of the BAH group (P &lt; 0.01), and the levels of plasma and urine aldosterone of the APA group were significantly higher than those of the BAH group (P &lt; 0.05 and P &lt; 0.01). The serum potassium of the UNAH group was higher than that of the APA group and lower than that of the BAH group, and the levels of plasma and urine aldosterone of the UNAH group were both higher than those of the APA group and lower than those of the BAH group, however all not significantly (all P &gt; 0.05). The coincidence rate of CT was 50% (7/14) in the UNAH group. The accuracy of AVS for diagnosis of UNAH was 85.7% (12/14). After operation, the serum potassium and plasma aldosterone concentrations returned normal in all the UNAH patients. Blood pressure returned to normal in 50% (7/14) of the UNAH patients, and was improved in the other 50% (7/14) patients. UNAH can be cured by adrenal surgery. The diagnostic values of clinical examination and adrenal CT are limited. AVS is essential in diagnosing UNAH patients. The prevalence of primary hyperaldosteronism is 5-10% of all hypertensive patients, and clearly above the estimated prevalence in the past. In nearly 30% of patients with therapy resistant hypertension, primary hyperaldosteronism is detected if they are investigated thoroughly. This will result in 1.5 to 2.5 million people in Germany suffering from primary hyperaldosteronism. Besides efficient diagnostic procedures, an effective treatment is of increasing importance. The aldosterone-producing adenoma (Conn's syndrome) is primarily cured by operation, in most cases performed endoscopically. Bilateral hyperplasia, which is found in two-thirds of primary hyperaldosteronism, is treated primarily by mineralocorticoid receptor antagonist: 12.5-50 mg/day spironolactone (in case of anti-androgenic side-effects alternatively by 50-100 mg/day eplerenone). If the blood pressure can not be lowered by this first-line treatment, an additional treatment with potassium-sparing diuretics, calcium-antagonists, ACE-inhibitors or angiotensin-2-antagonists is necessary. The start of medication should be closely monitored by serum electrolyte and creatinine controls. Diagnosis Other conditions such as Liddle's Syndrome can mimic the clinical features of AME, so diagnosis can be made by calculating the ratio of free urinary cortisol to free urinary cortisone. Since AME patients create less cortisone, the ratio will much be higher than non-affected patients. Alternatively, one could differentiate between the two syndromes by administering a potassium-sparing diuretic. Patients with Liddle's syndrome will only respond to a diuretic that binds the ENaC channel, whereas those with AME will respond to a diuretic that binds to ENaC or the mineralcorticoid receptor. Treatment The treatment for AME is based on the blood pressure control with Aldosterone antagonist like Spironolactone which also reverses the hypokalemic metabolic alkalosis and other anti-hypertensives. Renal transplant is found curative in almost all clinical cases.AME is exceedingly rare, with fewer than 100 cases recorded worldwide. We report one case of estimated glomerular filtration rate (eGFR) decline after taking unilateral adrenalectomy due to aldosterone adenoma. A 60-year-old male with 23-year history of hypertension was reported to the endocrinologist due to hypokalemia (serum potassium 3.01 mmol/L). Urine microalbumin/creatinine (ALB/CR) was 70.15 mg/g, serum creatinine was 82 μmol/L and eGFR was 89.79 mL/(min·1.73 m<sup2</sup). Random serum aldosterone was 172.2-203.5 ng/L, and random plasma rennin activity was 0-0.17 μg/(L·h). His captopril challenge test suggested that his aldosterone le-vels were suppressed by 8% (&lt; 30%) and the adrenal enhanced computed tomography scan revealed a left adrenal tumor. The patient was diagnosed with primary hyperaldosteronism (PA), aldosterone adenoma and underwent left laparoscopic adrenalectomy. Histological examination confirmed adrenal cortical adenoma. One week after the operation, his serum creatinine was increased to 127 μmol/L compared with preoperative level; eGFR was 32.34 mL/(min·1.73 m<sup2</sup). His systolic blood pressure (SBP) was 110 mmHg and diastolic blood pressure (DBP) was 60 mmHg (hypotensive drugs discontinued), and serum potassium level was 5.22 mmol/L. At the end of the 2-year follow up, the serum creatinine of this patient remained at 109-158 μmol/L and eGFR fluctuated from 63.28-40.12 mL/(min·1.73 m<sup2</sup). PA is one of the most common causes of secondary hypertension. Several studies have reported renal function deterioration of PA patients after unilateral adrenalectomy, like the patient in this article. Age, preoperative plasma aldosterone concentration, albuminuria and preoperative potassium level might be significant predictors of a decrease in the eGFR. Growing evidence suggests that aldosterone could contribute to structural kidney damage, arterial injury and hemodynamic disorder. At the same time, patients with PA exhibit glomerular hyperfiltration and glomerular vascular hypertension, leading to the misinterpretation of renal function in PA patients as subtle kidney damage may be masked by the glomerular hyperfiltration before treatment. After a unilateral adrenalectomy, glomerular hyperfiltration by aldosterone excess is resolved and renal damage can be unmasked. In conclusion, kidney function deterioration after adrenalectomy can be detected in some patients with PA. Thus, accurate evaluation of kidney function in patients with PA may be essential, especially for those with preoperative risk factors for postoperative renal impairment. After unilateral adrenalectomy, close monitoring of renal function and adequate management are required for PA patients. Primary hyperaldosteronism (PHA) represents less than 1 to 2% of all causes of hypertension (HT). We report 2 cases of primary hyperaldosteronism which emphasize the difficulty of distinguishing neoplastic PHA from idiopathic PHA, observed in a 60-year-old woman and a 42-year old woman, respectively. In both cases, the diagnosis of PHA was suggested by marked hypokalaemia with inappropriate potassium excretion and was confirmed by hyperaldosteronaemia and low and poorly stimulated renin activity. In the first case, computed tomography showed nodular hyperplasia of the 2 adrenal glands. The patient was treated with spironolactone and calcium channel blockers which controlled blood pressure and serum potassium. In the second case, computed tomography and magnetic resonance imaging revealed an adrenocortical adenoma confirmed by pathological examination after the operation. The diagnosis of primary hyperaldosteronism is based on three steps: detection, positive diagnosis and aetiological diagnosis. Detection is essentially based on demonstration of hypokalaemia. Positive diagnosis is based on demonstration of elevated aldosterone secretion with inhibited renin secretion. The aetiological diagnosis is dominated by the differentiation between Conn's adenoma and bilateral adrenal hyperplasia, which has therapeutic implications. Pseudohyperaldosteronism (also pseudoaldosteronism) is a medical condition which mimics the effects of elevated aldosterone (hyperaldosteronism) by presenting with high blood pressure (hypertension), low blood potassium levels (hypokalemia), metabolic alkalosis, and low levels of plasma renin activity (PRA). However, unlike hyperaldosteronism, this conditions exhibits low or normal levels of aldosterone in the blood. Causes include genetic disorders (e.g. Apparent mineralocorticoid excess syndrome, Liddle's syndrome, and types of Congenital adrenal hyperplasia), acquired conditions (e.g. Cushing's syndrome and mineralocorticoid-producing adrenal tumors), metabolic disorders, and dietary imbalances including excessive consumption of licorice. Confirmatory diagnosis depends on the specific root cause and may involve blood tests, urine tests, or genetic testing; however, all forms of this condition exhibit abnormally low concentrations of both plasma renin activity (PRA) and plasma We report the case of a 42-year-old male who was admitted to our hospital after an acute hypertensive crisis despite four-way anti-hypertensive therapy. The renal scintigraphy, the excretory urogram and the biochemical profile performed two years before were unremarkable, except for slightly elevated serum creatinine and plasma aldosterone, in presence of normal aldosterone/renin ratio. The renal arterial angiography that was performed despite a second unremarkable scintigraphy revealed high-grade bilateral arterial stenosis in the presence of multiple renal arteries. Following dilatation of the left stenosis, the aldosterone/renin ratio was pathologic. Recumbent and orthostatic aldosterone values were 830 pg/ml and 1824 pg/ml, respectively, and recumbent and orthostatic renin values were 0.82 and 1.21 ng angiotensin I/ml/h, respectively. The abdominal computed tomography performed to investigate a possible concomitant Conn's syndrome resulted in the detection of a left adrenal tumor. After resection of the lesion, plasma-aldosterone levels normalized and a pronounced rise in serum potassium levels was observed. Following angioplasty of the right renal artery stenosis, blood pressure could easily be managed with combined beta and calcium channel blocker therapy. Particularly in cases of bilateral (but also in the presence of unilateral) renal artery stenosis in association with Conn's syndrome, all the available screening methods for these disorders can fail. In cases of poor response to combination hypertensive therapies, renal arteriography and a fludrocortisone-suppression test should be performed in order to rule out both renal arterial stenosis and Conn's syndrome, even in the absence of clinical and biochemical findings suspicious for either disorder. Primary hyperaldosteronism (PHA) is characterized by an increased Aldosterone synthesis which is independent of the Renin-Angiotensin-Aldosterone-System (RAAS). The prevalence of PHA in patients who present in specialized hypertension centers is approx. 10 %. Besides patients with the classical symptoms known as \"Conn-Trias\" (hypertension, hypokalemia, metabolic alkalosis), the more frequent normokalemic patients with PHA also show a worse outcome compared to patients with essential hypertension. Identifying these patients is an important task in the evaluation of hypertension since targeted treatment options are available. Screening for PHA using the Aldosterone-Renin-Ratio (ARR) should be performed in patients with hypokalemic, severe or resistant hypertension. In addition, young patients with early onset of severe hypertension and/or positive family history should be screened. A positive screening result should be followed by a confirmatory test. The saline infusion test is the preferred clinical test for confirming a suspected PHA since it is accessible and time efficient. Other confirmatory tests are not used on a regular basis. After any confirmatory test, CT- or MRI-imaging and adrenal vein sampling (AVS) is used in order to differentiate between a unilateral adenoma, a bilateral hyperplasia or another cause of PHA. CT or MRI usually cannot discriminate smaller tumors form hyperplasia. Therefore AVS is used to detect lateralization of autonomous aldosterone production. Lateralization of aldosterone production indicates a unilateral adenoma. In these cases, laparoscopic adrenalectomy is the therapeutic option of choice with a hypertension cure rate of up to 60 %. If no lateralization is detectable, bilateral hyperplasia as the underlying cause of PHA is likely. Pharmacological inhibition of the mineralocorticoid receptor is the preferred treatment option in these cases. If Spironolactone is not well tolerated, Eplerenone and potassium-sparing diuretics should be prescribed. Often, however, in order to fully control hypertension, additional antihypertensive therapy is necessary. To show clinical, biochemical, and morphological data of 12 patients with primary hyperaldosteronism: eight with an aldosterone-producing adenoma and four with adrenal hyperplasia. To compare clinical and biochemical parameters of the patients with adenoma and hyperplasia. For those with adenoma, to verify clinical and biochemical modifications after adrenalectomy. In the 12 patients with hyperaldosteronism, retrospective analysis of clinical (age, sex, blood pressure), biochemical (plasmatic and urinary potassium, plasmatic aldosterone, plasma renin activity, and plasmatic aldosterone/renin activity ratio), and morphological (computed tomography, magnetic resonance, and norcholesterol scintigraphy) data was performed. 1--In the 12 patients with hyperaldosteronism (seven female), the age was 51.0 +/- 10.2 years (mean +/- standard deviation), the systolic pressure 200.9 +/- 34.5 mm Hg and the diastolic pressure 120.0 +/- 12.3 mm Hg. Hypertension was diagnosed 12.0 +/- 10.1 years before. As biochemical evidence, we found kalaemia of 3.06 +/- 0.28 and urinary potassium of 63.4 +/- 16.5 mEq/l, renin activity 0.98 +/- 1.02 ng/ml/h, plasmatic aldosterone of 49.4 +/- 36.0 ng/dl, aldosterone/renin activity &gt; 30 in 83% of the cases. As morphological evidence, computed tomography allowed diagnosis in nine patients, suggested it in two, being doubtful in one. Performed on four patients, resonance confirmed the tomography in three and was not contributive in one. The scintigraphy performed in four patients visualized two adenomas, was negative in one adenoma and in one hyperplasia. 2--In the eight patients with adenoma (six female), the youngest age and the highest diastolic pressure compared with patients with hyperplasia were statistically significant (p &lt; 0.01 and 0.05). In the adenomas, the biochemical changes were more pronounced, but not statistically significant. The plasmatic aldosterone/renin activity ratio was also higher in the adenoma cases. 3--After the adrenalectomy, blood pressure became normal in five patients and was more easily therapeutically controlled in three. The average systolic and diastolic pressures decreased and the biochemical parameters became normal in all patients. The pre/post surgical modification of these parameters had statistical significance (systolic pressure decrease, p &lt; 0.01; diastolic pressure decrease, p &lt; 0.01; kalaemia increase, p &lt; 0.001; renin activity increase, p &lt; 0.01; aldosterone decrease, p &lt; 0.02). The plasmatic aldosterone/renine activity ratio normalized in all patients. In diagnosing primary hyperaldosteronism, biochemical (kalaemia, urinary potassium, plasmatic aldosterone, renin activity, aldosterone plasmatic/renin activity) and tomography studies were important. On comparing the patients with hyperplasia with those with adenoma, we found that the latter are younger and exhibit higher diastolic pressure, both findings with statistical significance. After adenoma surgery, blood pressure became normal in five patients and improved in three, these findings, and the improvement of the kalaemia, plasmatic aldosterone, and renin activity parameters were statistically significant. A 36-year-old female case of normotensive normoreninemic primary aldosteronism with persistent hypokalemia and nephrocalcinosis is reported. She was referred to us for episodes of sudden muscle weakness during 8 years prior to admission. On the first day of admission, her blood pressure was 174/104 mmHg. On the second day of admission blood pressure normalized to 120/80 mmHg. Both of her parents were hypertensive. Arterial blood gas analysis showed metabolic alkalosis. Except an impaired urine concentration ability, renal functions were normal. Intravenous pyelogram showed numerous granular calcifications. Basal plasma renin activity was 1.0 approximately 1.5 ng/ml/hr and increased by sodium depletion. Plasma aldosterone concentration was 70 approximately 80 ng/dl and did not respond to various stimulations. Blood pressure was dependent on sodium balance. It fell on salt restriction and rose on salt loading. Blood pressure responses to vasoactive hormones were normal. Circulating plasma volume was within normal range. After removal of an adrenal adenoma, there was mild fall of blood pressure, serum potassium returned to normal level and plasma renin activity increased slightly. Histologically, there was renal tubular calcifications, and juxtaglomerular apparatus was normal. Blood pressure was elevated to 160/100 mmHg when patient was followed at out-patient clinic after discharge. We concluded that she had essential hypertension associated with primary aldosteronism. Although sodium loss and an increase in urinary kallikrein were found, they did not seem to be the cause of normoreninemic normotensive state of this patient, and the pathogenesis remains to be elucidated. Primary Primary aldosteronism (hyporeninemic hyperaldosteronism) was previously thought to be most commonly caused by an adrenal adenoma, termed Conn's syndrome. However, recent studies have shown that bilateral idiopathic adrenal hyperplasia is the cause in up to 70% of cases. Differentiating between the two is important, as this determines treatment. Also, see congenital adrenal hyperplasia. Adrenal carcinoma is an extremely rare cause of primary hyperaldosteronism. Two familial forms have been identified: type I (dexamethasone suppressible), and type II, which has been linked to the 7p22 gene. Features Hypertension Hypokalemia (e.g., may cause muscle weakness) Alkalosis Investigations High serum aldosterone Low serum renin High-resolution CT abdomen Management Adrenal adenoma: surgery Bilateral adrenocortical hyperplasia: aldosterone antagonist, e.g., spironolactone In patients with normal adrenal morphology and family history of early-onset, severe hypertension, a diagnosis of GRA should be Disorders of the Adrenal Cortex Clinical suspicion of mineralocorticoid excess Patients with hypertension and Severe hypertension (>3 BP drugs, drug-resistant) or Family history of early-onset hypertension or cerebrovascular events at < 40 years of age Measurement of aldosterone-renin ratio (ARR) on current blood pressure medication (stop spironolactone for 4 wks) and with hypokalemia corrected (ARR screen positive if ARR >750 pmol/L: ng/ml/h and aldosterone >450 pmol/L) (consider repeat off ˜-blockers for 2 wks if results are equivocal) Negative E.g., saline infusion test (2 liters physiologic saline over 4 h IV), oral sodium loading, fludrocortisone suppression Confirmation of diagnosis Rare: Both renin and Aldo suppressed Primary hyperaldosteronism has a number of causes. About 33% of cases are due to an adrenal adenoma that produces aldosterone, and 66% of cases are due to an enlargement of both adrenal glands. Other uncommon causes include adrenal cancer and an inherited disorder called familial hyperaldosteronism. Some recommend screening people with high blood pressure who are at increased risk, while others recommend screening all people with high blood pressure for the disease. Screening is usually done by measuring the aldosterone-to-renin ratio in the blood (ARR) whilst off interfering medications and a serum potassium over 4, with further testing used to confirm positive results. While low blood potassium is classically described in primary hyperaldosteronism, this is only present in about a quarter of people. To determine the underlying cause, medical imaging is carried out.\nHere is the question:\nCARDIOLOGY: A 58-year-old male with a history of arterial hypertension of 6 years of evolution, who consults for poor control of blood pressure figures despite receiving treatment with an angiotensin-converting enzyme inhibitor, a diuretic and a calcium antagonist. On consultation she presented with blood pressure of 149/100 mmHg. Laboratory tests: creatinine 1.2 mg/dl, potassium 2.2 mEq/l and compensated metabolic alkalosis; the rest of the biochemical study, blood count, coagulation and urinary sediment were normal. Mark the correct statement:\nHere are the potential choices:\n1. The origin of hypertension in this case is excessive aldosterone secretion caused by autonomic hyperfunction of the adrenal medulla.\n2. In most cases the anatomical substrate is bilateral hyperplasia of the adrenal cortex.\n3. CT scan is part of the diagnostic study in case of biochemical confirmation.\n4. Spironolactone is contraindicated in the management of this pathology.\nThe correct answer is: 3. CT scan is part of the diagnostic study in case of biochemical confirmation."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Osteoarthritis of the hip is a frequent disease affecting 2 to 4% adults. The main symptoms are inguinal pain, hip movement limitation and thigh muscular atrophy. The diagnosis is usually made of on antero-posterior radiograph of the pelvis and Lequesne's lateral view that show joint space narrowing and osteophytosis. There is no correlation between radiographic lesions and clinical symptoms. The mean rate of joint space narrowing progression was shown to be of about 0.30 mm/year but inter-patients variations are very large. The evolution is more sever in older patients and when there is no osteophyte. New imaging techniques are necessary only if diagnosis is impossible on standard radiographs but not for the surgical decision. The treatment of hip osteoarthritis requires analgesic, NSAIDs and symptomatic slow actin drugs for osteoarthritis. Total hip arthroplasty is necessary when medical treatment is non effective on pain and disability. Making an accurate preoperative diagnosis is critical to optimizing outcomes after hip arthroscopy. A detailed history, thorough physical examination, imaging studies, and diagnostic injections must all be considered in the decision-making process. In today's health care climate, it is imperative to obtain essential and indicated preoperative information while being mindful of health care dollars. Magnetic resonance imaging (MRI) of the hip has been shown to be a highly sensitive modality for hip and pelvis disorders. However, it is critical to recognize that acetabular labral tears and other hip pathology are highly prevalent in an asymptomatic young adult population. There are certainly situations when an MRI should be obtained (suspected arthritic symptoms, avascular necrosis, synovial disorders, uncommon osseous tumors); however, these patients generally present with atypical symptoms. In addition, obtaining an MRI can delay surgical intervention, which has been shown to lead to inferior outcomes in prior studies. MRI is not imperative when patients present with typical intermittent, deep anterior, lateral, groin pain with prolonged sitting, twisting and pivoting, and transitioning from sitting to standing. The typical physical examination includes positive hip impingement testing (FADIR / anterior impingement test) that recreates the patients presenting complaints. Appropriate imaging includes plain radiographs revealing adequate acetabular coverage (not significantly dysplastic) or acetabular overcoverage (pincer-type femoracetabular impingement), cam-type femoracetabular impingement, and well-maintained joint space on all views, including a false profile radiograph to further evaluate the anterior joint space. Finally, a diagnostic injection can be invaluable to further confirm the hip joint proper as the source of pain. If all of the above criteria are met, I strongly believe an MRI is unlikely to alter the surgical decision-making process. In the end, the treating clinician should determine when an MRI is necessary based on the presenting symptoms and examination, rather than insurers applying a blanket requirement for preauthorization. This physician autonomy would ultimately lead to more efficient and cost-effective patient care. Medicine is an art, and unjustified handcuffing of the artist without evidence could result in inferior results. Although MRI is frequently used to diagnose conditions affecting the hip, its cost-effectiveness has not been defined. We performed this retrospective study to determine for patients 40 to 80 years old: (1) the differences in hip MRI indications between orthopaedic and nonorthopaedic practitioners; (2) the clinical indications that most commonly influence treatment decisions; (3) the likelihood that hip MRI influences treatment decisions separate from plain radiographs; and (4) the cost of obtaining hip MRI studies that influence treatment decisions (impact studies). We retrospectively assessed 218 consecutive hip MRI studies (213 patients) at one institution over a 5-year interval. Medical records, plain radiographs, and MRI studies were reviewed to determine how frequently individual MRI findings determined treatment recommendations (impact study). The cost estimate of an impact study was calculated from the product of institutional MRI unit cost (USD 436) and the proportion of impact studies relative to all studies obtained either for a specific indication or by an orthopaedic/nonorthopaedic clinician. Nonorthopaedic clinicians more frequently ordered hip MRI without a clinical diagnosis (72% versus 30%, p &lt; 0.01), before plain radiographs (29% versus 3%, p &lt; 0.001), and with less frequent impact on treatment (6% versus 15%, p &lt; 0.05). Hip MRI most frequently influenced treatment when assessing for a tumor (58%, p &lt; 0.001) or infection (40%, p &lt; 0.001) and least frequently when assessing for pain (1%, p &lt; 0.002). Hip MRI impacted a treatment decision independent of plain radiographic findings in only 7% of studies (3% surgical, 4% nonsurgical). Hip MRI cost was least when assessing for a neoplasm (USD 750) and greatest when assessing undefined hip pain (USD 59,000). The cost of obtaining an impact study was also less when the ordering clinician was an orthopaedic clinician (USD 2800) than a nonorthopaedic clinician (USD 7800). Although MRI can be valuable for diagnosing or staging specific conditions, it is not cost-effective as a screening tool for hip pain that is not supported by history, clinical examination, and plain radiographic findings in patients between 40 and 80 years of age. Level IV, economic and decision analysis study. See Instructions for Authors for a complete description of levels of evidence. The prognosis for a patient with osteonecrosis of the hip is generally considered to be worse if a large volume of the femoral head is involved, the patient is symptomatic, and the stage of the lesion is advanced. In 1990, we began a prospective study to detect collapse in asymptomatic hips with a very small stage-I osteonecrotic lesion in the femoral head. We hypothesized that such patients would have a favorable prognosis. These hips were followed for a minimum of ten years after the diagnosis. A small asymptomatic stage-I osteonecrotic lesion (not seen on plain radiographs) was diagnosed with magnetic resonance imaging in forty patients (forty hips) contralateral to a hip with symptomatic osteonecrosis. The criterion for inclusion in the study was a lesion with a volume of &lt;5 cm(3) involving &lt;10% of the volume of the femoral head. Plain radiographs were made annually in six different projections for all patients. At the most recent follow-up evaluation (average, eleven years), patients with a symptomatic hip but without evidence of collapse on plain radiographs underwent a computerized tomography scan. Thirty-five (88%) of the forty hips became symptomatic, and twenty-nine (73%) demonstrated collapse. The mean interval between the diagnosis and the first symptoms was eighty months. Symptoms always preceded collapse by at least six months. The mean interval between the diagnosis and the collapse was ninety-two months (range, seventy-two to 140 months). The diagnosis of collapse could be made on only one or two of the six radiographic views obtained for each patient at each evaluation. The diagnosis of collapse for two patients was made only on a computerized tomography scan at the most recent follow-up evaluation. At the time of final follow-up, the twenty-nine hips with collapse had symptoms of intractable pain and required surgery. This study confirms that the diagnosis of collapse is difficult in hips with a very small stage-I osteonecrotic lesion. Multiple radiographic views and computerized tomography scans may be required to demonstrate small areas of collapse. Clinical and radiographic signs of progression of the disease in asymptomatic hips with a very small asymptomatic lesion progress more slowly than do those signs in hips with a large symptomatic stage-II lesion. Because hips with a small area of osteonecrosis do collapse in a large percentage of patients, such patients should be followed carefully over a long period of time. Prognostic study, Level I-1 (prospective study). See Instructions to Authors for a complete description of levels of evidence. Rapidly progressing degeneration of the hip joint is an uncommon condition presenting to physical therapy. Differential diagnosis can often be difficult, as clinical and radiographic findings do not always coincide leaving clinicians with difficult decision making regarding course of treatment. The purpose of this case report was to describe the differential diagnosis and early management of a patient with rapidly progressing hip pain. A 59-year-old male with a complicated medical history was referred with a diagnosis of severe bilateral hip osteoarthritis. Clinical presentation of insidious onset, severe bilateral groin and anterior thigh pain with rapid progression of functional decline lead to the differential diagnosis of bilateral avascular necrosis. The patient received seven manual physical therapy sessions over the course of one month. During this time, the patient's Lower Extremity Functional Scale score worsened from 33 to 21. The persistence of the patient's painful symptoms and continued functional decline helped determine cessation of manual therapy and referral back to his GP for further diagnostic testing and eventual correct diagnosis. This case highlights the importance of monitoring patient prognosis using outcome measures leading to a change in patient management strategies. Adult hip pathologies are mainly represented by the degenerative disease, so called \"osteoarthrosis, or more precisely coxarthrosis\". The means of imaging are exposed, according to their specific value: X Rays (measurement of the characteristic angles of the adult hip), Arthrography, CT Scanner, Arthro-CT Scanner, MRI, Bone Scintigraphy, Ultrasonography. Clinical findings differentiate a mechanical syndrome and an inflammatory syndrome. The coxarthrosis is the most frequent, under two forms: primary (idiopathic) coxarthrosis and secondary coxarthrosis. Primary (idiopathic) coxarthrosis has a localised narrowing of the joint space, osteophyte formation, subchondral sclerosis, cyst formation. The destruction progresses slowly, in 10 to 15 years leading to a complete destruction. Bilaterality is frequent. it is treated with total hip prosthesis. There is a rapid form (1 to 2 years) (Postel's Disease). Secondary coxarthrosis occurs after architectural vice, chondral diseases, lack of balance between the size of the head and the acetabulum as in the case of previous fracture or dislocation, avascular bone necrosis of the head of the femur, Paget's disease. Calcium pyrophosphate Deposition disease (CPPD) involves mostly aged women, and also leads to cox-arthrosis. Avascular bone necrosis of the head of the femur involves young adults. Bilateral involvement are frequent. MRI is the most sensitive and the most specific means of early diagnosis, The area of bone necrosis appears as well defined modifications of the upper head of the femur, precisely surrounded by a low signal intensity line on both Ti and T2 weighted imaging. MRI shows articular effusion, bone marrow edema. Scintigraphy gives early findings which are a characteristic, but non specific, hot spot. CT scanner is used for hip destruction evaluation. o Algodystrophy: transient osteoporosis of the hip has a cyclic course, lasting 3 to 9 months. MRI shows an inflammatory pattern in the area of the process(dark in Ti and white in T2, with positive Gadolinium response). Scintigraphy is positive. Staphylococcus location in the hip can be acute or chronic. MRI shows joint effusion, cystic formation and subchondral non specific modifications. Tuberculosis of the hip joint is relatively rare. Greater trochanteric tuberculous involvement is possible under special contexts. Chronic Inflammatory diseases are represented by Rheumatoid Arthritis, Spondylarthritis and other chronic inflammatory diseases. Synovial tumors such as Pigmented Villo Nodular Synovitis, Primary Osteochondromatosis, synovial sarcoma have special presentations. The subchondral bone can be involved by amorphous depositions such as in tophaceous gout, different varieties of lipidosis, amyloidosis, reticulo histiocytosis. Pen arthropathies are enthesopathies in the anterior rectus tendon, calcifying tendonitis (not to be confused with calcifying soft tissue tumor/chondrosarcoma). The pelvis bone and the femur are involved by primary and secondary tumors or by insufficiency fractures which can mislead to hip pathologies. Our objective was to evaluate the radiological appearances in different stages of idiopathic chondrolysis of hip (ICH) which will be helpful in the early diagnosis and guiding appropriate treatment for this condition to prevent progression of disease. We evaluated 14 patients of ICH in varying stages: Stage 1 (<in</i = 9), Stage 2 (<in</i = 3), Stage 3 (<in</i = 2). Average age at presentation was 10-11 years. Plain radiograph and magnetic resonance imaging (MRI) was done in all these patients. In the current study, we have attempted to stage ICH based on the radiological progression of the disease, where MRI was used as the primary tool. Stage 1 showed a wedge-shaped hyperintensity in T2 weighted (T2W) and hypointensity in T1 weighted (T1W) images involving the middle one-third of the femoral head and it is the earliest and characteristic finding in MRI. Associated findings like joint space narrowing, synovial hypertrophy with joint effusion may also be observed. Stage 2 showed acetabular edema in the affected hip in addition to the above-mentioned findings. Stage 3 showed more extensive involvement of femoral head and acetabulum, with collapse of the femoral head, degenerative changes in hip, early osteoporotic changes, and ultimately loss of joint space. Imaging-based staging system proves very useful in the early diagnosis, staging, and assessing the prognosis of ICH. One hundred and eighty-five hips from 152 patients with primary or secondary osteoarthritis were studied in an attempt to assess the degrees of hip pain in contrast to radiological and other clinical findings. In 30.8% and 26.4% of the primary and secondary osteoarthritic hips respectively, hip pain showed some gradual decrease as time elapsed. Pain relief probably in association with osteophyte formation at the craniolateral acetabular rim occurred in 62.5% and 33.3% of the primary and secondary osteoarthritic hips respectively. Significant parameters observed in the primary osteoarthritic cases of the decreasing pain group were as follows: A lesser extent of cranial displacement of the femoral head, poor capital drop development, well developed floor osteophyte. On the other hand significant parameters in the decreasing pain group of secondary osteoarthritis were as follows: Well developed floor osteophyte, a small size of cyst in both the femoral head and the acetabulum, few \"b\" or \"d\" type of bony sclerosis in the acetabulum. Careful observation of radiographic changes (cyst and sourcil) would be most important, especially in secondary osteoarthritis, to decide the indication of surgery. On the basis of histological studies of osteophyte at the craniolateral acetabular rim obtained at the operation, it was assumed that the osteophyte formation had initiated from metaplasia of the labrum or synovial membrane and progressed by a form of chondral ossification after the process of fibrous tissue formation. A well developed trabecular density in the osteophyte at the craniolateral acetabular rim was determined by the use of Muto digigrammer system, Model G-002. A few reports have shown that the reliability of the Japanese Orthopaedic Association stage classification of hip osteoarthritis was not high. The objective of this study was to assess the reliability of the stage classification of coxarthrosis, and to evaluate whether a modification of the classification improves reliability. We retrospectively investigated 200 hips in 100 patients with hip pain. We collected radiographs of their hip joints with the patients in both a supine and a standing position. Four orthopaedic surgeons evaluated the stage of coxarthrosis employing the JOA classification. The percentage of agreement of examiners and the value of the kappa statistic were calculated. Furthermore, to improve the reliability of classification, we modified the classification based on previous reports. Partial narrowing of the joint space and disappearance of the joint space were defined as maintained if it was 2 mm or more, and as the width of the loss of joint space that was 10 mm or more respectively. Using this classification, the same examiners assessed the stage on the same radiographs again three months after the previous evaluation. The percentages of agreement were 28.5% and 27% and the interobserver value of the kappa statistic was 0.45 and 0.44 in supine and standing position respectively. After modification of the classification, the percentages of agreement were 36.5% and 44% and the interobserver value of the kappa statistic was 0.48 and 0.56 in supine and standing positions respectively, and the intraobserver value of the kappa statistic was 0.55. The modification significantly improved the reliability only in the percentage of the agreement for the standing position. This study showed that the reliability of the JOA stage classification of coxarthrosis was not as high as previous reports have showed. Modification of the classification improved interobserver reliability. The goal of this study was to evaluate late results of hip shelf arthroplasty in adults after a minimum of 15 years follow-up. 65 hip shelf arthroplasty performed for painful hip dysplasia between 1964 and 1977 were studied retrospectively in 1992. These 65 procedures were performed in 57 patients mean aged 32 +/- 14 years [17-56]. Nine patients (9 hips) were excluded (2 deceaded, 5 lost for follow-up, and two reoperated because of severe infection). Consequently, the functional results were evaluated for 56 hips (48 patients). Before surgery, according to Merle d'Aubigné's hip rating system, all the hips were painfull (mean pain score was 2.6 +/- 1.7 [0-5]). On radiography, all the hips had a dysplastic acetabulum and arthritic changes. Arthritic changes were severe in 32 hips (57.1 per cent). The hip shelf arthroplasty was carried out according to Roy-Camille. 10 hips had additional varus femoral osteotomy. The 48 patients (56 hips) included were evaluated by means of Merle d'Aubigné's hip rating system and AP and false lateral weight-bearing Xrays. In 1992, 24 procedures were changed for total hip replacement (THR) (17 before 15 years (early failure) and 7 after 15 years of follow-up (late failure)). These 24 hips were included with their last hip rating observed just before THR. Survival analysis was performed according to Kaplan-Meier using date of revision for THR as end-point. After 16.1 +/- 5.6 years of follow-up the functional score for 56 hips was: excellent in 4 hips, very good in 7 hips, good in 10, satisfactory in 14, poor in 17, and bad in 4. The survival rate established for 65 hips was 60 per cent at 15 years and 40 per cent at 21 years. Only 39 hips shelf arthroplasties were still functional after 15 years (mean follow-up 19.1 +/- 3 years [16-28], but 18 hips (46.1 per cent) were painfree or slightly painful (pain score to 5 or 6). Among these 39 hips, the results were excellent in 4 hips, very good in 7 hips, good in 10, satisfactory in 10, poor in 6, and bad in 2. Arthritic change was the main reason for failures: the Kaplan-Meier survival rate at 21 years was 87 per cent when arthrosis was slight and only 15 per cent and 42 per cent when arthrosis was moderate to severe (p = 0.0001). The adverse effect of arthrosis was promoted by lack of congruency for early failures, and by severity of dysplasia and hip subluxation for late failures. The additional femoral varus osteotomies had no influence on functional or radiographic outcome. Our study indicated that hip shelf arthroplasty performed for painful acetabular dysplasia in adult has a 40 per cent probability survival rate at 21 years. The high rate of revision (42.8 per cent) could be related to the prevalence of severe pre-operative arthrosis. The low rate of lost for follow-up (8.7 per cent) and the long follow-up period (16.1 years) made our conclusion reliable. In spite of a high revision rate we recommend shelf athroplasty to treat acetabular dysplasia in adults. This procedure, very reliable in cases of moderate arthrosis, could be performed in cases of severe arthrosis to delay and make easier THR, but a low survival rate could be expected unless dysplasia, lack of congruency and subluxation were mild. To evaluate the structural effect of avocado/soybean unsaponifiables (ASU) in the treatment of patients with symptomatic osteoarthritis (OA) of the hip. Patients with regular painful primary OA of the hip (European League Against Rheumatism 1980 criteria) and a joint space still &gt; or = 1 mm (Kellgren grade 1 to 3, assessed by an independent observer prior to inclusion) entered a prospective, multicenter, randomized, parallel group, double-blind, placebo-controlled trial of 2 years duration. Patients had at least a 6-month history of regular pain and an algofunctional index (AFI) &gt; or = 4. The primary assessment criterion was a decrease of the joint space width (JSW) on plain anteroposterior radiographs of the pelvis performed in standing position, measured at the narrowest points by 2 independent readers, previously tested and selected and blinded to both the treatment and the time sequence. Secondary criteria were standard clinical outcome measurements (AFI, pain on a visual analog scale, consumption of nonsteroidal antiinflammatory drugs and patient's and investigator's global assessments). One hundred sixty-three patients were included: 102 men and 61 women (mean age 63.2 +/- 8.7 years). A total of 108 patients (72 men and 36 women; mean age 64 +/- 7.9 years) were radiologically evaluable at 23.7 +/- 2.6 months (ASU group; n = 55) and 23.7 +/- 3.2 months (placebo group; n = 53). Overall comparison of the evolution of JSW showed no difference between the ASU and placebo groups, from 2.35 +/- 0.93 to 1.87 +/- 1.10 mm and from 2.5 +/- 0.94 to 1.9 +/- 1.33 mm, respectively (intergroup P value at end point = 0.9). When patients were divided into 2 subgroups according to the median value of the baseline JSW (2.45 mm), the joint space loss in the most severely affected subgroup of patients (baseline JSW &lt; or = median) was significantly greater in the placebo group than in the ASU group: from 1.69 +/- 0.58 to 0.84 +/- 0.77 mm (-0.86 +/- 0.62 mm) and from 1.66 +/- 0.42 to 1.22 +/- 0.7 mm (-0.43 +/- 0.51 mm), respectively (P &lt; 0.01). The JSW decrease was identical, with no difference in ASU and placebo groups, in the less severely affected subgroup of patients (baseline JSW &gt; median). Clinical parameters in the 2 groups did not differ significantly throughout the study. This pilot randomized, double-blind, placebo-controlled trial failed to demonstrate a structural effect of ASU in hip OA. However, in a post-hoc analysis, ASU significantly reduced the progression of joint space loss as compared with placebo in the subgroup of patients with advanced joint space narrowing. These results suggest that ASU could have a structural effect but require confirmation in a larger placebo-controlled study in hip OA. The objective of the submitted work was to assess the long-term prognosis of Perthes disease. From the originally invited 142 patients 72 attended the check-up examination, complete X-ray documentation was assembled only in 32 patients with 38 affected hip joints. The time interval which had elapsed since the onset of the disease was on average 17 years. The authors evaluated the clinical and X-ray picture of the hip joints and assessed retrospectively the affection of the head according to Catterall's method, incl. signs of a head associated with risk. Treatment provided during the sixties and beginning of the seventies did not meet the principles of modern \"containment\" therapy. It comprised bed rest, application of a plaster spike and aftertreatment with a Thomas splint. During late check-up examinations Wiberg's angle, the epiphyseal index, the index of overlapping of the head, the distance of the head from the floor of the acetabulum and the height of the peak of the greater trochanter above the centre of the head of the femur were assessed. In addition to assessment of these partial X-ray parameters the authors evaluated the spherical properties of the head by Mose's method and subjectively the X-ray picture, using a three grade scale (satisfactory, feasible, poor). In the majority of assessed parameters the authors found a statistically significant correlation with the retrospective classification of the original X-ray pictures classified according to Catterall. The clinical picture was satisfactory in the majority, the authors did not find painful restriction of movement, while almost half the patients reported occasional subjective complaints as regards the hip joint. On the X-ray changes in the overgrowth of the greater trochanter were more marked than changes of the spherical character of the head and the extent of decentering. The follow-up of the group will continue to obtain a longer time interval from the onset of the disease. Key words: Perthes disease, late results, Catterall's classification. Osteoarthritis of the hip joint is a very common disease. There is a minor prevalence of males. By etiology one can distinguish primary (idiopathic) from secondary osteoarthritis. Secondary are due to well-known etiologies as overweight, repetitive traumata, malposture, muscle- and tendon-imbalance etc. Osteoarthritis includes not only cartilage abnormalities, but also such of the subchondral-region, synovialis, synovial fluid and periarticular muscles. The cartilage shows in osteoarthritis typically edema and swelling, defects with tears, fibrillation, and \"baldness\" and (or) cartilagenous repair-islands and joint space narrowing as well, while subchondrally micro-edema, necrosis, ev. microfractures, \"cysts\", demineralisation followed by sclerosis, osteophyte-formation and deformity is seen. With conventional radiographs and CT joint space narrowing, subchondral cysts, sclerosis and osteophytes and deformities are well delineated, MRI however allows visualization of subtle bone marrow and cartilage abnormalities. Clinically, the diagnosis of pre-osteoarthritis becomes more and more important. This includes e.g. deformities and malpostures, labrum-pathologies and structural imbalances. There are three prognostic different types of hip-osteoarthritis depending on the migration of the head of the hip joint: the most common are the latero-cranial and the medio-caudal ones, while the central one is found very rarely. Basic imaging method are conventional radiographs, and CT, followed by MRI. The diagnosis of an \"activated osteoarthritis\" is made by bone-scintigraphy or MRI with i.v. application of contrast-media. The labrum- and cartilage diagnosis should be done with MRI or MR-arthrography. Functional computer-animated analysis will be of great diagnostic value in the near future. MRI indications are differences between clinical results and imaging, missing clinical improvement of an \"activated\" osteoarthritis under standard therapy, unclear joint-pain and before any arthroscopy. Hip pain in the elderly is the main feature of osteoarthritis of the hip. In this prospective followup study, we wanted to determine which patients with hip pain show disease progression, and what the incidence of total hip replacement (THR) is in this group of patients after 3 and 6 years of followup. Within general practices in the area of Rotterdam (The Netherlands), persons age &gt; or = 50 years with incident hip pain were included. After 3 and 6 years, progression of hip pain was assessed. A total of 224 patients were included. After 3 years disease progressed in 29 (15%) patients and 23 (12%) received a THR. After 6 years disease progressed in 45 (28%) patients and 36 (22%) received a THR. The prognostic variables for a THR after 3 and 6 years related to history taking were age &gt; or = 60 years, morning stiffness, and pain in the groin/medial thigh; variables related to physical examination were decreased extension/adduction, painful internal rotation, and a body mass index &lt; or = 30 kg/m(2); and the variable related to radiologic findings was a Kellgren/Lawrence grade of 2 or higher. In this study population, approximately 12% of patients presenting with hip pain to their general practitioner will undergo a THR within 3 years, and approximately 22% after 6 years. Using the variables obtained from history taking, physical examination, and radiologic findings enables better identification of persons at high risk for a THR. Imaging is fundamental to the diagnosis and therapeutic follow-up of all hip diseases. Despite the advent of extremely sophisticated exploratory methods, the oldest imaging method, straightforward radiography, makes it possible to recognize, locate ans treat the lesion in most cases. Good interpretation of simple antero-posterior and lateral x-ray films therefore is very important. Among the new imaging methods, computerized tomography has brought the third dimension, while ultrasonography and nuclear magnetic resonance have enabled us to visualize cartilages and soft tissues. The contribution to diagnosis and follow-up of these modern methods is considerable, but since we are too near their beginning and since the number of examinations is still too small in many fields, the information they provide must be used with caution. A good knowledge of their principle, advantages and drawbacks should help us to utilize them at best by prescribing only those which are necessary and sufficient for diagnosis and treatment.\nHere is the question:\nRHEUMATOLOGY: You evaluate a 66-year-old patient with groin pain accentuated by prolonged standing for a few days per month. A plain radiograph of the hips shows narrowing of the femoroacetabular joint space, sclerosis and ostephytes.\nHere are the potential choices:\n1. I make the diagnosis of coxarthrosis and send to the traumatologist to place a hip prosthesis.\n2. Start treatment with weak opioids that have shown evidence in stopping the progression of the disease.\n3. Treatment with paracetamol, explaining that the evolution is very variable and the surgical indication depends on the functionality and pain control.\n4. Because of the radiological features described, I need a hip MRI before making a therapeutic decision.\nThe correct answer is: ",
        "gold_answer": "3 Treatment with paracetamol, explaining that the evolution is very variable and the surgical indication depends on the functionality and pain control.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Osteoarthritis of the hip is a frequent disease affecting 2 to 4% adults. The main symptoms are inguinal pain, hip movement limitation and thigh muscular atrophy. The diagnosis is usually made of on antero-posterior radiograph of the pelvis and Lequesne's lateral view that show joint space narrowing and osteophytosis. There is no correlation between radiographic lesions and clinical symptoms. The mean rate of joint space narrowing progression was shown to be of about 0.30 mm/year but inter-patients variations are very large. The evolution is more sever in older patients and when there is no osteophyte. New imaging techniques are necessary only if diagnosis is impossible on standard radiographs but not for the surgical decision. The treatment of hip osteoarthritis requires analgesic, NSAIDs and symptomatic slow actin drugs for osteoarthritis. Total hip arthroplasty is necessary when medical treatment is non effective on pain and disability. Making an accurate preoperative diagnosis is critical to optimizing outcomes after hip arthroscopy. A detailed history, thorough physical examination, imaging studies, and diagnostic injections must all be considered in the decision-making process. In today's health care climate, it is imperative to obtain essential and indicated preoperative information while being mindful of health care dollars. Magnetic resonance imaging (MRI) of the hip has been shown to be a highly sensitive modality for hip and pelvis disorders. However, it is critical to recognize that acetabular labral tears and other hip pathology are highly prevalent in an asymptomatic young adult population. There are certainly situations when an MRI should be obtained (suspected arthritic symptoms, avascular necrosis, synovial disorders, uncommon osseous tumors); however, these patients generally present with atypical symptoms. In addition, obtaining an MRI can delay surgical intervention, which has been shown to lead to inferior outcomes in prior studies. MRI is not imperative when patients present with typical intermittent, deep anterior, lateral, groin pain with prolonged sitting, twisting and pivoting, and transitioning from sitting to standing. The typical physical examination includes positive hip impingement testing (FADIR / anterior impingement test) that recreates the patients presenting complaints. Appropriate imaging includes plain radiographs revealing adequate acetabular coverage (not significantly dysplastic) or acetabular overcoverage (pincer-type femoracetabular impingement), cam-type femoracetabular impingement, and well-maintained joint space on all views, including a false profile radiograph to further evaluate the anterior joint space. Finally, a diagnostic injection can be invaluable to further confirm the hip joint proper as the source of pain. If all of the above criteria are met, I strongly believe an MRI is unlikely to alter the surgical decision-making process. In the end, the treating clinician should determine when an MRI is necessary based on the presenting symptoms and examination, rather than insurers applying a blanket requirement for preauthorization. This physician autonomy would ultimately lead to more efficient and cost-effective patient care. Medicine is an art, and unjustified handcuffing of the artist without evidence could result in inferior results. Although MRI is frequently used to diagnose conditions affecting the hip, its cost-effectiveness has not been defined. We performed this retrospective study to determine for patients 40 to 80 years old: (1) the differences in hip MRI indications between orthopaedic and nonorthopaedic practitioners; (2) the clinical indications that most commonly influence treatment decisions; (3) the likelihood that hip MRI influences treatment decisions separate from plain radiographs; and (4) the cost of obtaining hip MRI studies that influence treatment decisions (impact studies). We retrospectively assessed 218 consecutive hip MRI studies (213 patients) at one institution over a 5-year interval. Medical records, plain radiographs, and MRI studies were reviewed to determine how frequently individual MRI findings determined treatment recommendations (impact study). The cost estimate of an impact study was calculated from the product of institutional MRI unit cost (USD 436) and the proportion of impact studies relative to all studies obtained either for a specific indication or by an orthopaedic/nonorthopaedic clinician. Nonorthopaedic clinicians more frequently ordered hip MRI without a clinical diagnosis (72% versus 30%, p &lt; 0.01), before plain radiographs (29% versus 3%, p &lt; 0.001), and with less frequent impact on treatment (6% versus 15%, p &lt; 0.05). Hip MRI most frequently influenced treatment when assessing for a tumor (58%, p &lt; 0.001) or infection (40%, p &lt; 0.001) and least frequently when assessing for pain (1%, p &lt; 0.002). Hip MRI impacted a treatment decision independent of plain radiographic findings in only 7% of studies (3% surgical, 4% nonsurgical). Hip MRI cost was least when assessing for a neoplasm (USD 750) and greatest when assessing undefined hip pain (USD 59,000). The cost of obtaining an impact study was also less when the ordering clinician was an orthopaedic clinician (USD 2800) than a nonorthopaedic clinician (USD 7800). Although MRI can be valuable for diagnosing or staging specific conditions, it is not cost-effective as a screening tool for hip pain that is not supported by history, clinical examination, and plain radiographic findings in patients between 40 and 80 years of age. Level IV, economic and decision analysis study. See Instructions for Authors for a complete description of levels of evidence. The prognosis for a patient with osteonecrosis of the hip is generally considered to be worse if a large volume of the femoral head is involved, the patient is symptomatic, and the stage of the lesion is advanced. In 1990, we began a prospective study to detect collapse in asymptomatic hips with a very small stage-I osteonecrotic lesion in the femoral head. We hypothesized that such patients would have a favorable prognosis. These hips were followed for a minimum of ten years after the diagnosis. A small asymptomatic stage-I osteonecrotic lesion (not seen on plain radiographs) was diagnosed with magnetic resonance imaging in forty patients (forty hips) contralateral to a hip with symptomatic osteonecrosis. The criterion for inclusion in the study was a lesion with a volume of &lt;5 cm(3) involving &lt;10% of the volume of the femoral head. Plain radiographs were made annually in six different projections for all patients. At the most recent follow-up evaluation (average, eleven years), patients with a symptomatic hip but without evidence of collapse on plain radiographs underwent a computerized tomography scan. Thirty-five (88%) of the forty hips became symptomatic, and twenty-nine (73%) demonstrated collapse. The mean interval between the diagnosis and the first symptoms was eighty months. Symptoms always preceded collapse by at least six months. The mean interval between the diagnosis and the collapse was ninety-two months (range, seventy-two to 140 months). The diagnosis of collapse could be made on only one or two of the six radiographic views obtained for each patient at each evaluation. The diagnosis of collapse for two patients was made only on a computerized tomography scan at the most recent follow-up evaluation. At the time of final follow-up, the twenty-nine hips with collapse had symptoms of intractable pain and required surgery. This study confirms that the diagnosis of collapse is difficult in hips with a very small stage-I osteonecrotic lesion. Multiple radiographic views and computerized tomography scans may be required to demonstrate small areas of collapse. Clinical and radiographic signs of progression of the disease in asymptomatic hips with a very small asymptomatic lesion progress more slowly than do those signs in hips with a large symptomatic stage-II lesion. Because hips with a small area of osteonecrosis do collapse in a large percentage of patients, such patients should be followed carefully over a long period of time. Prognostic study, Level I-1 (prospective study). See Instructions to Authors for a complete description of levels of evidence. Rapidly progressing degeneration of the hip joint is an uncommon condition presenting to physical therapy. Differential diagnosis can often be difficult, as clinical and radiographic findings do not always coincide leaving clinicians with difficult decision making regarding course of treatment. The purpose of this case report was to describe the differential diagnosis and early management of a patient with rapidly progressing hip pain. A 59-year-old male with a complicated medical history was referred with a diagnosis of severe bilateral hip osteoarthritis. Clinical presentation of insidious onset, severe bilateral groin and anterior thigh pain with rapid progression of functional decline lead to the differential diagnosis of bilateral avascular necrosis. The patient received seven manual physical therapy sessions over the course of one month. During this time, the patient's Lower Extremity Functional Scale score worsened from 33 to 21. The persistence of the patient's painful symptoms and continued functional decline helped determine cessation of manual therapy and referral back to his GP for further diagnostic testing and eventual correct diagnosis. This case highlights the importance of monitoring patient prognosis using outcome measures leading to a change in patient management strategies. Adult hip pathologies are mainly represented by the degenerative disease, so called \"osteoarthrosis, or more precisely coxarthrosis\". The means of imaging are exposed, according to their specific value: X Rays (measurement of the characteristic angles of the adult hip), Arthrography, CT Scanner, Arthro-CT Scanner, MRI, Bone Scintigraphy, Ultrasonography. Clinical findings differentiate a mechanical syndrome and an inflammatory syndrome. The coxarthrosis is the most frequent, under two forms: primary (idiopathic) coxarthrosis and secondary coxarthrosis. Primary (idiopathic) coxarthrosis has a localised narrowing of the joint space, osteophyte formation, subchondral sclerosis, cyst formation. The destruction progresses slowly, in 10 to 15 years leading to a complete destruction. Bilaterality is frequent. it is treated with total hip prosthesis. There is a rapid form (1 to 2 years) (Postel's Disease). Secondary coxarthrosis occurs after architectural vice, chondral diseases, lack of balance between the size of the head and the acetabulum as in the case of previous fracture or dislocation, avascular bone necrosis of the head of the femur, Paget's disease. Calcium pyrophosphate Deposition disease (CPPD) involves mostly aged women, and also leads to cox-arthrosis. Avascular bone necrosis of the head of the femur involves young adults. Bilateral involvement are frequent. MRI is the most sensitive and the most specific means of early diagnosis, The area of bone necrosis appears as well defined modifications of the upper head of the femur, precisely surrounded by a low signal intensity line on both Ti and T2 weighted imaging. MRI shows articular effusion, bone marrow edema. Scintigraphy gives early findings which are a characteristic, but non specific, hot spot. CT scanner is used for hip destruction evaluation. o Algodystrophy: transient osteoporosis of the hip has a cyclic course, lasting 3 to 9 months. MRI shows an inflammatory pattern in the area of the process(dark in Ti and white in T2, with positive Gadolinium response). Scintigraphy is positive. Staphylococcus location in the hip can be acute or chronic. MRI shows joint effusion, cystic formation and subchondral non specific modifications. Tuberculosis of the hip joint is relatively rare. Greater trochanteric tuberculous involvement is possible under special contexts. Chronic Inflammatory diseases are represented by Rheumatoid Arthritis, Spondylarthritis and other chronic inflammatory diseases. Synovial tumors such as Pigmented Villo Nodular Synovitis, Primary Osteochondromatosis, synovial sarcoma have special presentations. The subchondral bone can be involved by amorphous depositions such as in tophaceous gout, different varieties of lipidosis, amyloidosis, reticulo histiocytosis. Pen arthropathies are enthesopathies in the anterior rectus tendon, calcifying tendonitis (not to be confused with calcifying soft tissue tumor/chondrosarcoma). The pelvis bone and the femur are involved by primary and secondary tumors or by insufficiency fractures which can mislead to hip pathologies. Our objective was to evaluate the radiological appearances in different stages of idiopathic chondrolysis of hip (ICH) which will be helpful in the early diagnosis and guiding appropriate treatment for this condition to prevent progression of disease. We evaluated 14 patients of ICH in varying stages: Stage 1 (<in</i = 9), Stage 2 (<in</i = 3), Stage 3 (<in</i = 2). Average age at presentation was 10-11 years. Plain radiograph and magnetic resonance imaging (MRI) was done in all these patients. In the current study, we have attempted to stage ICH based on the radiological progression of the disease, where MRI was used as the primary tool. Stage 1 showed a wedge-shaped hyperintensity in T2 weighted (T2W) and hypointensity in T1 weighted (T1W) images involving the middle one-third of the femoral head and it is the earliest and characteristic finding in MRI. Associated findings like joint space narrowing, synovial hypertrophy with joint effusion may also be observed. Stage 2 showed acetabular edema in the affected hip in addition to the above-mentioned findings. Stage 3 showed more extensive involvement of femoral head and acetabulum, with collapse of the femoral head, degenerative changes in hip, early osteoporotic changes, and ultimately loss of joint space. Imaging-based staging system proves very useful in the early diagnosis, staging, and assessing the prognosis of ICH. One hundred and eighty-five hips from 152 patients with primary or secondary osteoarthritis were studied in an attempt to assess the degrees of hip pain in contrast to radiological and other clinical findings. In 30.8% and 26.4% of the primary and secondary osteoarthritic hips respectively, hip pain showed some gradual decrease as time elapsed. Pain relief probably in association with osteophyte formation at the craniolateral acetabular rim occurred in 62.5% and 33.3% of the primary and secondary osteoarthritic hips respectively. Significant parameters observed in the primary osteoarthritic cases of the decreasing pain group were as follows: A lesser extent of cranial displacement of the femoral head, poor capital drop development, well developed floor osteophyte. On the other hand significant parameters in the decreasing pain group of secondary osteoarthritis were as follows: Well developed floor osteophyte, a small size of cyst in both the femoral head and the acetabulum, few \"b\" or \"d\" type of bony sclerosis in the acetabulum. Careful observation of radiographic changes (cyst and sourcil) would be most important, especially in secondary osteoarthritis, to decide the indication of surgery. On the basis of histological studies of osteophyte at the craniolateral acetabular rim obtained at the operation, it was assumed that the osteophyte formation had initiated from metaplasia of the labrum or synovial membrane and progressed by a form of chondral ossification after the process of fibrous tissue formation. A well developed trabecular density in the osteophyte at the craniolateral acetabular rim was determined by the use of Muto digigrammer system, Model G-002. A few reports have shown that the reliability of the Japanese Orthopaedic Association stage classification of hip osteoarthritis was not high. The objective of this study was to assess the reliability of the stage classification of coxarthrosis, and to evaluate whether a modification of the classification improves reliability. We retrospectively investigated 200 hips in 100 patients with hip pain. We collected radiographs of their hip joints with the patients in both a supine and a standing position. Four orthopaedic surgeons evaluated the stage of coxarthrosis employing the JOA classification. The percentage of agreement of examiners and the value of the kappa statistic were calculated. Furthermore, to improve the reliability of classification, we modified the classification based on previous reports. Partial narrowing of the joint space and disappearance of the joint space were defined as maintained if it was 2 mm or more, and as the width of the loss of joint space that was 10 mm or more respectively. Using this classification, the same examiners assessed the stage on the same radiographs again three months after the previous evaluation. The percentages of agreement were 28.5% and 27% and the interobserver value of the kappa statistic was 0.45 and 0.44 in supine and standing position respectively. After modification of the classification, the percentages of agreement were 36.5% and 44% and the interobserver value of the kappa statistic was 0.48 and 0.56 in supine and standing positions respectively, and the intraobserver value of the kappa statistic was 0.55. The modification significantly improved the reliability only in the percentage of the agreement for the standing position. This study showed that the reliability of the JOA stage classification of coxarthrosis was not as high as previous reports have showed. Modification of the classification improved interobserver reliability. The goal of this study was to evaluate late results of hip shelf arthroplasty in adults after a minimum of 15 years follow-up. 65 hip shelf arthroplasty performed for painful hip dysplasia between 1964 and 1977 were studied retrospectively in 1992. These 65 procedures were performed in 57 patients mean aged 32 +/- 14 years [17-56]. Nine patients (9 hips) were excluded (2 deceaded, 5 lost for follow-up, and two reoperated because of severe infection). Consequently, the functional results were evaluated for 56 hips (48 patients). Before surgery, according to Merle d'Aubigné's hip rating system, all the hips were painfull (mean pain score was 2.6 +/- 1.7 [0-5]). On radiography, all the hips had a dysplastic acetabulum and arthritic changes. Arthritic changes were severe in 32 hips (57.1 per cent). The hip shelf arthroplasty was carried out according to Roy-Camille. 10 hips had additional varus femoral osteotomy. The 48 patients (56 hips) included were evaluated by means of Merle d'Aubigné's hip rating system and AP and false lateral weight-bearing Xrays. In 1992, 24 procedures were changed for total hip replacement (THR) (17 before 15 years (early failure) and 7 after 15 years of follow-up (late failure)). These 24 hips were included with their last hip rating observed just before THR. Survival analysis was performed according to Kaplan-Meier using date of revision for THR as end-point. After 16.1 +/- 5.6 years of follow-up the functional score for 56 hips was: excellent in 4 hips, very good in 7 hips, good in 10, satisfactory in 14, poor in 17, and bad in 4. The survival rate established for 65 hips was 60 per cent at 15 years and 40 per cent at 21 years. Only 39 hips shelf arthroplasties were still functional after 15 years (mean follow-up 19.1 +/- 3 years [16-28], but 18 hips (46.1 per cent) were painfree or slightly painful (pain score to 5 or 6). Among these 39 hips, the results were excellent in 4 hips, very good in 7 hips, good in 10, satisfactory in 10, poor in 6, and bad in 2. Arthritic change was the main reason for failures: the Kaplan-Meier survival rate at 21 years was 87 per cent when arthrosis was slight and only 15 per cent and 42 per cent when arthrosis was moderate to severe (p = 0.0001). The adverse effect of arthrosis was promoted by lack of congruency for early failures, and by severity of dysplasia and hip subluxation for late failures. The additional femoral varus osteotomies had no influence on functional or radiographic outcome. Our study indicated that hip shelf arthroplasty performed for painful acetabular dysplasia in adult has a 40 per cent probability survival rate at 21 years. The high rate of revision (42.8 per cent) could be related to the prevalence of severe pre-operative arthrosis. The low rate of lost for follow-up (8.7 per cent) and the long follow-up period (16.1 years) made our conclusion reliable. In spite of a high revision rate we recommend shelf athroplasty to treat acetabular dysplasia in adults. This procedure, very reliable in cases of moderate arthrosis, could be performed in cases of severe arthrosis to delay and make easier THR, but a low survival rate could be expected unless dysplasia, lack of congruency and subluxation were mild. To evaluate the structural effect of avocado/soybean unsaponifiables (ASU) in the treatment of patients with symptomatic osteoarthritis (OA) of the hip. Patients with regular painful primary OA of the hip (European League Against Rheumatism 1980 criteria) and a joint space still &gt; or = 1 mm (Kellgren grade 1 to 3, assessed by an independent observer prior to inclusion) entered a prospective, multicenter, randomized, parallel group, double-blind, placebo-controlled trial of 2 years duration. Patients had at least a 6-month history of regular pain and an algofunctional index (AFI) &gt; or = 4. The primary assessment criterion was a decrease of the joint space width (JSW) on plain anteroposterior radiographs of the pelvis performed in standing position, measured at the narrowest points by 2 independent readers, previously tested and selected and blinded to both the treatment and the time sequence. Secondary criteria were standard clinical outcome measurements (AFI, pain on a visual analog scale, consumption of nonsteroidal antiinflammatory drugs and patient's and investigator's global assessments). One hundred sixty-three patients were included: 102 men and 61 women (mean age 63.2 +/- 8.7 years). A total of 108 patients (72 men and 36 women; mean age 64 +/- 7.9 years) were radiologically evaluable at 23.7 +/- 2.6 months (ASU group; n = 55) and 23.7 +/- 3.2 months (placebo group; n = 53). Overall comparison of the evolution of JSW showed no difference between the ASU and placebo groups, from 2.35 +/- 0.93 to 1.87 +/- 1.10 mm and from 2.5 +/- 0.94 to 1.9 +/- 1.33 mm, respectively (intergroup P value at end point = 0.9). When patients were divided into 2 subgroups according to the median value of the baseline JSW (2.45 mm), the joint space loss in the most severely affected subgroup of patients (baseline JSW &lt; or = median) was significantly greater in the placebo group than in the ASU group: from 1.69 +/- 0.58 to 0.84 +/- 0.77 mm (-0.86 +/- 0.62 mm) and from 1.66 +/- 0.42 to 1.22 +/- 0.7 mm (-0.43 +/- 0.51 mm), respectively (P &lt; 0.01). The JSW decrease was identical, with no difference in ASU and placebo groups, in the less severely affected subgroup of patients (baseline JSW &gt; median). Clinical parameters in the 2 groups did not differ significantly throughout the study. This pilot randomized, double-blind, placebo-controlled trial failed to demonstrate a structural effect of ASU in hip OA. However, in a post-hoc analysis, ASU significantly reduced the progression of joint space loss as compared with placebo in the subgroup of patients with advanced joint space narrowing. These results suggest that ASU could have a structural effect but require confirmation in a larger placebo-controlled study in hip OA. The objective of the submitted work was to assess the long-term prognosis of Perthes disease. From the originally invited 142 patients 72 attended the check-up examination, complete X-ray documentation was assembled only in 32 patients with 38 affected hip joints. The time interval which had elapsed since the onset of the disease was on average 17 years. The authors evaluated the clinical and X-ray picture of the hip joints and assessed retrospectively the affection of the head according to Catterall's method, incl. signs of a head associated with risk. Treatment provided during the sixties and beginning of the seventies did not meet the principles of modern \"containment\" therapy. It comprised bed rest, application of a plaster spike and aftertreatment with a Thomas splint. During late check-up examinations Wiberg's angle, the epiphyseal index, the index of overlapping of the head, the distance of the head from the floor of the acetabulum and the height of the peak of the greater trochanter above the centre of the head of the femur were assessed. In addition to assessment of these partial X-ray parameters the authors evaluated the spherical properties of the head by Mose's method and subjectively the X-ray picture, using a three grade scale (satisfactory, feasible, poor). In the majority of assessed parameters the authors found a statistically significant correlation with the retrospective classification of the original X-ray pictures classified according to Catterall. The clinical picture was satisfactory in the majority, the authors did not find painful restriction of movement, while almost half the patients reported occasional subjective complaints as regards the hip joint. On the X-ray changes in the overgrowth of the greater trochanter were more marked than changes of the spherical character of the head and the extent of decentering. The follow-up of the group will continue to obtain a longer time interval from the onset of the disease. Key words: Perthes disease, late results, Catterall's classification. Osteoarthritis of the hip joint is a very common disease. There is a minor prevalence of males. By etiology one can distinguish primary (idiopathic) from secondary osteoarthritis. Secondary are due to well-known etiologies as overweight, repetitive traumata, malposture, muscle- and tendon-imbalance etc. Osteoarthritis includes not only cartilage abnormalities, but also such of the subchondral-region, synovialis, synovial fluid and periarticular muscles. The cartilage shows in osteoarthritis typically edema and swelling, defects with tears, fibrillation, and \"baldness\" and (or) cartilagenous repair-islands and joint space narrowing as well, while subchondrally micro-edema, necrosis, ev. microfractures, \"cysts\", demineralisation followed by sclerosis, osteophyte-formation and deformity is seen. With conventional radiographs and CT joint space narrowing, subchondral cysts, sclerosis and osteophytes and deformities are well delineated, MRI however allows visualization of subtle bone marrow and cartilage abnormalities. Clinically, the diagnosis of pre-osteoarthritis becomes more and more important. This includes e.g. deformities and malpostures, labrum-pathologies and structural imbalances. There are three prognostic different types of hip-osteoarthritis depending on the migration of the head of the hip joint: the most common are the latero-cranial and the medio-caudal ones, while the central one is found very rarely. Basic imaging method are conventional radiographs, and CT, followed by MRI. The diagnosis of an \"activated osteoarthritis\" is made by bone-scintigraphy or MRI with i.v. application of contrast-media. The labrum- and cartilage diagnosis should be done with MRI or MR-arthrography. Functional computer-animated analysis will be of great diagnostic value in the near future. MRI indications are differences between clinical results and imaging, missing clinical improvement of an \"activated\" osteoarthritis under standard therapy, unclear joint-pain and before any arthroscopy. Hip pain in the elderly is the main feature of osteoarthritis of the hip. In this prospective followup study, we wanted to determine which patients with hip pain show disease progression, and what the incidence of total hip replacement (THR) is in this group of patients after 3 and 6 years of followup. Within general practices in the area of Rotterdam (The Netherlands), persons age &gt; or = 50 years with incident hip pain were included. After 3 and 6 years, progression of hip pain was assessed. A total of 224 patients were included. After 3 years disease progressed in 29 (15%) patients and 23 (12%) received a THR. After 6 years disease progressed in 45 (28%) patients and 36 (22%) received a THR. The prognostic variables for a THR after 3 and 6 years related to history taking were age &gt; or = 60 years, morning stiffness, and pain in the groin/medial thigh; variables related to physical examination were decreased extension/adduction, painful internal rotation, and a body mass index &lt; or = 30 kg/m(2); and the variable related to radiologic findings was a Kellgren/Lawrence grade of 2 or higher. In this study population, approximately 12% of patients presenting with hip pain to their general practitioner will undergo a THR within 3 years, and approximately 22% after 6 years. Using the variables obtained from history taking, physical examination, and radiologic findings enables better identification of persons at high risk for a THR. Imaging is fundamental to the diagnosis and therapeutic follow-up of all hip diseases. Despite the advent of extremely sophisticated exploratory methods, the oldest imaging method, straightforward radiography, makes it possible to recognize, locate ans treat the lesion in most cases. Good interpretation of simple antero-posterior and lateral x-ray films therefore is very important. Among the new imaging methods, computerized tomography has brought the third dimension, while ultrasonography and nuclear magnetic resonance have enabled us to visualize cartilages and soft tissues. The contribution to diagnosis and follow-up of these modern methods is considerable, but since we are too near their beginning and since the number of examinations is still too small in many fields, the information they provide must be used with caution. A good knowledge of their principle, advantages and drawbacks should help us to utilize them at best by prescribing only those which are necessary and sufficient for diagnosis and treatment.\nHere is the question:\nRHEUMATOLOGY: You evaluate a 66-year-old patient with groin pain accentuated by prolonged standing for a few days per month. A plain radiograph of the hips shows narrowing of the femoroacetabular joint space, sclerosis and ostephytes.\nHere are the potential choices:\n1. I make the diagnosis of coxarthrosis and send to the traumatologist to place a hip prosthesis.\n2. Start treatment with weak opioids that have shown evidence in stopping the progression of the disease.\n3. Treatment with paracetamol, explaining that the evolution is very variable and the surgical indication depends on the functionality and pain control.\n4. Because of the radiological features described, I need a hip MRI before making a therapeutic decision.\nThe correct answer is: 3. Treatment with paracetamol, explaining that the evolution is very variable and the surgical indication depends on the functionality and pain control."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n In 1990, Tracey Gold began group therapy in an eating disorder program but only learned more ways to lose weight. That season, her weight loss problem was touched upon slightly on her television series, when Gold is seen looking at her body in a carnival mirror and describes to another character the distorted image in her head. In 1991, she started starving herself more than ever and vomiting, and lost a massive amount of weight, to the point that she was admitted to a hospital in early 1992. Her lowest weight is estimated to have been near 80 pounds. She was suspended from the show for her skeletal appearance. Photos of Gold's emaciated body were plastered all over tabloid magazines, and she was one of the first celebrities ever to be formally outed for anorexia. She last appeared in the 1991 episode, \"Menage a Luke,\" after missing the two prior episodes where her problem is very obvious in some scenes and did not return until the last two episodes of the series in the late spring of During the course of the documentary, Redknapp visited different locations to talk to people. She visited with friend and actress Denise van Outen in Los Angeles, and they discussed van Outen's experiences with people the pressure to lose weight. She went to Rhodes Farm Clinic to meet with several young women who are recovering from anorexia or bulimia to talk about their experiences with eating disorders. She also met with Spice Girl Mel C (\"Sporty Spice\") to discuss her severe eating disorder during her time the Spice Girls and the media portrayal. She met with her school friend, \"Sophie,\" who had suffered with a severe eating disorder during her teenage years, and they talked about the experience of low caloric intake. She visited her old stage school the Italia Conti Academy of Theatre Arts to talk with students and warn them about the horrors of crash dieting. She presented Clothes Show Live in Birmingham, and while she was there, she interviewed some models, and talked to a Reports concerning the percentage of first-degree relatives of anorectic patients with bipolar disease are also inconsistent. An increased prevalence of neurosis or alcoholism has been noted in other members of the family. However, psychiatrists seem to agree that the patient does not have symptoms that conform to any of the major neuroses or psychoses. Certainly loss of appetite, lack of self-esteem and interest in personal appearance, and self-destructive behavior—common features of anorexia nervosa—are also symptoms of depressive illness, yet most of the patients do not look or admit to being dejected. Moreover, endogenous depression affects both sexes. The pathologic fear of becoming fat and the obsession with weight might be interpreted as a phobic or obsessional neurosis. Trichotillomania (TTM) is defined by the Diagnostics and Statistic Manual of Mental Disorders, 4th edition (DMS-IV) as hair loss from a patient`s repetitive self-pulling of hair. The disorder is included under anxiety disorders because it shares some obsessive-compulsive features. Patients have the tendency towards feelings of unattractiveness, body dissatisfaction, and low self-esteem (1,2). It is a major psychiatric problem, but many patients with this disorder first present to a dermatologist. An 11-year-old girl came to our department with a 2-month history of diffuse hair loss on the frontoparietal and parietotemporal area (Figure 1). She had originally been examined by a pediatrician with the diagnosis of alopecia areata. The patient`s personal history included hay fever and shortsightedness, and she suffered from varicella and mononucleosis. Nobody in the family history suffered from alopecia areata, but her father has male androgenetic alopecia (Norwood/Hamilton MAGA C3F3). The mother noticed that the child had had changeable mood for about 2 months and did not want to communicate with other persons in the family. The family did not have any pet at home. At school, her favorite subjects were Math and Computer Studies. She did not like Physical Education and did not participate in any sport activities during her free time. This was very strange because she was obese (body-mass index (BMI) 24.69). She was sometimes angry with her 13-year-old sister who had better results at school. The girl had suddenly started to wear a blue scarf. The parents did not notice that she pulled out her hair at home. Dermatological examination of the capillitium found a zone of incomplete alopecia in the frontoparietal and parietotemporal area, without inflammation, desquamation, and scaring. Hairs were of variable length (Figure 1). There was a patch of incomplete alopecia above the forehead between two stripes of hair of variable length (Figure 2). The hair pull test was negative along the edges of the alopecia. Mycological examination from the skin capillitium was negative. The trichoscopy and skin biopsy of the parietotemporal region of the capillitium (Figure 3) confirmed trichotillomania. Laboratory tests (blood count, iron, ferritin, transferrin, selenium, zinc, vitamin B12, folic acid, serology and hormones of thyroid gland) were negative. We referred the girl for ophthalmologic and psychological examination. Ophthalmologic examination proved that there was no need to add any more diopters. The psychological examination provided us with a picture in which she drew her family (Figure 4). The strongest authority in the family was the mother because she looked after the girls for most of the day. She was in the first place in the picture. The father had longer working hours and spent more time outside the home. He worked as a long vehicle driver. He was in the second place in the picture. There was sibling rivalry between the girls, but the parents did not notice this problem and preferred the older daughter. She was successful at school and was prettier (slim, higher, curly brown hair, without spectacles). Our 11-years-old patient noticed all these differences between them, but at her level of mental development was not able to cope with this problem. She wanted to be her sister's equal. The sister is drawn in the picture in the third place next to father, while the patient's own figure was drawn larger and slim even though she was obese. Notably, all three female figures had very nice long brown hair. It seemed that the mother and our patient had better quality of hair and more intense color than the sister in the drawing. The only hairless person in the picture was the father. The girl did not want to talk about her problems and feelings at home. Then it was confirmed that our patient was very sensitive, anxious, willful, and withdrawn. She was interested in her body and very perceptive of her physical appearance. From the psychological point of view, the parents started to pay more interest to their younger daughter and tried to understand and help her. After consultation with the psychiatrist, we did not start psychopharmacologic therapy for trichotillomania; instead, we started treatment with cognitive behavioral therapy, mild shampoo, mild topical steroids (e.g. hydrocortisone butyrate 0.1%) in solution and methionine in capsules. With parents' cooperation, the treatment was successful. The name trichotillomania was first employed by the French dermatologist Francois Henri Hallopeau in 1889, who described a young man pulling his hair out in tufts (3-5). The word is derived from the Greek thrix (hair), tillein (to pull), and mania (madness) (5). The prevalence of TTM in the general adult population ranges from 0.6% to 4%, and 2-4% of the general psychiatric outpatient population meet the criteria for TTM (2-5). The prevalence among children and adolescents has been estimated at less than 1% (5). The disease can occur at any age and in any sex. The age of onset of hair pulling is significantly later for men than for women (3). There are three subsets of age: preschool children, preadolescents to young adults, and adults. The mean age of onset is pre-pubertal. It ranges from 8 to 13 years (on average 11.3 years) (2-5). The occurrence of hair-pulling in the first year of life is a rare event, probably comprising &lt;1% of cases (5). The etiology of TTM is complex and may be triggered by a psychosocial stressor within the family, such as separation from an attachment figure, hospitalization of the child or parent, birth of a younger sibling, sibling rivalry, moving to a new house, or problems with school performance. It has been hypothesized that the habit may begin with \"playing\" with the hair, with later chronic pulling resulting in obvious hair loss (2). Environment is a factor because children usually pull their hair when alone and in relaxed surroundings. The bedroom, bathroom, or family room are \"high-risk\" situations for hair-pulling (5). Men and women also differed in terms of the hair pulling site (men pull hair from the stomach/back and the moustache/beard areas, while women pull from the scalp) (3). Pulling hair from siblings, pets, dolls, and stuffed animals has also been documented, often occurring in the same pattern as in the patient (5). Genetic factors contributing to the development of TTM are mutations of the SLITRK1 gene, which plays a role in cortex development and neuronal growth. The protein SAPAP3 has been present in 4.2% of TTM cases and patients with obsessive-compulsive disorder (OCD). It may be involved in the development of the spectrum of OCD. A significantly different concordance rate for TTM was found in monozygotic (38.1%) compared with dizygotic (0%) twins in 34 pairs (3). The core diagnostic feature is the repetitive pulling of hairs from one`s own body, resulting in hair loss. The targeted hair is mostly on the scalp (75%), but may also be from the eyebrows (42%), eyelashes (53%), beard (10%), and pubic area (17%) (3,5). There are three subtypes of hair pulling - early onset, automatic, and focused. Diagnostic criteria for TTM according to DSM-IV criteria are (2,3,5): 1) recurrent pulling of one`s hair resulting in noticeable hair loss; 2) an increasing sense of tension immediately prior to pulling out the hair or when attempting to resist the behavior; 3) pleasure, gratification, or relief when pulling out the hair; 4) the disturbance is not better accounted for by another mental disorder and is not due to a general medical condition (e.g., a dermatologic condition); 5) the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. The differential diagnosis includes alopecia areata (Table 1) (6), tinea capitis, telogen effluvium, secondary syphilis, traction alopecia, loose anagen syndrome, lichen planopilaris, alopecia mucinosa, and scleroderma (2-5). Biopsy of an involved area (ideally from a recent site of hair loss) can help to confirm the diagnosis (5). On histologic examination, there are typically increased numbers of catagen and telogen hairs without evidence of inflammation. Chronic hair pulling induces a catagen phase, and more hairs will be telogen hairs. Pigment casts and empty anagen follicles are often seen. Perifollicular hemorrhage near the hair bulb is an indicator of TTM (2). Complications of TTM are rare, but they comprise secondary bacterial infections with regional lymphadenopathy as a result of picking and scratching at the scalp. Many patients play with and ingest the pulled hairs (e.g. touching the hair to lips, biting, and chewing). Trichophagia (ingestion of the hair) can lead to a rare complication named trichobezoar (a \"hair ball\" in stomach). This habit is present in approximately 5% to 30% of adult patients, but it is less frequent in children. Patient with trichophagia present with pallor, nausea, vomiting, anorexia, and weight loss. Radiologic examination and gastroscopy should not be delayed (2,4,5). The management of the disease is difficult and requires strong cooperation between the physician, patient, and parents. The dermatologist cannot take part in the therapy, strictly speaking, but without the psychological, psychopharmacologic, and topic dermatologic treatment a vicious circle will be perpetuated.  <bIntroduction</b Personality disorders (PD) are among the most common comorbid disorders in female patients with Anorexia Nervosa (AN). Recent research findings suggest that comorbid PD are associated with a higher treatment drop-out rate and a worse therapeutic outcome. However, no study to date has distinguished between certain age groups concerning these issues. <bResearch questions</b Therefore, the present study focuses on the prevalence of PD (1), treatment drop-out rates (2) and weight gain (3) in female in-patients with AN. Thereby, we differentiate among three age groups (17-24 years; 25-34 years; 35-65 years). <bMaterial &amp; Methods</b We assessed female in-patients (N=331) with AN at the Helios Clinic in Bad Grönenbach in Germany using the Eating Disorders Inventory-2 and the psychotherapeutic-medical basic documentation at the beginning and at the end of their treatment. Furthermore, we investigated the drop-out rate and weight gain by comparing anorexic patients with and without comorbid PD that were diagnosed by clinicians using ICD-10 criteria. <bResults</b In sum, our patients with AN demonstrated a prevalence rate of 34% for one or more comorbid PD. Interestingly, patients between 17-24 years showed a lower prevalence rate of 22% compared to those between 25-34 years (42%) and 35-65 years (41%). Furthermore, younger age and comorbid PD seemed to be significant predictors for treatment dropout. One of the most striking results was that younger patients (17-24) without a comorbid PD had the highest weight gain during treatment. This could not be observed in patients with a comorbid PD, who demonstrated the highest weight gain between 25 and 34 years of age. <bConclusion</b Our findings support the hypothesis that comorbid PD are related to a worse outcome in patients with eating disorders. Future studies might do well in assessing dimensional scores of personality disorders and other relevant aspects like for example the amount of social support to draw further conclusions on these associations. Our results emphasize the need for more disorder-specific interventions tailoring at patients with AN and comorbid PD to improve treatment outcome. Dear Editor, Next to focal neurological symptoms, epileptic seizures and head aches, brain tumors can less frequently bring about cognitive changes, slowed speech, difficulty sustaining mental functioning and psychiatric symptoms of personality changes and. loss of interest in daily activities, these symptoms may be evaluated as anxiety or depression. Depression is known to be a complication of brain tumours and may sometimes be seen after the presentation of neurological symptoms linked to brain tumours, and sometimes after tumor treatment (Oğuz et al. 2005, Litofsky et al. 2004, Moise and Madhusoodanan 2006, Oreskovic M et al. 2007, Rooney A et al. 2010). The dorsolateral prefrontal, orbitofrontal and medial frontal circuits constitute the three subcortical neuronal circuits in the frontal cortex. The dorsolateral prefrontal circuit is associated with planning and operational functions and lesions on it may give rise to apathy, abulia, perseveration, personality changes and planning disorder. Lesions involving the orbitofrontal circuit, which is associated with response suppression and disinhibition, may involve emotional lability and memory problems. Whereas lesions affecting the right orbitofrontal circuit give rise to elevated mood, lesions on the left orbitofrontal circuit lead to depressed mood. In cases with medial frontal circuit involvement, akinetic mutism may result from lesions in the superior medial region and anteroretrograde amnesia and confabulation are observed with lesions in the inferior medial region (Tosun et al. 2016, Chirchiglia 2018). A diagnosis of psychiatric disorder may be given during the first examination of patieants with primary brain tumours, especially if localized in the frontal lobe. Thorough history taking and physical examination are necessary for early diagnosis. The case reported here concerns a 29-year-old university graduate female patient, living with her partner and children, who consulted the clinic with complaints of tendency to frequent crying, anhedonia, having difficulty with speech fluency, forgetfulness and distractedness that had presented suddenly, 2 months previously, without any causative stressor. In her mental status examination, she appeared having normal self-care with appearance at her actual age. She was fully conscious and oriented, not willing to cooperate with the interview, had distinct difficulty in maintaining attention and with fluency of speech. Her mood was depressive. She described loss of appetite, fatigue and energy loss. Her difficulty in paying attention was pronounced. She did not have a history of psychotropic medication use or family history of psychiatric disease. She did not smoke or use alcohol or substance. After evaluating the clinical interview, a preliminary diagnosis of major depressive disorder was considered on the basis of the DSM-5 criteria. Routine blood tests were requested. Given the continuation of her complaints, the difficulty with fluent speech and the increase in tendency to sleep at the first week follow up, cranial MRI was planned. The MRI results showed on the right, in the frontal lobe a multilocular mass with precallosal extension, undiscernable margins with the right lateral aspect of the corpus callosum genu and dispersed cystic-necrotic areas with T2 signal series. The dimensions of the mass were nearly 5 x 3 cm causing a 1-cm right-to-left shift of the midline (Figure 1) DEPRESSION AS THE FIRST SYMPTOM OF FRONTAL LOBE GRADE 2 MALIGNANT GLIOMA 2 Türk Psikiyatri Dergisi 2 Turkish Journal of Psychiatry Letter to the Editor 143 144 The patient was referred for surgery with the preliminary diagnosis of high-grade glial tumour. Pathology results identified a grade 2 glioma. It was learned that radiotherapy sessions were begun after surgery. The patient did not have any symptoms of psychopathology during the 2 monthly psychiatric interviews made after surgery. Brain tumours generally indicate their presence with headache, seizures and other neurological symptoms and very rarely with depression as seen in the case of our patient. It should be kept in mind that atypical psychiatric symptoms may have an underlying organic lesion and subtle neurological symptoms should be investigated in detail. A recent meta-analysis on 37 observational studies determined a 21.7% prevalence of depression in a total of 4518 patients with intracranial tumours. Comorbidity of depression with brain tumor was demonstrated to worsen the quality of life, increase suicidal risk and lower the chance of survival (Huang et al. 2017). The possibility of psychiatric symptoms being the clinical clues for brain cancer was noted and the necessity of neuroimaging tests in cases of recent-onset psychosis or mood disorder symptoms, atypical personality changes and anorexia without body dysmorphic disorder was emphasized (Madhusoodanan et al. 2015). Loss of interest, tendency to frequent weeping, introversion and anhedonia were the sole complaints in the case discussed here. The increase in psychomotor retardation and slowing down of movements at the very first weekly control follow up necessitated neuroimaging. Despite the reports in the literature on the frequent association of unpreventable excessive behavior, disinhibition and irritability with right frontal injury and lesions (Okumuş and Hocaoğlu 2018), depression was the dominant symptom in the case presented here. There are differences between primary major depression and depression presenting with underlying somatic diseases which is known to occur at later ages (Rouchell et al. 2002). However, our patient was aged 29 years. Also, cases of depression due to somatic disease are less associated with family history of depression and suicidal ideation and attempts, while cognitive symptoms come to the foreground during mental status examination. (Sertöz and Mete 2004, Rouchell et al. 2002). Our patient did not have suicidal ideation or attempts, or a family history of depression. In apathy, which may be explained as emotional blunting, indifference or detachment from the external world, targeted behavior is also reduced next to the lack of emotional expression. The individual discussed here was learned not to sit at the table or change the television channel unless reminded to do so. When the reason was asked, she could not think of one. The reduction in emotional expression accompanies reduced insight, abulia and lack of empathy (Sözeri Varma et al. 2019). In depression, apathy is defined as 'sorrowless depression'. Our patient cried but had very blunted mimics and gestures. She explained that she could not help weeping even at times when she did not feel internally distressed. The seriousness of apathy, as a symptom difficult to differentiate from depression, is still not understood. Neuroimaging Figure 1- Cranial MRI of the patient 145 Received: 16.08.2020, Accepted: 04.12.2020, Available Online Date: 05.10.2021 1MD., Antalya Kepez State Hospital, Department of Psychiatry, Antalya, 2MD., Ordu University Training and Research Hospital, Department of Psychiatry, Ordu, Turkey e-mail: bosbora@yahoo.com https://doi.org/10.5080/u25957 studies indicate apathy to be a reflect of impaired frontal-subcortical circuits and the functional disorder of the connections between the ventromedial prefrontal cortex and the basal ganglia (Chase 2011). Comparison of 45 individuals with depression due to aging and 43 healthy individuals showed apathy to be associated with fronto-limbic gray and white matter abnormalities which continued after antidepressant treatment. The structural anomalies of the posterior subgenual cingulate gyrus and the uncinate fasciculus were discussed (Yuen 2014). The case discussed here is presented to emphasize the importance of brain imaging methods and detailed investigation of atypical symptoms for diagnostic approaches to psychiatric disorders. Especially, complaints at young age of depression with psychomotor retardation, reduced fluency of speech and sudden onset withdrawal without stressors should be a warning of secondary depression. Yours sincerely... Şerif Bora Nazlı1 , Muhammet Sevindik2 REFERENCES Chase TN (2011) Apathy in Neuropsychiatric Disease: Diagnosis, Pathophysiology, and Treatment. Neurotox Res 19:266-78. Chirchiglia D (2018) Pseudodepression as an Anticipatory Symptom of Frontal Lobe Brain Tumors. Int J Depress Anxiety 1:007. Huang J, Zeng C, Xiao J et al (2017) Association between depression and brain tumor: a systematic review and meta-analysis. Oncotarget 8:94932-43. Litofsky NS, Farace E, Anderson F et al (2004) Depression in patients with high-grade glioma: Results of the glioma outcomes project. Neurosurgery 54:358-67. Madhusoodanan S, Ting MB, Farah T et al (2015) Pyschiatric aspects of brain tumors: A review. World J Psychiatry 5:273-85. Moise D, Madhusoodanan S (2006) Psychiatric symptoms associated with brain tumors: a clinical enigma. CNS Spectr 2006;11:28-31. Oğuz N, Ilnem C, Yener F (2005) Psychiatric symptoms in brain tumors: Case reports. Bulletin of Clinical Psychopharmacology 15:18-21. Hocaoğlu Ç, Okumuş B (2018) Psychiatric manifestations and brain tumor: A case report and brief review. The Medical Journal of Mustafa Kemal University 9:42-9. Oreskovic NM, Strother CG, Zibners LM (2007) An unusual case of a central nervous system tumor presenting as a chief complaint of depression. Pediatric Emergency Care 23:486-8. Rooney A, Carson A, Grant R (2011) Depression in cerebral glioma patients: a systematic review of observational studies. J Natl Cancer Inst103:61-76. Rouchell AM, Pounds R, Tierney JG (2002) Depression Textbook of Consultation-Liaison Psychiatry, 2nd Edition, Volume 1. MG Wise, JR Rundell (Ed), Washington DC American Psychiatric Publishing, Inc, p.307-38. Özen SÖ, Hayriye ME (2004) Bedensel Hastalıklarda Depresyon. Klinik Psikiyatri Ek 2:63-9. Sözeri Varma G , Bingöl C , Topak O et al (2019) Relationship of apathy with depressive symptom severity and cognitive functions in geriatric depression. Arch Neuropsychiatry 56:133-8. Yuen GS, Gunning FM, Woods E et al (2014) Neuroanatomical correlates of apathy in late-life depression and antidepressant treatment response. J Affect Disord 166:179-86. In the early 1990s, London struggled with anorexia, binge eating, and other weight issues. Standing , she was at her lightest weight and at her heaviest. In a 2007 interview with Sirens magazine, she said of the experience, \"I have been every size in my life. I've been smaller than a zero, up through a size 16. I've had lots of issues with body image and weight my whole life and it really took a great deal of work to recognize that at all those weights, no matter how I felt, I could still find a dress that made me feel sexy and powerful.\" Chloe is a 9-year-old gal whose mother made an initial visit to a new pediatrician for concerns about her behavior. Chloe is apprehensive about the visit and frequently hides behind her mother.Her parents first noticed Chloe becoming angry and more emotional 3 years ago, which her parents did not initially understand. However, over the past year, she has started to have more worries and unusual behavior.Chloe and her mother report that when she walks through doorways, she will almost always go back and walks through again. At home, she will walk through doorways multiple times and at school, she will pretend she forgot something so her friends do not notice. She often will not walk downstairs and occasionally her mother has to carry her. Clothes are problematic for Chloe. If her father touches something of a specific color and then touches Chloe, she will have to change her clothes or take a shower. Sometimes, she will never be able to wear those clothes again. She had a recent episode where she could not stop tapping a red paper, because if she stopped, she said it would burst into flame. During the 2 weeks before the pediatric visit, symptoms increased to the point that she is now refusing to go to school. When she stays home, she lays in 1 place all day.Chloe is a fourth grade student. The family does not report academic concerns. She has friends. She denies any appetite or sleep problems. She endorses periods of sadness, lack of energy, and decreased interest in social activities, mostly because she worries and is embarrassed. She kept her behaviors hidden from her 5 siblings for the past year, and she talked only to her mother about them. She is worried her friends might discover her behaviors.The family history is notable for multiple paternal family members with anxiety and bipolar disorder and depression on mother's side. A few months ago, Chloe's family adopted a 7-year-old child with special needs from China.Her growth, vital signs, and physical examination are unremarkable. Her mother filled out the Short Mood and Feelings Questionnaire and the Screen for Child Anxiety-Related Emotional Disorders, which both had elevated scores. Reece-Wilmore revealed she came up with the idea for the bulimia storyline, saying \"When I came back from my Christmas holiday, I'd lost tons of weight. Everyone commented on my new figure and I thought to myself 'If there was anything wrong with me, those sorts of comments would have made me really paranoid about my weight.'\" The actress then suggested the storyline, believing it was a subject familiar with a lot of teenage girls. The Neighbours bosses were initially \"wary\" of tackling such a difficult and sensitive storyline and a spokesperson said \"We try to tackle serious issues such as bulimia as much as possible. We may not be able to wave a magic wand and make the problems go away, but by dealing with current situations they become topics for wider discussion.\" Reece-Wilmore added that she could see how eating disorders were connected to teenagers' anxieties about approaching adulthood as she used to make herself sick to avoid going to school. Bulimia sufferer Joanna Goodfellow is staging an exhibition of photographs portraying the distorted perceptions she has of her body and the self-hatred she sometimes feels. Joanna has suffered from an eating disorder for the past five years and wants people to understand the 'frustration and anger' she feels when she looks at her bod)'. The exhibition, at the Barbican Theatre in Plymouth, runs until February 12. Nicole is a 15-year-old girl presenting to the Developmental Behavioral Pediatrics Clinic with symptoms of the inattentive type of Attention-Deficit/Hyperactivity Disorder (ADHD) and declining school performance over the last year. She expressed frustration over her inability to concentrate on schoolwork. Assuming that her poor grades were secondary to lack of effort, her parents withdrew privileges. Nicole became increasingly depressed. She stopped participating in activities, she previously enjoyed, and her parents reported that she stopped singing in the shower. After talking to a cousin with ADHD, Nicole concluded that she had ADHD as well. She asked her parents to arrange for an evaluation.Nicole met DSM-5 criteria for the diagnosis of inattentive ADHD and was started on a stimulant medication (mixed amphetamine salts). She had symptoms of a coexisting depression, although she did not meet criteria for diagnosis of a depressive disorder. At a 3-week follow-up visit, she showed improvement in targeted ADHD symptoms; homework was now easier and her grades improved. At a 2-month follow-up, Nicole's weight dropped from 53 kg (47th percentile) prestimulant treatment to 49 kg (31st percentile). She reported appetite suppression after taking the stimulant but did not feel that her eating habits had changed significantly. Her father reported that she had a preference for junk food and snacks. Nicole did not enjoy exercising and did not participate in extracurricular sports.She weighed herself several times a day, as she was worried about losing too much weight. Nicole's mood continued to be low, despite the fact that her grades improved, and her parents were more understanding of her challenges. She was otherwise healthy and reported regular menstrual cycles. Nicole requested an increase in the dose of stimulant medication for greater improvement in concentration during homework and in school.Her pediatric clinician was concerned about the possibility of an eating disorder in addition to depression. She asked herself, \"Are we treating inattentive ADHD effectively or are we enabling an eating disorder?\"\nHere is the question:\nPSYCHIATRY: A 19-year-old female university student comes to the clinic accompanied by her parents, reporting feeling progressively more asthenic in the last two months, with loss of appetite and weight and with greater difficulty in concentrating on her studies. The anamnesis also highlights that she has lost interest in going out with friends, has ideas of death without self-harming ideation and pessimistic cognitions of the future. Her weight is 90% of that considered ideal for age and gender. She does not present weight phobia or body image distortion. The most appropriate diagnosis is:\nHere are the potential choices:\n1. Anorexia nervosa.\n2. Anxiety disorder.\n3. Borderline personality disorder.\n4. Dysthymia.\n5. Major depressive disorder.\nThe correct answer is: ",
        "gold_answer": "5 Major depressive disorder.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n In 1990, Tracey Gold began group therapy in an eating disorder program but only learned more ways to lose weight. That season, her weight loss problem was touched upon slightly on her television series, when Gold is seen looking at her body in a carnival mirror and describes to another character the distorted image in her head. In 1991, she started starving herself more than ever and vomiting, and lost a massive amount of weight, to the point that she was admitted to a hospital in early 1992. Her lowest weight is estimated to have been near 80 pounds. She was suspended from the show for her skeletal appearance. Photos of Gold's emaciated body were plastered all over tabloid magazines, and she was one of the first celebrities ever to be formally outed for anorexia. She last appeared in the 1991 episode, \"Menage a Luke,\" after missing the two prior episodes where her problem is very obvious in some scenes and did not return until the last two episodes of the series in the late spring of During the course of the documentary, Redknapp visited different locations to talk to people. She visited with friend and actress Denise van Outen in Los Angeles, and they discussed van Outen's experiences with people the pressure to lose weight. She went to Rhodes Farm Clinic to meet with several young women who are recovering from anorexia or bulimia to talk about their experiences with eating disorders. She also met with Spice Girl Mel C (\"Sporty Spice\") to discuss her severe eating disorder during her time the Spice Girls and the media portrayal. She met with her school friend, \"Sophie,\" who had suffered with a severe eating disorder during her teenage years, and they talked about the experience of low caloric intake. She visited her old stage school the Italia Conti Academy of Theatre Arts to talk with students and warn them about the horrors of crash dieting. She presented Clothes Show Live in Birmingham, and while she was there, she interviewed some models, and talked to a Reports concerning the percentage of first-degree relatives of anorectic patients with bipolar disease are also inconsistent. An increased prevalence of neurosis or alcoholism has been noted in other members of the family. However, psychiatrists seem to agree that the patient does not have symptoms that conform to any of the major neuroses or psychoses. Certainly loss of appetite, lack of self-esteem and interest in personal appearance, and self-destructive behavior—common features of anorexia nervosa—are also symptoms of depressive illness, yet most of the patients do not look or admit to being dejected. Moreover, endogenous depression affects both sexes. The pathologic fear of becoming fat and the obsession with weight might be interpreted as a phobic or obsessional neurosis. Trichotillomania (TTM) is defined by the Diagnostics and Statistic Manual of Mental Disorders, 4th edition (DMS-IV) as hair loss from a patient`s repetitive self-pulling of hair. The disorder is included under anxiety disorders because it shares some obsessive-compulsive features. Patients have the tendency towards feelings of unattractiveness, body dissatisfaction, and low self-esteem (1,2). It is a major psychiatric problem, but many patients with this disorder first present to a dermatologist. An 11-year-old girl came to our department with a 2-month history of diffuse hair loss on the frontoparietal and parietotemporal area (Figure 1). She had originally been examined by a pediatrician with the diagnosis of alopecia areata. The patient`s personal history included hay fever and shortsightedness, and she suffered from varicella and mononucleosis. Nobody in the family history suffered from alopecia areata, but her father has male androgenetic alopecia (Norwood/Hamilton MAGA C3F3). The mother noticed that the child had had changeable mood for about 2 months and did not want to communicate with other persons in the family. The family did not have any pet at home. At school, her favorite subjects were Math and Computer Studies. She did not like Physical Education and did not participate in any sport activities during her free time. This was very strange because she was obese (body-mass index (BMI) 24.69). She was sometimes angry with her 13-year-old sister who had better results at school. The girl had suddenly started to wear a blue scarf. The parents did not notice that she pulled out her hair at home. Dermatological examination of the capillitium found a zone of incomplete alopecia in the frontoparietal and parietotemporal area, without inflammation, desquamation, and scaring. Hairs were of variable length (Figure 1). There was a patch of incomplete alopecia above the forehead between two stripes of hair of variable length (Figure 2). The hair pull test was negative along the edges of the alopecia. Mycological examination from the skin capillitium was negative. The trichoscopy and skin biopsy of the parietotemporal region of the capillitium (Figure 3) confirmed trichotillomania. Laboratory tests (blood count, iron, ferritin, transferrin, selenium, zinc, vitamin B12, folic acid, serology and hormones of thyroid gland) were negative. We referred the girl for ophthalmologic and psychological examination. Ophthalmologic examination proved that there was no need to add any more diopters. The psychological examination provided us with a picture in which she drew her family (Figure 4). The strongest authority in the family was the mother because she looked after the girls for most of the day. She was in the first place in the picture. The father had longer working hours and spent more time outside the home. He worked as a long vehicle driver. He was in the second place in the picture. There was sibling rivalry between the girls, but the parents did not notice this problem and preferred the older daughter. She was successful at school and was prettier (slim, higher, curly brown hair, without spectacles). Our 11-years-old patient noticed all these differences between them, but at her level of mental development was not able to cope with this problem. She wanted to be her sister's equal. The sister is drawn in the picture in the third place next to father, while the patient's own figure was drawn larger and slim even though she was obese. Notably, all three female figures had very nice long brown hair. It seemed that the mother and our patient had better quality of hair and more intense color than the sister in the drawing. The only hairless person in the picture was the father. The girl did not want to talk about her problems and feelings at home. Then it was confirmed that our patient was very sensitive, anxious, willful, and withdrawn. She was interested in her body and very perceptive of her physical appearance. From the psychological point of view, the parents started to pay more interest to their younger daughter and tried to understand and help her. After consultation with the psychiatrist, we did not start psychopharmacologic therapy for trichotillomania; instead, we started treatment with cognitive behavioral therapy, mild shampoo, mild topical steroids (e.g. hydrocortisone butyrate 0.1%) in solution and methionine in capsules. With parents' cooperation, the treatment was successful. The name trichotillomania was first employed by the French dermatologist Francois Henri Hallopeau in 1889, who described a young man pulling his hair out in tufts (3-5). The word is derived from the Greek thrix (hair), tillein (to pull), and mania (madness) (5). The prevalence of TTM in the general adult population ranges from 0.6% to 4%, and 2-4% of the general psychiatric outpatient population meet the criteria for TTM (2-5). The prevalence among children and adolescents has been estimated at less than 1% (5). The disease can occur at any age and in any sex. The age of onset of hair pulling is significantly later for men than for women (3). There are three subsets of age: preschool children, preadolescents to young adults, and adults. The mean age of onset is pre-pubertal. It ranges from 8 to 13 years (on average 11.3 years) (2-5). The occurrence of hair-pulling in the first year of life is a rare event, probably comprising &lt;1% of cases (5). The etiology of TTM is complex and may be triggered by a psychosocial stressor within the family, such as separation from an attachment figure, hospitalization of the child or parent, birth of a younger sibling, sibling rivalry, moving to a new house, or problems with school performance. It has been hypothesized that the habit may begin with \"playing\" with the hair, with later chronic pulling resulting in obvious hair loss (2). Environment is a factor because children usually pull their hair when alone and in relaxed surroundings. The bedroom, bathroom, or family room are \"high-risk\" situations for hair-pulling (5). Men and women also differed in terms of the hair pulling site (men pull hair from the stomach/back and the moustache/beard areas, while women pull from the scalp) (3). Pulling hair from siblings, pets, dolls, and stuffed animals has also been documented, often occurring in the same pattern as in the patient (5). Genetic factors contributing to the development of TTM are mutations of the SLITRK1 gene, which plays a role in cortex development and neuronal growth. The protein SAPAP3 has been present in 4.2% of TTM cases and patients with obsessive-compulsive disorder (OCD). It may be involved in the development of the spectrum of OCD. A significantly different concordance rate for TTM was found in monozygotic (38.1%) compared with dizygotic (0%) twins in 34 pairs (3). The core diagnostic feature is the repetitive pulling of hairs from one`s own body, resulting in hair loss. The targeted hair is mostly on the scalp (75%), but may also be from the eyebrows (42%), eyelashes (53%), beard (10%), and pubic area (17%) (3,5). There are three subtypes of hair pulling - early onset, automatic, and focused. Diagnostic criteria for TTM according to DSM-IV criteria are (2,3,5): 1) recurrent pulling of one`s hair resulting in noticeable hair loss; 2) an increasing sense of tension immediately prior to pulling out the hair or when attempting to resist the behavior; 3) pleasure, gratification, or relief when pulling out the hair; 4) the disturbance is not better accounted for by another mental disorder and is not due to a general medical condition (e.g., a dermatologic condition); 5) the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. The differential diagnosis includes alopecia areata (Table 1) (6), tinea capitis, telogen effluvium, secondary syphilis, traction alopecia, loose anagen syndrome, lichen planopilaris, alopecia mucinosa, and scleroderma (2-5). Biopsy of an involved area (ideally from a recent site of hair loss) can help to confirm the diagnosis (5). On histologic examination, there are typically increased numbers of catagen and telogen hairs without evidence of inflammation. Chronic hair pulling induces a catagen phase, and more hairs will be telogen hairs. Pigment casts and empty anagen follicles are often seen. Perifollicular hemorrhage near the hair bulb is an indicator of TTM (2). Complications of TTM are rare, but they comprise secondary bacterial infections with regional lymphadenopathy as a result of picking and scratching at the scalp. Many patients play with and ingest the pulled hairs (e.g. touching the hair to lips, biting, and chewing). Trichophagia (ingestion of the hair) can lead to a rare complication named trichobezoar (a \"hair ball\" in stomach). This habit is present in approximately 5% to 30% of adult patients, but it is less frequent in children. Patient with trichophagia present with pallor, nausea, vomiting, anorexia, and weight loss. Radiologic examination and gastroscopy should not be delayed (2,4,5). The management of the disease is difficult and requires strong cooperation between the physician, patient, and parents. The dermatologist cannot take part in the therapy, strictly speaking, but without the psychological, psychopharmacologic, and topic dermatologic treatment a vicious circle will be perpetuated.  <bIntroduction</b Personality disorders (PD) are among the most common comorbid disorders in female patients with Anorexia Nervosa (AN). Recent research findings suggest that comorbid PD are associated with a higher treatment drop-out rate and a worse therapeutic outcome. However, no study to date has distinguished between certain age groups concerning these issues. <bResearch questions</b Therefore, the present study focuses on the prevalence of PD (1), treatment drop-out rates (2) and weight gain (3) in female in-patients with AN. Thereby, we differentiate among three age groups (17-24 years; 25-34 years; 35-65 years). <bMaterial &amp; Methods</b We assessed female in-patients (N=331) with AN at the Helios Clinic in Bad Grönenbach in Germany using the Eating Disorders Inventory-2 and the psychotherapeutic-medical basic documentation at the beginning and at the end of their treatment. Furthermore, we investigated the drop-out rate and weight gain by comparing anorexic patients with and without comorbid PD that were diagnosed by clinicians using ICD-10 criteria. <bResults</b In sum, our patients with AN demonstrated a prevalence rate of 34% for one or more comorbid PD. Interestingly, patients between 17-24 years showed a lower prevalence rate of 22% compared to those between 25-34 years (42%) and 35-65 years (41%). Furthermore, younger age and comorbid PD seemed to be significant predictors for treatment dropout. One of the most striking results was that younger patients (17-24) without a comorbid PD had the highest weight gain during treatment. This could not be observed in patients with a comorbid PD, who demonstrated the highest weight gain between 25 and 34 years of age. <bConclusion</b Our findings support the hypothesis that comorbid PD are related to a worse outcome in patients with eating disorders. Future studies might do well in assessing dimensional scores of personality disorders and other relevant aspects like for example the amount of social support to draw further conclusions on these associations. Our results emphasize the need for more disorder-specific interventions tailoring at patients with AN and comorbid PD to improve treatment outcome. Dear Editor, Next to focal neurological symptoms, epileptic seizures and head aches, brain tumors can less frequently bring about cognitive changes, slowed speech, difficulty sustaining mental functioning and psychiatric symptoms of personality changes and. loss of interest in daily activities, these symptoms may be evaluated as anxiety or depression. Depression is known to be a complication of brain tumours and may sometimes be seen after the presentation of neurological symptoms linked to brain tumours, and sometimes after tumor treatment (Oğuz et al. 2005, Litofsky et al. 2004, Moise and Madhusoodanan 2006, Oreskovic M et al. 2007, Rooney A et al. 2010). The dorsolateral prefrontal, orbitofrontal and medial frontal circuits constitute the three subcortical neuronal circuits in the frontal cortex. The dorsolateral prefrontal circuit is associated with planning and operational functions and lesions on it may give rise to apathy, abulia, perseveration, personality changes and planning disorder. Lesions involving the orbitofrontal circuit, which is associated with response suppression and disinhibition, may involve emotional lability and memory problems. Whereas lesions affecting the right orbitofrontal circuit give rise to elevated mood, lesions on the left orbitofrontal circuit lead to depressed mood. In cases with medial frontal circuit involvement, akinetic mutism may result from lesions in the superior medial region and anteroretrograde amnesia and confabulation are observed with lesions in the inferior medial region (Tosun et al. 2016, Chirchiglia 2018). A diagnosis of psychiatric disorder may be given during the first examination of patieants with primary brain tumours, especially if localized in the frontal lobe. Thorough history taking and physical examination are necessary for early diagnosis. The case reported here concerns a 29-year-old university graduate female patient, living with her partner and children, who consulted the clinic with complaints of tendency to frequent crying, anhedonia, having difficulty with speech fluency, forgetfulness and distractedness that had presented suddenly, 2 months previously, without any causative stressor. In her mental status examination, she appeared having normal self-care with appearance at her actual age. She was fully conscious and oriented, not willing to cooperate with the interview, had distinct difficulty in maintaining attention and with fluency of speech. Her mood was depressive. She described loss of appetite, fatigue and energy loss. Her difficulty in paying attention was pronounced. She did not have a history of psychotropic medication use or family history of psychiatric disease. She did not smoke or use alcohol or substance. After evaluating the clinical interview, a preliminary diagnosis of major depressive disorder was considered on the basis of the DSM-5 criteria. Routine blood tests were requested. Given the continuation of her complaints, the difficulty with fluent speech and the increase in tendency to sleep at the first week follow up, cranial MRI was planned. The MRI results showed on the right, in the frontal lobe a multilocular mass with precallosal extension, undiscernable margins with the right lateral aspect of the corpus callosum genu and dispersed cystic-necrotic areas with T2 signal series. The dimensions of the mass were nearly 5 x 3 cm causing a 1-cm right-to-left shift of the midline (Figure 1) DEPRESSION AS THE FIRST SYMPTOM OF FRONTAL LOBE GRADE 2 MALIGNANT GLIOMA 2 Türk Psikiyatri Dergisi 2 Turkish Journal of Psychiatry Letter to the Editor 143 144 The patient was referred for surgery with the preliminary diagnosis of high-grade glial tumour. Pathology results identified a grade 2 glioma. It was learned that radiotherapy sessions were begun after surgery. The patient did not have any symptoms of psychopathology during the 2 monthly psychiatric interviews made after surgery. Brain tumours generally indicate their presence with headache, seizures and other neurological symptoms and very rarely with depression as seen in the case of our patient. It should be kept in mind that atypical psychiatric symptoms may have an underlying organic lesion and subtle neurological symptoms should be investigated in detail. A recent meta-analysis on 37 observational studies determined a 21.7% prevalence of depression in a total of 4518 patients with intracranial tumours. Comorbidity of depression with brain tumor was demonstrated to worsen the quality of life, increase suicidal risk and lower the chance of survival (Huang et al. 2017). The possibility of psychiatric symptoms being the clinical clues for brain cancer was noted and the necessity of neuroimaging tests in cases of recent-onset psychosis or mood disorder symptoms, atypical personality changes and anorexia without body dysmorphic disorder was emphasized (Madhusoodanan et al. 2015). Loss of interest, tendency to frequent weeping, introversion and anhedonia were the sole complaints in the case discussed here. The increase in psychomotor retardation and slowing down of movements at the very first weekly control follow up necessitated neuroimaging. Despite the reports in the literature on the frequent association of unpreventable excessive behavior, disinhibition and irritability with right frontal injury and lesions (Okumuş and Hocaoğlu 2018), depression was the dominant symptom in the case presented here. There are differences between primary major depression and depression presenting with underlying somatic diseases which is known to occur at later ages (Rouchell et al. 2002). However, our patient was aged 29 years. Also, cases of depression due to somatic disease are less associated with family history of depression and suicidal ideation and attempts, while cognitive symptoms come to the foreground during mental status examination. (Sertöz and Mete 2004, Rouchell et al. 2002). Our patient did not have suicidal ideation or attempts, or a family history of depression. In apathy, which may be explained as emotional blunting, indifference or detachment from the external world, targeted behavior is also reduced next to the lack of emotional expression. The individual discussed here was learned not to sit at the table or change the television channel unless reminded to do so. When the reason was asked, she could not think of one. The reduction in emotional expression accompanies reduced insight, abulia and lack of empathy (Sözeri Varma et al. 2019). In depression, apathy is defined as 'sorrowless depression'. Our patient cried but had very blunted mimics and gestures. She explained that she could not help weeping even at times when she did not feel internally distressed. The seriousness of apathy, as a symptom difficult to differentiate from depression, is still not understood. Neuroimaging Figure 1- Cranial MRI of the patient 145 Received: 16.08.2020, Accepted: 04.12.2020, Available Online Date: 05.10.2021 1MD., Antalya Kepez State Hospital, Department of Psychiatry, Antalya, 2MD., Ordu University Training and Research Hospital, Department of Psychiatry, Ordu, Turkey e-mail: bosbora@yahoo.com https://doi.org/10.5080/u25957 studies indicate apathy to be a reflect of impaired frontal-subcortical circuits and the functional disorder of the connections between the ventromedial prefrontal cortex and the basal ganglia (Chase 2011). Comparison of 45 individuals with depression due to aging and 43 healthy individuals showed apathy to be associated with fronto-limbic gray and white matter abnormalities which continued after antidepressant treatment. The structural anomalies of the posterior subgenual cingulate gyrus and the uncinate fasciculus were discussed (Yuen 2014). The case discussed here is presented to emphasize the importance of brain imaging methods and detailed investigation of atypical symptoms for diagnostic approaches to psychiatric disorders. Especially, complaints at young age of depression with psychomotor retardation, reduced fluency of speech and sudden onset withdrawal without stressors should be a warning of secondary depression. Yours sincerely... Şerif Bora Nazlı1 , Muhammet Sevindik2 REFERENCES Chase TN (2011) Apathy in Neuropsychiatric Disease: Diagnosis, Pathophysiology, and Treatment. Neurotox Res 19:266-78. Chirchiglia D (2018) Pseudodepression as an Anticipatory Symptom of Frontal Lobe Brain Tumors. Int J Depress Anxiety 1:007. Huang J, Zeng C, Xiao J et al (2017) Association between depression and brain tumor: a systematic review and meta-analysis. Oncotarget 8:94932-43. Litofsky NS, Farace E, Anderson F et al (2004) Depression in patients with high-grade glioma: Results of the glioma outcomes project. Neurosurgery 54:358-67. Madhusoodanan S, Ting MB, Farah T et al (2015) Pyschiatric aspects of brain tumors: A review. World J Psychiatry 5:273-85. Moise D, Madhusoodanan S (2006) Psychiatric symptoms associated with brain tumors: a clinical enigma. CNS Spectr 2006;11:28-31. Oğuz N, Ilnem C, Yener F (2005) Psychiatric symptoms in brain tumors: Case reports. Bulletin of Clinical Psychopharmacology 15:18-21. Hocaoğlu Ç, Okumuş B (2018) Psychiatric manifestations and brain tumor: A case report and brief review. The Medical Journal of Mustafa Kemal University 9:42-9. Oreskovic NM, Strother CG, Zibners LM (2007) An unusual case of a central nervous system tumor presenting as a chief complaint of depression. Pediatric Emergency Care 23:486-8. Rooney A, Carson A, Grant R (2011) Depression in cerebral glioma patients: a systematic review of observational studies. J Natl Cancer Inst103:61-76. Rouchell AM, Pounds R, Tierney JG (2002) Depression Textbook of Consultation-Liaison Psychiatry, 2nd Edition, Volume 1. MG Wise, JR Rundell (Ed), Washington DC American Psychiatric Publishing, Inc, p.307-38. Özen SÖ, Hayriye ME (2004) Bedensel Hastalıklarda Depresyon. Klinik Psikiyatri Ek 2:63-9. Sözeri Varma G , Bingöl C , Topak O et al (2019) Relationship of apathy with depressive symptom severity and cognitive functions in geriatric depression. Arch Neuropsychiatry 56:133-8. Yuen GS, Gunning FM, Woods E et al (2014) Neuroanatomical correlates of apathy in late-life depression and antidepressant treatment response. J Affect Disord 166:179-86. In the early 1990s, London struggled with anorexia, binge eating, and other weight issues. Standing , she was at her lightest weight and at her heaviest. In a 2007 interview with Sirens magazine, she said of the experience, \"I have been every size in my life. I've been smaller than a zero, up through a size 16. I've had lots of issues with body image and weight my whole life and it really took a great deal of work to recognize that at all those weights, no matter how I felt, I could still find a dress that made me feel sexy and powerful.\" Chloe is a 9-year-old gal whose mother made an initial visit to a new pediatrician for concerns about her behavior. Chloe is apprehensive about the visit and frequently hides behind her mother.Her parents first noticed Chloe becoming angry and more emotional 3 years ago, which her parents did not initially understand. However, over the past year, she has started to have more worries and unusual behavior.Chloe and her mother report that when she walks through doorways, she will almost always go back and walks through again. At home, she will walk through doorways multiple times and at school, she will pretend she forgot something so her friends do not notice. She often will not walk downstairs and occasionally her mother has to carry her. Clothes are problematic for Chloe. If her father touches something of a specific color and then touches Chloe, she will have to change her clothes or take a shower. Sometimes, she will never be able to wear those clothes again. She had a recent episode where she could not stop tapping a red paper, because if she stopped, she said it would burst into flame. During the 2 weeks before the pediatric visit, symptoms increased to the point that she is now refusing to go to school. When she stays home, she lays in 1 place all day.Chloe is a fourth grade student. The family does not report academic concerns. She has friends. She denies any appetite or sleep problems. She endorses periods of sadness, lack of energy, and decreased interest in social activities, mostly because she worries and is embarrassed. She kept her behaviors hidden from her 5 siblings for the past year, and she talked only to her mother about them. She is worried her friends might discover her behaviors.The family history is notable for multiple paternal family members with anxiety and bipolar disorder and depression on mother's side. A few months ago, Chloe's family adopted a 7-year-old child with special needs from China.Her growth, vital signs, and physical examination are unremarkable. Her mother filled out the Short Mood and Feelings Questionnaire and the Screen for Child Anxiety-Related Emotional Disorders, which both had elevated scores. Reece-Wilmore revealed she came up with the idea for the bulimia storyline, saying \"When I came back from my Christmas holiday, I'd lost tons of weight. Everyone commented on my new figure and I thought to myself 'If there was anything wrong with me, those sorts of comments would have made me really paranoid about my weight.'\" The actress then suggested the storyline, believing it was a subject familiar with a lot of teenage girls. The Neighbours bosses were initially \"wary\" of tackling such a difficult and sensitive storyline and a spokesperson said \"We try to tackle serious issues such as bulimia as much as possible. We may not be able to wave a magic wand and make the problems go away, but by dealing with current situations they become topics for wider discussion.\" Reece-Wilmore added that she could see how eating disorders were connected to teenagers' anxieties about approaching adulthood as she used to make herself sick to avoid going to school. Bulimia sufferer Joanna Goodfellow is staging an exhibition of photographs portraying the distorted perceptions she has of her body and the self-hatred she sometimes feels. Joanna has suffered from an eating disorder for the past five years and wants people to understand the 'frustration and anger' she feels when she looks at her bod)'. The exhibition, at the Barbican Theatre in Plymouth, runs until February 12. Nicole is a 15-year-old girl presenting to the Developmental Behavioral Pediatrics Clinic with symptoms of the inattentive type of Attention-Deficit/Hyperactivity Disorder (ADHD) and declining school performance over the last year. She expressed frustration over her inability to concentrate on schoolwork. Assuming that her poor grades were secondary to lack of effort, her parents withdrew privileges. Nicole became increasingly depressed. She stopped participating in activities, she previously enjoyed, and her parents reported that she stopped singing in the shower. After talking to a cousin with ADHD, Nicole concluded that she had ADHD as well. She asked her parents to arrange for an evaluation.Nicole met DSM-5 criteria for the diagnosis of inattentive ADHD and was started on a stimulant medication (mixed amphetamine salts). She had symptoms of a coexisting depression, although she did not meet criteria for diagnosis of a depressive disorder. At a 3-week follow-up visit, she showed improvement in targeted ADHD symptoms; homework was now easier and her grades improved. At a 2-month follow-up, Nicole's weight dropped from 53 kg (47th percentile) prestimulant treatment to 49 kg (31st percentile). She reported appetite suppression after taking the stimulant but did not feel that her eating habits had changed significantly. Her father reported that she had a preference for junk food and snacks. Nicole did not enjoy exercising and did not participate in extracurricular sports.She weighed herself several times a day, as she was worried about losing too much weight. Nicole's mood continued to be low, despite the fact that her grades improved, and her parents were more understanding of her challenges. She was otherwise healthy and reported regular menstrual cycles. Nicole requested an increase in the dose of stimulant medication for greater improvement in concentration during homework and in school.Her pediatric clinician was concerned about the possibility of an eating disorder in addition to depression. She asked herself, \"Are we treating inattentive ADHD effectively or are we enabling an eating disorder?\"\nHere is the question:\nPSYCHIATRY: A 19-year-old female university student comes to the clinic accompanied by her parents, reporting feeling progressively more asthenic in the last two months, with loss of appetite and weight and with greater difficulty in concentrating on her studies. The anamnesis also highlights that she has lost interest in going out with friends, has ideas of death without self-harming ideation and pessimistic cognitions of the future. Her weight is 90% of that considered ideal for age and gender. She does not present weight phobia or body image distortion. The most appropriate diagnosis is:\nHere are the potential choices:\n1. Anorexia nervosa.\n2. Anxiety disorder.\n3. Borderline personality disorder.\n4. Dysthymia.\n5. Major depressive disorder.\nThe correct answer is: 5. Major depressive disorder."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Patients often present with advanced chronic kidney disease (CKD) complicated with severe hypocalcemia that may be accompanied by electrocardiographic changes. The management of this kind of patients may require hemodialysis (HD). However, initiation of renal replacement therapy in this scenario needs special attention to avoid complications such as cardiac arrhythmias. A 22-year-old male presented to our emergency department with severe renal failure, hypocalcemia, hyperphosphatemia, severe acidosis, and QT prolongation on electrocardiography. The patient was kept in the emergency department under cardiac monitoring. He was started on IV calcium gluconate 1 g every 6 h aiming to increase his adjusted calcium level to 1.8 mmol/L. He subsequently received the first HD session with low blood flow, increased calcium, and decreased bicarbonate dialysate bath. There were no arrhythmias or hemodynamic instability. Intravenous calcium was discontinued; adjusted calcium improved progressively after dialysis and reached 1.9 mmol/L by the time of discharge and after receiving three sessions of HD. This case describes a not so infrequent presentation of advanced renal impairment with profound hypocalcemia, hyperphosphatemia in the setting of CKD-associated mineral bone disorder. Intravenous calcium administration may promote vascular and metastatic calcification, particularly with the coexistence of hyperphosphatemia, and hence, it is best avoided. There are no guidelines to direct initiating HD in this context. However, it appears that using a high calcium bath is prudent to minimize cardiovascular complications, particularly if there is the prolongation of the corrected QT interval on electrocardiography. Hemodialysis patients with hypercalcemia are less likely to manifest the usual electrocardiographic changes associated with hyperkalemia than in those with normal renal function. This study was conducted to determine whether electrocardiography (ECG) is a reliable indicator to detect severe life-threatening hyperkalemia in non-dialysis CKD patients. The study was conducted at three referral university hospitals between July 2017 and June 2018. Severe hyperkalemia was defined as serum potassium concentration ≥ 8.0 mEq/L. Serum potassium, sodium, bicarbonate, calcium, and creatinine concentrations were measured and simultaneous 12-lead ECG was obtained. Patients with end-stage renal disease receiving renal replacement therapy were excluded. Also excluded were patients with the usual ECG abnormalities to hyperkalemia. Of the 438 patients screened, 10 (2.3%) aged 2-14 years with severe hyperkalemia and normal ECG findings were identified. Median serum potassium level was 8.6 mEq/L (range 8.2-9.0). All had regular sinus rhythm. P, QRS, ST segment, T morphology, PR and QT interval, and QRS duration were all normal. Hyperkalemia was associated with CKD, metabolic acidosis, and hypercalcemia in all cases. Therapy with intravenous 0.9% saline, sodium bicarbonate, glucose, insulin, calcium, and salbutamol corrected the hyperkalemia in 7 patients. The remaining three patients evinced arrhythmias requiring hemodialysis. Although rare, non-dialysis CKD patients with hypercalcemia may not manifest the usual electrographic abnormalities associated with hyperkalemia. Thus, a normal ECG finding in non-dialysis CKD patients should be interpreted with caution. CKD patients present deficient elimination of potassium. Ambulatory treatment with hypotensors, mainly angiotensin-renin system inhibitors, can be associated in these patients with potassium retention and risk of hyperkalemia. In pre-dialysis stage-5 CKD patients, the use of medication accompanied by hyperkalemia increases risks of developing it. Using diuretics like spironolactone also increases this risk. Serum potassium can also increase in case of inappropriate consumption of potassium-rich food (bananas). Since ambulatory care does not always rigorously control hyperkalemia in CKD patients we consider it is useful to screen patients when they are referred to dialysis services. The screening can reflect the management of ambulatory CKD patients under treatment with ACE-I and ARB hypotensors. We remark that beta-blockers are attributed a (limited) role in increasing the values of serum K. We studied a group of 477 stage-5 CKD patients referred for dialysis to The Dialysis Centre of the Emergency County Hospital Timişoara. The average age of the patients was 57.41 +/- 14.26 years. 260 were males and 217 females. All were stage-5 CKD with GFR &lt; 15 mL/min/1.73 m2, with a group average value of eGFR of 5.72 +/- 2.81 mL/min/1.73m2. Our investigations showed hypokalemia in 14 patients (2.93%). Hyperkalemia was found in 179 patients. Of these, 124 had mild hyperkalemia (5.5-6.4 mEq/L), 45 patients had medium hyperkalemia (6.5-7.5 mEq/L) and 10 (2.09%) had severe hyperkalemia (K &gt; 7.5 mEq/L). Hyperkalemia was more frequent in patients who had been treated with blockers of the renin-angiotensin system than in patients who had used other hypotensors or who had not needed hypotensors and had not taken diuretics. Severe hyperkalemia (K &gt; 7.5 mEq/L) was present both in patients treated with blockers of the renin-angiotensin system and in those treated with other hypotensors and in 1 case without hypotensor or diuretic treatment. 2 cases treated with blockers of the renin-angiotensin-aldosterone system with severe hyperpotassemia associated antialdosteronic diuretics, cumulating hyperpotassemic effects. Diuretic treatments with loop diuretics influenced the values of serum K of most patients. Hyperkalemia represents an important problem in nephrology because of the risks it induces in the treatment ofpre-dialysis CKD patients and it requires attentive monitoring. A 62-year-old female presented to the emergency department (ED) with fatigue and generalized body weakness for the last three days. Upon arrival, initial ECG showed wide complex tachycardia with sine waves and a heart rate (HR) ranging between 100-170 bpm. She was otherwise vitally stable. The patient had a past medical history of hyperaldosteronism, type 2 diabetes mellitus (DM), chronic kidney disease (CKD) with microalbuminuria, and hypertension. She also had a history of cerebrovascular accident (CVA) and residual left-sided weakness more pronounced in the upper limb. Initial venous blood gas (VBG) analysis showed a potassium level of more than 10 mmol/L, chloride 114 mmol/L, bicarbonate 9 mmol/L, sodium 135 mmol/L, and pH of 7.1. Treatment for hyperkalemia was started immediately with calcium gluconate 1 gm that effectively narrowed her QRS complex and normalized her ECG. Salbutamol nebulization, glucose/insulin infusion, and calcium polystyrene syrup were given. Later, she was started on 100 mg sodium bicarbonate infusion, and Foley's catheter was inserted to follow urine output (UOP) strictly. However, she did not show a decrease in serum potassium levels. Then the patient underwent hemodialysis for two hours. Her first potassium reading after hemodialysis was 5.2 mmol/L. The purpose of this case report is to emphasize the importance of hemodialysis in patients with persistent severe life-threatening hyperkalemia. The foremost step in the initial clinical management of hyperkalemia is to decide whether a hyperkalemic patient requires immediate treatment to avoid a life-threatening situation (serum potassium concentration &gt;6.0 mEq/l and EKG changes). When the decision for urgent treatment of hyperkalemia is based on EKG changes, an important caveat for clinicians is that absent or atypical EKG changes do not exclude the necessity for immediate intervention. Once an urgent situation has being handled with intravenous push of a 10% calcium salt, the initiation of short-term measures can be launched by either a single or combined regimen of the three agents that cause a transcellular shift of potassium - insulin with glucose, beta(2)-agonist (albuterol), and NaHCO(3). As the first choice among these available options, we favor an intravenous bolus of 10 units of insulin with 50 ml of 50% glucose alone or in combination with 10-20 mg of albuterol by nebulizer. These can be repeated as required until the institution of hemodialysis. The combination of insulin with glucose and NaHCO(3) as an another option needs further clarification for its additive effects. However, NaHCO(3) has lost its favor because of its poor efficacy as a potassium-lowering agent when used alone. The next step is to remove potassium from the body - diuretics (furosemide), cation exchange resin (kayexelate) with sorbitol, and dialysis (preferably hemodialysis). The final important step for the managements of hyperkalemia is a long-term plan to prevent its recurrence or worsening. In addition to every effort to elucidate underlying causes and pathophysiologic mechanisms for hyperkalemia, an extensive search must be made to uncover overt or sometimes covert medications that may have led to the development of hyperkalemia. Furthermore, one must obtain detailed dietary and medical history of hyperkalemic patients. Hyponatremia is the most common form of electrolyte disorder in the emergency room. The symptoms are unspecific and include nausea, dizziness and often falls. Typical symptoms of severe hypernatremia are vomiting, cerebral seizures, somnolence and even coma. The specific initial laboratory diagnostics include measurement of serum electrolytes, serum glucose, serum and urine osmolarity and sodium in urine. The main aim of the clinical examination is to estimate the volume status. If a patient has hypovolemia an infusion of isotonic sodium chloride solution (0.9 %) is the method of choice. If the patient is euvolemic the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or (neurotropic) drugs might be the cause. In these cases the primary measure is restriction of fluid intake. As a rapid correction of sodium levels can lead to pontine myelinolysis, the increase in sodium concentration must not be less than 10 mmol/l within the first 24 h and 18 mmol/l within the first 48 h. Clinical symptoms of hyperkalemia include neurological (e.g. muscle weakness, paresis, hyperreflexia, cramps and dysesthesia), gastrointestinal (e.g. nausea, vomiting and diarrhea) and cardiac symptoms (e.g. dysrhythmia and conductance disorders). Calcium injection stabilizes cardiac rhythm disorders immediately. For a rapid drop in potassium by shifting the potassium to the intracellular space, administration of glucose with insulin and high-dose inhalative administration of betamimetics can be used. Potassium elimination is achieved by infusion of isotonic sodium choride (0.9 %) with i.v. administration of furosemide, ion exchange resins and hemodialysis. Several electrolyte abnormalities may be present. Hypocalcemia should only be treated if the patient is symptomatic since the patient may later develop hypercalcemia. Start with 10 mL of intravenous calcium gluconate 10% or 5 mL of intravenous calcium chloride 10% over 2 minutes.  Hyperkalemia should be monitored and treated based on the potassium level and electrocardiographic changes.   The ECG may not change in some situations where the potassium level is dangerously elevated.  If there are severe or life-threatening electrocardiographic changes or arrhythmias such as the widening of the QRS to third-degree heart block or pulseless electrical activity, the intravenous calcium gluconate or chloride should be given immediately. It may be necessary to give several doses every 10 minutes to achieve the cardioprotective effects of calcium. If the patient is acidotic then sodium bicarbonate 1 meq/kg should be given immediately IV over several minutes.  To drive the potassium into the cells, 10 units of intravenous insulin, together with 1 to 2 ampules of D50, should be given.   The Beta agonist effect of albuterol inhalation treatments can also help transiently decrease potassium levels.  Kaexylate with sorbitol can be given orally at 25 to 50 gm, or it may be given as a retention enema.  Patients with life-threatening hyperkalemia need the potassium removed from their system.  The medications and treatments are temporizing measures to provide time for excretion of removal of potassium from the body.  The patient may require emergent dialysis.  Critiques of recent disaster responses were that there was an insufficient number of dialysis machines to treat those with renal failure secondary to crush injuries.  Blood products should be given as necessary and when indicated. A common presentation of hyperkalemia is in the patient with end-stage renal disease who has missed a dialysis appointment and presents with weakness, nausea, and broad QRS complexes on the electrocardiogram. (Note however that patients with chronic kidney disease are often more tolerant of high potassium levels as their body often adapts to it.) Several medications, for example the antibiotic trimethoprim/sulfamethoxazole or an ACE inhibitor, can also lead to the development of significant hyperkalemia. The electrocardiogram will show tall, peaked T waves (often larger than the R wave) or can degenerate into a sine wave as the QRS complex widens. Immediate initial therapy is the administration of calcium, either as calcium gluconate or calcium chloride. This stabilizes the electrochemical potential of cardiac myocytes, thereby preventing the development of fatal arrhythmias. This is, however, only a temporizing measure. Other temporizing measures may include nebulized salbutamol, Intravenous hydration of up to 1.5 L/h should continue to prevent hypotension. A urinary output of at least 300 mL/h should be maintained with IV fluids and mannitol, and hemodialysis considered if an increase in urine is not achieved. Use intravenous sodium bicarbonate to keep the urine pH at 6.5 or greater, to prevent myoglobin and uric acid deposition in kidneys. To prevent hyperkalemia/hypocalcemia, consider the following adult doses: calcium gluconate 10% 10 mL or calcium chloride 10% 5 mL IV over 2 minutes sodium bicarbonate 1 meq/kg IV slow push regular insulin 5–10 U 50% glucose 1–2 ampules IV bolus kayexalate 25–50 g with sorbitol 20% 100 mL by mouth or rectum. Even so, abnormal heart rhythms may develop; electrocardiographic monitoring is advised, and specific treatment begun promptly. References External links Life or Limb: What happens when your leg gets trapped under a building? Injuries Early complications of trauma Nephrology Syndromes Initial treatment in those with ECG changes is salts, such as calcium gluconate or calcium chloride. Other medications used to rapidly reduce blood potassium levels include insulin with dextrose, salbutamol, and sodium bicarbonate. Medications that might worsen the condition should be stopped and a low potassium diet should be started. Measures to remove potassium from the body include diuretics such as furosemide, potassium-binders such as polystyrene sulfonate and sodium zirconium cyclosilicate, and hemodialysis. Hemodialysis is the most effective method. Hyperkalemia is rare among those who are otherwise healthy. Among those who are hospitalized, rates are between 1% and 2.5%. It is associated with an increased mortality, whether due to hyperkalaemia itself or as a marker of severe illness, especially in those without chronic kidney disease. The word hyperkalemia comes from hyper- 'high' + kalium 'potassium' + -emia 'blood condition'. Hyperkalemia is common in patients with end-stage renal disease, and may result in serious electrocardiographic abnormalities. Dialysis is the definitive treatment of hyperkalemia in these patients. Intravenous calcium is used to stabilize the myocardium. Intravenous insulin and nebulized albuterol lower serum potassium acutely, by shifting it into the cells. Despite their widespread use, neither intravenous bicarbonate nor cation exchange resins are effective in lowering serum potassium acutely. Prevention of hyperkalemia currently rests largely upon dietary compliance and avoidance of medications that may promote hyperkalemia. Prolonged fasting may provoke hyperkalemia, which can be prevented by administration of intravenous dextrose. Intravenous bicarbonate has no role in the acute treatment of hyperkalemia, but may slowly attenuate hyperkalemia with sustained administration over several hours. It should not be given repeatedly as a hypertonic intravenous bolus of undiluted ampules, given the risk of associated hypernatremia, but should instead be infused in an isotonic or hypotonic fluid (e.g., 150 mEqu in 1 L of D5W). In patients with metabolic acidosis, a delayed drop in plasma K+ concentration can be seen after 4–6 h of isotonic bicarbonate infusion. 3. Removal of potassium. This is typically accomplished using cation exchange resins, diuretics, and/or dialysis. The cation exchange resin sodium polystyrene sulfonate (SPS) exchanges Na+ for K+ in the gastrointestinal tract and increases the fecal excretion of K+; alternative calcium-based resins, when available, may Hyperkalemia is common in patients with ESRD, undergoing hemodialysis (HD), and is associated with an increase in hospitalization and mortality. Residual kidney function in long-term dialysis patients is associated with lower morbidity and mortality in HD patients. Although the 2015 National Kidney Foundation-Kidney Disease Outcomes Quality Initiate (NKD-KDOQI) guidelines allow the reduction in the weekly HD dose for patients with a residual kidney urea clearance (Kur) &gt;3 mL/min/1.73 m<sup2</sup, very few centers adjust the dialysis dose based on these criteria. In our center, the pattern of incremental hemodialysis (iHD) with once-a-week schedule (1 HD/W) has been an option for a group of patients showing very good results. This pattern is maintained as long as residual diuresis is &gt;1,000 mL/24 h, Kur is &gt;4 mL/min, and there is no presence of edema or volume overload, as well as no analytical parameters persistently outside the advisable range (serum phosphorus &gt;6 mg/dL or potassium [K<sup+</sup] &gt;6.5 mmol/L). Management of hyperkalemia in HD patients includes reduction of dietary intake, dosing of medications that contribute to hyperkalemia, and use of cation-exchange resins such as calcium or sodium polystyrene sulfonate. Two newer potassium binders, patiromer sorbitex calcium and sodium zirconium cyclosilicate, have been safely used for potassium imbalance treatment in patients with ESRD in HD with a conventional regimen of thrice weekly, but has not yet been studied in 1 HD/W schedules. We present the case of a 76-year-old woman in iHD (1 HD/W) treated with patiromer for severe HK and describe her clinical characteristics and outcomes. In addition, we review the corresponding literature. Based on these data, it can be anticipated that the use of patiromer may overcome the risk of hyperkalemia in patients with incident ESRD treated with less-frequent HD regimens. 1. The kidneys are the key organs to maintain the balance of the different electrolytes in the body and the acid-base balance. Progressive loss of kidney function results in a number of adaptive and compensatory renal and extrarenal changes that allow homeostasis to be maintained with glomerular filtration rates in the range of 10-25 ml/min. With glomerular filtration rates below 10 ml/min, there are almost always abnormalites in the body's internal environment with clinical repercussions. 2. Water Balance Disorders: In advanced chronic kidney disease (CKD), the range of urine osmolality progressively approaches plasma osmolality and becomes isostenuric. This manifests clinically as symptoms of nocturia and polyuria, especially in tubulointerstitial kidney diseases. Water overload will result in hyponatremia and a decrease in water intake will lead to hypernatremia. Routine analyses of serum Na levels should be performed in all patients with advanced CKD (Strength of Recommendation C). Except in edematous states, a daily fluid intake of 1.5-2 liters should be recommended (Strength of Recommendation C). Hyponatremia does not usually occur with glomerular filtration rates above 10 ml/min (Strength of Recommendation B). If it occurs, an excessive intake of free water should be considered or nonosmotic release of vasopressin by stimuli such as pain, anesthetics, hypoxemia or hypovolemia, or the use of diuretics. Hypernatremia is less frequent than hyponatremia in CKD. It can occur because of the provision of hypertonic parenteral solutions, or more frequently as a consequence of osmotic diuresis due to inadequate water intake during intercurrent disease, or in some circumstance that limits access to water (obtundation, immobility). 3. Sodium Balance Disorders: In CKD, fractional excretion of sodium increases so that absolute sodium excretion is not modified until glomerular filtration rates below 15 ml/min (Strength of Recommendation B). Total body content of sodium is the main determinant of extracellular volume and therefore disturbances in sodium balance will lead to clinical situations of volume depletion or overload: Volume depletion due to renal sodium loss occurs in abrupt restrictions of salt intake in advanced CKD. It occurs more frequently in certain tubulointerstitial kidney diseases (salt losing nephropathies). Volume overload due to sodium retention can occur with glomerular filtration rates below 25 ml/min and leads to edema, arterial hypertension and heart failure. The use of diuretics in volume overload in CKD is useful to force natriuresis (Strength of Recommendation B). Thiazides have little effect in advanced CKD. Loop diuretics are effective and should be used in higher than normal doses (Strength of Recommendation B). The combination of thiazides and loop diuretics can be useful in refractory cases (Strength of Recommendation B). Weight and volume should be monitored regularly in the hospitalized patient with CKD (Strength of Recommendation C). 4. Potassium Balance Disorders: In CKD, the ability of the kidneys to excrete potassium decreases proportionally to the loss of glomerular filtration. Stimulation of aldosterone and the increase in intestinal excretion of potassium are the main adaptive mechanisms to maintain potassium homeostasis until glomerular filtration rates of 10 ml/min. The main causes of hyperkalemia in CKD are the following: Use of drugs that alter the ability of the kidneys to excrete potassium: ACEIs, ARBs, NSAIDs, aldosterone antagonists, nonselective beta-blockers, heparin, trimetoprim, calcineurin inhibitors. Determination of serum potassium two weeks after the initiation of treatment with ACEIs/ARBs is recommended (Strength of Recommendation C). Routine use of aldosterone antagonists in advanced CKD is not recommended (Strength of Recommendation C). Abrupt reduction in glomerular filtration rate: Constipation. Prolonged fasting. Metabolic acidosis. A low-potassium diet is recommended with GFR less than 20 ml/min, or GFR less than 50 ml/min if drugs that raise serum potassium are taken (Strength of Recommendation C). In the absence of symptoms or electrocardiographic abnormalities, review of medications, restriction of dietary potassium and use of oral ion exchange resins are usually sufficient therapeutic measures (Strength of Recommendation C). If symptoms and/or electrocardiographic abnormalities are present, the usual parenteral pharmacological measures should be used (10% calcium gluconate, insulin and glucose, salbutamol, resins, diuretics) (Strength of Recommendation A). Parenteral bicarbonate and ion exchange resins in enemas are not recommended as first-line treatment (Strength of Recommendation C). Hemodialysis should be considered in patients with glomerular filtration rates below 10 ml/min (Strength of Recommendation C). 5. Acid-Base Disorders in CKD: Moderate metabolic acidosis (Bic 16-20) mEq/L is common with glomerular filtration rates below 20 ml/min, and favors bone demineralization due to the release of calcium and phosphate from the bone, chronic hyperventilation, and muscular weakness and atrophy. Its treatment consists of administration of sodium bicarbonate, usually orally (0.5-1 mEq/kg/day), with the goal of achieving a serum bicarbonate level of 22-24 mmol/L (Strength of Recommendation C). Limitation of daily protein intake to less than 1 g/kg/day is also useful (Strength of Recommendation C). Use of sevelamer as a phosphate binder aggravates metabolic acidosis since it favors endogenous acid production and therefore acidosis should be monitored and corrected if it occurs (Strength of Recommendation C). Hypocalcemia should always be corrected before metabolic acidosis in CKD (Strength of Recommendation B). Metabolic acidosis is an infrequent disorder and requires exogenous alkali administration (bicarbonate, phosphate binders) or vomiting. The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g., proteinuria): 0) Normal kidney function – GFR above 90 (mL/min)/(1.73 m2) and no proteinuria 1) CKD1 – GFR above 90 (mL/min)/(1.73 m2) with evidence of kidney damage 2) CKD2 (mild) – GFR of 60 to 89 (mL/min)/(1.73 m2) with evidence of kidney damage 3) CKD3 (moderate) – GFR of 30 to 59 (mL/min)/(1.73 m2) 4) CKD4 (severe) – GFR of 15 to 29 (mL/min)/(1.73 m2) 5) CKD5 kidney failure – GFR less than 15 (mL/min)/(1.73 m2) Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis. Note: others add a \"T\" to patients who have had a transplant regardless of stage. The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g., proteinuria): 0) Normal kidney function – GFR above 90 mL/min/1.73 m2 and no proteinuria 1) CKD1 – GFR above 90 mL/min/1.73 m2 with evidence of kidney damage 2) CKD2 (mild) – GFR of 60 to 89 mL/min/1.73 m2 with evidence of kidney damage 3) CKD3 (moderate) – GFR of 30 to 59 mL/min/1.73 m2 4) CKD4 (severe) – GFR of 15 to 29 mL/min/1.73 m2 5) CKD5 kidney failure – GFR less than 15 mL/min/1.73 m2 Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis. Note: others add a \"T\" to patients who have had a transplant regardless of stage. Eight patients with life threatening hyperkalemia were treated in the intensive care unit over a period of 2 years. Serum potassium at admission was 7.1-11.2. Two patients had to be resuscitated and 3 exhibited quadriplegia or paralyses but were alert. Seven showed marked ECG change: in 5 the QRS-complexes were extremely broadened and in one case an AV-rhythm was observed; the atrial wave was absent in all 7 patients. Renal failure was present in 7 of 8 patients. In 6 of these 8 cases drugs were also involved in the development of hyperkalemia. The following therapeutic procedure is recommended for hyperkalemia: (1) injection of calcium, (2) inhalation or injection of beta 2-mimetics (well documented in the literature; clinical experience limited), (3) insulin and glucose i.v., (4) sodium bicarbonate, but only in case of metabolic acidosis, (5) hemodialysis, (6) cation exchange resins or furosemide in non-acute situations.\nHere is the question:\nNEPHROLOGY: In a patient with known advanced chronic kidney disease (CKD G4, eGFR 20 ml/min) who comes to the emergency department for general weakness and is found to have severe hyperkalemia (K 7 mEq/l) with electrocardiographic abnormalities. What would be the first measure to take?\nHere are the potential choices:\n1. Administration of cation exchange resins.\n2. Placement of a catheter to initiate dialysis.\n3. Administration of intravenous calcium gluconate.\n4. Administration of oral furosemide.\nThe correct answer is: ",
        "gold_answer": "3 Administration of intravenous calcium gluconate.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Patients often present with advanced chronic kidney disease (CKD) complicated with severe hypocalcemia that may be accompanied by electrocardiographic changes. The management of this kind of patients may require hemodialysis (HD). However, initiation of renal replacement therapy in this scenario needs special attention to avoid complications such as cardiac arrhythmias. A 22-year-old male presented to our emergency department with severe renal failure, hypocalcemia, hyperphosphatemia, severe acidosis, and QT prolongation on electrocardiography. The patient was kept in the emergency department under cardiac monitoring. He was started on IV calcium gluconate 1 g every 6 h aiming to increase his adjusted calcium level to 1.8 mmol/L. He subsequently received the first HD session with low blood flow, increased calcium, and decreased bicarbonate dialysate bath. There were no arrhythmias or hemodynamic instability. Intravenous calcium was discontinued; adjusted calcium improved progressively after dialysis and reached 1.9 mmol/L by the time of discharge and after receiving three sessions of HD. This case describes a not so infrequent presentation of advanced renal impairment with profound hypocalcemia, hyperphosphatemia in the setting of CKD-associated mineral bone disorder. Intravenous calcium administration may promote vascular and metastatic calcification, particularly with the coexistence of hyperphosphatemia, and hence, it is best avoided. There are no guidelines to direct initiating HD in this context. However, it appears that using a high calcium bath is prudent to minimize cardiovascular complications, particularly if there is the prolongation of the corrected QT interval on electrocardiography. Hemodialysis patients with hypercalcemia are less likely to manifest the usual electrocardiographic changes associated with hyperkalemia than in those with normal renal function. This study was conducted to determine whether electrocardiography (ECG) is a reliable indicator to detect severe life-threatening hyperkalemia in non-dialysis CKD patients. The study was conducted at three referral university hospitals between July 2017 and June 2018. Severe hyperkalemia was defined as serum potassium concentration ≥ 8.0 mEq/L. Serum potassium, sodium, bicarbonate, calcium, and creatinine concentrations were measured and simultaneous 12-lead ECG was obtained. Patients with end-stage renal disease receiving renal replacement therapy were excluded. Also excluded were patients with the usual ECG abnormalities to hyperkalemia. Of the 438 patients screened, 10 (2.3%) aged 2-14 years with severe hyperkalemia and normal ECG findings were identified. Median serum potassium level was 8.6 mEq/L (range 8.2-9.0). All had regular sinus rhythm. P, QRS, ST segment, T morphology, PR and QT interval, and QRS duration were all normal. Hyperkalemia was associated with CKD, metabolic acidosis, and hypercalcemia in all cases. Therapy with intravenous 0.9% saline, sodium bicarbonate, glucose, insulin, calcium, and salbutamol corrected the hyperkalemia in 7 patients. The remaining three patients evinced arrhythmias requiring hemodialysis. Although rare, non-dialysis CKD patients with hypercalcemia may not manifest the usual electrographic abnormalities associated with hyperkalemia. Thus, a normal ECG finding in non-dialysis CKD patients should be interpreted with caution. CKD patients present deficient elimination of potassium. Ambulatory treatment with hypotensors, mainly angiotensin-renin system inhibitors, can be associated in these patients with potassium retention and risk of hyperkalemia. In pre-dialysis stage-5 CKD patients, the use of medication accompanied by hyperkalemia increases risks of developing it. Using diuretics like spironolactone also increases this risk. Serum potassium can also increase in case of inappropriate consumption of potassium-rich food (bananas). Since ambulatory care does not always rigorously control hyperkalemia in CKD patients we consider it is useful to screen patients when they are referred to dialysis services. The screening can reflect the management of ambulatory CKD patients under treatment with ACE-I and ARB hypotensors. We remark that beta-blockers are attributed a (limited) role in increasing the values of serum K. We studied a group of 477 stage-5 CKD patients referred for dialysis to The Dialysis Centre of the Emergency County Hospital Timişoara. The average age of the patients was 57.41 +/- 14.26 years. 260 were males and 217 females. All were stage-5 CKD with GFR &lt; 15 mL/min/1.73 m2, with a group average value of eGFR of 5.72 +/- 2.81 mL/min/1.73m2. Our investigations showed hypokalemia in 14 patients (2.93%). Hyperkalemia was found in 179 patients. Of these, 124 had mild hyperkalemia (5.5-6.4 mEq/L), 45 patients had medium hyperkalemia (6.5-7.5 mEq/L) and 10 (2.09%) had severe hyperkalemia (K &gt; 7.5 mEq/L). Hyperkalemia was more frequent in patients who had been treated with blockers of the renin-angiotensin system than in patients who had used other hypotensors or who had not needed hypotensors and had not taken diuretics. Severe hyperkalemia (K &gt; 7.5 mEq/L) was present both in patients treated with blockers of the renin-angiotensin system and in those treated with other hypotensors and in 1 case without hypotensor or diuretic treatment. 2 cases treated with blockers of the renin-angiotensin-aldosterone system with severe hyperpotassemia associated antialdosteronic diuretics, cumulating hyperpotassemic effects. Diuretic treatments with loop diuretics influenced the values of serum K of most patients. Hyperkalemia represents an important problem in nephrology because of the risks it induces in the treatment ofpre-dialysis CKD patients and it requires attentive monitoring. A 62-year-old female presented to the emergency department (ED) with fatigue and generalized body weakness for the last three days. Upon arrival, initial ECG showed wide complex tachycardia with sine waves and a heart rate (HR) ranging between 100-170 bpm. She was otherwise vitally stable. The patient had a past medical history of hyperaldosteronism, type 2 diabetes mellitus (DM), chronic kidney disease (CKD) with microalbuminuria, and hypertension. She also had a history of cerebrovascular accident (CVA) and residual left-sided weakness more pronounced in the upper limb. Initial venous blood gas (VBG) analysis showed a potassium level of more than 10 mmol/L, chloride 114 mmol/L, bicarbonate 9 mmol/L, sodium 135 mmol/L, and pH of 7.1. Treatment for hyperkalemia was started immediately with calcium gluconate 1 gm that effectively narrowed her QRS complex and normalized her ECG. Salbutamol nebulization, glucose/insulin infusion, and calcium polystyrene syrup were given. Later, she was started on 100 mg sodium bicarbonate infusion, and Foley's catheter was inserted to follow urine output (UOP) strictly. However, she did not show a decrease in serum potassium levels. Then the patient underwent hemodialysis for two hours. Her first potassium reading after hemodialysis was 5.2 mmol/L. The purpose of this case report is to emphasize the importance of hemodialysis in patients with persistent severe life-threatening hyperkalemia. The foremost step in the initial clinical management of hyperkalemia is to decide whether a hyperkalemic patient requires immediate treatment to avoid a life-threatening situation (serum potassium concentration &gt;6.0 mEq/l and EKG changes). When the decision for urgent treatment of hyperkalemia is based on EKG changes, an important caveat for clinicians is that absent or atypical EKG changes do not exclude the necessity for immediate intervention. Once an urgent situation has being handled with intravenous push of a 10% calcium salt, the initiation of short-term measures can be launched by either a single or combined regimen of the three agents that cause a transcellular shift of potassium - insulin with glucose, beta(2)-agonist (albuterol), and NaHCO(3). As the first choice among these available options, we favor an intravenous bolus of 10 units of insulin with 50 ml of 50% glucose alone or in combination with 10-20 mg of albuterol by nebulizer. These can be repeated as required until the institution of hemodialysis. The combination of insulin with glucose and NaHCO(3) as an another option needs further clarification for its additive effects. However, NaHCO(3) has lost its favor because of its poor efficacy as a potassium-lowering agent when used alone. The next step is to remove potassium from the body - diuretics (furosemide), cation exchange resin (kayexelate) with sorbitol, and dialysis (preferably hemodialysis). The final important step for the managements of hyperkalemia is a long-term plan to prevent its recurrence or worsening. In addition to every effort to elucidate underlying causes and pathophysiologic mechanisms for hyperkalemia, an extensive search must be made to uncover overt or sometimes covert medications that may have led to the development of hyperkalemia. Furthermore, one must obtain detailed dietary and medical history of hyperkalemic patients. Hyponatremia is the most common form of electrolyte disorder in the emergency room. The symptoms are unspecific and include nausea, dizziness and often falls. Typical symptoms of severe hypernatremia are vomiting, cerebral seizures, somnolence and even coma. The specific initial laboratory diagnostics include measurement of serum electrolytes, serum glucose, serum and urine osmolarity and sodium in urine. The main aim of the clinical examination is to estimate the volume status. If a patient has hypovolemia an infusion of isotonic sodium chloride solution (0.9 %) is the method of choice. If the patient is euvolemic the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or (neurotropic) drugs might be the cause. In these cases the primary measure is restriction of fluid intake. As a rapid correction of sodium levels can lead to pontine myelinolysis, the increase in sodium concentration must not be less than 10 mmol/l within the first 24 h and 18 mmol/l within the first 48 h. Clinical symptoms of hyperkalemia include neurological (e.g. muscle weakness, paresis, hyperreflexia, cramps and dysesthesia), gastrointestinal (e.g. nausea, vomiting and diarrhea) and cardiac symptoms (e.g. dysrhythmia and conductance disorders). Calcium injection stabilizes cardiac rhythm disorders immediately. For a rapid drop in potassium by shifting the potassium to the intracellular space, administration of glucose with insulin and high-dose inhalative administration of betamimetics can be used. Potassium elimination is achieved by infusion of isotonic sodium choride (0.9 %) with i.v. administration of furosemide, ion exchange resins and hemodialysis. Several electrolyte abnormalities may be present. Hypocalcemia should only be treated if the patient is symptomatic since the patient may later develop hypercalcemia. Start with 10 mL of intravenous calcium gluconate 10% or 5 mL of intravenous calcium chloride 10% over 2 minutes.  Hyperkalemia should be monitored and treated based on the potassium level and electrocardiographic changes.   The ECG may not change in some situations where the potassium level is dangerously elevated.  If there are severe or life-threatening electrocardiographic changes or arrhythmias such as the widening of the QRS to third-degree heart block or pulseless electrical activity, the intravenous calcium gluconate or chloride should be given immediately. It may be necessary to give several doses every 10 minutes to achieve the cardioprotective effects of calcium. If the patient is acidotic then sodium bicarbonate 1 meq/kg should be given immediately IV over several minutes.  To drive the potassium into the cells, 10 units of intravenous insulin, together with 1 to 2 ampules of D50, should be given.   The Beta agonist effect of albuterol inhalation treatments can also help transiently decrease potassium levels.  Kaexylate with sorbitol can be given orally at 25 to 50 gm, or it may be given as a retention enema.  Patients with life-threatening hyperkalemia need the potassium removed from their system.  The medications and treatments are temporizing measures to provide time for excretion of removal of potassium from the body.  The patient may require emergent dialysis.  Critiques of recent disaster responses were that there was an insufficient number of dialysis machines to treat those with renal failure secondary to crush injuries.  Blood products should be given as necessary and when indicated. A common presentation of hyperkalemia is in the patient with end-stage renal disease who has missed a dialysis appointment and presents with weakness, nausea, and broad QRS complexes on the electrocardiogram. (Note however that patients with chronic kidney disease are often more tolerant of high potassium levels as their body often adapts to it.) Several medications, for example the antibiotic trimethoprim/sulfamethoxazole or an ACE inhibitor, can also lead to the development of significant hyperkalemia. The electrocardiogram will show tall, peaked T waves (often larger than the R wave) or can degenerate into a sine wave as the QRS complex widens. Immediate initial therapy is the administration of calcium, either as calcium gluconate or calcium chloride. This stabilizes the electrochemical potential of cardiac myocytes, thereby preventing the development of fatal arrhythmias. This is, however, only a temporizing measure. Other temporizing measures may include nebulized salbutamol, Intravenous hydration of up to 1.5 L/h should continue to prevent hypotension. A urinary output of at least 300 mL/h should be maintained with IV fluids and mannitol, and hemodialysis considered if an increase in urine is not achieved. Use intravenous sodium bicarbonate to keep the urine pH at 6.5 or greater, to prevent myoglobin and uric acid deposition in kidneys. To prevent hyperkalemia/hypocalcemia, consider the following adult doses: calcium gluconate 10% 10 mL or calcium chloride 10% 5 mL IV over 2 minutes sodium bicarbonate 1 meq/kg IV slow push regular insulin 5–10 U 50% glucose 1–2 ampules IV bolus kayexalate 25–50 g with sorbitol 20% 100 mL by mouth or rectum. Even so, abnormal heart rhythms may develop; electrocardiographic monitoring is advised, and specific treatment begun promptly. References External links Life or Limb: What happens when your leg gets trapped under a building? Injuries Early complications of trauma Nephrology Syndromes Initial treatment in those with ECG changes is salts, such as calcium gluconate or calcium chloride. Other medications used to rapidly reduce blood potassium levels include insulin with dextrose, salbutamol, and sodium bicarbonate. Medications that might worsen the condition should be stopped and a low potassium diet should be started. Measures to remove potassium from the body include diuretics such as furosemide, potassium-binders such as polystyrene sulfonate and sodium zirconium cyclosilicate, and hemodialysis. Hemodialysis is the most effective method. Hyperkalemia is rare among those who are otherwise healthy. Among those who are hospitalized, rates are between 1% and 2.5%. It is associated with an increased mortality, whether due to hyperkalaemia itself or as a marker of severe illness, especially in those without chronic kidney disease. The word hyperkalemia comes from hyper- 'high' + kalium 'potassium' + -emia 'blood condition'. Hyperkalemia is common in patients with end-stage renal disease, and may result in serious electrocardiographic abnormalities. Dialysis is the definitive treatment of hyperkalemia in these patients. Intravenous calcium is used to stabilize the myocardium. Intravenous insulin and nebulized albuterol lower serum potassium acutely, by shifting it into the cells. Despite their widespread use, neither intravenous bicarbonate nor cation exchange resins are effective in lowering serum potassium acutely. Prevention of hyperkalemia currently rests largely upon dietary compliance and avoidance of medications that may promote hyperkalemia. Prolonged fasting may provoke hyperkalemia, which can be prevented by administration of intravenous dextrose. Intravenous bicarbonate has no role in the acute treatment of hyperkalemia, but may slowly attenuate hyperkalemia with sustained administration over several hours. It should not be given repeatedly as a hypertonic intravenous bolus of undiluted ampules, given the risk of associated hypernatremia, but should instead be infused in an isotonic or hypotonic fluid (e.g., 150 mEqu in 1 L of D5W). In patients with metabolic acidosis, a delayed drop in plasma K+ concentration can be seen after 4–6 h of isotonic bicarbonate infusion. 3. Removal of potassium. This is typically accomplished using cation exchange resins, diuretics, and/or dialysis. The cation exchange resin sodium polystyrene sulfonate (SPS) exchanges Na+ for K+ in the gastrointestinal tract and increases the fecal excretion of K+; alternative calcium-based resins, when available, may Hyperkalemia is common in patients with ESRD, undergoing hemodialysis (HD), and is associated with an increase in hospitalization and mortality. Residual kidney function in long-term dialysis patients is associated with lower morbidity and mortality in HD patients. Although the 2015 National Kidney Foundation-Kidney Disease Outcomes Quality Initiate (NKD-KDOQI) guidelines allow the reduction in the weekly HD dose for patients with a residual kidney urea clearance (Kur) &gt;3 mL/min/1.73 m<sup2</sup, very few centers adjust the dialysis dose based on these criteria. In our center, the pattern of incremental hemodialysis (iHD) with once-a-week schedule (1 HD/W) has been an option for a group of patients showing very good results. This pattern is maintained as long as residual diuresis is &gt;1,000 mL/24 h, Kur is &gt;4 mL/min, and there is no presence of edema or volume overload, as well as no analytical parameters persistently outside the advisable range (serum phosphorus &gt;6 mg/dL or potassium [K<sup+</sup] &gt;6.5 mmol/L). Management of hyperkalemia in HD patients includes reduction of dietary intake, dosing of medications that contribute to hyperkalemia, and use of cation-exchange resins such as calcium or sodium polystyrene sulfonate. Two newer potassium binders, patiromer sorbitex calcium and sodium zirconium cyclosilicate, have been safely used for potassium imbalance treatment in patients with ESRD in HD with a conventional regimen of thrice weekly, but has not yet been studied in 1 HD/W schedules. We present the case of a 76-year-old woman in iHD (1 HD/W) treated with patiromer for severe HK and describe her clinical characteristics and outcomes. In addition, we review the corresponding literature. Based on these data, it can be anticipated that the use of patiromer may overcome the risk of hyperkalemia in patients with incident ESRD treated with less-frequent HD regimens. 1. The kidneys are the key organs to maintain the balance of the different electrolytes in the body and the acid-base balance. Progressive loss of kidney function results in a number of adaptive and compensatory renal and extrarenal changes that allow homeostasis to be maintained with glomerular filtration rates in the range of 10-25 ml/min. With glomerular filtration rates below 10 ml/min, there are almost always abnormalites in the body's internal environment with clinical repercussions. 2. Water Balance Disorders: In advanced chronic kidney disease (CKD), the range of urine osmolality progressively approaches plasma osmolality and becomes isostenuric. This manifests clinically as symptoms of nocturia and polyuria, especially in tubulointerstitial kidney diseases. Water overload will result in hyponatremia and a decrease in water intake will lead to hypernatremia. Routine analyses of serum Na levels should be performed in all patients with advanced CKD (Strength of Recommendation C). Except in edematous states, a daily fluid intake of 1.5-2 liters should be recommended (Strength of Recommendation C). Hyponatremia does not usually occur with glomerular filtration rates above 10 ml/min (Strength of Recommendation B). If it occurs, an excessive intake of free water should be considered or nonosmotic release of vasopressin by stimuli such as pain, anesthetics, hypoxemia or hypovolemia, or the use of diuretics. Hypernatremia is less frequent than hyponatremia in CKD. It can occur because of the provision of hypertonic parenteral solutions, or more frequently as a consequence of osmotic diuresis due to inadequate water intake during intercurrent disease, or in some circumstance that limits access to water (obtundation, immobility). 3. Sodium Balance Disorders: In CKD, fractional excretion of sodium increases so that absolute sodium excretion is not modified until glomerular filtration rates below 15 ml/min (Strength of Recommendation B). Total body content of sodium is the main determinant of extracellular volume and therefore disturbances in sodium balance will lead to clinical situations of volume depletion or overload: Volume depletion due to renal sodium loss occurs in abrupt restrictions of salt intake in advanced CKD. It occurs more frequently in certain tubulointerstitial kidney diseases (salt losing nephropathies). Volume overload due to sodium retention can occur with glomerular filtration rates below 25 ml/min and leads to edema, arterial hypertension and heart failure. The use of diuretics in volume overload in CKD is useful to force natriuresis (Strength of Recommendation B). Thiazides have little effect in advanced CKD. Loop diuretics are effective and should be used in higher than normal doses (Strength of Recommendation B). The combination of thiazides and loop diuretics can be useful in refractory cases (Strength of Recommendation B). Weight and volume should be monitored regularly in the hospitalized patient with CKD (Strength of Recommendation C). 4. Potassium Balance Disorders: In CKD, the ability of the kidneys to excrete potassium decreases proportionally to the loss of glomerular filtration. Stimulation of aldosterone and the increase in intestinal excretion of potassium are the main adaptive mechanisms to maintain potassium homeostasis until glomerular filtration rates of 10 ml/min. The main causes of hyperkalemia in CKD are the following: Use of drugs that alter the ability of the kidneys to excrete potassium: ACEIs, ARBs, NSAIDs, aldosterone antagonists, nonselective beta-blockers, heparin, trimetoprim, calcineurin inhibitors. Determination of serum potassium two weeks after the initiation of treatment with ACEIs/ARBs is recommended (Strength of Recommendation C). Routine use of aldosterone antagonists in advanced CKD is not recommended (Strength of Recommendation C). Abrupt reduction in glomerular filtration rate: Constipation. Prolonged fasting. Metabolic acidosis. A low-potassium diet is recommended with GFR less than 20 ml/min, or GFR less than 50 ml/min if drugs that raise serum potassium are taken (Strength of Recommendation C). In the absence of symptoms or electrocardiographic abnormalities, review of medications, restriction of dietary potassium and use of oral ion exchange resins are usually sufficient therapeutic measures (Strength of Recommendation C). If symptoms and/or electrocardiographic abnormalities are present, the usual parenteral pharmacological measures should be used (10% calcium gluconate, insulin and glucose, salbutamol, resins, diuretics) (Strength of Recommendation A). Parenteral bicarbonate and ion exchange resins in enemas are not recommended as first-line treatment (Strength of Recommendation C). Hemodialysis should be considered in patients with glomerular filtration rates below 10 ml/min (Strength of Recommendation C). 5. Acid-Base Disorders in CKD: Moderate metabolic acidosis (Bic 16-20) mEq/L is common with glomerular filtration rates below 20 ml/min, and favors bone demineralization due to the release of calcium and phosphate from the bone, chronic hyperventilation, and muscular weakness and atrophy. Its treatment consists of administration of sodium bicarbonate, usually orally (0.5-1 mEq/kg/day), with the goal of achieving a serum bicarbonate level of 22-24 mmol/L (Strength of Recommendation C). Limitation of daily protein intake to less than 1 g/kg/day is also useful (Strength of Recommendation C). Use of sevelamer as a phosphate binder aggravates metabolic acidosis since it favors endogenous acid production and therefore acidosis should be monitored and corrected if it occurs (Strength of Recommendation C). Hypocalcemia should always be corrected before metabolic acidosis in CKD (Strength of Recommendation B). Metabolic acidosis is an infrequent disorder and requires exogenous alkali administration (bicarbonate, phosphate binders) or vomiting. The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g., proteinuria): 0) Normal kidney function – GFR above 90 (mL/min)/(1.73 m2) and no proteinuria 1) CKD1 – GFR above 90 (mL/min)/(1.73 m2) with evidence of kidney damage 2) CKD2 (mild) – GFR of 60 to 89 (mL/min)/(1.73 m2) with evidence of kidney damage 3) CKD3 (moderate) – GFR of 30 to 59 (mL/min)/(1.73 m2) 4) CKD4 (severe) – GFR of 15 to 29 (mL/min)/(1.73 m2) 5) CKD5 kidney failure – GFR less than 15 (mL/min)/(1.73 m2) Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis. Note: others add a \"T\" to patients who have had a transplant regardless of stage. The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g., proteinuria): 0) Normal kidney function – GFR above 90 mL/min/1.73 m2 and no proteinuria 1) CKD1 – GFR above 90 mL/min/1.73 m2 with evidence of kidney damage 2) CKD2 (mild) – GFR of 60 to 89 mL/min/1.73 m2 with evidence of kidney damage 3) CKD3 (moderate) – GFR of 30 to 59 mL/min/1.73 m2 4) CKD4 (severe) – GFR of 15 to 29 mL/min/1.73 m2 5) CKD5 kidney failure – GFR less than 15 mL/min/1.73 m2 Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis. Note: others add a \"T\" to patients who have had a transplant regardless of stage. Eight patients with life threatening hyperkalemia were treated in the intensive care unit over a period of 2 years. Serum potassium at admission was 7.1-11.2. Two patients had to be resuscitated and 3 exhibited quadriplegia or paralyses but were alert. Seven showed marked ECG change: in 5 the QRS-complexes were extremely broadened and in one case an AV-rhythm was observed; the atrial wave was absent in all 7 patients. Renal failure was present in 7 of 8 patients. In 6 of these 8 cases drugs were also involved in the development of hyperkalemia. The following therapeutic procedure is recommended for hyperkalemia: (1) injection of calcium, (2) inhalation or injection of beta 2-mimetics (well documented in the literature; clinical experience limited), (3) insulin and glucose i.v., (4) sodium bicarbonate, but only in case of metabolic acidosis, (5) hemodialysis, (6) cation exchange resins or furosemide in non-acute situations.\nHere is the question:\nNEPHROLOGY: In a patient with known advanced chronic kidney disease (CKD G4, eGFR 20 ml/min) who comes to the emergency department for general weakness and is found to have severe hyperkalemia (K 7 mEq/l) with electrocardiographic abnormalities. What would be the first measure to take?\nHere are the potential choices:\n1. Administration of cation exchange resins.\n2. Placement of a catheter to initiate dialysis.\n3. Administration of intravenous calcium gluconate.\n4. Administration of oral furosemide.\nThe correct answer is: 3. Administration of intravenous calcium gluconate."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Hairy cell leukemia (HCL), a rare and slow-progressive B-cell lymphoproliferative disease, enhances predisposition to infectious complications, especially to disseminated mycobacterial infections. Although the association between HCL and mycobacterial disease has been established, disseminated Mycobacterium tuberculosis infection has been reported only in a few case series. In this report, a disseminated tuberculosis (TB) case who had been diagnosed as HCL with histopathologic examination of the bone marrow after being investigated for the etiology of fever of unknown origin, was presented. A 56-year-old male patient who was admitted to our clinic with the complaints of three weeks' duration fever, chills, night sweats and cough was hospitalized. On physical examination, the body temperature of the patient who appeared very ill, was 39°C. Dispersed macular rash that turned pale when pressure was applied, was detected on the legs, arms and back. There were no signs of peripheral lymphadenopathy, hepatomegaly or splenomegaly. Laboratory results revealed haemoglobin 10 g/dl, white blood cell count 1000/mm3, thrombocytes 143.000/mm3, erythrocyte sedimentation rate 41 mm/h, CRP 200 mg/L, uric acid 9.5 mg/dl, AST 118 IU/L, ALT 102 IU/L and LDH 429 IU/L. Thorax computed tomography showed mediastinal and bilateral hilary lymphadenopathy. Although preliminary diagnosis was lymphoma, examination of acid-fast bacilli in three days sequential sputum samples and sputum culture for the growth of mycobacteria (Bactec MGIT 960 TB system, Becton Dickinson, Md) were performed to rule out miliary TB. Blood cultures were also performed with non-radiometric fully automated TB hemoculture bottles (Bactec TB, Becton Dickinson, Md). Sputum cultures yielded no mycobacterial growth, however M.tuberculosis growth was detected in blood culture on the 27th day of inoculation. Bone marrow biopsy revealed HCL. However the patient died on the 14th day of hospitalization. In conclusion, disseminated tuberculosis should be considered for differentional diagnosis in patients with HCL or similar hematologic malignancies since TB is endemic in Turkey. The peritoneal mesothelioma is a rare pathology with unspecific symptoms reason to be a difficult diagnosis. We report a case of a 58 year old man with diabetes mellitus type 2, arterial hypertension and smoking; without precedent of asbestos exposure. The patient presented a one month history characterized by progressive increase of the abdominal volume and sensation of fullness; three weeks later they added breathlessness and hyporexia. The patient was in regular general condition; he was not presenting hepatic stigmas, edema or adenomegalies. The examination of thorax and cardiovascular it was normal. The abdomen distended by ascites, not painful, liver and spleen not examined. Laboratory: Hemoglobin 11,9 gr/dl, WBC 6840/mm3 Bands 1 %, lymphocytes 10 %, platelets 620000/mm3, PT 12 seconds, PTT 34 seconds, glucose 158 mg/dl, BUN 20,5 mg/ dl, creatinine 1,2 mg/dl, proteins 6,1 gr/dl, albumin 2,6 gr/dl. LDH 316 U/l, beta2microglobulin 2,2 mg/l (0.83-1.15 mg/l). HBV and HCV negative. Ca 19.9, CEA, AFP and PSA negative. Hemocultive negative. Ascitic fluid: ADA 20,3 U/l, serum-ascitic albumin gradient (SAAG) 1,1. Leukocytes 2237 cells/mm3, PMN 6 %, lymphocytes 90 %, mesothelial cells 4 %, proteins 4,6 gr/dl, albumin 2,34 gr/dl, glucose 44 mg/dl, LDH 1918 U/l. Gram and cultive: negatives. BAAR and cultive: negative . Cytology: mesothelial cells with changes of type reagent, Block cell for tumour cells: negative. Abdominal US: increased peritoneum and abundant ascitic fluid. Thoracic-abdominal CT: left side pleural effusion, severe ascites with thick epyplon. Upper GI endoscopy: moderate gastritis. Colonoscopy: two small sessile polyps in sigmoid colon. The finds of the laparoscopy were interpreted like carcinomatosis or peritoneal tuberculosis. The report of the peritoneal biopsy was informed as suggestive of undifferentiated carcinoma; the reappraisal with inmunohystochemic (calretinin +,cytokeratin +, vimentin +) indicated malignant peritoneal mesothelioma, type epithelial. The evolution was torpid. The patient was transferred to the Service of Oncology where they initiated chemotherapy with Cysplatin (CDDP) and died 20 days later. The malignant mesothelioma peritoneal is a unfrequent entity, with limited therapeutic options; generally detected late, with a palliative treatment. Acute pancreatitis not secondary to gallstones At admission: Blood glucose > 11.11 mmol/L (> 200 mg/dL) Age > 55 years Serum LDH > 350 IU/L Serum AST > 250 IU/L WBC count > 16000 cells/mm3 Within 48 hours: Serum calcium < 2.0 mmol/L (< 8.0 mg/dL) Hematocrit decreased by > 10% Oxygen (hypoxemia with PaO2 < 60 mmHg) BUN increased by 1.8 or more mmol/L (5 or more mg/dL) after IV fluid hydration Base deficit (negative base excess) > 4 mEq/L Sequestration of fluids > 6 L Acute pancreatitis secondary to gallstones At admission: Glucose > 220 mg/dl Age > 70 years LDH > 400 IU/L AST > 250 IU/ 100 ml WBC count > 18000 cells/mm3 Within 48 hours: Serum calcium < 8 mg/dL Hematocrit decreased by > 10% Base deficit > 4 mEq/L BUN increased by > 2 mg/dL Sequestered fluid > 6L Crimean-Congo haemorrhagic fever (CCHF) is a tick-borne disease caused by Nairovirus, of the family Bunyaviridae. This is the first case report of a confirmed CCHF case without laboratory abnormality. A 36-year-old woman was admitted to our clinic with the complaints of fever, chills, myalgia and vomiting. She was living in a CCHF-endemic region and had received a tick bite ten days previously. Her complaints had started five days after the tick bite, and bleeding of the nose and vagen followed. Under laboratory analysis, serum white blood cell (WBC) was 7300/mm3, haemoglobin (Hb)11.9 gr/dL, platelet (Plt) count 293000/mm3, aspartate transaminase (AST) was 23 U/L, alanine transaminase (ALT) 14 U/L, lactate dehydrogenase (LDH) 139 U/L, creatinine phosphokinase (CPK) 39 U/L, INR 0.8 and APTT 26.2 seconds. Based on these clinical and epidemiological findings, a diagnosis of CCHF infection was suspected, and the diagnosis of CCHF was confirmed with a blood sample tested by TaqMan-based one-step RT-PCR positivity and IgM antibody positivity. We suggest that patients from an endemic region who have typical epidemiological and clinical findings should be evaluated as a possible case for CCHF even if the laboratory findings are not compatible.  Fever ˜38.3° C (101° F) and illness lasting ˜3 weeks and no known immunocompromised state History and physical examination Stop antibiotic treatment and glucocorticoids Obligatory investigations: ESR and CRP, hemoglobin, platelet count, leukocyte count and differential, electrolytes, creatinine, total protein, protein electrophoresis, alkaline phosphatase, AST, ALT, LDH, creatine kinase, antinuclear antibodies, rheumatoid factor, urinalysis, blood cultures (n=3), urine culture, chest x-ray, abdominal ultrasonography, and tuberculin skin test Fever >38.3°C (101°F) on at least two occasions 2. Illness duration of ≥3 weeks 3. 4. Diagnosis that remains uncertain after a thorough history-taking, physical examination, and the following obligatory investigations: determination of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level; platelet count; leukocyte count and differential; measurement of levels of hemoglobin, electrolytes, creatinine, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, ferritin, antinuclear antibodies, and rheumatoid factor; protein electrophoresis; urinalysis; blood cultures (n = 3); urine culture; chest x-ray; abdominal ultrasonography; and tuberculin skin test (TST). The range of FUO etiologies has evolved over time as a result of changes in the spectrum of diseases causing FUO, the widespread Percentage of Cases Due to Indicated Cause At admission age in years > 55 years white blood cell count > 16000 cells/mm3 blood glucose > 11.1 mmol/L (> 200 mg/dL) serum AST > 250 IU/L serum LDH > 350 IU/L At 48 hours Calcium (serum calcium < 2.0 mmol/L (< 8.0 mg/dL) Hematocrit fall >10% Oxygen (hypoxemia PO2 < 60 mmHg) BUN increased by 1.8 or more mmol/L (5 or more mg/dL) after IV fluid hydration Base deficit (negative base excess) > 4 mEq/L Sequestration of fluids > 6 L The criteria for point assignment is that a certain breakpoint be met at any time during that 48 hour period, so that in some situations it can be calculated shortly after admission. It is applicable to both gallstone and alcoholic pancreatitis. Alternatively, pancreatitis can be diagnosed by meeting any of the following:[2] Alternative Ranson score Ranson's score of ≥ 8 Organ failure Substantial pancreatic necrosis (at least 30% glandular necrosis according to contrast-enhanced CT) Practice guidelines state: 2006: \"The two tests that are most helpful at admission in distinguishing mild from severe acute pancreatitis are APACHE-II score and serum hematocrit. It is recommended that APACHE-II scores be generated during the first 3 days of hospitalization and thereafter as needed to help in this distinction. It is also recommended that serum hematocrit be obtained at admission, 12 h after admission, and 24 h after admission to help gauge adequacy of fluid resuscitation.\" 2005: \"Immediate assessment should include clinical evaluation, particularly of any cardiovascular, respiratory, and renal compromise, body mass index, chest x ray, and APACHE II score\" Ranson score The Ranson score is used to predict the severity of acute pancreatitis. They were introduced in 1974. At admission age in years > 55 years white blood cell count > 16000 cells/mm3 blood glucose > 11.1 mmol/L (> 200 mg/dL) serum AST > 250 IU/L serum LDH > 350 IU/L At 48 hours It is now quite well accepted that laboratory test results are indispensable or of primary significance to accurately diagnose a new patient's disease. Furthermore, most doctors recently find difficulty in appropriately selecting and ordering necessary but not excess laboratory tests and to read and interpret all the given test results correctly. In our hospital the system of the outpatient clinic will be changed basically on a specialty clinic system. In order to operate such a specialty clinic system effectively, it appears quite important to set up a unit to discriminate new unspecified patients properly and to consult them to an appropriate specialty clinic. As a preliminary trial, we opened a new patient clinic in July, 1992. The aim of this clinic is to accurately diagnose the new patients' disease immediately and to send them to the specialty clinic on the day of their first visit. Prior to history taking and physical examination by the attending doctor, the patients are instructed to take a set of laboratory tests. These include urinalysis, chest X-P, ECG, hematological examinations (RBC, WBC, Ht, Hb, PLT and ESR) and biochemical tests (AST, ALT, ALP, gamma GTP, LDH, CPK, Chol, T-Bil, TP, Alb, TG, BUN, Cr, Glu, Na, K, Ca, P and CRP). These results are transferred to the clinic within one hour so that the doctor is able to make the diagnosis effectively and to refer the patients to an appropriate clinic.(ABSTRACT TRUNCATED AT 250 WORDS) A 15-year-old boy with T-cell acute lymphoblastic leukemia (ALL) (FAB L1), diagnosed in 1995, received combination chemotherapy consisting of 6 weeks of induction (vincristine, epirubicin, L-asparaginase, prednisolone) and 2 weeks of consolidation (cytosine arabinosides, etoposide). After achieving remission, for further maintenance of remission, he was treated with 14 cycles of intensive chemotherapy consisting of 6-MP, 10 mg/kg orally on the first 4 days, and cyclophosphamide, 1200 mg/m2, vincristine, 1.5 mg/m2, epirubicin, 15 mg/m2, and cytosine arabinoside, 40 mg/m2, intravenously on days 4, 11, 39, and 40, respectively. On day 18 of each cycle, he received intravenous methotrexate (MTX) infusion in a total dose of 150 mg/m2 plus oral leucovorin (30 mg/m2 ) rescue 36 h after starting MTX therapy. In addition, oral trimethoprim-sulfamethoxazole was given regularly to prevent Pneumocystis carinii infection. The patient achieved remission during the first course of treatment, but 8 months later the disease relapsed. He then received four doses of MTX (800 mg intravenously) plus leucovorin rescue in the following 4 months. During the last MTX therapy, small hemorrhagic bullae were found on the lateral side of the right ankle, but subsided after a few days. Due to partial remission of the disease, he was admitted again in January 1999 for high-dose MTX therapy. An initial hemogram on admission revealed hemoglobin 7.2 g/dL, white cell count 15,200/mm3, platelet count 153/mm3, blood creatinine 0.5 mg/dL, and alanine leucine aminotransferase (ALT) 20 U/L. He received 8500 mg of MTX (5000 mg/m2 ) as a continuous intravenous infusion for 24 h. Thirty-six hours after the start of MTX infusion, leucovorin (30 mg, intravenous) rescue was initiated every 6 h for 3 days. Another preventive measure to cover MTX toxicity included aggressive intravenous fluid replacement (4 L/m2 /day) and the addition of 25 meq/L sodium bicarbonate to the intravenous fluid to alkalinize the urine. Concurrent medication included 6-MP (50 mg) once daily and trimethoprim-sulfamethoxazole (120 mg, 600 mg) twice daily every other day. Plasma MTX levels were 52.36 micromol/L 24 h after MTX infusion, 1.87 micromol/L after 48 h, 0.57 micromol/L after 72 h, and 0.41 micromol/L after 96 h. These indicated delayed MTX plasma clearance. The blood creatinine level was mildly elevated from 0.5 mg/dL to 0.7 mg/dL. Thirty-six hours after the administration of MTX, the patient developed an erythematous painful swelling on the right middle finger. The erythema, with subsequent large bulla formation, progressed to all the fingers, toes, palms, and the soles of the feet. Some erythematous to hemorrhagic papules also appeared on the bilateral elbows. Subsequently, diffuse tender erythema with extensive erosions and focal tiny pustules developed on the back, abdomen, proximal extremities, and face (Fig. 1a,b). A positive Nikolsky's sign was also present. A biopsy specimen of the right dorsal hand lesion revealed parakeratosis, detached acanthotic epidermis with scattered necrotic keratinocytes, dyskeratotic cells and nuclear atypia, neutrophilic exocytosis, and many neutrophils in the papillary dermis (Fig. 2). The skin condition deteriorated rapidly. Toxic epidermal necrolysis-like lesions involved 90% of the total body surface on the fifth day after MTX infusion. Mucositis, diarrhea, involuntary tremor, fever, and chills were noted. The patient was then sent to the burn unit for intensive skin care. Ten days after MTX therapy, profound agranulocytosis and thrombocytopenia (white cell count 100/mm3, platelets 14,000/mm3, and hemoglobin 5.6 g/dL) were found. The patient was then started on granulocyte colony stimulation factor (G-CSF, 5 microg/kg/day), but his general condition deteriorated rapidly and he died 6 days later due to septic shock and multiple organ failure. Modern medicine can not be practiced without laboratory tests. Laboratory tests play a vital role from the initial stage of clinical examination. The Japanese Society of Clinical Pathology has formed a committee specifically dealing with the effective and economic use of lab tests without missing or duplicating the important tests. As is shown in table 1 in the main text \"Essential Laboratory Tests\" were initially agreed as those tests a patient should take when visiting a clinic regardless of the complaint. From an early stage, laboratory tests were done simultaneously with history-taking and physical examinations. Then the \"Initial Impression\" is obtained and \"Organ-oriented 1st and 2nd screening tests\" and confirmatory tests will be done to make the final diagnosis. To evaluate the validity of the \"Essential Laboratory Tests\", we performed the tests on 1026 patients who visited our general medicine clinic for the first time. We compared the Initial Impression with or without Essential Laboratory Tests. Cases in which a diagnosis could not be made by history-taking and physical examination were decreased from 17.4% to 8.0% by performing the essential laboratory tests. Diagnoses made without the essential laboratory tests were found to be mistaken in 10.4% and the additional use of the tests was suggested to lead to a more accurate diagnosis. In 110 cases, diseases unrelated to the chief complaints, were discovered. Even for the respiratory tract infection, CRP and WBC count, which were included in the essential laboratory tests, were very informative. To examine the incidence rate by age and gender of leukopenia caused by chemotherapy including rifampicin (RFP) and isoniazid (INH), and to study the relationships between the leukopenia and the hepatic side effect or other haematological disorders such as thrombocytopenia. Out of the tuberculosis patients who were admitted to our hospital in 1987-88, 1991-92, and 1996-2000, 1,525 patients (1,153 men, 372 women) were chosen for our study who had the white blood cell counts (WBC) in the peripheral blood more than 3,000/mm3 before chemotherapy, and underwent haematologic examination at least twice within 3 months after starting chemotherapy. The definition of leukopenia was as follows: 1) WBC became less than 3,000/mm3 during chemotherapy for patients with pre-treatment WBC more than 4,000/mm3, or 2) WBC decreased more than 1,000/mm3 in patients with pre-treatment WBC between 3,000 and 4,000/mm3. The incidence rates of leukopenia by age, gender, and regimens of chemotherapy were calculated. The case-control study was done between the control and the leukopenia groups excluding patients suffered from agranulocytosis to clarify the hematological and biochemical characteristics of the leukopenia group. The control patients were chosen in the following way. For each patient with leukopenia, a patient with the same admission year, same gender, same regimen of chemotherapy, and the nearest age was chosen as a control patient. The changes in counts of white blood cell, granulocyte, and platelet, in hemoglobin concentration, and in hepatic enzyme levels before and during chemotherapy were compared between the leukopenia and the control groups. Thrombocytopenia was defined as platelet count less than 15 x 10(4)/mm3 and hepatic dysfunction as either asparate aminotransferase (AST) higher than 31 IU/l or alanine aminotransferase (ALT) higher than 34 IU/l. (1) Incidence rate of leukopenia The leukopenia appeared in 36 patients (14 men, 22 women), two (one man, one woman) of whom showed agranulocytosis. The incidence rate was 1.2% (14/1,153) for men and 5.9% (22/372) for women. The incidence rate of women was higher than that of men in the age groups between 20 to 79 y.o., but no difference was seen in the age groups elder than 80 y.o. There were no differences in the incidence rate among groups treated with HRE (E: ethambutol), HRS (S: streptomycin), and HREZ (Z: pyrazinamide). The chemotherapy was continued in 30 patients after the appearance of leukopenia, and the natural recovery from leukopenia was seen in 19 patients, while the leukopenic state lasted during the chemotherapy in the remaining 11 patients. In two patients who exhibited agranulocytosis all drugs were discontinued. In the remaining 4 patients one or more drugs were discontinued. (2) Case-control study between leukopenia (N = 34) and the control (N = 34) groups There were no differences in age, sputum culture positivity on admission, degree of roentgenographic extent of the disease, ratio of cavity formation, and quantity of daily doses between the two groups. There was also no difference between the days until leukopenia appeared after starting chemotherapy (47.6 +/- 29.5 days) in the leukopenia group, and the days until WBC count became minimum within 3 months after starting chemotherapy (41.7 +/- 21.0 days) in the control group. The negativity of tuberculin skin testing was higher in the leukopenia group [7/14 (50%)] than in the control group [1/10 (10%)], however, the difference was statistically not significant due to rather small size of cases. Before the starting chemotherapy, the counts of WBC (7,230 +/- 1,530 vs 5,500 +/- 1,510/mm3, p &lt; 0.001), neutrophil (5,230 +/- 1,450 vs 4,320 +/- 1,620/mm3, p &lt; 0.05), lymphocyte (1,440 +/- 830 vs 830 +/- 440/mm3, p &lt; 0.001) and platelet (34.9 +/- 12.2 vs 24.1 +/- 6.4 x 10(4)/mm3, p &lt; 0.001) in the peripheral blood and the globulin level (3.71 +/- 0.61 vs 3.35 +/- 0.61 g/dl, p &lt; 0.05) in the serum were significantly higher in the control group than in the leukopenia group. The decrements in the counts of WBC and granulocyte during chemotherapy were larger in the leukopenia group than in the control group (delta WBC: 2,880 +/- 1,530 vs 1,910 +/- 1,520/mm3, and delta Neut: 2,840 +/- 1,510 vs 1,820 +/- 1,380/mm3, p = 0.01, respectively), but the counts of lymphocyte were similar in both groups. The platelet counts also decreased in both groups, but to the mid-normal level in the control group, and to the lowest normal level in the leukopenia group, in which 15 out of 34 patients (44%) showed thrombocytopenia. The levels in the serum of hepatic enzymes such as AST, ALT, and gamma-GTP (gamma-glutamyl aminotransferase) increased during chemotherapy in the leukopenia group, while decreased in the control group, and the facts indicate that in the former not only bone marrow cells but also hepatic cells were impaired by anti-tuberculosis drugs. Leukopenia may occur in the course of treatment with anti-tuberculosis drugs, but it is not necessary to stop the chemotherapy immediately, because the WBC count recovers spontaneously or remains under stable leukopenic state during chemotherapy in most cases. But when leukopenia appears, the peripheral blood counts must be checked cautiously, and the chemotherapy should be stopped if the WBC count progressively decreases. The patients who showed leukopenia due to anti-tuberculosis drugs may have had weaker natural and acquired (cell-mediated) immunologic response to tuberculosis infection, and more vulnerable bone marrow cells and hepatic cells to anti-tuberculosis drugs than the control.\nHere is the question:\nHEMATOLOGY: A 26-year-old woman consults for a feeling of generalized weakness that has progressively set in over the course of three weeks, becoming particularly intense in the last two days. For the last couple of years, she reports episodes of joint pain in the hands that have required the use of anti-inflammatory drugs, as well as the appearance of an erythematous lesion of unclear cause in the neckline area, mainly in summer. In the physical examination there was only an evident cutaneous-mucosal pallor and a heart rate of 100 bpm. The hemogram shows: Hb 6 gr/dL, Hto 27 %, MCV 105 fL, 3,420 leukocytes/mm3 (2300 neutrophils/mm3, 800 lymphocytes/mm3, 250 monocytes/mm3, 50 eosinophils/mm3, 20 basophils/mm3), platelets 170,000/mm3. Biochemistry: AST 30 IU/L, ALT 35 IU/L, GGT 59 IU/L, alkaline phosphatase 105 IU/L, LDH 490 IU/L, urea 20 mg/dL, creatinine 0.8 mg/dL. Taking into account the available information, indicate which of the following additional analytical parameters you would need to know in order to make the most appropriate immediate decision:\nHere are the potential choices:\n1. Vitamin B12.\n2. Antinuclear antibodies.\n3. Direct Coombs' test.\n4. Anti-DNA antibodies.\nThe correct answer is: ",
        "gold_answer": "3 Direct Coombs' test.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Hairy cell leukemia (HCL), a rare and slow-progressive B-cell lymphoproliferative disease, enhances predisposition to infectious complications, especially to disseminated mycobacterial infections. Although the association between HCL and mycobacterial disease has been established, disseminated Mycobacterium tuberculosis infection has been reported only in a few case series. In this report, a disseminated tuberculosis (TB) case who had been diagnosed as HCL with histopathologic examination of the bone marrow after being investigated for the etiology of fever of unknown origin, was presented. A 56-year-old male patient who was admitted to our clinic with the complaints of three weeks' duration fever, chills, night sweats and cough was hospitalized. On physical examination, the body temperature of the patient who appeared very ill, was 39°C. Dispersed macular rash that turned pale when pressure was applied, was detected on the legs, arms and back. There were no signs of peripheral lymphadenopathy, hepatomegaly or splenomegaly. Laboratory results revealed haemoglobin 10 g/dl, white blood cell count 1000/mm3, thrombocytes 143.000/mm3, erythrocyte sedimentation rate 41 mm/h, CRP 200 mg/L, uric acid 9.5 mg/dl, AST 118 IU/L, ALT 102 IU/L and LDH 429 IU/L. Thorax computed tomography showed mediastinal and bilateral hilary lymphadenopathy. Although preliminary diagnosis was lymphoma, examination of acid-fast bacilli in three days sequential sputum samples and sputum culture for the growth of mycobacteria (Bactec MGIT 960 TB system, Becton Dickinson, Md) were performed to rule out miliary TB. Blood cultures were also performed with non-radiometric fully automated TB hemoculture bottles (Bactec TB, Becton Dickinson, Md). Sputum cultures yielded no mycobacterial growth, however M.tuberculosis growth was detected in blood culture on the 27th day of inoculation. Bone marrow biopsy revealed HCL. However the patient died on the 14th day of hospitalization. In conclusion, disseminated tuberculosis should be considered for differentional diagnosis in patients with HCL or similar hematologic malignancies since TB is endemic in Turkey. The peritoneal mesothelioma is a rare pathology with unspecific symptoms reason to be a difficult diagnosis. We report a case of a 58 year old man with diabetes mellitus type 2, arterial hypertension and smoking; without precedent of asbestos exposure. The patient presented a one month history characterized by progressive increase of the abdominal volume and sensation of fullness; three weeks later they added breathlessness and hyporexia. The patient was in regular general condition; he was not presenting hepatic stigmas, edema or adenomegalies. The examination of thorax and cardiovascular it was normal. The abdomen distended by ascites, not painful, liver and spleen not examined. Laboratory: Hemoglobin 11,9 gr/dl, WBC 6840/mm3 Bands 1 %, lymphocytes 10 %, platelets 620000/mm3, PT 12 seconds, PTT 34 seconds, glucose 158 mg/dl, BUN 20,5 mg/ dl, creatinine 1,2 mg/dl, proteins 6,1 gr/dl, albumin 2,6 gr/dl. LDH 316 U/l, beta2microglobulin 2,2 mg/l (0.83-1.15 mg/l). HBV and HCV negative. Ca 19.9, CEA, AFP and PSA negative. Hemocultive negative. Ascitic fluid: ADA 20,3 U/l, serum-ascitic albumin gradient (SAAG) 1,1. Leukocytes 2237 cells/mm3, PMN 6 %, lymphocytes 90 %, mesothelial cells 4 %, proteins 4,6 gr/dl, albumin 2,34 gr/dl, glucose 44 mg/dl, LDH 1918 U/l. Gram and cultive: negatives. BAAR and cultive: negative . Cytology: mesothelial cells with changes of type reagent, Block cell for tumour cells: negative. Abdominal US: increased peritoneum and abundant ascitic fluid. Thoracic-abdominal CT: left side pleural effusion, severe ascites with thick epyplon. Upper GI endoscopy: moderate gastritis. Colonoscopy: two small sessile polyps in sigmoid colon. The finds of the laparoscopy were interpreted like carcinomatosis or peritoneal tuberculosis. The report of the peritoneal biopsy was informed as suggestive of undifferentiated carcinoma; the reappraisal with inmunohystochemic (calretinin +,cytokeratin +, vimentin +) indicated malignant peritoneal mesothelioma, type epithelial. The evolution was torpid. The patient was transferred to the Service of Oncology where they initiated chemotherapy with Cysplatin (CDDP) and died 20 days later. The malignant mesothelioma peritoneal is a unfrequent entity, with limited therapeutic options; generally detected late, with a palliative treatment. Acute pancreatitis not secondary to gallstones At admission: Blood glucose > 11.11 mmol/L (> 200 mg/dL) Age > 55 years Serum LDH > 350 IU/L Serum AST > 250 IU/L WBC count > 16000 cells/mm3 Within 48 hours: Serum calcium < 2.0 mmol/L (< 8.0 mg/dL) Hematocrit decreased by > 10% Oxygen (hypoxemia with PaO2 < 60 mmHg) BUN increased by 1.8 or more mmol/L (5 or more mg/dL) after IV fluid hydration Base deficit (negative base excess) > 4 mEq/L Sequestration of fluids > 6 L Acute pancreatitis secondary to gallstones At admission: Glucose > 220 mg/dl Age > 70 years LDH > 400 IU/L AST > 250 IU/ 100 ml WBC count > 18000 cells/mm3 Within 48 hours: Serum calcium < 8 mg/dL Hematocrit decreased by > 10% Base deficit > 4 mEq/L BUN increased by > 2 mg/dL Sequestered fluid > 6L Crimean-Congo haemorrhagic fever (CCHF) is a tick-borne disease caused by Nairovirus, of the family Bunyaviridae. This is the first case report of a confirmed CCHF case without laboratory abnormality. A 36-year-old woman was admitted to our clinic with the complaints of fever, chills, myalgia and vomiting. She was living in a CCHF-endemic region and had received a tick bite ten days previously. Her complaints had started five days after the tick bite, and bleeding of the nose and vagen followed. Under laboratory analysis, serum white blood cell (WBC) was 7300/mm3, haemoglobin (Hb)11.9 gr/dL, platelet (Plt) count 293000/mm3, aspartate transaminase (AST) was 23 U/L, alanine transaminase (ALT) 14 U/L, lactate dehydrogenase (LDH) 139 U/L, creatinine phosphokinase (CPK) 39 U/L, INR 0.8 and APTT 26.2 seconds. Based on these clinical and epidemiological findings, a diagnosis of CCHF infection was suspected, and the diagnosis of CCHF was confirmed with a blood sample tested by TaqMan-based one-step RT-PCR positivity and IgM antibody positivity. We suggest that patients from an endemic region who have typical epidemiological and clinical findings should be evaluated as a possible case for CCHF even if the laboratory findings are not compatible.  Fever ˜38.3° C (101° F) and illness lasting ˜3 weeks and no known immunocompromised state History and physical examination Stop antibiotic treatment and glucocorticoids Obligatory investigations: ESR and CRP, hemoglobin, platelet count, leukocyte count and differential, electrolytes, creatinine, total protein, protein electrophoresis, alkaline phosphatase, AST, ALT, LDH, creatine kinase, antinuclear antibodies, rheumatoid factor, urinalysis, blood cultures (n=3), urine culture, chest x-ray, abdominal ultrasonography, and tuberculin skin test Fever >38.3°C (101°F) on at least two occasions 2. Illness duration of ≥3 weeks 3. 4. Diagnosis that remains uncertain after a thorough history-taking, physical examination, and the following obligatory investigations: determination of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level; platelet count; leukocyte count and differential; measurement of levels of hemoglobin, electrolytes, creatinine, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, ferritin, antinuclear antibodies, and rheumatoid factor; protein electrophoresis; urinalysis; blood cultures (n = 3); urine culture; chest x-ray; abdominal ultrasonography; and tuberculin skin test (TST). The range of FUO etiologies has evolved over time as a result of changes in the spectrum of diseases causing FUO, the widespread Percentage of Cases Due to Indicated Cause At admission age in years > 55 years white blood cell count > 16000 cells/mm3 blood glucose > 11.1 mmol/L (> 200 mg/dL) serum AST > 250 IU/L serum LDH > 350 IU/L At 48 hours Calcium (serum calcium < 2.0 mmol/L (< 8.0 mg/dL) Hematocrit fall >10% Oxygen (hypoxemia PO2 < 60 mmHg) BUN increased by 1.8 or more mmol/L (5 or more mg/dL) after IV fluid hydration Base deficit (negative base excess) > 4 mEq/L Sequestration of fluids > 6 L The criteria for point assignment is that a certain breakpoint be met at any time during that 48 hour period, so that in some situations it can be calculated shortly after admission. It is applicable to both gallstone and alcoholic pancreatitis. Alternatively, pancreatitis can be diagnosed by meeting any of the following:[2] Alternative Ranson score Ranson's score of ≥ 8 Organ failure Substantial pancreatic necrosis (at least 30% glandular necrosis according to contrast-enhanced CT) Practice guidelines state: 2006: \"The two tests that are most helpful at admission in distinguishing mild from severe acute pancreatitis are APACHE-II score and serum hematocrit. It is recommended that APACHE-II scores be generated during the first 3 days of hospitalization and thereafter as needed to help in this distinction. It is also recommended that serum hematocrit be obtained at admission, 12 h after admission, and 24 h after admission to help gauge adequacy of fluid resuscitation.\" 2005: \"Immediate assessment should include clinical evaluation, particularly of any cardiovascular, respiratory, and renal compromise, body mass index, chest x ray, and APACHE II score\" Ranson score The Ranson score is used to predict the severity of acute pancreatitis. They were introduced in 1974. At admission age in years > 55 years white blood cell count > 16000 cells/mm3 blood glucose > 11.1 mmol/L (> 200 mg/dL) serum AST > 250 IU/L serum LDH > 350 IU/L At 48 hours It is now quite well accepted that laboratory test results are indispensable or of primary significance to accurately diagnose a new patient's disease. Furthermore, most doctors recently find difficulty in appropriately selecting and ordering necessary but not excess laboratory tests and to read and interpret all the given test results correctly. In our hospital the system of the outpatient clinic will be changed basically on a specialty clinic system. In order to operate such a specialty clinic system effectively, it appears quite important to set up a unit to discriminate new unspecified patients properly and to consult them to an appropriate specialty clinic. As a preliminary trial, we opened a new patient clinic in July, 1992. The aim of this clinic is to accurately diagnose the new patients' disease immediately and to send them to the specialty clinic on the day of their first visit. Prior to history taking and physical examination by the attending doctor, the patients are instructed to take a set of laboratory tests. These include urinalysis, chest X-P, ECG, hematological examinations (RBC, WBC, Ht, Hb, PLT and ESR) and biochemical tests (AST, ALT, ALP, gamma GTP, LDH, CPK, Chol, T-Bil, TP, Alb, TG, BUN, Cr, Glu, Na, K, Ca, P and CRP). These results are transferred to the clinic within one hour so that the doctor is able to make the diagnosis effectively and to refer the patients to an appropriate clinic.(ABSTRACT TRUNCATED AT 250 WORDS) A 15-year-old boy with T-cell acute lymphoblastic leukemia (ALL) (FAB L1), diagnosed in 1995, received combination chemotherapy consisting of 6 weeks of induction (vincristine, epirubicin, L-asparaginase, prednisolone) and 2 weeks of consolidation (cytosine arabinosides, etoposide). After achieving remission, for further maintenance of remission, he was treated with 14 cycles of intensive chemotherapy consisting of 6-MP, 10 mg/kg orally on the first 4 days, and cyclophosphamide, 1200 mg/m2, vincristine, 1.5 mg/m2, epirubicin, 15 mg/m2, and cytosine arabinoside, 40 mg/m2, intravenously on days 4, 11, 39, and 40, respectively. On day 18 of each cycle, he received intravenous methotrexate (MTX) infusion in a total dose of 150 mg/m2 plus oral leucovorin (30 mg/m2 ) rescue 36 h after starting MTX therapy. In addition, oral trimethoprim-sulfamethoxazole was given regularly to prevent Pneumocystis carinii infection. The patient achieved remission during the first course of treatment, but 8 months later the disease relapsed. He then received four doses of MTX (800 mg intravenously) plus leucovorin rescue in the following 4 months. During the last MTX therapy, small hemorrhagic bullae were found on the lateral side of the right ankle, but subsided after a few days. Due to partial remission of the disease, he was admitted again in January 1999 for high-dose MTX therapy. An initial hemogram on admission revealed hemoglobin 7.2 g/dL, white cell count 15,200/mm3, platelet count 153/mm3, blood creatinine 0.5 mg/dL, and alanine leucine aminotransferase (ALT) 20 U/L. He received 8500 mg of MTX (5000 mg/m2 ) as a continuous intravenous infusion for 24 h. Thirty-six hours after the start of MTX infusion, leucovorin (30 mg, intravenous) rescue was initiated every 6 h for 3 days. Another preventive measure to cover MTX toxicity included aggressive intravenous fluid replacement (4 L/m2 /day) and the addition of 25 meq/L sodium bicarbonate to the intravenous fluid to alkalinize the urine. Concurrent medication included 6-MP (50 mg) once daily and trimethoprim-sulfamethoxazole (120 mg, 600 mg) twice daily every other day. Plasma MTX levels were 52.36 micromol/L 24 h after MTX infusion, 1.87 micromol/L after 48 h, 0.57 micromol/L after 72 h, and 0.41 micromol/L after 96 h. These indicated delayed MTX plasma clearance. The blood creatinine level was mildly elevated from 0.5 mg/dL to 0.7 mg/dL. Thirty-six hours after the administration of MTX, the patient developed an erythematous painful swelling on the right middle finger. The erythema, with subsequent large bulla formation, progressed to all the fingers, toes, palms, and the soles of the feet. Some erythematous to hemorrhagic papules also appeared on the bilateral elbows. Subsequently, diffuse tender erythema with extensive erosions and focal tiny pustules developed on the back, abdomen, proximal extremities, and face (Fig. 1a,b). A positive Nikolsky's sign was also present. A biopsy specimen of the right dorsal hand lesion revealed parakeratosis, detached acanthotic epidermis with scattered necrotic keratinocytes, dyskeratotic cells and nuclear atypia, neutrophilic exocytosis, and many neutrophils in the papillary dermis (Fig. 2). The skin condition deteriorated rapidly. Toxic epidermal necrolysis-like lesions involved 90% of the total body surface on the fifth day after MTX infusion. Mucositis, diarrhea, involuntary tremor, fever, and chills were noted. The patient was then sent to the burn unit for intensive skin care. Ten days after MTX therapy, profound agranulocytosis and thrombocytopenia (white cell count 100/mm3, platelets 14,000/mm3, and hemoglobin 5.6 g/dL) were found. The patient was then started on granulocyte colony stimulation factor (G-CSF, 5 microg/kg/day), but his general condition deteriorated rapidly and he died 6 days later due to septic shock and multiple organ failure. Modern medicine can not be practiced without laboratory tests. Laboratory tests play a vital role from the initial stage of clinical examination. The Japanese Society of Clinical Pathology has formed a committee specifically dealing with the effective and economic use of lab tests without missing or duplicating the important tests. As is shown in table 1 in the main text \"Essential Laboratory Tests\" were initially agreed as those tests a patient should take when visiting a clinic regardless of the complaint. From an early stage, laboratory tests were done simultaneously with history-taking and physical examinations. Then the \"Initial Impression\" is obtained and \"Organ-oriented 1st and 2nd screening tests\" and confirmatory tests will be done to make the final diagnosis. To evaluate the validity of the \"Essential Laboratory Tests\", we performed the tests on 1026 patients who visited our general medicine clinic for the first time. We compared the Initial Impression with or without Essential Laboratory Tests. Cases in which a diagnosis could not be made by history-taking and physical examination were decreased from 17.4% to 8.0% by performing the essential laboratory tests. Diagnoses made without the essential laboratory tests were found to be mistaken in 10.4% and the additional use of the tests was suggested to lead to a more accurate diagnosis. In 110 cases, diseases unrelated to the chief complaints, were discovered. Even for the respiratory tract infection, CRP and WBC count, which were included in the essential laboratory tests, were very informative. To examine the incidence rate by age and gender of leukopenia caused by chemotherapy including rifampicin (RFP) and isoniazid (INH), and to study the relationships between the leukopenia and the hepatic side effect or other haematological disorders such as thrombocytopenia. Out of the tuberculosis patients who were admitted to our hospital in 1987-88, 1991-92, and 1996-2000, 1,525 patients (1,153 men, 372 women) were chosen for our study who had the white blood cell counts (WBC) in the peripheral blood more than 3,000/mm3 before chemotherapy, and underwent haematologic examination at least twice within 3 months after starting chemotherapy. The definition of leukopenia was as follows: 1) WBC became less than 3,000/mm3 during chemotherapy for patients with pre-treatment WBC more than 4,000/mm3, or 2) WBC decreased more than 1,000/mm3 in patients with pre-treatment WBC between 3,000 and 4,000/mm3. The incidence rates of leukopenia by age, gender, and regimens of chemotherapy were calculated. The case-control study was done between the control and the leukopenia groups excluding patients suffered from agranulocytosis to clarify the hematological and biochemical characteristics of the leukopenia group. The control patients were chosen in the following way. For each patient with leukopenia, a patient with the same admission year, same gender, same regimen of chemotherapy, and the nearest age was chosen as a control patient. The changes in counts of white blood cell, granulocyte, and platelet, in hemoglobin concentration, and in hepatic enzyme levels before and during chemotherapy were compared between the leukopenia and the control groups. Thrombocytopenia was defined as platelet count less than 15 x 10(4)/mm3 and hepatic dysfunction as either asparate aminotransferase (AST) higher than 31 IU/l or alanine aminotransferase (ALT) higher than 34 IU/l. (1) Incidence rate of leukopenia The leukopenia appeared in 36 patients (14 men, 22 women), two (one man, one woman) of whom showed agranulocytosis. The incidence rate was 1.2% (14/1,153) for men and 5.9% (22/372) for women. The incidence rate of women was higher than that of men in the age groups between 20 to 79 y.o., but no difference was seen in the age groups elder than 80 y.o. There were no differences in the incidence rate among groups treated with HRE (E: ethambutol), HRS (S: streptomycin), and HREZ (Z: pyrazinamide). The chemotherapy was continued in 30 patients after the appearance of leukopenia, and the natural recovery from leukopenia was seen in 19 patients, while the leukopenic state lasted during the chemotherapy in the remaining 11 patients. In two patients who exhibited agranulocytosis all drugs were discontinued. In the remaining 4 patients one or more drugs were discontinued. (2) Case-control study between leukopenia (N = 34) and the control (N = 34) groups There were no differences in age, sputum culture positivity on admission, degree of roentgenographic extent of the disease, ratio of cavity formation, and quantity of daily doses between the two groups. There was also no difference between the days until leukopenia appeared after starting chemotherapy (47.6 +/- 29.5 days) in the leukopenia group, and the days until WBC count became minimum within 3 months after starting chemotherapy (41.7 +/- 21.0 days) in the control group. The negativity of tuberculin skin testing was higher in the leukopenia group [7/14 (50%)] than in the control group [1/10 (10%)], however, the difference was statistically not significant due to rather small size of cases. Before the starting chemotherapy, the counts of WBC (7,230 +/- 1,530 vs 5,500 +/- 1,510/mm3, p &lt; 0.001), neutrophil (5,230 +/- 1,450 vs 4,320 +/- 1,620/mm3, p &lt; 0.05), lymphocyte (1,440 +/- 830 vs 830 +/- 440/mm3, p &lt; 0.001) and platelet (34.9 +/- 12.2 vs 24.1 +/- 6.4 x 10(4)/mm3, p &lt; 0.001) in the peripheral blood and the globulin level (3.71 +/- 0.61 vs 3.35 +/- 0.61 g/dl, p &lt; 0.05) in the serum were significantly higher in the control group than in the leukopenia group. The decrements in the counts of WBC and granulocyte during chemotherapy were larger in the leukopenia group than in the control group (delta WBC: 2,880 +/- 1,530 vs 1,910 +/- 1,520/mm3, and delta Neut: 2,840 +/- 1,510 vs 1,820 +/- 1,380/mm3, p = 0.01, respectively), but the counts of lymphocyte were similar in both groups. The platelet counts also decreased in both groups, but to the mid-normal level in the control group, and to the lowest normal level in the leukopenia group, in which 15 out of 34 patients (44%) showed thrombocytopenia. The levels in the serum of hepatic enzymes such as AST, ALT, and gamma-GTP (gamma-glutamyl aminotransferase) increased during chemotherapy in the leukopenia group, while decreased in the control group, and the facts indicate that in the former not only bone marrow cells but also hepatic cells were impaired by anti-tuberculosis drugs. Leukopenia may occur in the course of treatment with anti-tuberculosis drugs, but it is not necessary to stop the chemotherapy immediately, because the WBC count recovers spontaneously or remains under stable leukopenic state during chemotherapy in most cases. But when leukopenia appears, the peripheral blood counts must be checked cautiously, and the chemotherapy should be stopped if the WBC count progressively decreases. The patients who showed leukopenia due to anti-tuberculosis drugs may have had weaker natural and acquired (cell-mediated) immunologic response to tuberculosis infection, and more vulnerable bone marrow cells and hepatic cells to anti-tuberculosis drugs than the control.\nHere is the question:\nHEMATOLOGY: A 26-year-old woman consults for a feeling of generalized weakness that has progressively set in over the course of three weeks, becoming particularly intense in the last two days. For the last couple of years, she reports episodes of joint pain in the hands that have required the use of anti-inflammatory drugs, as well as the appearance of an erythematous lesion of unclear cause in the neckline area, mainly in summer. In the physical examination there was only an evident cutaneous-mucosal pallor and a heart rate of 100 bpm. The hemogram shows: Hb 6 gr/dL, Hto 27 %, MCV 105 fL, 3,420 leukocytes/mm3 (2300 neutrophils/mm3, 800 lymphocytes/mm3, 250 monocytes/mm3, 50 eosinophils/mm3, 20 basophils/mm3), platelets 170,000/mm3. Biochemistry: AST 30 IU/L, ALT 35 IU/L, GGT 59 IU/L, alkaline phosphatase 105 IU/L, LDH 490 IU/L, urea 20 mg/dL, creatinine 0.8 mg/dL. Taking into account the available information, indicate which of the following additional analytical parameters you would need to know in order to make the most appropriate immediate decision:\nHere are the potential choices:\n1. Vitamin B12.\n2. Antinuclear antibodies.\n3. Direct Coombs' test.\n4. Anti-DNA antibodies.\nThe correct answer is: 3. Direct Coombs' test."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n When a patient with a parapneumonic pleural effusion is first evaluated, a therapeutic thoracentesis should be performed if more than a minimal amount of pleural fluid is present. Fluid obtained at the therapeutic thoracentesis should be gram-stained and cultured and analyzed for glucose, pH, LDH, white blood cells, and differential cell count. If the fluid cannot be drained because of loculations, a chest tube should be inserted and thrombolytic agents administered. If the pleural fluid recurs after the initial therapeutic thoracentesis but the patient is doing well clinically and the initial pleural fluid glucose was greater than 60 mg/dL; the pH, greater than 7.2; the LDH, less than three times the upper normal limit for serum and the cultures are negative; he or she can be observed. If one or more of the aforementioned criteria are not met, a second therapeutic thoracentesis should be performed, with repeat diagnostic evaluations of the pleural fluid. If the fluid recurs a second time, a small chest tube should be placed if the pleural fluid glucose and pH were lower and the LDH higher on the second thoracentesis than on the first thoracentesis. Patients with loculated-parapneumonic effusions should be treated with tube thoracostomy and thrombolytic agents. If drainage is incomplete, thoracoscopy, with breakdown of adhesions and debridement of the pleural space, is indicated. If thoracoscopy is unsuccessful, then thoracotomy, with decortication, is indicated unless the patient is too debilitated. The objective of the present paper is to describe the clinical and computed tomography features of 'explosive pleuritis', an entity first named by Braman and Donat in 1986, and to propose a case definition. A case report of a previously healthy, 45-year-old man admitted to hospital with acute onset pleuritic chest pain is presented. The patient arrived at the emergency room at 15:00 in mild respiratory distress; the initial chest x-ray revealed a small right lower lobe effusion. The subsequent clinical course in hospital was dramatic. Within 18 h of admission, he developed severe respiratory distress with oxygen desaturation to 83% on room air and dullness of the right lung field. A repeat chest x-ray, taken the morning after admission, revealed complete opacification of the right hemithorax. A computed tomography scan of the thorax demonstrated a massive pleural effusion with compression of pulmonary tissue and mediastinal shift. Pleural fluid biochemical analysis revealed the following concentrations: glucose 3.5 mmol/L, lactate dehydrogenase 1550 U/L, protein 56.98 g/L, amylase 68 U/L and white blood cell count 600 cells/mL. The pleural fluid cultures demonstrated light growth of coagulase-negative staphylococcus and viridans streptococcus, and very light growth of Candida albicans. Cytology was negative for malignant cells. Thoracotomy was performed, which demonstrated a loculated parapneumonic effusion that required decortication. The patient responded favourably to the empirical administration of intravenous levofloxacin and ceftriaxone, and conservative surgical methods in the management of the empyema. This report also discusses the patient's rapidly progressing pleural effusion and offers a potential case definition for explosive pleuritis. Explosive pleuritis is a medical emergency defined by the rapid development of a pleural effusion involving more than 90% of the hemithorax over 24 h, which causes compression of pulmonary tissue and mediastinal shift to the contralateral side. About 20% of hospitalized patients with bacterial pneumonia have an accompanying pleural effusion. Parapneumonic effusions (PPE) are associated with a considerable morbidity and mortality. The main decision in managing a patient with a PPE is whether to insert a chest tube (complicated PPE). Imaging (i.e., chest radiograph, ultrasound and computed tomography) and pleural fluid analysis (i.e., pH, glucose, lactate dehydrogenase, bacterial cults) provide essential information for patient management. Therefore, all PPEs should be aspirated for diagnostic purposes. This may require image-guidance if the effusion is small or heavily loculated. According to the current guidelines, any PPE that fulfills at least one of the following criteria should be drained: size &gt; or = 1/2 of the hemithorax, loculations, pleural fluid pH &lt; 7.20 (or alternatively pleural fluid glucose &lt; 60 mg/dl), positive pleural fluid Gram stain or culture, or purulent appearance. The key components of the treatment of complicated PPE and empyema are the use of appropriate antibiotics, provision of nutritional support, and drainage of the pleural space by one of the following methods: therapeutic thoracentesis, tube thoracostomy, intrapleural fibrinolytics, thoracoscopy with breakdown of adhesions or thoracotomy with decortication. The routine use of intrapleural fibrinolytic therapy remains controversial. (c) 2009 Elsevier España, S.L. All rights reserved. Diagnostic thoracentesis is imperative when pneumonia is accompanied by an effusion (parapneumonic effusion). Examination of the pleural fluid is the only way to differentiate empyema and complicated parapneumonic effusions from uncomplicated parapneumonic effusions, and this differentiation is vital in deciding whether chest tube drainage is needed. If the aspirated pleural fluid contains pus or bacteria, closed chest tube drainage and antibiotic therapy should be started promptly. The same management approach is indicated if the pleural fluid pH is less than 7.00 or the glucose level is less than 40 mg/ml, since these effusions almost invariably are complicated parapneumonic effusions that do not resolve without fluid drainage. If the pleural fluid pH is greater than 7.20 and glucose level is more than 40 mg/ml, antibiotic therapy alone will suffice. Management of parapneumonic effusions with a pH of 7.00 to 7.20 should be based on serial observations of clinical status and pleural fluid findings. This review summarizes current strategies in the treatment of patients with pleural effusion. To determine whether a patient has a transudative or exudative pleural effusion, Light's criteria should be applied to measure the concentrations of protein and lactate dehydrogenase (LDH) in the pleural fluid and serum. If the effusion is transudative, therapy should be directed toward the underlying congestive heart failure, cirrhosis, or nephrosis. Consideration should be given to pleurodesis with a sclerosant if patients with recurrent transudative effusion have severe dyspnea due to their effusion. If the effusion is exudative, attempts should be made to define the etiology. The diagnosis of pleural malignancy is most easily established via pleural fluid cytology. If this is negative and the patient is suspected of having pleural malignancy, thoracoscopy is indicated. The concentrations of adenosine deaminase and gamma-interferon in pleural fluid are useful in the diagnosis of pleural tuberculosis. Patients with pneumonia and pleural effusion should undergo therapeutic thoracentesis; the pleural fluid should be Gram-stained and cultured, and the differential cell count, glucose and LDH concentration, and pH should be determined. Indicators of a poor prognosis include the presence of frank pus, a positive Gram-stain, a pleural glucose concentration of less than 2.2 mmol/L, a pH less than 7.00, the presence of pleural loculations, and an LDH concentration greater than three times the upper limit of normal in serum. If the pleural fluid cannot be completely evacuated because of loculations, intrapleural thrombolytic therapy should be considered. If thrombolytics are ineffective, thoracoscopy or thoracotomy with decortication should be performed. Dyspneic patients with malignant pleural effusions whose dyspnea is relieved with therapeutic thoracentesis should be considered for pleurodesis using a tetracycline derivative. Talc is not recommended because it induces acute respiratory distress syndrome in about 5% of patients, with an overall mortality of 1%. Parapneumonic effusions occur in 20 to 40% of patients who are hospitalized with pneumonia. The mortality rate in patients with a parapneumonic effusion is higher than that in patients with pneumonia without a parapneumonic effusion. Some of the excess mortality is due to mismanagement of the parapneumonic effusion. Characteristics of patients that indicate that an invasive procedure will be necessary for its resolution include the following: an effusion occupying more than 50% of the hemithorax or one that is loculated; a positive Gram stain or culture of the pleural fluid; and a purulent pleural fluid that has a pH below 7.20 or a glucose below 60, or has a lactic acid dehydrogenase level of more than three times the upper normal limit for serum. Patients with pneumonia and an effusion of more than minimal size should have a therapeutic thoracentesis. If the fluid cannot be removed with a therapeutic thoracentesis, a chest tube should be inserted and consideration be given to the intrapleural instillation of fibrinolytics. If the loculated effusion persists, the patient should be subjected to video-assisted thoracoscopic surgery, and if the lung cannot be expanded with this procedure, a full thoracotomy with decortication should be performed. The definitive procedure should be performed within 14 d. Nearly 50 per cent of patients with acute bacterial pneumonia have an accompanying pleural effusion (parapneumonic effusion). With appropriate antibiotic therapy, the pleural effusion will resolve along with the pneumonia in the majority of patients. However, in a small fraction, the pleural effusion will not resolve unless drainage of the pleural space is instituted. Such patients are said to have complicated parapneumonic effusions. It is important to identify patients with complicated parapneumonic effusions as early as possible, since tube drainage of the pleural space becomes increasingly difficult the longer its institution is delayed. The possibility of a complicated parapneumonic effusion should be considered in every patient with bacterial pneumonia. If both diaphragms cannot be distinctly identified throughout their length on the lateral chest radiograph, decubitus chest radiographs should be obtained. If the thickness of the fluid on the decubitus radiograph is greater than 10 mm, a diagnostic thoracentesis should be performed. Only pleural fluid analysis can identify patients with complicated parapneumonic effusions. Complicated parapneumonic effusions are characterized by low pleural fluid pH and glucose levels, a high pleural fluid LDH, and a positive Gram stain of the pleural fluid. Tube thoracostomy should be performed immediately in a patient with an acute bacterial pneumonia if the pleural fluid glucose is below 40 mg per 100 ml, the pleural fluid pH is below 7.00, or if the Gram stain of the pleural fluid is positive. Patients with pleural fluid pH above 7.20, pleural fluid LDH below 1000 IU per L, and pleural fluid glucose levels above 40 mg per 100 ml respond well to only the administration of appropriate antibiotics.(ABSTRACT TRUNCATED AT 250 WORDS) In complicated parapneumonic effusion (CPPE), antibiotics and evacuation of the infected pleural fluid are mandatory. The first-line evacuation treatment is still controversial. The aim of this article is to highlight the usefulness of repeated therapeutic thoracentesis (RTT) as a first-line treatment. In the most recent study on RTT in CPPE, disposable pleural needles were used and the median number of thoracentesis was 3. The success rate was 81%, and only 4% of the patients were referred for thoracic surgery. The 1-year survival rate was 88%. On multivariate analysis, the observation of microorganisms in the pleural fluid after Gram staining and first thoracentesis volume at least 450 ml was associated with a higher risk of RTT failure. RTT is less invasive and can target different loculated pleural collections. Patients are less confined to beds between each procedure, and could even be ambulatory managed. The use of intrapleural fibrinolytics in association with DNase could most likely enhance the efficacy of RTT. RTT is efficient and well tolerated in the management of CPPE, including pleural empyema, and could be proposed as a first-line therapy for CPPE. This technique could be used in association with intrapleural fibrinolytics and DNase. There is no readily available evidence on the route of administration and duration of antibiotics in patients with pleural empyema. Experts agree that all patients should be hospitalized and treated with antibiotics intravenously. The specific antimicrobial agent should be chosen based on Gram stain and culture, or on local epidemiologic data when these are not available. Anaerobic coverage must be included in all adults, and in children if aspiration is likely. Good pleural fluid and empyema penetration has been reported in adults for penicillins, ceftriaxone, metronidazole, clindamycin, vancomycin, gentamicin and ciprofloxacin. Aminoglycosides should typically be avoided as they have poor penetration into the pleural space. There is no clear consensus on duration of intravenous and oral therapy. Switching to oral antibiotics can be considered upon clinical and objective improvement (adequate drainage and removal of chest tube, declining CRP, temperature normalization). Oral Complicated parapneumonic effusion is one in which an invasive procedure is necessary for its resolution and empyema means pus in the pleural space. An early diagnosis and therapy of these conditions results in less morbidity and mortality. CT of the chest is important to study complex pleural effusions. Loculated effusions, those occupying more than 50% of the thorax, or which show positive Gram stain or bacterial culture, or a purulent effusion with a pH below 7.20, with a glucose level below 60 mg/dl or a LDH level more than three times the upper limit of normal for serum, are indications for an invasive procedure. These characteristics result from the evolution of a not well treated parapneumonic effusion, through the three stages: (1) exsudative; (2) fibrinopurulent; (3) fibrotic. Depending on the stage therapeutic methods vary from therapeutic thoracentesis, insertion of a chest tube with or without instillation of fibrinolytics, video-assisted thoracoscopic surgery, and lung decortication. A review of all these aspects are done based on a series of three cases reports with very different clinical presentation: one patient with empyema by Streptococcus pyogenes and that died rapidly due to massive hemoptysis; a patient with empyema due to acute pneumonia developing during an airflight; a patient with empyema and bacteraemia by Streptococcus pneumonia leading to the diagnosis of an unknown HIV infection. Pleural effusion, empyema, and abscess In pneumonia, a collection of fluid may form in the space that surrounds the lung. Occasionally, microorganisms will infect this fluid, causing an empyema. To distinguish an empyema from the more common simple parapneumonic effusion, the fluid may be collected with a needle (thoracentesis), and examined. If this shows evidence of empyema, complete drainage of the fluid is necessary, often requiring a drainage catheter. In severe cases of empyema, surgery may be needed. If the infected fluid is not drained, the infection may persist, because antibiotics do not penetrate well into the pleural cavity. If the fluid is sterile, it must be drained only if it is causing symptoms or remains unresolved. Thoracentesis Once a pleural effusion is diagnosed, its cause must be determined. Pleural fluid is drawn out of the pleural space in a process called thoracentesis, and it should be done in almost all patients who have pleural fluid that is at least 10 mm in thickness on CT, ultrasonography, or lateral decubitus X-ray and that is new or of uncertain etiology. In general, the only patients who do not require thoracentesis are those who have heart failure with symmetric pleural effusions and no chest pain or fever; in these patients, diuresis can be tried, and thoracentesis is avoided unless effusions persist for more than 3 days. In a thoracentesis, a needle is inserted through the back of the chest wall in the sixth, seventh, or eighth intercostal space on the midaxillary line, into the pleural space. The use of ultrasound to guide the procedure is now standard of care as it increases accuracy and decreases complications. After removal, the fluid may then be evaluated for: Prior attempts to create an animal model of empyema by direct inoculation of bacteria alone into the pleural space have been unsuccessful. The animals either died of overwhelming sepsis or cleared the infection from the pleural space without development of an empyema. We hypothesized that injection of bacteria with a nutrient agar into the pleural space would allow the bacteria to remain in the pleural space for an extended time period, permitting an empyema to develop. The bacterium Pasteurella multocida in brain heart infusion (BHI) agar was injected into the right hemithorax of 12 New Zealand white male rabbits. Our preliminary studies showed that the animals died in less than 7 days if they were not given parenteral antibiotics. For this reason, the rabbits were given penicillin, 200,000 U, IM, every 24 h starting 24 h after bacterial injection. Pleural fluid was sampled by thoracentesis at 12, 24, 48, 72, and 96 h after bacterial injection. Pleural fluid pH, glucose, lactate dehydrogenase (LDH), leukocyte count, and Gram's stain and culture (in one half of the animals) were obtained at each time point. Pleural biopsy specimens were obtained at autopsy after 96 h. The mean pleural fluid pH reached a nadir of 7.01 at 24 h and remained less than 7.1 throughout the experiment. The mean pleural fluid glucose level reached a nadir of 10 mg/dL at 24 h. The mean pleural fluid LDH peaked at 21,000 IU/L at 24 h and the mean pleural fluid leukocyte count peaked at 12 h with a value of 67,000 cells per cubic millimeter. Gram's stains revealed organisms and cultures were positive for growth in all animals at 12 and 24 h. Some animals had positive Gram's stains and growth on cultures up to 72 h after bacterial injection. At autopsy, all rabbits injected with bacteria had gross pus in the right pleural space and had developed a thick pleural peel. Microscopic specimens of the pleura revealed large numbers of leukocytes (primarily polymorphonuclear lymphocytes) with invasion of the adjacent lung and chest wall. In conclusion, this model more closely mimics the empyema that occurs in humans, relative to previous animal models. This model appears appropriate for additional randomized studies in which different methods for the treatment of empyema can be evaluated. 2. Pleural fluid pH <7.20 3. Pleural fluid glucose <3.3 mmol/L (<60 mg/dL) 4. Positive Gram stain or culture of the pleural fluid 5. Presence of gross pus in the pleural space If the fluid recurs after the initial therapeutic thoracentesis and if any of these characteristics are present, a repeat thoracentesis should be performed. If the fluid cannot be completely removed with the therapeutic thoracentesis, consideration should be given to inserting a chest tube and instilling the combination of a fibrinolytic agent (e.g., tissue plasminogen activator, 10 mg) and deoxyribonuclease (5 mg) or performing a thoracoscopy with the breakdown of adhesions. Decortication should be considered when these measures are ineffective. The recommendation is for diagnostic fluid sampling via thoracentesis in all patients with pleural effusions with greater than 2 cm depth on lateral decubitus film or computed tomography, associated with a pneumonic illness, recent chest trauma, surgery or features of ongoing sepsis. [12] [13] Frank pus in the pleural space invariably necessitates surgical drainage. However, if there is uncertainty whether a turbid fluid is infected, a pH less than 7.2 measured via a blood gas analyzer warrants an invasive procedure for drainage. [14] Polymorphonucleocyte predominance, low glucose, and LDH over 1000 on biochemical analysis of pleural fluid support the diagnosis of empyema. Furthermore, fluid culture data should be used to guide appropriate antimicrobial therapy. Research shows that culture yield can be increased significantly if the pleural fluid gets injected into blood culture bottles immediately after aspiration. [15] A parapneumonic effusion is a type of pleural effusion that arises as a result of a pneumonia, lung abscess, or bronchiectasis. There are three types of parapneumonic effusions: uncomplicated effusions, complicated effusions, and empyema. Uncomplicated effusions generally respond well to appropriate antibiotic treatment. Diagnosis The criteria for a complicated parapneumonic effusion include Gram stain–positive or culture-positive pleural fluid, pleural fluid pH <7.20, and pleural fluid LDH that is greater than three times the upper limit of normal of serum LDH. Diagnostic techniques available include plain film chest x-ray, computed tomography (CT), and ultrasound. Ultrasound can be useful in differentiating between empyema and other transudative and exudative effusions due in part to relative echogenicity of different organs such as the liver (often isoechogenic with empyema). The possibility of a parapneumonic effusion should be considered whenever a patient with bacterial pneumonia is initially evaluated. The presence of free pleural fluid can be demonstrated with a lateral decubitus radiograph, computed tomography (CT) of the chest, or ultrasound. If the free fluid separates the lung from the chest wall by >10 mm, a therapeutic thoracentesis should be performed. Factors indicating the likely need for a procedure more invasive than a thoracentesis (in increasing order of importance) include the following: 1. 2. Pleural fluid pH <7.20 3. Pleural fluid glucose <3.3 mmol/L (<60 mg/dL) 4. Positive Gram stain or culture of the pleural fluid 5. Presence of gross pus in the pleural space Treatment Pleural fluid drainage Proven empyema (as defined by the \"golden\" criteria mentioned earlier) is an indication for prompt chest tube drainage. This has been shown to improve resolution of the infection and shorten hospital admission. Data from a meta-analysis has shown that a pleural fluid pH of <7.2 is the most powerful indicator to predict the need for chest tube drainage in patients with non-purulent, culture negative fluid. Because of the viscous, lumpy nature of infected pleural fluid, in combination with possible septation and loculation, it has been proposed that intrapleural fibrinolytic or mucolytic therapy might improve drainage and therefore might have a positive effect on the clinical outcome. Intrapleural fibrinolysis with urokinase decreased the need for surgery but there is a trend to increased serious side effects. In an emergency room or hospital setting, appropriate evaluation and treatment for an asplenic febrile patient should include a complete blood count with differential, blood culture with Gram stain, arterial blood gas analysis, chest x-ray, and consideration for lumbar puncture with CSF studies. None of these evaluations should delay the initiation of appropriate broad-spectrum intravenous antibiotics. The Surviving Sepsis Campaign guidelines state that antibiotics should be administered to a patient suspected of sepsis within 1 hour of presentation. Delay in starting antibiotics for any reason is associated with a poor outcome. The presence of organisms by gram stain or culture leads to a diagnosis of empyema and necessitates a chest tube for drainage of pus. Cytology is necessary for determining the presence of malignant cells in the pleural fluid. The sensitivity of pleural fluid cytology in the presence of malignant effusion in the first thoracentesis is around 60%, and the yield increases with further attempts, approaching 95% by three samples on different days.  However, if a malignant effusion is strongly suspected and cytology is negative, then medical thoracoscopy with pleural biopsy can be performed after two to three thoracenteses to obtain a diagnosis. Treatment of parapneumonic effusion includes appropriate antibiotic therapy together with drainage of pleural fluid as indicated. Parapneumonic effusion is classified into 4 groups based on risk for the poor outcome: Category 1 (very low risk): The effusion is small (less than 10-mm thickness on decubitus) and free-flowing. No thoracentesis is indicated. Category 2 (low risk): The effusion is small to moderate (equal to 10 mm and less than half the hemithorax) and free-flowing with negative culture and Gram stain regardless of the prior use of antibiotics and pH equal to 7.20. Category 3 (moderate risk), in which one of the following criteria is present: the fluid equal to half the hemithorax, loculated effusion, thicken pleura on contrast-enhanced CT scan, positive Gram stain or culture or pH less than 7.20. Category 4 (high risk): This is when pleural fluid is in the form of pure pus. Tension pneumothorax is a medical emergency that requires emergent needle decompression before a chest tube is placed. Indications This procedure is indicated when unexplained fluid accumulates in the chest cavity outside the lung. In more than 90% of cases analysis of pleural fluid yields clinically useful information. If a large amount of fluid is present, then this procedure can also be used therapeutically to remove that fluid and improve patient comfort and lung function. The most common causes of pleural effusions are cancer, congestive heart failure, pneumonia, and recent surgery. In countries where tuberculosis is common, this is also a common cause of pleural effusions. Cultures and stains If the effusion is caused by infection, microbiological culture may yield the infectious organism responsible for the infection, sometimes before other cultures (e.g. blood cultures and sputum cultures) become positive. A Gram stain may give a rough indication of the causative organism. A Ziehl–Neelsen stain may identify tuberculosis or other mycobacterial diseases. Cytology Cytology is an important tool in identifying effusions due to malignancy. The most common causes for pleural fluid are lung cancer, metastasis from elsewhere and pleural mesothelioma. The latter often presents with an effusion. Normal cytology results do not reliably rule out malignancy, but make the diagnosis more unlikely. References External links A photo gallery of thoracentesis showing the procedure step-by-step. V. Dimov, B. Altaqi, Clinical Notes, 2005. A free PDA version. Medical tests Respiratory system procedures Veterinary diagnosis Interventional radiology 1850 introductions can be avoided in patients with small effusions associated with resolving pneumonia. These patients typically present with cough, fever, leukocytosis, and uni-lateral infiltrate, and the effusion is usually a result of a reactive, parapneumonic process. If the effusion is small and the patient responds to antibiotics, a diagnostic thoracentesis may be unneces-sary. If the effusion is large and compromising respiratory efforts, or if the patient has a persistent white blood cell count despite improving signs of pneumonia, an empyema of the pleural space must be considered. In these patients, early and aggressive drainage with chest tubes is required, possibly with surgical intervention.Once the decision is made to access a pleural effusion, the next step is to determine if a sample of the fluid or complete drainage of the pleural space is desired. This step is influenced by the clinical history, the type and amount of fluid present, the Brunicardi_Ch19_p0661-p0750.indd 73601/03/19 A category 3 effusion may also be defined as a pH of <7.20 or a positive gram stain/culture (empyema). [13] Category 4 effusions are defined by purulent material on thoracentesis. [13] Category 3 and 4 effusions are recommended to have thoracostomy drainage. [13] Empyema, or category 4 effusions, may require surgical evacuation and decortication. Due to the high mortality of the categories 3 and 4 pleural effusions (30%), additional methods for the complete drainage of the infected pleural fluid include intrapleural fibrinolytic followed by drainage and/or surgical decortication. [14] The MIST 2 trial compared intrapleural placebo, intrapleural DNase, intrapleural tPA, and combination tPA/DNAse in patients with category 3 or 4 effusions. The most often used \"golden\" criteria for empyema are pleural effusion with macroscopic presence of pus, a positive Gram stain or culture of pleural fluid, or a pleural fluid pH under 7.2 with normal peripheral blood pH. Clinical guidelines for adult patients therefore advocate diagnostic pleural fluid aspiration in patients with pleural effusion in association with sepsis or pneumonic illness. Because pleural effusion in the pediatric population is almost always parapneumonic and the need for chest tube drainage can be made on clinical grounds, British guidelines for the management of pleural infection in children do not recommend diagnostic pleural fluid sampling. The use of ultrasound for needle guidance can minimize the complication rate. Follow-up imaging While chest X-ray has traditionally been performed to assess for pneumothorax following the procedure, it may no longer be necessary to do so in asymptomatic, non-ventilated persons given the widespread use of ultrasound to guide this procedure. Interpretation of pleural fluid analysis Several diagnostic tools are available to determine the etiology of pleural fluid. Transudate versus exudate First the fluid is either transudate or exudate. A transudate is defined as pleural fluid to serum total protein ratio of less than 0.5, pleural fluid to serum LDH ratio > 0.6, and absolute pleural fluid LDH > 200 IU or > 2/3 of the normal.\nHere is the question:\nINFECTOLOGY: A 64-year-old male presents with fever, cough, dyspnea and right pleuritic pain of 1 week's evolution. Chest X-ray shows a loculated right pleural effusion occupying two thirds of the hemithorax. During thoracentesis, a yellowish fluid is drawn and analysis shows: leukocytes 15,000/uL, 92% neutrophils, glucose 30 mg/dL, pH 7, lactate dehydrogenase 3500 U/L, adenosine deaminase 45 U/L and absence of germs on GRAM stain. What is the most appropriate next course of action in this patient?\nHere are the potential choices:\n1. Intravenous antibiotic therapy.\n2. Intravenous antibiotic therapy and repeat diagnostic thoracentesis in 24 hours.\n3. Intravenous antibiotic therapy and repeat diagnostic thoracentesis if there is no improvement in 48 hours.\n4. Intravenous antibiotic therapy and evacuative (therapeutic) thoracentesis if any germ is isolated in the pleural fluid culture.\n5. Intravenous antibiotic therapy and placement of a chest tube or catheter to drain all pleural fluid.\nThe correct answer is: ",
        "gold_answer": "5 Intravenous antibiotic therapy and placement of a chest tube or catheter to drain all pleural fluid.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n When a patient with a parapneumonic pleural effusion is first evaluated, a therapeutic thoracentesis should be performed if more than a minimal amount of pleural fluid is present. Fluid obtained at the therapeutic thoracentesis should be gram-stained and cultured and analyzed for glucose, pH, LDH, white blood cells, and differential cell count. If the fluid cannot be drained because of loculations, a chest tube should be inserted and thrombolytic agents administered. If the pleural fluid recurs after the initial therapeutic thoracentesis but the patient is doing well clinically and the initial pleural fluid glucose was greater than 60 mg/dL; the pH, greater than 7.2; the LDH, less than three times the upper normal limit for serum and the cultures are negative; he or she can be observed. If one or more of the aforementioned criteria are not met, a second therapeutic thoracentesis should be performed, with repeat diagnostic evaluations of the pleural fluid. If the fluid recurs a second time, a small chest tube should be placed if the pleural fluid glucose and pH were lower and the LDH higher on the second thoracentesis than on the first thoracentesis. Patients with loculated-parapneumonic effusions should be treated with tube thoracostomy and thrombolytic agents. If drainage is incomplete, thoracoscopy, with breakdown of adhesions and debridement of the pleural space, is indicated. If thoracoscopy is unsuccessful, then thoracotomy, with decortication, is indicated unless the patient is too debilitated. The objective of the present paper is to describe the clinical and computed tomography features of 'explosive pleuritis', an entity first named by Braman and Donat in 1986, and to propose a case definition. A case report of a previously healthy, 45-year-old man admitted to hospital with acute onset pleuritic chest pain is presented. The patient arrived at the emergency room at 15:00 in mild respiratory distress; the initial chest x-ray revealed a small right lower lobe effusion. The subsequent clinical course in hospital was dramatic. Within 18 h of admission, he developed severe respiratory distress with oxygen desaturation to 83% on room air and dullness of the right lung field. A repeat chest x-ray, taken the morning after admission, revealed complete opacification of the right hemithorax. A computed tomography scan of the thorax demonstrated a massive pleural effusion with compression of pulmonary tissue and mediastinal shift. Pleural fluid biochemical analysis revealed the following concentrations: glucose 3.5 mmol/L, lactate dehydrogenase 1550 U/L, protein 56.98 g/L, amylase 68 U/L and white blood cell count 600 cells/mL. The pleural fluid cultures demonstrated light growth of coagulase-negative staphylococcus and viridans streptococcus, and very light growth of Candida albicans. Cytology was negative for malignant cells. Thoracotomy was performed, which demonstrated a loculated parapneumonic effusion that required decortication. The patient responded favourably to the empirical administration of intravenous levofloxacin and ceftriaxone, and conservative surgical methods in the management of the empyema. This report also discusses the patient's rapidly progressing pleural effusion and offers a potential case definition for explosive pleuritis. Explosive pleuritis is a medical emergency defined by the rapid development of a pleural effusion involving more than 90% of the hemithorax over 24 h, which causes compression of pulmonary tissue and mediastinal shift to the contralateral side. About 20% of hospitalized patients with bacterial pneumonia have an accompanying pleural effusion. Parapneumonic effusions (PPE) are associated with a considerable morbidity and mortality. The main decision in managing a patient with a PPE is whether to insert a chest tube (complicated PPE). Imaging (i.e., chest radiograph, ultrasound and computed tomography) and pleural fluid analysis (i.e., pH, glucose, lactate dehydrogenase, bacterial cults) provide essential information for patient management. Therefore, all PPEs should be aspirated for diagnostic purposes. This may require image-guidance if the effusion is small or heavily loculated. According to the current guidelines, any PPE that fulfills at least one of the following criteria should be drained: size &gt; or = 1/2 of the hemithorax, loculations, pleural fluid pH &lt; 7.20 (or alternatively pleural fluid glucose &lt; 60 mg/dl), positive pleural fluid Gram stain or culture, or purulent appearance. The key components of the treatment of complicated PPE and empyema are the use of appropriate antibiotics, provision of nutritional support, and drainage of the pleural space by one of the following methods: therapeutic thoracentesis, tube thoracostomy, intrapleural fibrinolytics, thoracoscopy with breakdown of adhesions or thoracotomy with decortication. The routine use of intrapleural fibrinolytic therapy remains controversial. (c) 2009 Elsevier España, S.L. All rights reserved. Diagnostic thoracentesis is imperative when pneumonia is accompanied by an effusion (parapneumonic effusion). Examination of the pleural fluid is the only way to differentiate empyema and complicated parapneumonic effusions from uncomplicated parapneumonic effusions, and this differentiation is vital in deciding whether chest tube drainage is needed. If the aspirated pleural fluid contains pus or bacteria, closed chest tube drainage and antibiotic therapy should be started promptly. The same management approach is indicated if the pleural fluid pH is less than 7.00 or the glucose level is less than 40 mg/ml, since these effusions almost invariably are complicated parapneumonic effusions that do not resolve without fluid drainage. If the pleural fluid pH is greater than 7.20 and glucose level is more than 40 mg/ml, antibiotic therapy alone will suffice. Management of parapneumonic effusions with a pH of 7.00 to 7.20 should be based on serial observations of clinical status and pleural fluid findings. This review summarizes current strategies in the treatment of patients with pleural effusion. To determine whether a patient has a transudative or exudative pleural effusion, Light's criteria should be applied to measure the concentrations of protein and lactate dehydrogenase (LDH) in the pleural fluid and serum. If the effusion is transudative, therapy should be directed toward the underlying congestive heart failure, cirrhosis, or nephrosis. Consideration should be given to pleurodesis with a sclerosant if patients with recurrent transudative effusion have severe dyspnea due to their effusion. If the effusion is exudative, attempts should be made to define the etiology. The diagnosis of pleural malignancy is most easily established via pleural fluid cytology. If this is negative and the patient is suspected of having pleural malignancy, thoracoscopy is indicated. The concentrations of adenosine deaminase and gamma-interferon in pleural fluid are useful in the diagnosis of pleural tuberculosis. Patients with pneumonia and pleural effusion should undergo therapeutic thoracentesis; the pleural fluid should be Gram-stained and cultured, and the differential cell count, glucose and LDH concentration, and pH should be determined. Indicators of a poor prognosis include the presence of frank pus, a positive Gram-stain, a pleural glucose concentration of less than 2.2 mmol/L, a pH less than 7.00, the presence of pleural loculations, and an LDH concentration greater than three times the upper limit of normal in serum. If the pleural fluid cannot be completely evacuated because of loculations, intrapleural thrombolytic therapy should be considered. If thrombolytics are ineffective, thoracoscopy or thoracotomy with decortication should be performed. Dyspneic patients with malignant pleural effusions whose dyspnea is relieved with therapeutic thoracentesis should be considered for pleurodesis using a tetracycline derivative. Talc is not recommended because it induces acute respiratory distress syndrome in about 5% of patients, with an overall mortality of 1%. Parapneumonic effusions occur in 20 to 40% of patients who are hospitalized with pneumonia. The mortality rate in patients with a parapneumonic effusion is higher than that in patients with pneumonia without a parapneumonic effusion. Some of the excess mortality is due to mismanagement of the parapneumonic effusion. Characteristics of patients that indicate that an invasive procedure will be necessary for its resolution include the following: an effusion occupying more than 50% of the hemithorax or one that is loculated; a positive Gram stain or culture of the pleural fluid; and a purulent pleural fluid that has a pH below 7.20 or a glucose below 60, or has a lactic acid dehydrogenase level of more than three times the upper normal limit for serum. Patients with pneumonia and an effusion of more than minimal size should have a therapeutic thoracentesis. If the fluid cannot be removed with a therapeutic thoracentesis, a chest tube should be inserted and consideration be given to the intrapleural instillation of fibrinolytics. If the loculated effusion persists, the patient should be subjected to video-assisted thoracoscopic surgery, and if the lung cannot be expanded with this procedure, a full thoracotomy with decortication should be performed. The definitive procedure should be performed within 14 d. Nearly 50 per cent of patients with acute bacterial pneumonia have an accompanying pleural effusion (parapneumonic effusion). With appropriate antibiotic therapy, the pleural effusion will resolve along with the pneumonia in the majority of patients. However, in a small fraction, the pleural effusion will not resolve unless drainage of the pleural space is instituted. Such patients are said to have complicated parapneumonic effusions. It is important to identify patients with complicated parapneumonic effusions as early as possible, since tube drainage of the pleural space becomes increasingly difficult the longer its institution is delayed. The possibility of a complicated parapneumonic effusion should be considered in every patient with bacterial pneumonia. If both diaphragms cannot be distinctly identified throughout their length on the lateral chest radiograph, decubitus chest radiographs should be obtained. If the thickness of the fluid on the decubitus radiograph is greater than 10 mm, a diagnostic thoracentesis should be performed. Only pleural fluid analysis can identify patients with complicated parapneumonic effusions. Complicated parapneumonic effusions are characterized by low pleural fluid pH and glucose levels, a high pleural fluid LDH, and a positive Gram stain of the pleural fluid. Tube thoracostomy should be performed immediately in a patient with an acute bacterial pneumonia if the pleural fluid glucose is below 40 mg per 100 ml, the pleural fluid pH is below 7.00, or if the Gram stain of the pleural fluid is positive. Patients with pleural fluid pH above 7.20, pleural fluid LDH below 1000 IU per L, and pleural fluid glucose levels above 40 mg per 100 ml respond well to only the administration of appropriate antibiotics.(ABSTRACT TRUNCATED AT 250 WORDS) In complicated parapneumonic effusion (CPPE), antibiotics and evacuation of the infected pleural fluid are mandatory. The first-line evacuation treatment is still controversial. The aim of this article is to highlight the usefulness of repeated therapeutic thoracentesis (RTT) as a first-line treatment. In the most recent study on RTT in CPPE, disposable pleural needles were used and the median number of thoracentesis was 3. The success rate was 81%, and only 4% of the patients were referred for thoracic surgery. The 1-year survival rate was 88%. On multivariate analysis, the observation of microorganisms in the pleural fluid after Gram staining and first thoracentesis volume at least 450 ml was associated with a higher risk of RTT failure. RTT is less invasive and can target different loculated pleural collections. Patients are less confined to beds between each procedure, and could even be ambulatory managed. The use of intrapleural fibrinolytics in association with DNase could most likely enhance the efficacy of RTT. RTT is efficient and well tolerated in the management of CPPE, including pleural empyema, and could be proposed as a first-line therapy for CPPE. This technique could be used in association with intrapleural fibrinolytics and DNase. There is no readily available evidence on the route of administration and duration of antibiotics in patients with pleural empyema. Experts agree that all patients should be hospitalized and treated with antibiotics intravenously. The specific antimicrobial agent should be chosen based on Gram stain and culture, or on local epidemiologic data when these are not available. Anaerobic coverage must be included in all adults, and in children if aspiration is likely. Good pleural fluid and empyema penetration has been reported in adults for penicillins, ceftriaxone, metronidazole, clindamycin, vancomycin, gentamicin and ciprofloxacin. Aminoglycosides should typically be avoided as they have poor penetration into the pleural space. There is no clear consensus on duration of intravenous and oral therapy. Switching to oral antibiotics can be considered upon clinical and objective improvement (adequate drainage and removal of chest tube, declining CRP, temperature normalization). Oral Complicated parapneumonic effusion is one in which an invasive procedure is necessary for its resolution and empyema means pus in the pleural space. An early diagnosis and therapy of these conditions results in less morbidity and mortality. CT of the chest is important to study complex pleural effusions. Loculated effusions, those occupying more than 50% of the thorax, or which show positive Gram stain or bacterial culture, or a purulent effusion with a pH below 7.20, with a glucose level below 60 mg/dl or a LDH level more than three times the upper limit of normal for serum, are indications for an invasive procedure. These characteristics result from the evolution of a not well treated parapneumonic effusion, through the three stages: (1) exsudative; (2) fibrinopurulent; (3) fibrotic. Depending on the stage therapeutic methods vary from therapeutic thoracentesis, insertion of a chest tube with or without instillation of fibrinolytics, video-assisted thoracoscopic surgery, and lung decortication. A review of all these aspects are done based on a series of three cases reports with very different clinical presentation: one patient with empyema by Streptococcus pyogenes and that died rapidly due to massive hemoptysis; a patient with empyema due to acute pneumonia developing during an airflight; a patient with empyema and bacteraemia by Streptococcus pneumonia leading to the diagnosis of an unknown HIV infection. Pleural effusion, empyema, and abscess In pneumonia, a collection of fluid may form in the space that surrounds the lung. Occasionally, microorganisms will infect this fluid, causing an empyema. To distinguish an empyema from the more common simple parapneumonic effusion, the fluid may be collected with a needle (thoracentesis), and examined. If this shows evidence of empyema, complete drainage of the fluid is necessary, often requiring a drainage catheter. In severe cases of empyema, surgery may be needed. If the infected fluid is not drained, the infection may persist, because antibiotics do not penetrate well into the pleural cavity. If the fluid is sterile, it must be drained only if it is causing symptoms or remains unresolved. Thoracentesis Once a pleural effusion is diagnosed, its cause must be determined. Pleural fluid is drawn out of the pleural space in a process called thoracentesis, and it should be done in almost all patients who have pleural fluid that is at least 10 mm in thickness on CT, ultrasonography, or lateral decubitus X-ray and that is new or of uncertain etiology. In general, the only patients who do not require thoracentesis are those who have heart failure with symmetric pleural effusions and no chest pain or fever; in these patients, diuresis can be tried, and thoracentesis is avoided unless effusions persist for more than 3 days. In a thoracentesis, a needle is inserted through the back of the chest wall in the sixth, seventh, or eighth intercostal space on the midaxillary line, into the pleural space. The use of ultrasound to guide the procedure is now standard of care as it increases accuracy and decreases complications. After removal, the fluid may then be evaluated for: Prior attempts to create an animal model of empyema by direct inoculation of bacteria alone into the pleural space have been unsuccessful. The animals either died of overwhelming sepsis or cleared the infection from the pleural space without development of an empyema. We hypothesized that injection of bacteria with a nutrient agar into the pleural space would allow the bacteria to remain in the pleural space for an extended time period, permitting an empyema to develop. The bacterium Pasteurella multocida in brain heart infusion (BHI) agar was injected into the right hemithorax of 12 New Zealand white male rabbits. Our preliminary studies showed that the animals died in less than 7 days if they were not given parenteral antibiotics. For this reason, the rabbits were given penicillin, 200,000 U, IM, every 24 h starting 24 h after bacterial injection. Pleural fluid was sampled by thoracentesis at 12, 24, 48, 72, and 96 h after bacterial injection. Pleural fluid pH, glucose, lactate dehydrogenase (LDH), leukocyte count, and Gram's stain and culture (in one half of the animals) were obtained at each time point. Pleural biopsy specimens were obtained at autopsy after 96 h. The mean pleural fluid pH reached a nadir of 7.01 at 24 h and remained less than 7.1 throughout the experiment. The mean pleural fluid glucose level reached a nadir of 10 mg/dL at 24 h. The mean pleural fluid LDH peaked at 21,000 IU/L at 24 h and the mean pleural fluid leukocyte count peaked at 12 h with a value of 67,000 cells per cubic millimeter. Gram's stains revealed organisms and cultures were positive for growth in all animals at 12 and 24 h. Some animals had positive Gram's stains and growth on cultures up to 72 h after bacterial injection. At autopsy, all rabbits injected with bacteria had gross pus in the right pleural space and had developed a thick pleural peel. Microscopic specimens of the pleura revealed large numbers of leukocytes (primarily polymorphonuclear lymphocytes) with invasion of the adjacent lung and chest wall. In conclusion, this model more closely mimics the empyema that occurs in humans, relative to previous animal models. This model appears appropriate for additional randomized studies in which different methods for the treatment of empyema can be evaluated. 2. Pleural fluid pH <7.20 3. Pleural fluid glucose <3.3 mmol/L (<60 mg/dL) 4. Positive Gram stain or culture of the pleural fluid 5. Presence of gross pus in the pleural space If the fluid recurs after the initial therapeutic thoracentesis and if any of these characteristics are present, a repeat thoracentesis should be performed. If the fluid cannot be completely removed with the therapeutic thoracentesis, consideration should be given to inserting a chest tube and instilling the combination of a fibrinolytic agent (e.g., tissue plasminogen activator, 10 mg) and deoxyribonuclease (5 mg) or performing a thoracoscopy with the breakdown of adhesions. Decortication should be considered when these measures are ineffective. The recommendation is for diagnostic fluid sampling via thoracentesis in all patients with pleural effusions with greater than 2 cm depth on lateral decubitus film or computed tomography, associated with a pneumonic illness, recent chest trauma, surgery or features of ongoing sepsis. [12] [13] Frank pus in the pleural space invariably necessitates surgical drainage. However, if there is uncertainty whether a turbid fluid is infected, a pH less than 7.2 measured via a blood gas analyzer warrants an invasive procedure for drainage. [14] Polymorphonucleocyte predominance, low glucose, and LDH over 1000 on biochemical analysis of pleural fluid support the diagnosis of empyema. Furthermore, fluid culture data should be used to guide appropriate antimicrobial therapy. Research shows that culture yield can be increased significantly if the pleural fluid gets injected into blood culture bottles immediately after aspiration. [15] A parapneumonic effusion is a type of pleural effusion that arises as a result of a pneumonia, lung abscess, or bronchiectasis. There are three types of parapneumonic effusions: uncomplicated effusions, complicated effusions, and empyema. Uncomplicated effusions generally respond well to appropriate antibiotic treatment. Diagnosis The criteria for a complicated parapneumonic effusion include Gram stain–positive or culture-positive pleural fluid, pleural fluid pH <7.20, and pleural fluid LDH that is greater than three times the upper limit of normal of serum LDH. Diagnostic techniques available include plain film chest x-ray, computed tomography (CT), and ultrasound. Ultrasound can be useful in differentiating between empyema and other transudative and exudative effusions due in part to relative echogenicity of different organs such as the liver (often isoechogenic with empyema). The possibility of a parapneumonic effusion should be considered whenever a patient with bacterial pneumonia is initially evaluated. The presence of free pleural fluid can be demonstrated with a lateral decubitus radiograph, computed tomography (CT) of the chest, or ultrasound. If the free fluid separates the lung from the chest wall by >10 mm, a therapeutic thoracentesis should be performed. Factors indicating the likely need for a procedure more invasive than a thoracentesis (in increasing order of importance) include the following: 1. 2. Pleural fluid pH <7.20 3. Pleural fluid glucose <3.3 mmol/L (<60 mg/dL) 4. Positive Gram stain or culture of the pleural fluid 5. Presence of gross pus in the pleural space Treatment Pleural fluid drainage Proven empyema (as defined by the \"golden\" criteria mentioned earlier) is an indication for prompt chest tube drainage. This has been shown to improve resolution of the infection and shorten hospital admission. Data from a meta-analysis has shown that a pleural fluid pH of <7.2 is the most powerful indicator to predict the need for chest tube drainage in patients with non-purulent, culture negative fluid. Because of the viscous, lumpy nature of infected pleural fluid, in combination with possible septation and loculation, it has been proposed that intrapleural fibrinolytic or mucolytic therapy might improve drainage and therefore might have a positive effect on the clinical outcome. Intrapleural fibrinolysis with urokinase decreased the need for surgery but there is a trend to increased serious side effects. In an emergency room or hospital setting, appropriate evaluation and treatment for an asplenic febrile patient should include a complete blood count with differential, blood culture with Gram stain, arterial blood gas analysis, chest x-ray, and consideration for lumbar puncture with CSF studies. None of these evaluations should delay the initiation of appropriate broad-spectrum intravenous antibiotics. The Surviving Sepsis Campaign guidelines state that antibiotics should be administered to a patient suspected of sepsis within 1 hour of presentation. Delay in starting antibiotics for any reason is associated with a poor outcome. The presence of organisms by gram stain or culture leads to a diagnosis of empyema and necessitates a chest tube for drainage of pus. Cytology is necessary for determining the presence of malignant cells in the pleural fluid. The sensitivity of pleural fluid cytology in the presence of malignant effusion in the first thoracentesis is around 60%, and the yield increases with further attempts, approaching 95% by three samples on different days.  However, if a malignant effusion is strongly suspected and cytology is negative, then medical thoracoscopy with pleural biopsy can be performed after two to three thoracenteses to obtain a diagnosis. Treatment of parapneumonic effusion includes appropriate antibiotic therapy together with drainage of pleural fluid as indicated. Parapneumonic effusion is classified into 4 groups based on risk for the poor outcome: Category 1 (very low risk): The effusion is small (less than 10-mm thickness on decubitus) and free-flowing. No thoracentesis is indicated. Category 2 (low risk): The effusion is small to moderate (equal to 10 mm and less than half the hemithorax) and free-flowing with negative culture and Gram stain regardless of the prior use of antibiotics and pH equal to 7.20. Category 3 (moderate risk), in which one of the following criteria is present: the fluid equal to half the hemithorax, loculated effusion, thicken pleura on contrast-enhanced CT scan, positive Gram stain or culture or pH less than 7.20. Category 4 (high risk): This is when pleural fluid is in the form of pure pus. Tension pneumothorax is a medical emergency that requires emergent needle decompression before a chest tube is placed. Indications This procedure is indicated when unexplained fluid accumulates in the chest cavity outside the lung. In more than 90% of cases analysis of pleural fluid yields clinically useful information. If a large amount of fluid is present, then this procedure can also be used therapeutically to remove that fluid and improve patient comfort and lung function. The most common causes of pleural effusions are cancer, congestive heart failure, pneumonia, and recent surgery. In countries where tuberculosis is common, this is also a common cause of pleural effusions. Cultures and stains If the effusion is caused by infection, microbiological culture may yield the infectious organism responsible for the infection, sometimes before other cultures (e.g. blood cultures and sputum cultures) become positive. A Gram stain may give a rough indication of the causative organism. A Ziehl–Neelsen stain may identify tuberculosis or other mycobacterial diseases. Cytology Cytology is an important tool in identifying effusions due to malignancy. The most common causes for pleural fluid are lung cancer, metastasis from elsewhere and pleural mesothelioma. The latter often presents with an effusion. Normal cytology results do not reliably rule out malignancy, but make the diagnosis more unlikely. References External links A photo gallery of thoracentesis showing the procedure step-by-step. V. Dimov, B. Altaqi, Clinical Notes, 2005. A free PDA version. Medical tests Respiratory system procedures Veterinary diagnosis Interventional radiology 1850 introductions can be avoided in patients with small effusions associated with resolving pneumonia. These patients typically present with cough, fever, leukocytosis, and uni-lateral infiltrate, and the effusion is usually a result of a reactive, parapneumonic process. If the effusion is small and the patient responds to antibiotics, a diagnostic thoracentesis may be unneces-sary. If the effusion is large and compromising respiratory efforts, or if the patient has a persistent white blood cell count despite improving signs of pneumonia, an empyema of the pleural space must be considered. In these patients, early and aggressive drainage with chest tubes is required, possibly with surgical intervention.Once the decision is made to access a pleural effusion, the next step is to determine if a sample of the fluid or complete drainage of the pleural space is desired. This step is influenced by the clinical history, the type and amount of fluid present, the Brunicardi_Ch19_p0661-p0750.indd 73601/03/19 A category 3 effusion may also be defined as a pH of <7.20 or a positive gram stain/culture (empyema). [13] Category 4 effusions are defined by purulent material on thoracentesis. [13] Category 3 and 4 effusions are recommended to have thoracostomy drainage. [13] Empyema, or category 4 effusions, may require surgical evacuation and decortication. Due to the high mortality of the categories 3 and 4 pleural effusions (30%), additional methods for the complete drainage of the infected pleural fluid include intrapleural fibrinolytic followed by drainage and/or surgical decortication. [14] The MIST 2 trial compared intrapleural placebo, intrapleural DNase, intrapleural tPA, and combination tPA/DNAse in patients with category 3 or 4 effusions. The most often used \"golden\" criteria for empyema are pleural effusion with macroscopic presence of pus, a positive Gram stain or culture of pleural fluid, or a pleural fluid pH under 7.2 with normal peripheral blood pH. Clinical guidelines for adult patients therefore advocate diagnostic pleural fluid aspiration in patients with pleural effusion in association with sepsis or pneumonic illness. Because pleural effusion in the pediatric population is almost always parapneumonic and the need for chest tube drainage can be made on clinical grounds, British guidelines for the management of pleural infection in children do not recommend diagnostic pleural fluid sampling. The use of ultrasound for needle guidance can minimize the complication rate. Follow-up imaging While chest X-ray has traditionally been performed to assess for pneumothorax following the procedure, it may no longer be necessary to do so in asymptomatic, non-ventilated persons given the widespread use of ultrasound to guide this procedure. Interpretation of pleural fluid analysis Several diagnostic tools are available to determine the etiology of pleural fluid. Transudate versus exudate First the fluid is either transudate or exudate. A transudate is defined as pleural fluid to serum total protein ratio of less than 0.5, pleural fluid to serum LDH ratio > 0.6, and absolute pleural fluid LDH > 200 IU or > 2/3 of the normal.\nHere is the question:\nINFECTOLOGY: A 64-year-old male presents with fever, cough, dyspnea and right pleuritic pain of 1 week's evolution. Chest X-ray shows a loculated right pleural effusion occupying two thirds of the hemithorax. During thoracentesis, a yellowish fluid is drawn and analysis shows: leukocytes 15,000/uL, 92% neutrophils, glucose 30 mg/dL, pH 7, lactate dehydrogenase 3500 U/L, adenosine deaminase 45 U/L and absence of germs on GRAM stain. What is the most appropriate next course of action in this patient?\nHere are the potential choices:\n1. Intravenous antibiotic therapy.\n2. Intravenous antibiotic therapy and repeat diagnostic thoracentesis in 24 hours.\n3. Intravenous antibiotic therapy and repeat diagnostic thoracentesis if there is no improvement in 48 hours.\n4. Intravenous antibiotic therapy and evacuative (therapeutic) thoracentesis if any germ is isolated in the pleural fluid culture.\n5. Intravenous antibiotic therapy and placement of a chest tube or catheter to drain all pleural fluid.\nThe correct answer is: 5. Intravenous antibiotic therapy and placement of a chest tube or catheter to drain all pleural fluid."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Between 1987 and 1991 219 patients (1.3% of all hospitalized patients) with acute infectious diarrhea were investigated retrospectively. 52% of the patients were hospitalized and 48% were outpatients. In 55% the inducing diarrhea microorganism could be identified. The most frequently detected pathogens were endemic Salmonella sp. and Campylobacter jejuni (65%). Imported diarrheas (Shigella sp. and parasites) were rare, as only 15% of the patients had a history of travel. All Clostridium difficile infections were associated with antibiotic treatment. The stool examinations for bacteria were positive in 92/160 patients (57%). Stool examinations for occult blood or fecal leukocytes were highly useful in detecting the infectious agent. In 70% of the patients with positive occult blood test or 81% of the patients with fecal leukocytes, an infectious agent in the stool was found. All patients recovered with few complications. 31% of the patients were treated by antibiotics because of septic disease or pathogenic parasites. During a 5-year period (1995-1999) a total of 7090 stool samples obtained from patients with acute diarrhoea, mostly community-acquired, were examined for bacterial pathogens, in the Greek island of Crete. One or more enteric pathogens were isolated from 987 patients (14%). Salmonella enterica were the most commonly isolated bacteria (6%), followed by Campylobacter spp. (4.2%), and enteropathogenic Escherichia coli (EPEC) (1.8%). Yersinia enterocolitica (0.6%), Shigella spp. (0.3%), and Aeromonas hydrophila (0.04%), were less frequently isolated. Clostridium difficile was isolated from 65 out of 451 diarrhoeal specimens examined (14.4%). Toxin B was detected in all cases. No verotoxigenic E. coli strains were identified. Resistance to ampicillin was observed in 31.5% of the Salmonella, 58.3% of the Shigella and 31.5% of the EPEC isolates. Resistance to trimethoprim-sulfamethoxazole was observed in 4.4% of the Salmonella, 30.5% of the Shigella, and 18.5% of the EPEC isolates. High percentages of resistance to quinolones (44.5% to norfloxacin, and 40.5% to ciprofloxacin), were found among Campylobacter isolates, while resistance to erythromycin was observed in 14.9% of them. With the present study we continue the surveillance of bacterial pathogens associated with diarrhoeal disease on the island of Crete. Toxigenic Clostridium difficile is an important cause of diarrhea that occurs more often in the elderly. Infants can carry these bacteria without developing symptoms. It is a common cause of diarrhea in those who are hospitalized and is frequently associated with antibiotic use. Staphylococcus aureus infectious diarrhea may also occur in those who have used antibiotics. Acute \"traveler's diarrhea\" is usually a type of bacterial gastroenteritis, while the persistent form is usually parasitic. Acid-suppressing medication appears to increase the risk of significant infection after exposure to a number of organisms, including Clostridium difficile, Salmonella, and Campylobacter species. The risk is greater in those taking proton pump inhibitors than with H2 antagonists. In the management of acute diarrhea, administration of antibiotics may be indicated. Appropriate antimicrobial therapy can shorten illness, reduce morbidity and can be life-saving in invasive infections. Emergence of microbial strains resistant to commonly used antibiotics means that treatment failures may become common. Because of changing patterns of resistance, knowledge of recent local patterns of susceptibility can guide the initial choice of antibiotics. A retrospective study was conducted to investigate the epidemiology of infective gastroenteritis in patients over 14years old in the region of Chania (Crete). We reviewed all positive stool cultures and susceptibilities of the pathogens recovered from patients with symptoms of acute diarrhea, from 2003 until October 2010. Out of 194 positive stool cultures, we observed 139 cases of Salmonella enterica and 48 cases of Campylobacter jejuni. During the last 3years of observation there was an increased incidence of C. jejuni, especially after the tap water outbreak that occurred in our region in 2009. In the vast majority of acute diarrhea in adults, antibiotics are of no benefit and overprescription may confer to side effects, costs and emergence of resistance. Antibiotics are initiated in cases of febrile diarrheas especially those believed to have moderate to severe disease. Considering the increased incidence of C. jejuni and the resistance of the great majority of isolated strains to quinolones as well as the sensitivity of Salmonella spp. to azithromycin, administration of azithromycin empirically for acute diarrhea, when indicated, could be appropriate in our region. Haemophilus influenzae tends to form part of the usual respiratory flora in adults, especially if they have a chronic underlying disease or are smokers. Pneumonia due to H. influenzae is frequently involved in respiratory infections and its level of resistance to ampicillin has remained stable over the last five years. Most of the literature on the subject was published more than 10 years ago. In this study, we describe the clinical features and evolution of 58 adult patients admitted to hospital for pneumonia due to H. influenzae over a 2-year period, with this group accounting for 6.5% of all the patients admitted with pneumonia during this time period. The etiological diagnosis was made using a good quality sputum sample. Forty patients (69%) were male. The mean age (+/- SD) of the group was 67 (+/-16.8) years and all the patients had at least one underlying disease. The mean duration of the symptoms was 6.7 days. All patients presented an increase in the quantity or purulence of the sputum. On admittance, respiratory failure was present in 52 patients (90%). Gram-negative coccus-bacilli were observed in the direct sputum test and H. influenzae grew in the culture. In two cases, H. influenzae was recovered from the blood culture and in one from bronchial aspiration obtained through bronchoscopy. Another pathogen was identified in 28 patients (48%). In 21 it was another pyogenic bacteria (15 S. pneumoniae, 4 M. catharralis, 1 K. pneumoniae, 1 E. coli), an atypical microorganism in 5 (3 C. pneumoniae, 2 C. burnetii) and a respiratory virus in 2 (syncytial and influenza A). Atypical bacteria and respiratory virus were detected using serological techniques. The radiographic infiltrate was unilobar in 54 of the 58 patients and all showed an alveolar pattern. The empirical treatment included the administration of a third generation cephalosporin (or a fluoroquinolone in patients allergic to penicillin). The evolution was favorable in all the cases in which H. influenzae was the only pathogen or was accompanied by an atypical microorganism or a respiratory virus. Four patients with mixed bacterial pneumonia died (2 S. pneumoniae, 1 E. coli and 1 M. catharralis). The study indicates that pneumoniae due to H. influenzae affects a population with an underlying disease, preferably pulmonary, that it has a longer clinical period than that for pneumococcal pneumonia, that it is slightly bacteremic and, that, usually, it evolves benignly with a low mortality. Signs and symptoms Enteritis After a short incubation period of a few hours to one day, the bacteria multiply in the small intestine, causing an intestinal inflammation (enteritis). Most people with salmonellosis develop diarrhea, fever, vomiting, and abdominal cramps 12 to 72 hours after infection. Diarrhea is often watery and non-bloody but may be mucoid and bloody. In most cases, the illness lasts four to seven days, and does not require treatment. In some cases, though, the diarrhea may be so severe that the patient becomes dangerously dehydrated and must be hospitalized. At the hospital, the patient may receive fluids intravenously to treat the dehydration, and may be given medications to provide symptomatic relief, such as fever reduction. In severe cases, the Salmonella infection may spread from the intestines to the blood stream, and then to other body sites, and can cause death, unless the person is treated promptly with antibiotics. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection emerged in China at the end of 2019 and caused coronavirus disease 2019 (COVID-19). The lymphopenia seen in COVID-19 increases the incidence of susceptibility to other microorganisms and may cause co-infections. As the signs and symptoms of the diseases overlap with other infectious diseases and due to the intensity in health services, the diagnosis of co-infections becomes difficult and the treatment may be delayed. Therefore, infections accompanying COVID-19 cause an increase in morbidity and mortality.The isolation and quarantine measures taken during the COVID-19 process have reduced the number of infections transmitted from person to person. However, there was no significant decrease in diseases transmitted by food, such as salmonellosis. During the pandemic, salmonellosis continued to be a problem, especially in endemic areas such as Pakistan, and an increase in Salmonella infections associated with backyard poultry has been reported in countries such as the United States. A co-infection of COVID-19 and enteric fever associated with travel to Pakistan was reported for the first time in the literature in February 2021. In this case report, the first co-infection of COVID-19 and Salmonella in our country was presented. A 56-yearold male patient with no known systemic disease was admitted to the hospital with fever, shortness of breath, weakness and myalgia lasting for three days. SARS-CoV-2 polymerase chain reaction test was positive. The patient has been hospitalized and favipiravir, moxifloxacin, and methylprednisolone were started. Blood cultures were taken from the patient whose clinical picture worsened and fever continued despite of the medical treatment. Salmonella enterica spp. enterica was isolated and ceftriaxone treatment was started. The patient's anamnesis was deepened, but no diarrhea, abdominal pain, suspicious food consumption, travel history were determined. From the second day of the ceftriaxone treatment, the patient's fever decreased and no growth was detected in the control blood cultures. Ceftriaxone treatment was completed in 14 days and the patient was discharged on the 28th day. Approximately 87-95% of Salmonella strains isolated in our country are S.enterica spp. enterica, and S.enterica spp. enterica was also isolated in our case. Salmonella infections most commonly present as gastroenteritis, but the risk of bacteremia increases in case of immunosuppression. Although there was no additional disease in our case, it was considered that the infection in the form of bacteremia occurred due to an immunosuppression caused by COVID-19. In this context; drawing blood cultures of patients hospitalized with the diagnosis of COVID-19 is very important in terms of detecting co-infections and superinfections, and administering appropriate antibiotic therapy at appropriate treatment times. Presentation of first case of Salmonella bacteremia and simultaneous COVID-19 infection in our country was the strong side of our report. In addition, our case is also important as being the first SARS-CoV-2 and Salmonella co-infection unrelated to Pakistan in the literature. The limitation of our case was that S.enterica spp. enterica detected in the blood culture could not be subtyped and the stool culture could not be examined. However, this does not constitute a diagnostic requirement. In addition, the patient's pre-COVID-19 Salmonella carrier status was also unknown. As a result, patients become vulnerable to other infections due to the lymphopenia seen in COVID-19. Therefore, Salmonella bacteremia can be seen with SARS-CoV-2 infection without a comorbid condition. Drawing blood cultures in hospitalized patients with the diagnosis of COVID-19 is very important in terms of detecting concomitant infections in a short time. In patients whose clinical condition does not improve and fever continues despite of treatment, blood cultures should be taken, especially in the case of an advanced immunosuppresive treatment plan, and it should always be kept in mind that secondary infections and co-infections may occur. Treatment Treatment of salmonella infections depends on age and pre-disposition of the infected person and the severity of the symptoms. One of the side-effects from salmonella infection is dehydration, making the replacement of fluids and electrolytes the main treatment for less severe infections. In severe cases, patients are treated with antibiotics, rehydrated with intravenous (IV) fluids and hospitalized. In cases where the infection spreads from the intestines to the bloodstream, quick treatment with antibiotics is required to prevent the risk of death. Possible complications include resistances to certain antibiotics in the salmonella streaks, that might require treatment with different antibiotics than commonly prescribed antibiotics. In this case, whole-genome sequencing (WGS) analysis identified no antibiotic resistance in 112 of 127 isolates. Prevention and Structural Consequences A prospective epidemiological and clinical study of acute diarrhea in children under 5 years old was done at King Mongkut Prachomklao Hospital in order to provide baseline data for health officers to make a strategic plan to reduce the diarrheal mortality and morbidity, which is one of the mid-decade goals for children. There were 105 cases of acute diarrhea patients admitted to the Pediatric ward between May 1995 and April 1996. Seventy-six per cent of them were in the younger age group (&gt; 1 month-2 years old) while 23.8 per cent were in the older age group (2-5 years old). Causative pathogens were identified in 64 patients (61%). Younger patients had a higher percentage of identifiable pathogens (66.7%) than older patients (44.4%). Rotavirus was the most common pathogen isolated (17.2%). The other common pathogens identified were Eschericia coli (14.1%), Campylobacter jejuni (14.1%), Shigella (12.5%), Entamoeba histolytica (7.8%) and Salmonella (3.1%). Mixed infections were reported in 31.3 per cent of these patients. Clinical presentations and stool characteristics were difficult to distinguish from most of the pathogens. However, Rotavirus was highly suspected if a younger child presented with fever, watery to loose stool with the predominant symptom of vomiting. Mucous, mucous-bloody stool gave a clue to the diagnosis of Shigella and Entamoeba histolytica. Most cases had at least mild to moderate dehydration, so oral rehydration solution (ORS) was successfully given in only 31.4 per cent of patients. Antibiotics were prescribed to 51.4 per cent of patients in this study. Healthcare personnel should emphasize to parents and caretakers about good hygienic behavior to reduce the episodes of diarrhea and the use of ORS every time when their children have diarrheal episodes to reduce the disease severity. Haemophilus influenzae tends to form part of the usual respiratory flora in adults, especially if they have a chronic underlying disease or are smokers. Pneumonia due to H. influenzae is frequently involved in respiratory infections and its level of resistance to ampicillin has remained stable over the last five years. Most of the literature on the subject was published more than 10 years ago. In this study, we describe the clinical features and evolution of 58 adult patients admitted to hospital for pneumonia due to H. influenzae over a 2-year period, with this group accounting for 6.5&amp;#37; of all the patients admitted with pneumonia during this time period. The etiological diagnosis was made using a good quality sputum sample. Forty patients (69&amp;#37;) were male. The mean age (+/- SD) of the group was 67 (+/-16.8) years and all the patients had at least one underlying disease. The mean duration of the symptoms was 6.7 days. All patients presented an increase in the quantity or purulence of the sputum. On admittance, respiratory failure was present in 52 patients (90&amp;#37;). Gram-negative coccus-bacilli were observed in the direct sputum test and H. influenzae grew in the culture. In two cases, H. influenzae was recovered from the blood culture and in one from bronchial aspiration obtained through bronchoscopy. Another pathogen was identified in 28 patients (48&amp;#37;). In 21 it was another pyogenic bacteria (15 S. pneumoniae, 4 M. catharralis, 1 K. pneumoniae, 1 E. coli), an atypical microorganism in 5 (3 C. pneumoniae, 2 C. burnetii) and a respiratory virus in 2 (syncytial and influenza A). Atypical bacteria and respiratory virus were detected using serological techniques. The radiographic infiltrate was unilobar in 54 of the 58 patients and all showed an alveolar pattern. The empirical treatment included the administration of a third generation cephalosporin (or a fluoroquinolone in patients allergic to penicillin). The evolution was favorable in all the cases in which H. influenzae was the only pathogen or was accompanied by an atypical microorganism or a respiratory virus. Four patients with mixed bacterial pneumonia died (2 S. pneumoniae, 1 E. coli and 1 M. catharralis). The study indicates that pneumoniae due to H. influenzae affects a population with an underlying disease, preferably pulmonary, that it has a longer clinical period than that for pneumococcal pneumonia, that it is slightly bacteremic and, that, usually, it evolves benignly with a low mortality. A retrospective study of 45 patients with Clostridium difficile infection over a 4-year period in a department of Internal Medicine. Mean age was 79 years; sex-ratio (F/M)=1.5; 38% of the patients had neurological or severe psychiatric disorders; 20% had a neoplastic disease. Ninety-three percent of cases had received one or more antibiotics before onset of diarrhea, prescribed mainly for a pulmonary infection. Amoxicillin clavulanic acid and cephalosporins were the most frequently used treatments, respectively in 48% and 40% of cases. For 25 patients (56%) Clostridium difficile-associated diarrhea was considered as a nosocomial infection, and as community-acquired diarrhea in 20 cases (44%). Treatment included isolation of the patient as soon as bacteriological diagnosis was known and specific therapy was instituted by metronidazole or vancomycin for a mean of 18 days. The addition of Saccharomyces boulardii was used in of cases. The clinical course was rapidly favorable for 80% of patients. Five patients died with complications of severe colitis in 2 cases. Mean hospital stay was 49 days (annual mean of the department=10 days). Clostridium difficile diarrhea concerns above all elderly patients with one or more underlying pathologies. Amoxicillin clavulanic acid and third-generation cephalosporins are the most frequently prescribed antibiotics in these cases and have the highest correlation with this infectious complication. This medical problem requires greater knowledge as it causes significant morbidity and increases the risk of prolonged hospital stays. Treatment CAP is treated with an antibiotic that kills the infecting microorganism; treatment also aims at managing complications. If the causative microorganism is unidentified, which is often the case, the laboratory identifies the most effective antibiotic; this may take several days. Health professionals consider a person's risk factors for various organisms when choosing an initial antibiotic. Additional consideration is given to the treatment setting; most patients are cured by oral medication, while others must be hospitalized for intravenous therapy or intensive care. Current treatment guidelines recommend a beta lactam, like amoxicillin and a macrolide, like azithromycin or clarithromycin, or a quinolone, such as levofloxacin. Doxycycline is the antibiotic of choice in the UK for atypical bacteria, due to increased clostridium difficile colitis in hospital patients linked to the increased use of clarithromycin. Signs and Symptoms Salmonella is a bacterium that produces the symptoms of diarrhoea, fever and abdominal cramps in infected individuals 12-72 hours after exposure. Most people recover without treatment and the illness usually lasts for 4-7 days. Some people may need hospitalization due to severe symptoms and in rare cases, Salmonella can cause death unless the person is treated with antibiotics promptly. Those most likely to develop severe salmonella are children under the age of 5, adults over the age of 65 and people with compromised immune systems. Treatment Gram positive Clostridium difficile Clostridium difficile is a nosocomial pathogen that causes diarrheal disease worldwide. Diarrhea caused by C. difficile can be life-threatening. Infections are most frequent in people who have had recent medical and/or antibiotic treatment. C. difficile infections commonly occur during hospitalization. According to a 2015 CDC report, C. difficile caused almost 500,000 infections in the United States over a year period. Associated with these infections were an estimated 15,000 deaths. The CDC estimates that C. difficile infection costs could amount to $3.8 billion over a 5-year span. C. difficile colitis is most strongly associated with fluoroquinolones, cephalosporins, carbapenems, and clindamycin. Some research suggests the overuse of antibiotics in the raising of livestock is contributing to outbreaks of bacterial infections such as C. difficile.[16] During 1986-1994 the etiological structure of diarrhoea in hospitalized patients at the Infectious Diseases Clinic, University Hospital Plzen was analyzed. In children under four years most frequently (in 26%) rotaviruses were involved, in older patients their ratio was lower and the decisive pathogenetic organism were salmonellae. In rotavirus infections the shortest hospitalization period was recorded. These infections were encountered all round the year with a maximum prevalence in the winter months. At the Central Laboratory of the Medical School, University of Milano, Italy, 44 Salmonella strains were isolated from morbid materials other than stools during the three-years period 1977-79 (blood 26, urine 6, pus 3, pleural fluid 4, bile 3, upper respiratory mucus 2). In the present paper, nine cases of Salmonella infections, selected for their unusual localization a/o their peculiar clinical onset, are reviewed. From most of the clinical histories it appears that, in quite a few occasions, the episode due to Salmonella has been favoured or conditioned by a preexisting disease, therefore suggesting a nosocomial-type event. It also appears that the help from the microbiologist was often requested less than promptly, and minimal requirements for its efficacy were seldom achieved. Treatment Patients with Campylobacter infection should drink plenty of fluids as long as the diarrhea lasts to maintain hydration. Patients should also get rest. If he or she cannot drink enough fluids to prevent dehydration or if the symptoms are severe, medical help is indicated. In more severe cases, certain antibiotics can be used and can shorten the duration of symptoms if given early in the illness. Moreover, maintenance of electrolyte balance, not antibiotic treatment, is the cornerstone of treatment for Campylobacter enteritis. Indeed, most patients with this infection have a self-limited illness and do not require antibiotics at all. Nevertheless, antibiotics should be used in specific clinical circumstances. These include high fevers, bloody stools, prolonged illness (symptoms that last >1 week), pregnancy, infection with HIV, and other immunocompromised states. To analyze the etiology and evolution of patients with acute gastroenteritis hospitalized in our pediatric department and to study the clinical and laboratory differences between acute viral and bacterial gastroenteritis. We studied the children with a diagnosis of acute gastroenteritis, aged between 0 and 14 years, who were consecutively admitted between 1987 and 2000. Differences were considered statistically significant if p &lt; 0.05. A total of 2,613 patients diagnosed with acute gastroenteritis were hospitalized (10.4 % of hospital admissions). The most common pathogens isolated were rotaviruses (46.5 %), followed by Salmonella (32.6 %) and Campylobacter (19.3 %). Hospital admissions due to Salmonella (p &lt; 0.0001), other bacteria (Escherichia coli and Shigella) (p &lt; 0.002) and adenoviruses (p &lt; 0.01) significantly decreased. Rotaviruses were the most frequently detected pathogens in winter and in children aged less than 1 year (p &lt; 0.0001). The incidence of Salmonella spp was greater in summer and in children older than 2 years (p &lt; 0.0001). The incidence of hyperthermia (rectal temperature higher than 38.5 degreeC) (p &lt; 0.0001), dehydration (p &lt; 0.0005) and fecal blood (p &lt; 0.0001) was higher in bacterial diarrheas. Erythrocyte sedimentation rate (p &lt; 0.001) and leukocyte counts were higher in bacterial gastroenteritis (p &lt; 0.01). Rotaviruses were the most frequently isolated enteropathogens. The features that best distinguished between bacterial and viral diarrhea were hyperthermia and fecal blood. Hospital admissions due to Salmonella Shigella E. coli, and adenoviruses significantly decreased. Endocarditis and bacteremia Evaluation for the replacement of a prosthetic valve is considered. Appropriate antibiotic therapy may be administered for up to six weeks. Four to six weeks of antibiotic treatment is often recommended, and is dependent upon the extent of MRSA infection. Respiratory infections CA-MRSA in hospitalized patients pneumonia treatment begins before culture results. After the susceptibility to antibiotics is performed, the infection may be treated with vancomycin or linezolid for up to 21 days. If the pneumonia is complicated by the accumulation of pus in the pleural cavity surrounding the lungs, drainage may be done along with antibiotic therapy. People with cystic fibrosis may develop respiratory complications related to MRSA infection. The incidence of MRSA in those with cystic fibrosis increased during 2000 to 2015 by five times. Most of these infections were HA-MRSA. MRSA accounts for 26% of lung infections in those with cystic fibrosis. Usage The purpose of the PSI is to classify the severity of a patient's pneumonia to determine the amount of resources to be allocated for care. Most commonly, the PSI scoring system has been used to decide whether patients with pneumonia can be treated as outpatients or as (hospitalized) inpatients. A Risk Class I or Risk Class II pneumonia patient can be sent home on oral antibiotics. A Risk Class III patient, after evaluation of other factors including home environment and follow-up, may either: be sent home with oral antibiotics be admitted for a short hospital stay with antibiotics and monitoring. Patients with Risk Class IV-V pneumonia patient should be hospitalized for treatment. Algorithm\nHere is the question:\nINFECTIOUS: A 52-year-old patient is admitted to the Hospital for severe pneumonia. With appropriate antibiotic treatment, the patient's respiratory symptoms improved. After 4 days of stay in the ward, his evolution is complicated by the appearance of a severe diarrhea. What is the most frequent microorganism responsible for this condition?\nHere are the potential choices:\n1. Salmonella enterica.\n2. The bacterium itself causing pneumonia that has become resistant to the antibiotic.\n3. Campylobacter jejuni.\n4. Clostridium difficile.\n5. Yersinia enterocolitica.\nThe correct answer is: ",
        "gold_answer": "4 Clostridium difficile.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Between 1987 and 1991 219 patients (1.3% of all hospitalized patients) with acute infectious diarrhea were investigated retrospectively. 52% of the patients were hospitalized and 48% were outpatients. In 55% the inducing diarrhea microorganism could be identified. The most frequently detected pathogens were endemic Salmonella sp. and Campylobacter jejuni (65%). Imported diarrheas (Shigella sp. and parasites) were rare, as only 15% of the patients had a history of travel. All Clostridium difficile infections were associated with antibiotic treatment. The stool examinations for bacteria were positive in 92/160 patients (57%). Stool examinations for occult blood or fecal leukocytes were highly useful in detecting the infectious agent. In 70% of the patients with positive occult blood test or 81% of the patients with fecal leukocytes, an infectious agent in the stool was found. All patients recovered with few complications. 31% of the patients were treated by antibiotics because of septic disease or pathogenic parasites. During a 5-year period (1995-1999) a total of 7090 stool samples obtained from patients with acute diarrhoea, mostly community-acquired, were examined for bacterial pathogens, in the Greek island of Crete. One or more enteric pathogens were isolated from 987 patients (14%). Salmonella enterica were the most commonly isolated bacteria (6%), followed by Campylobacter spp. (4.2%), and enteropathogenic Escherichia coli (EPEC) (1.8%). Yersinia enterocolitica (0.6%), Shigella spp. (0.3%), and Aeromonas hydrophila (0.04%), were less frequently isolated. Clostridium difficile was isolated from 65 out of 451 diarrhoeal specimens examined (14.4%). Toxin B was detected in all cases. No verotoxigenic E. coli strains were identified. Resistance to ampicillin was observed in 31.5% of the Salmonella, 58.3% of the Shigella and 31.5% of the EPEC isolates. Resistance to trimethoprim-sulfamethoxazole was observed in 4.4% of the Salmonella, 30.5% of the Shigella, and 18.5% of the EPEC isolates. High percentages of resistance to quinolones (44.5% to norfloxacin, and 40.5% to ciprofloxacin), were found among Campylobacter isolates, while resistance to erythromycin was observed in 14.9% of them. With the present study we continue the surveillance of bacterial pathogens associated with diarrhoeal disease on the island of Crete. Toxigenic Clostridium difficile is an important cause of diarrhea that occurs more often in the elderly. Infants can carry these bacteria without developing symptoms. It is a common cause of diarrhea in those who are hospitalized and is frequently associated with antibiotic use. Staphylococcus aureus infectious diarrhea may also occur in those who have used antibiotics. Acute \"traveler's diarrhea\" is usually a type of bacterial gastroenteritis, while the persistent form is usually parasitic. Acid-suppressing medication appears to increase the risk of significant infection after exposure to a number of organisms, including Clostridium difficile, Salmonella, and Campylobacter species. The risk is greater in those taking proton pump inhibitors than with H2 antagonists. In the management of acute diarrhea, administration of antibiotics may be indicated. Appropriate antimicrobial therapy can shorten illness, reduce morbidity and can be life-saving in invasive infections. Emergence of microbial strains resistant to commonly used antibiotics means that treatment failures may become common. Because of changing patterns of resistance, knowledge of recent local patterns of susceptibility can guide the initial choice of antibiotics. A retrospective study was conducted to investigate the epidemiology of infective gastroenteritis in patients over 14years old in the region of Chania (Crete). We reviewed all positive stool cultures and susceptibilities of the pathogens recovered from patients with symptoms of acute diarrhea, from 2003 until October 2010. Out of 194 positive stool cultures, we observed 139 cases of Salmonella enterica and 48 cases of Campylobacter jejuni. During the last 3years of observation there was an increased incidence of C. jejuni, especially after the tap water outbreak that occurred in our region in 2009. In the vast majority of acute diarrhea in adults, antibiotics are of no benefit and overprescription may confer to side effects, costs and emergence of resistance. Antibiotics are initiated in cases of febrile diarrheas especially those believed to have moderate to severe disease. Considering the increased incidence of C. jejuni and the resistance of the great majority of isolated strains to quinolones as well as the sensitivity of Salmonella spp. to azithromycin, administration of azithromycin empirically for acute diarrhea, when indicated, could be appropriate in our region. Haemophilus influenzae tends to form part of the usual respiratory flora in adults, especially if they have a chronic underlying disease or are smokers. Pneumonia due to H. influenzae is frequently involved in respiratory infections and its level of resistance to ampicillin has remained stable over the last five years. Most of the literature on the subject was published more than 10 years ago. In this study, we describe the clinical features and evolution of 58 adult patients admitted to hospital for pneumonia due to H. influenzae over a 2-year period, with this group accounting for 6.5% of all the patients admitted with pneumonia during this time period. The etiological diagnosis was made using a good quality sputum sample. Forty patients (69%) were male. The mean age (+/- SD) of the group was 67 (+/-16.8) years and all the patients had at least one underlying disease. The mean duration of the symptoms was 6.7 days. All patients presented an increase in the quantity or purulence of the sputum. On admittance, respiratory failure was present in 52 patients (90%). Gram-negative coccus-bacilli were observed in the direct sputum test and H. influenzae grew in the culture. In two cases, H. influenzae was recovered from the blood culture and in one from bronchial aspiration obtained through bronchoscopy. Another pathogen was identified in 28 patients (48%). In 21 it was another pyogenic bacteria (15 S. pneumoniae, 4 M. catharralis, 1 K. pneumoniae, 1 E. coli), an atypical microorganism in 5 (3 C. pneumoniae, 2 C. burnetii) and a respiratory virus in 2 (syncytial and influenza A). Atypical bacteria and respiratory virus were detected using serological techniques. The radiographic infiltrate was unilobar in 54 of the 58 patients and all showed an alveolar pattern. The empirical treatment included the administration of a third generation cephalosporin (or a fluoroquinolone in patients allergic to penicillin). The evolution was favorable in all the cases in which H. influenzae was the only pathogen or was accompanied by an atypical microorganism or a respiratory virus. Four patients with mixed bacterial pneumonia died (2 S. pneumoniae, 1 E. coli and 1 M. catharralis). The study indicates that pneumoniae due to H. influenzae affects a population with an underlying disease, preferably pulmonary, that it has a longer clinical period than that for pneumococcal pneumonia, that it is slightly bacteremic and, that, usually, it evolves benignly with a low mortality. Signs and symptoms Enteritis After a short incubation period of a few hours to one day, the bacteria multiply in the small intestine, causing an intestinal inflammation (enteritis). Most people with salmonellosis develop diarrhea, fever, vomiting, and abdominal cramps 12 to 72 hours after infection. Diarrhea is often watery and non-bloody but may be mucoid and bloody. In most cases, the illness lasts four to seven days, and does not require treatment. In some cases, though, the diarrhea may be so severe that the patient becomes dangerously dehydrated and must be hospitalized. At the hospital, the patient may receive fluids intravenously to treat the dehydration, and may be given medications to provide symptomatic relief, such as fever reduction. In severe cases, the Salmonella infection may spread from the intestines to the blood stream, and then to other body sites, and can cause death, unless the person is treated promptly with antibiotics. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection emerged in China at the end of 2019 and caused coronavirus disease 2019 (COVID-19). The lymphopenia seen in COVID-19 increases the incidence of susceptibility to other microorganisms and may cause co-infections. As the signs and symptoms of the diseases overlap with other infectious diseases and due to the intensity in health services, the diagnosis of co-infections becomes difficult and the treatment may be delayed. Therefore, infections accompanying COVID-19 cause an increase in morbidity and mortality.The isolation and quarantine measures taken during the COVID-19 process have reduced the number of infections transmitted from person to person. However, there was no significant decrease in diseases transmitted by food, such as salmonellosis. During the pandemic, salmonellosis continued to be a problem, especially in endemic areas such as Pakistan, and an increase in Salmonella infections associated with backyard poultry has been reported in countries such as the United States. A co-infection of COVID-19 and enteric fever associated with travel to Pakistan was reported for the first time in the literature in February 2021. In this case report, the first co-infection of COVID-19 and Salmonella in our country was presented. A 56-yearold male patient with no known systemic disease was admitted to the hospital with fever, shortness of breath, weakness and myalgia lasting for three days. SARS-CoV-2 polymerase chain reaction test was positive. The patient has been hospitalized and favipiravir, moxifloxacin, and methylprednisolone were started. Blood cultures were taken from the patient whose clinical picture worsened and fever continued despite of the medical treatment. Salmonella enterica spp. enterica was isolated and ceftriaxone treatment was started. The patient's anamnesis was deepened, but no diarrhea, abdominal pain, suspicious food consumption, travel history were determined. From the second day of the ceftriaxone treatment, the patient's fever decreased and no growth was detected in the control blood cultures. Ceftriaxone treatment was completed in 14 days and the patient was discharged on the 28th day. Approximately 87-95% of Salmonella strains isolated in our country are S.enterica spp. enterica, and S.enterica spp. enterica was also isolated in our case. Salmonella infections most commonly present as gastroenteritis, but the risk of bacteremia increases in case of immunosuppression. Although there was no additional disease in our case, it was considered that the infection in the form of bacteremia occurred due to an immunosuppression caused by COVID-19. In this context; drawing blood cultures of patients hospitalized with the diagnosis of COVID-19 is very important in terms of detecting co-infections and superinfections, and administering appropriate antibiotic therapy at appropriate treatment times. Presentation of first case of Salmonella bacteremia and simultaneous COVID-19 infection in our country was the strong side of our report. In addition, our case is also important as being the first SARS-CoV-2 and Salmonella co-infection unrelated to Pakistan in the literature. The limitation of our case was that S.enterica spp. enterica detected in the blood culture could not be subtyped and the stool culture could not be examined. However, this does not constitute a diagnostic requirement. In addition, the patient's pre-COVID-19 Salmonella carrier status was also unknown. As a result, patients become vulnerable to other infections due to the lymphopenia seen in COVID-19. Therefore, Salmonella bacteremia can be seen with SARS-CoV-2 infection without a comorbid condition. Drawing blood cultures in hospitalized patients with the diagnosis of COVID-19 is very important in terms of detecting concomitant infections in a short time. In patients whose clinical condition does not improve and fever continues despite of treatment, blood cultures should be taken, especially in the case of an advanced immunosuppresive treatment plan, and it should always be kept in mind that secondary infections and co-infections may occur. Treatment Treatment of salmonella infections depends on age and pre-disposition of the infected person and the severity of the symptoms. One of the side-effects from salmonella infection is dehydration, making the replacement of fluids and electrolytes the main treatment for less severe infections. In severe cases, patients are treated with antibiotics, rehydrated with intravenous (IV) fluids and hospitalized. In cases where the infection spreads from the intestines to the bloodstream, quick treatment with antibiotics is required to prevent the risk of death. Possible complications include resistances to certain antibiotics in the salmonella streaks, that might require treatment with different antibiotics than commonly prescribed antibiotics. In this case, whole-genome sequencing (WGS) analysis identified no antibiotic resistance in 112 of 127 isolates. Prevention and Structural Consequences A prospective epidemiological and clinical study of acute diarrhea in children under 5 years old was done at King Mongkut Prachomklao Hospital in order to provide baseline data for health officers to make a strategic plan to reduce the diarrheal mortality and morbidity, which is one of the mid-decade goals for children. There were 105 cases of acute diarrhea patients admitted to the Pediatric ward between May 1995 and April 1996. Seventy-six per cent of them were in the younger age group (&gt; 1 month-2 years old) while 23.8 per cent were in the older age group (2-5 years old). Causative pathogens were identified in 64 patients (61%). Younger patients had a higher percentage of identifiable pathogens (66.7%) than older patients (44.4%). Rotavirus was the most common pathogen isolated (17.2%). The other common pathogens identified were Eschericia coli (14.1%), Campylobacter jejuni (14.1%), Shigella (12.5%), Entamoeba histolytica (7.8%) and Salmonella (3.1%). Mixed infections were reported in 31.3 per cent of these patients. Clinical presentations and stool characteristics were difficult to distinguish from most of the pathogens. However, Rotavirus was highly suspected if a younger child presented with fever, watery to loose stool with the predominant symptom of vomiting. Mucous, mucous-bloody stool gave a clue to the diagnosis of Shigella and Entamoeba histolytica. Most cases had at least mild to moderate dehydration, so oral rehydration solution (ORS) was successfully given in only 31.4 per cent of patients. Antibiotics were prescribed to 51.4 per cent of patients in this study. Healthcare personnel should emphasize to parents and caretakers about good hygienic behavior to reduce the episodes of diarrhea and the use of ORS every time when their children have diarrheal episodes to reduce the disease severity. Haemophilus influenzae tends to form part of the usual respiratory flora in adults, especially if they have a chronic underlying disease or are smokers. Pneumonia due to H. influenzae is frequently involved in respiratory infections and its level of resistance to ampicillin has remained stable over the last five years. Most of the literature on the subject was published more than 10 years ago. In this study, we describe the clinical features and evolution of 58 adult patients admitted to hospital for pneumonia due to H. influenzae over a 2-year period, with this group accounting for 6.5&amp;#37; of all the patients admitted with pneumonia during this time period. The etiological diagnosis was made using a good quality sputum sample. Forty patients (69&amp;#37;) were male. The mean age (+/- SD) of the group was 67 (+/-16.8) years and all the patients had at least one underlying disease. The mean duration of the symptoms was 6.7 days. All patients presented an increase in the quantity or purulence of the sputum. On admittance, respiratory failure was present in 52 patients (90&amp;#37;). Gram-negative coccus-bacilli were observed in the direct sputum test and H. influenzae grew in the culture. In two cases, H. influenzae was recovered from the blood culture and in one from bronchial aspiration obtained through bronchoscopy. Another pathogen was identified in 28 patients (48&amp;#37;). In 21 it was another pyogenic bacteria (15 S. pneumoniae, 4 M. catharralis, 1 K. pneumoniae, 1 E. coli), an atypical microorganism in 5 (3 C. pneumoniae, 2 C. burnetii) and a respiratory virus in 2 (syncytial and influenza A). Atypical bacteria and respiratory virus were detected using serological techniques. The radiographic infiltrate was unilobar in 54 of the 58 patients and all showed an alveolar pattern. The empirical treatment included the administration of a third generation cephalosporin (or a fluoroquinolone in patients allergic to penicillin). The evolution was favorable in all the cases in which H. influenzae was the only pathogen or was accompanied by an atypical microorganism or a respiratory virus. Four patients with mixed bacterial pneumonia died (2 S. pneumoniae, 1 E. coli and 1 M. catharralis). The study indicates that pneumoniae due to H. influenzae affects a population with an underlying disease, preferably pulmonary, that it has a longer clinical period than that for pneumococcal pneumonia, that it is slightly bacteremic and, that, usually, it evolves benignly with a low mortality. A retrospective study of 45 patients with Clostridium difficile infection over a 4-year period in a department of Internal Medicine. Mean age was 79 years; sex-ratio (F/M)=1.5; 38% of the patients had neurological or severe psychiatric disorders; 20% had a neoplastic disease. Ninety-three percent of cases had received one or more antibiotics before onset of diarrhea, prescribed mainly for a pulmonary infection. Amoxicillin clavulanic acid and cephalosporins were the most frequently used treatments, respectively in 48% and 40% of cases. For 25 patients (56%) Clostridium difficile-associated diarrhea was considered as a nosocomial infection, and as community-acquired diarrhea in 20 cases (44%). Treatment included isolation of the patient as soon as bacteriological diagnosis was known and specific therapy was instituted by metronidazole or vancomycin for a mean of 18 days. The addition of Saccharomyces boulardii was used in of cases. The clinical course was rapidly favorable for 80% of patients. Five patients died with complications of severe colitis in 2 cases. Mean hospital stay was 49 days (annual mean of the department=10 days). Clostridium difficile diarrhea concerns above all elderly patients with one or more underlying pathologies. Amoxicillin clavulanic acid and third-generation cephalosporins are the most frequently prescribed antibiotics in these cases and have the highest correlation with this infectious complication. This medical problem requires greater knowledge as it causes significant morbidity and increases the risk of prolonged hospital stays. Treatment CAP is treated with an antibiotic that kills the infecting microorganism; treatment also aims at managing complications. If the causative microorganism is unidentified, which is often the case, the laboratory identifies the most effective antibiotic; this may take several days. Health professionals consider a person's risk factors for various organisms when choosing an initial antibiotic. Additional consideration is given to the treatment setting; most patients are cured by oral medication, while others must be hospitalized for intravenous therapy or intensive care. Current treatment guidelines recommend a beta lactam, like amoxicillin and a macrolide, like azithromycin or clarithromycin, or a quinolone, such as levofloxacin. Doxycycline is the antibiotic of choice in the UK for atypical bacteria, due to increased clostridium difficile colitis in hospital patients linked to the increased use of clarithromycin. Signs and Symptoms Salmonella is a bacterium that produces the symptoms of diarrhoea, fever and abdominal cramps in infected individuals 12-72 hours after exposure. Most people recover without treatment and the illness usually lasts for 4-7 days. Some people may need hospitalization due to severe symptoms and in rare cases, Salmonella can cause death unless the person is treated with antibiotics promptly. Those most likely to develop severe salmonella are children under the age of 5, adults over the age of 65 and people with compromised immune systems. Treatment Gram positive Clostridium difficile Clostridium difficile is a nosocomial pathogen that causes diarrheal disease worldwide. Diarrhea caused by C. difficile can be life-threatening. Infections are most frequent in people who have had recent medical and/or antibiotic treatment. C. difficile infections commonly occur during hospitalization. According to a 2015 CDC report, C. difficile caused almost 500,000 infections in the United States over a year period. Associated with these infections were an estimated 15,000 deaths. The CDC estimates that C. difficile infection costs could amount to $3.8 billion over a 5-year span. C. difficile colitis is most strongly associated with fluoroquinolones, cephalosporins, carbapenems, and clindamycin. Some research suggests the overuse of antibiotics in the raising of livestock is contributing to outbreaks of bacterial infections such as C. difficile.[16] During 1986-1994 the etiological structure of diarrhoea in hospitalized patients at the Infectious Diseases Clinic, University Hospital Plzen was analyzed. In children under four years most frequently (in 26%) rotaviruses were involved, in older patients their ratio was lower and the decisive pathogenetic organism were salmonellae. In rotavirus infections the shortest hospitalization period was recorded. These infections were encountered all round the year with a maximum prevalence in the winter months. At the Central Laboratory of the Medical School, University of Milano, Italy, 44 Salmonella strains were isolated from morbid materials other than stools during the three-years period 1977-79 (blood 26, urine 6, pus 3, pleural fluid 4, bile 3, upper respiratory mucus 2). In the present paper, nine cases of Salmonella infections, selected for their unusual localization a/o their peculiar clinical onset, are reviewed. From most of the clinical histories it appears that, in quite a few occasions, the episode due to Salmonella has been favoured or conditioned by a preexisting disease, therefore suggesting a nosocomial-type event. It also appears that the help from the microbiologist was often requested less than promptly, and minimal requirements for its efficacy were seldom achieved. Treatment Patients with Campylobacter infection should drink plenty of fluids as long as the diarrhea lasts to maintain hydration. Patients should also get rest. If he or she cannot drink enough fluids to prevent dehydration or if the symptoms are severe, medical help is indicated. In more severe cases, certain antibiotics can be used and can shorten the duration of symptoms if given early in the illness. Moreover, maintenance of electrolyte balance, not antibiotic treatment, is the cornerstone of treatment for Campylobacter enteritis. Indeed, most patients with this infection have a self-limited illness and do not require antibiotics at all. Nevertheless, antibiotics should be used in specific clinical circumstances. These include high fevers, bloody stools, prolonged illness (symptoms that last >1 week), pregnancy, infection with HIV, and other immunocompromised states. To analyze the etiology and evolution of patients with acute gastroenteritis hospitalized in our pediatric department and to study the clinical and laboratory differences between acute viral and bacterial gastroenteritis. We studied the children with a diagnosis of acute gastroenteritis, aged between 0 and 14 years, who were consecutively admitted between 1987 and 2000. Differences were considered statistically significant if p &lt; 0.05. A total of 2,613 patients diagnosed with acute gastroenteritis were hospitalized (10.4 % of hospital admissions). The most common pathogens isolated were rotaviruses (46.5 %), followed by Salmonella (32.6 %) and Campylobacter (19.3 %). Hospital admissions due to Salmonella (p &lt; 0.0001), other bacteria (Escherichia coli and Shigella) (p &lt; 0.002) and adenoviruses (p &lt; 0.01) significantly decreased. Rotaviruses were the most frequently detected pathogens in winter and in children aged less than 1 year (p &lt; 0.0001). The incidence of Salmonella spp was greater in summer and in children older than 2 years (p &lt; 0.0001). The incidence of hyperthermia (rectal temperature higher than 38.5 degreeC) (p &lt; 0.0001), dehydration (p &lt; 0.0005) and fecal blood (p &lt; 0.0001) was higher in bacterial diarrheas. Erythrocyte sedimentation rate (p &lt; 0.001) and leukocyte counts were higher in bacterial gastroenteritis (p &lt; 0.01). Rotaviruses were the most frequently isolated enteropathogens. The features that best distinguished between bacterial and viral diarrhea were hyperthermia and fecal blood. Hospital admissions due to Salmonella Shigella E. coli, and adenoviruses significantly decreased. Endocarditis and bacteremia Evaluation for the replacement of a prosthetic valve is considered. Appropriate antibiotic therapy may be administered for up to six weeks. Four to six weeks of antibiotic treatment is often recommended, and is dependent upon the extent of MRSA infection. Respiratory infections CA-MRSA in hospitalized patients pneumonia treatment begins before culture results. After the susceptibility to antibiotics is performed, the infection may be treated with vancomycin or linezolid for up to 21 days. If the pneumonia is complicated by the accumulation of pus in the pleural cavity surrounding the lungs, drainage may be done along with antibiotic therapy. People with cystic fibrosis may develop respiratory complications related to MRSA infection. The incidence of MRSA in those with cystic fibrosis increased during 2000 to 2015 by five times. Most of these infections were HA-MRSA. MRSA accounts for 26% of lung infections in those with cystic fibrosis. Usage The purpose of the PSI is to classify the severity of a patient's pneumonia to determine the amount of resources to be allocated for care. Most commonly, the PSI scoring system has been used to decide whether patients with pneumonia can be treated as outpatients or as (hospitalized) inpatients. A Risk Class I or Risk Class II pneumonia patient can be sent home on oral antibiotics. A Risk Class III patient, after evaluation of other factors including home environment and follow-up, may either: be sent home with oral antibiotics be admitted for a short hospital stay with antibiotics and monitoring. Patients with Risk Class IV-V pneumonia patient should be hospitalized for treatment. Algorithm\nHere is the question:\nINFECTIOUS: A 52-year-old patient is admitted to the Hospital for severe pneumonia. With appropriate antibiotic treatment, the patient's respiratory symptoms improved. After 4 days of stay in the ward, his evolution is complicated by the appearance of a severe diarrhea. What is the most frequent microorganism responsible for this condition?\nHere are the potential choices:\n1. Salmonella enterica.\n2. The bacterium itself causing pneumonia that has become resistant to the antibiotic.\n3. Campylobacter jejuni.\n4. Clostridium difficile.\n5. Yersinia enterocolitica.\nThe correct answer is: 4. Clostridium difficile."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Before the 18th century, distal radius fracture was believed to be due to dislocation of the carpal bones or the displacement of the distal radioulnar articulation. In the 18th century, Petit first suggested that these types of injuries might be due to fractures rather than dislocations. Another author, Pouteau, suggested the common mechanism of injury which leads to this type of fractures - injury to the wrist when a person falls on an outstretched hand with dorsal displacement of the wrist. However, he also suggested that volar displacement of the wrist was due to the ulnar fracture. His work was met with skepticism from colleagues and little recognition, since the article was published after he died. In 1814, Abraham Colles described the characteristics of distal end radius fracture. In 1841, Guilaume Dupuytren acknowledged the contributions by Petit and Pouteau, agreeing that the distal end radius fracture is indeed a fracture, not a dislocation. In 1847, Malgaigne described the Occult dislocations can accompany extremity fractures and may lead to serious complications if undetected and untreated. Physicians, therefore, need to watch for uncommon trauma like distal radius fractures with radioulnar joint disruption (Galeazzi fractures), proximal ulna fractures with radial head dislocation (Monteggia fractures), and midfoot dislocations with or without fracture (Lisfranc injuries). Injury recognition involves comparing important historical features like a fall onto an outstretched hand, physical exam findings such as the nature of the pain, and sometimes-subtle radiographic clues. Treatment is usually surgical. Distal radius fractures are common, and are the most common type of fractures that are seen in children. Distal radius fractures represent between 25% and 50% of all broken bones and occur most commonly in young males and older females. A year or two may be required for healing to occur. Most children with a buckle wrist fracture experience a full recovery to their previous level of wrist function and do not have an increased chance of re-fracturing the same spot or other adverse effects. Signs and symptoms People usually present with a history of falling on an outstretched hand and complaint of pain and swelling around the wrist, sometimes with deformity around the wrist. Any numbness should be asked to exclude median and ulnar nerve injuries. Any pain in the limb of the same side should also be investigated to exclude associated injuries to the same limb. A Scapholunate ligament injury commonly presents following a fall onto a dorsally extended and ulnar deviated hand. Wrist pain is usually dorsal-radial and accompanied by an inability to bear weight with the wrist extended, such as in a push-up position. The physical exam may show tenderness over the location of the scapholunate ligament, which is palpable on the dorsum of the wrist, immediately distal to the head of the radius. A scaphoid shift test can be performed as part of the physical exam to aid in the diagnosis with a positive likelihood ratio of 2.76 and a negative likelihood ratio of 0.25. [6] Dynamic imaging with a clenched fist, as well as contralateral wrist views, can improve the sensitivity of imaging with plain films. [7] Simultaneous dislocation of the elbow, radioulnar joint and proximal radius fracture with rotary noose injury to the medial ulna tubercle is extremely rare. An emergency surgery was performed to reduce it. The radial head with the backbone was reset after two hammers were fixed, then the radial capitulum safety was fixed with a locking plate. After the ulnar instability was examined, two Kirschner wires were drilled percutaneously to fix the elbow flexion at 100° under closed reduction, and two Kirschner wires were drilled percutaneously to fix the ulnar joint. Good follow-up results were achieved. To the best of our knowledge, this is the first report on this particular type of injury and on this approach to treating this type of injury. We report the case of a 36-year-old male, who extended and landed on his left hand to protect his child in right arm before felling, resulting in severe pain and deformity of his left elbow and wrist and loss of movement in these joints. X-ray examination found proximal distal radioulnar joints, a proximal radial fracture and a dislocation bowstring in the ulna nodule. For a timely diagnosis in an emergency open reduction situation, accurate judgment of this injury is highly important. After 12 months of postoperative follow-up, the patient was symptom-free, and radiographs showed fracture healing. We performed emergency reduction and internal fixation of the elbow and successfully saved elbow function, no stability decrease and movement restriction. This case also provides a new reference for the treatment of this type of elbow fracture dislocation. The fracture occurs when a patient has direct traumatic to the elbow or falls with the wrist and the hand in extension. The usual signs are pain and functional impotence, there may be blockages in the elbow. Nightstick fracture is a fracture of the middle portion of the ulna without other fractures. Distal ulna fractures typically occur along with distal radius fractures. Hume fracture - a fracture of the olecranon with an associated anterior dislocation of the radial head. Monteggia fracture - a fracture of the near to elbow end of the ulna with the dislocation of the head of the radius at the elbow joint. Galeazzi fracture - not a fracture of the ulna but a displaced fracture of the radius accompanied by a dislocation of the ulna at the wrist, where the radius and ulna come together. Essex-Lopresti fracture – a fracture of the radial head with concomitant dislocation of the distal radio-ulnar joint with disruption of the interosseous membrane. Radial shaft fracture Distal radius fracture Galeazzi fracture – a fracture of the radius with dislocation of the distal radioulnar joint Colles' fracture – a distal fracture of the radius with dorsal (posterior) displacement of the wrist and hand Smith's fracture – a distal fracture of the radius with volar (ventral) displacement of the wrist and hand Barton's fracture – an intra-articular fracture of the distal radius with dislocation of the radiocarpal joint. History The word radius is Latin for \"ray\". In the context of the radius bone, a ray can be thought of rotating around an axis line extending diagonally from center of capitulum to the center of distal ulna. While the ulna is the major contributor to the elbow joint, the radius primarily contributes to the wrist joint. From the time of Hippocrates to the beginning of the nineteenth century, fractures of the distal end of the radius were mistaken for dislocations of the wrist. Clinical observations, anatomic dissections, and experiments on cadavers dispelled this error. It was not, however, until after the discovery of roentgenograms that the variety and complexity of these common injuries could be appreciated. From the large group of fractures of the distal end of the radius, three distinct varieties can be distinguished rather easily, and to them the eponyms of Colles (Pouteau-Colles), Smith, and Barton have been applied. The remainder, which consist of a substantial number, do not fit into any specific category and must be described individually. We report an extremely rare combination of Monteggia equivalent Type 1 lesion (diaphyseal ulna and radial neck fractures without dislocation) with ipsilateral radius shaft and distal radius fractures in a 13-year-old boy. There are only a few cases of Monteggia or Monteggia equivalent injury with ipsilateral forearm fractures in children, and injury pattern being reported by us is not only rare but also the only case reported, thus far to the best of our knowledge. A 13-year-old, right-hand dominant boy presented in casualty with a history of fall 1 day back with pain, swelling and deformity in the left forearm with bleeding from the left forearm, and restriction of movement of fingers and thumb of the left hand. On examination, there was a wound of size 1.5 cm on the upper third-forearm over the ulnar aspect. No neurovascular deficit was present. X-rays were performed, which suggested Type I Monteggia fracture equivalent lesion (diaphyseal ulna and radial neck fractures without dislocation) with ipsilateral distal radius and radial shaft fractures. The patient was operated with toileting, debridement, and close reduction of proximal ulnar fracture with titanium elastic nail (TENS) Distal radius was managed by percutaneous fixation with two K-wires under the guidance of image intensifier, while the shaft of radius fracture was managed by close reduction and internal fixation with elastic TENS nail with a lateral entry point and radial neck fracture was managed by the Metaizeau technique. Follow-up of the patient showed subsequent union of all fractures with good functional outcome. We have highlighted an extremely rare combination of injuries. Early recognition and prompt surgical intervention can lead to a satisfactory outcome, even in these complex injuries. He is reported missing by Donna. Days later, on 8 November 1982 his body is discovered floating in the canal by DCI Gene Hunt on the day he was to have flown to Turkey. The coroner opines that the low volume of water in his lungs suggests that he was killed on dry land, and notes the blunt force trauma to his right frontal lobe. The two facts suggesting murder to DI Alex Drake; while Hunt agrees with the possibility, he offers the alternative theory that Mitchell was drunk, fell, hit his head and fell in the river. Drake and the coroner agree that the scabbing on Mitchell's wrist wounds suggest they were received at the same time as the head wound. A 44-year-old multiple injured patient presented with several fractures including a dislocated, comminuted radial head fracture after a 4 meter fall from a ladder. He was treated with radial head resection. However, at routine follow-up he indicated pain and loss of function of his wrist due to a distal radio-ulnar dislocation with a high position of the ulna, causing loss of pronation and supination. This is also known as the Essex-Lopresti lesion. Operative treatment included reduction and fixation of the distal radio-ulnar joint after resection osteotomy of the distal ulnar shaft according to Sauvé and Kapandji. It is spring and you are meeting for the first time, Eddie, a recently turned 6-year-old boy who moved to the area in September of the previous year and is here for his 6-year-old health maintenance visit. Eddie's mother is concerned that although he is \"only\" in kindergarten, he is not retaining any information at school. His mother reports he knew some of his letters before kindergarten. Currently, when he is trying to write a word, for example, \"daddy\" he will need to ask his mother: \"what letter is the letter D?\" Before kindergarten, he knew his numbers 1 to 10. At times now, Eddie will forget these numbers. For example, \"if he is counting he will forget what comes after 4 and what comes after 9.\" Mother reports he will start crying for no apparent reason and if she asks why, he will say \"I don't know why.\" Mother is worried that Eddie is sad, although she denies suicidal ideation. She reports he used to like making noise with other kids, and now he cannot stand when the children are noisy. Eddie will comment he does not want to go to school because the kids make lots of noise and his head hurts. He complains of headaches as often as 2 to 3 times a month. She next states, \"This was not an issue before his head trauma.\" At this point, she reveals to you that in August, before the family relocated, Eddie fell from a 7-foot deck onto concrete while playing. He struck his head on the left side and lost consciousness for several seconds until shaken awake. He was nauseous and disoriented initially but without emesis or incontinence. He was taken to the local emergency department where he was admitted for 1 day and diagnosed with closed head injury, left frontal epidural hematoma, and question of postconcussive syndrome. Eddie has gone back to see the neurosurgeon twice over the last 6 months for scheduled visits and since the accident has had no further treatment.Eddie's mother reports that before the accident, if she read him a story from a book, he could remember the details from the story. Currently, he does not have good memory recall. Before the trauma, he did not attend a preschool program but stayed home with his mother full time. Eddie's first formal schooling has been kindergarten this year. When they moved, the neurosurgeon recommended he start school at the end of September given his head trauma in August. He had a recent computed tomography completed 3 months ago showing the epidural hematoma had completely resolved and the study was otherwise normal. His mother reports he had an evaluation the spring before the accident for a kindergarten screening test and was reported as \"excellent.\" Eddie's birth and medical history are otherwise unremarkable except for some seasonal allergies. He has not had a loss in language skill, although his mother reports he did not speak during his hospitalization. He would just stare and nod his head if someone would ask him a question. No family history of any learning or behavioral difficulties on either side of the family. Eddie has 2 older brothers, 10 and 7 years of age, with no learning issues.What would you do next? With his feud with Triple H now over, Chris Jericho decided to enter the King of the Ring tournament, with the winner to receive a WWE Undisputed Championship match on August 25 at SummerSlam. Jericho was scheduled to compete against Edge in the first round tournament, but Edge forfeited his match to Jericho due to a legitimate shoulder injury. Jericho advanced as far as the semi-finals, losing to Rob Van Dam. On the May 30 episode of SmackDown!, The Undertaker defeated Randy Orton to retain the WWE Undisputed Championship. Afterward, Triple H assaulted The Undertaker and demanded a title shot. During Triple H's match against Test, The Undertaker interfered, enabling Test to nail Triple H with a big boot for the pin. Afterwards, The Undertaker nailed Triple H with multiple chair shots to his elbow. On the June 6 episode of SmackDown!, Triple H became the number one contender to the WWE Undisputed Championship by defeating Hollywood Hulk Hogan. Triple H faced The Undertaker for the A 7-year-old boy attended the emergency department after falling from a climbing frame onto his outstretched left wrist. On examination, there was mild swelling to the left elbow and tenderness to the antecubital fossa. There was also tenderness diffusely to the distal ulnar and radius. There was no neurovascular deficit. Radiographs revealed a plastic deformation fracture of the left radius and ulna, with dislocations of the ipsilateral radiocapitellar joint and distal radioulnar joint. A diagnosis of combined Monteggia and Galeazzi-type fractures of the left forearm was made. It is rare to find cases of combined Monteggia and Galeazzi fractures to the same forearm. Furthermore, to our knowledge, ipsilateral plastic deformation Monteggia and Galeazzi-type fractures in children have not been reported in the literature. Patients with distal radial fractures will often complain of post-traumatic distal upper extremity pain. DR fractures can also be present as part of a larger multiple trauma presentation. In either case, it is vital not to fixate on an obvious DR injury, and to do a complete evaluation for other possible life-threatening injuries or problems. A systematic approach in trauma situations will prevent a provider from missing occult injuries. Children are also diagnostically difficult as their presentations are often subtle. Children can suffer unwitnessed falls or trauma, and they are often unable to verbalize their symptoms. They can appear well and favoring the uninjured arm may be the only sign of an underlying fracture. [10] [8] We report a case of Type 1 Monteggia equivalent injury with intact radio-capitellar congruity, associated with epiphyseal fracture of distal radius and distal ulna shaft in an 11-year-old boy. There are only a few cases of Monteggia or Monteggia equivalent injury with ipsilateral forearm fractures in children, and injury pattern being reported by us is not only rare but also the only case reported thus far to the best of our knowledge, Sood et al. described Type 1 equivalent with epiphyseal injuries of both radius and ulna Osada et al. also described injury pattern same as Sood et al. with epiphyseal separation in both distal radius and ulna. Our case was slightly different than above two in that distally, there was ulna shaft fracture with Salter Harris Type 2 epiphyseal separation in the radius. An 11-year-old, right-hand dominant boy presented in casualty with a history of fall one day back with pain, swelling and deformity in the left forearm with bleeding from left forearm and loss of movement of fingers and thumb of the left hand. On examination, there was a wound of size one centimeter on mid-forearm over the ulnar aspect. Extension of fingers and thumb at metacarpophalangeal joints was lost with intact sensations suggestive of posterior interosseus nerve involvement. No vascular was deficit was present. X-rays were performed which suggested type two epiphyseal separation proximal radius with fracture shaft ulna with lateral angulation in elbow and proximal forearm. Radiocapitellar joint congruity was maintained in the views performed. X-rays of wrist suggested fracture both bones distal forearm epiphysis in distal radius and distal shaft in ulna. The patient was operated with toileting, debridement, and open reduction of proximal ulnar fracture with K-wire. Proximal radius epiphyseal separation was approached by Kocher approach and fixed with two K-wires, while for distal radius epiphyseal separation open reduction and internal fixation was performed. Follow-up of the patient showed posterior interosseus nerve recovery and subsequent union of all fractures with good functional outcome. This type of lesion is rare in children probably because the annular ligament is relatively lax and the radial head dislocates more easily anteriorly, rather than occurrence of fracture as seen in our case, and associated fracture of distal forearm is a very rare injury. The radiological diagnosis of distal radial fractures is usually easy, but some fractures without displacement cannot be detected at the first examination. In this retrospective study of 626 wrist injuries diagnosed as \"wrist sprain\" we found 39 distal radial fractures which were discovered only after repeated examinations. The incidence of distal radial fractures was much higher than other wrist fractures that were diagnosed after repeated examinations. Repeat standard four-view X-ray examination, as well as other imaging methods, are necessary to diagnose these fractures. Diagnosis Diagnosis may be evident clinically when the distal radius is deformed, but should be confirmed by X-ray. The differential diagnosis includes scaphoid fractures and wrist dislocations, which can also co-exist with a distal radius fracture. Occasionally, fractures may not be seen on X-rays immediately after the injury. Delayed X-rays, X-ray computed tomography (CT scan), or Magnetic resonance imaging (MRI) can confirm the diagnosis. Medical imaging X-ray of the affected wrist is required if a fracture is suspected. Posteroanterior, lateral, and oblique views can be used together to describe the fracture. X-ray of the uninjured wrist should also be taken to determine if any normal anatomic variations exist before surgery. A CT scan is often performed to further investigate the articular anatomy of the fracture, especially for fracture and displacement within the distal radio-ulnar joint. Various kinds of information can be obtained from X-rays of the wrist: Though Sweden was still at war with Denmark a revolution took place in 1568 and King Erik XIV was dethroned by his brothers Johan (John) and Karl (Charles). The situation was chaotic and the brothers didn't know how to dispose of the King. To execute or to expatriate him was far too dangerous, consequently remained to keep him imprisoned. This solution to the problem was not without hazards since Erik had many friends who repeatedly tried to free him. The former king, however, also had many enemies, one of whom was Olof Gustafsson Stenbock a man who was responsible for the guarding of Erik. Olof Gustafsson had himself been sentenced to death by King Erik but been reprieved. His brother Abraham Gustafsson Stenbock was on the other hand executed on the order of the King. On the 19th September 1569 Olof Gustafsson visited the imprisoned king, who rushed to his feet, attacking Olof Gustafsson. Olof retreated, took out his gun and shot the King in his left forearm. The King survived 8 years with a badly wounded arm which probably was of no use to him. In this article I have tried to put together all pieces of evidence to prove that the King really was shot. This includes old tales as well as written evidence and facts brought to light during the latest examination of King Erik's remains. This investigation was done in 1958 by professor Carl-Herman Hjortsjö and his collaborators. At the opening of the sarcophagi a defect healed fracture on the left humerus was still clearly visible. Many facts in this article originate from works by L.-I. Jönsson who in a very thorough and accurate way tried to reconstruct this interesting and exciting historical crime. This case report documents a rare inversion of a closed metacarpal head fracture in the setting of polytrauma. Although rare, hemispherical articular bones can fracture and rotate 180°. Because of the symmetry of the bone and the rarity of an inverted, metacarpal head fracture, a delay in diagnosis and subsequent treatment can occur, which can lead to a poor outcome. This is particularly true in the setting of polytrauma. A 38-year-old male, polytrauma patient presented to the emergency department (ED) after falling off a bridge and being struck by an oncoming vehicle. He presented with multiple surgical fractures of the upper and lower extremities as well as his pelvis. Three days after he was brought to the ED, x-rays were performed of his painful left hand, which revealed an extra-articular third metacarpal head fracture, for which he underwent open reduction of the closed fracture. Both collateral ligaments were intact and the head fragment had inverted within the constraints of these ligaments. Some of the ligament and capsular tissue remained attached to the head fragment along the radial and ulnar margins but was otherwise entirely covered with cartilage. The reduction maneuver was difficult but after the reduction was achieved, the fracture appeared stable and no internal fixation was used. Post reduction, the injury was splinted for 2 weeks and then early motion was allowed. The fracture has since healed, and the patient has attained near-full function of the finger and joint. As with Tommy Tune, Rick Springfield initially signed a one-year contract. Despite becoming the newest victim in EFX long history of performance-related accidents, fracturing his arm and spraining his wrist early on in his run, Springfield renewed his full contract and stayed with the show until it closed permanently on December 31, 2002. The final performances of EFX Alive! were shot with several cameras. The result was a complete DVD video of EFX Alive! (compiling footage from multiple performances) released exclusively by Springfield's Gomer Records as part of a three-disc limited edition of his 2005 studio album, The Day After Yesterday and available only through the official Rick Springfield merchandise site. An original cast album of the Springfield version of EFX was not released. References Monteggia fractures are rare but commonly discussed lesions, with increasing complications due to late diagnosis. This article describes a case of a Monteggia fracture with delayed dislocation of the radial head. Previous radiographs of a 2-year 8-month-old boy show complete fracture of the distal ulna, with no radial head dislocation. The radial head remained well positioned after 4 weeks. Seven years later, he sustained another arm injury. He was diagnosed with a hematoma but was later believed to have nursemaid's elbow. He presented to our institution 5 weeks after the injury, and the radial head was found to be chronically dislocated, indicating a displacement occurring sometime during the past 7 years. After failing conservative treatment, the patient underwent surgical repair. The annular ligament was reconstructed using a harvested triceps fascia band, and an ulnar osteotomy was performed. A review of the literature found few reports of delayed Monteggia fractures, which accounted the delayed dislocations to ulnar angulation. However, our patient showed minimal ulnar angular deformity. We propose that the initial fracture disrupted the annular ligament and the radial head spontaneously relocated prior to being seen, which put the radial head at risk for later dislocation. We present an alternative hypothesis of dislocation after fracture healing and report the longest known period of delay between fracture and dislocation. Elbow dislocations are relatively uncommon in children. Rupture of the brachial artery associated with closed elbow dislocations in children is rare. This is a report of an 8-year-old boy, the youngest patient ever to be reported to have a closed posterior dislocation of the elbow associated with a brachial artery laceration. The boy incurred a closed elbow dislocation after a fall onto his outstretched arm. On physical examination, both radial and ulnar (ulnar) pulses were absent. Radiographs showed a posterolateral dislocation of the right elbow and distal fractures of the radius and ulna. Operative exploration of the antecubital fossa showed complete transection of the brachial artery. Repair of the vessel was performed using an interposition vein graft. The distal forearm fractures were managed by closed reduction. At the two-year postoperative follow-up examination, the patient had a normal neurovascular examination with full range of motion of his elbow and wrist. Surgical treatment should include exploration of the antecubital fossa and reconstruction of the injured vessels. On 3 July 1958, The Bulletin newspaper reported that Dixon was to have an operation that Sunday, quoting him as saying \"A nerve in my right elbow is affecting the hand\". It was \"the result of an injury received in a motorcycle smash when I was a youth.\" The Bulletin reported that \"He wanted to postpone the operation until the end of the season, but doctors have warned him that delay might mean losing the use of the hand\". He returned to the ballroom and its Wurlitzer later in the same month, having made over 2,000 broadcasts. Isolated fracture of the radial diaphysis with dislocation of the radial head is a rare injury, which requires careful evaluation. Combined injuries associated with forearm shaft fractures and elbow dislocations are well recognized. A 35-year-old male presented to our emergency department with a history of fall in ditch under influence of alcohol with swelling of her right elbow and deformity of right upper limb. Roentgenograms showed oblique fracture of the radial shaft and dislocation of radial head posteriorly. He underwent open reduction and internal fixation of fracture with limited contact dynamic compression plate and reduction of radial head and fixing with radiocapitellar wire. After 4 months, the fracture healed fully and he had complete full range of elbow movements. Ipsilateral radial head dislocation and radial shaft fracture are extremely rare injury in a child. A good outcome can be achieved by applying principles of the management of proximal forearm fracture-dislocation. Ipsilateral radial head dislocation and radial shaft fracture is extremely rare injury in a child. A good outcome can be achieved by applying principles of management of proximal forearm fracture-dislocation. Trainer Trainer Ray Hutchins stood by Frank Reys after a horrible two years in which he had suffered a broken shoulder, two pelvis fractures, a broken cheek bone and a broken ankle, and earned himself the nickname \"Autumn Leaves\". Despite these injuries Hutchins entrusted Reys with the ride on the four-year-old gelding Gala Supreme in the 1973 Caulfield Cup, in which Gala Supreme ran second. Hutchins had long before mapped out the Melbourne Cup as his mission, and after the Caulfield Cup second he prepared Gala Supreme for the Cup. We present an unusual case in which a combination of Monteggia and Galeazzi fractures occurred in the same forearm. The patient was a 10-year-old male who climbed up the pole of a basketball net, caught hold of the net, then lost his grip, and fell onto his right hand. On physical examination, a complete paralysis of the radial ulnar and median nerves was recognized. X-rays showed an olecranon fracture and lateral dislocation of the radial head in the elbow joint, a dorsal dislocation of the distal bone fragments due to a fracture of the distal third of the radius, and a palmar dislocation of the distal end of the ulna at the wrist joint. The injuries were diagnosed as a combination of a Bado type III Monteggia fracture and a palmar-type Galeazzi fracture of the same arm. Manual reduction and immobilization in a plaster cast were performed. Three years after the injury, both the distal and proximal radioulnar joints were maintained in the reduction position. Range of motion was reduced minimally in extension at the patient's elbow, and there was complete recovery of all three nerves. A combination of Monteggia and Galeazzi fractures in the same arm has been reported in only two pediatric patients worldwide and in eight cases total when adult patients are included, indicating that this is an extremely rare trauma. It is uncertain when Rhun's reign and life ended. One possibility is that Rhun died in 876, when Causantín seems to have been slain by Vikings. Causantín's death is dated to 876 by the Annals of Ulster. The Chronicle of the Kings of Alba appears to locate his fall in Atholl, whilst several king-lists locate his demise to a place variously called , an otherwise uncertain location that could refer to Inverdovat in Fife. If Causantín indeed enjoyed overlordship of Strathclyde at this date, Rhun could have fallen alongside him as a supporting vassal. It is likewise unknown who succeeded to the kingship of Strathclyde. If Rhun and Causantín both died in 876, Eochaid could well have inherited the British kingship in their absence. Certainly, Causantín's brother, Áed mac Cináeda, succeeded as King of the Picts, and ruled as such upon his death two years later. Whilst it is possible that the Pictish kingship was then assumed by a certain Giric, another possibility is that Eochaid succeeded to\nHere is the question:\nORTHOPEDIC SURGERY AND TRAUMATOLOGY: A 7-year-old boy brought to the emergency department after falling off a swing onto his right hand. He has no history of interest. He presents with fork dorsum deformity of the wrist and functional impotence, with normal distal neurovascular status. What lesion would you expect to find on the urgent x-ray you request?\nHere are the potential choices:\n1. Fracture - dislocation of Monteggia.\n2. Radial head fracture.\n3. Epiphysiolysis of the distal radius.\n4. Fracture in green stem of ulna.\nThe correct answer is: ",
        "gold_answer": "3 Epiphysiolysis of the distal radius.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Before the 18th century, distal radius fracture was believed to be due to dislocation of the carpal bones or the displacement of the distal radioulnar articulation. In the 18th century, Petit first suggested that these types of injuries might be due to fractures rather than dislocations. Another author, Pouteau, suggested the common mechanism of injury which leads to this type of fractures - injury to the wrist when a person falls on an outstretched hand with dorsal displacement of the wrist. However, he also suggested that volar displacement of the wrist was due to the ulnar fracture. His work was met with skepticism from colleagues and little recognition, since the article was published after he died. In 1814, Abraham Colles described the characteristics of distal end radius fracture. In 1841, Guilaume Dupuytren acknowledged the contributions by Petit and Pouteau, agreeing that the distal end radius fracture is indeed a fracture, not a dislocation. In 1847, Malgaigne described the Occult dislocations can accompany extremity fractures and may lead to serious complications if undetected and untreated. Physicians, therefore, need to watch for uncommon trauma like distal radius fractures with radioulnar joint disruption (Galeazzi fractures), proximal ulna fractures with radial head dislocation (Monteggia fractures), and midfoot dislocations with or without fracture (Lisfranc injuries). Injury recognition involves comparing important historical features like a fall onto an outstretched hand, physical exam findings such as the nature of the pain, and sometimes-subtle radiographic clues. Treatment is usually surgical. Distal radius fractures are common, and are the most common type of fractures that are seen in children. Distal radius fractures represent between 25% and 50% of all broken bones and occur most commonly in young males and older females. A year or two may be required for healing to occur. Most children with a buckle wrist fracture experience a full recovery to their previous level of wrist function and do not have an increased chance of re-fracturing the same spot or other adverse effects. Signs and symptoms People usually present with a history of falling on an outstretched hand and complaint of pain and swelling around the wrist, sometimes with deformity around the wrist. Any numbness should be asked to exclude median and ulnar nerve injuries. Any pain in the limb of the same side should also be investigated to exclude associated injuries to the same limb. A Scapholunate ligament injury commonly presents following a fall onto a dorsally extended and ulnar deviated hand. Wrist pain is usually dorsal-radial and accompanied by an inability to bear weight with the wrist extended, such as in a push-up position. The physical exam may show tenderness over the location of the scapholunate ligament, which is palpable on the dorsum of the wrist, immediately distal to the head of the radius. A scaphoid shift test can be performed as part of the physical exam to aid in the diagnosis with a positive likelihood ratio of 2.76 and a negative likelihood ratio of 0.25. [6] Dynamic imaging with a clenched fist, as well as contralateral wrist views, can improve the sensitivity of imaging with plain films. [7] Simultaneous dislocation of the elbow, radioulnar joint and proximal radius fracture with rotary noose injury to the medial ulna tubercle is extremely rare. An emergency surgery was performed to reduce it. The radial head with the backbone was reset after two hammers were fixed, then the radial capitulum safety was fixed with a locking plate. After the ulnar instability was examined, two Kirschner wires were drilled percutaneously to fix the elbow flexion at 100° under closed reduction, and two Kirschner wires were drilled percutaneously to fix the ulnar joint. Good follow-up results were achieved. To the best of our knowledge, this is the first report on this particular type of injury and on this approach to treating this type of injury. We report the case of a 36-year-old male, who extended and landed on his left hand to protect his child in right arm before felling, resulting in severe pain and deformity of his left elbow and wrist and loss of movement in these joints. X-ray examination found proximal distal radioulnar joints, a proximal radial fracture and a dislocation bowstring in the ulna nodule. For a timely diagnosis in an emergency open reduction situation, accurate judgment of this injury is highly important. After 12 months of postoperative follow-up, the patient was symptom-free, and radiographs showed fracture healing. We performed emergency reduction and internal fixation of the elbow and successfully saved elbow function, no stability decrease and movement restriction. This case also provides a new reference for the treatment of this type of elbow fracture dislocation. The fracture occurs when a patient has direct traumatic to the elbow or falls with the wrist and the hand in extension. The usual signs are pain and functional impotence, there may be blockages in the elbow. Nightstick fracture is a fracture of the middle portion of the ulna without other fractures. Distal ulna fractures typically occur along with distal radius fractures. Hume fracture - a fracture of the olecranon with an associated anterior dislocation of the radial head. Monteggia fracture - a fracture of the near to elbow end of the ulna with the dislocation of the head of the radius at the elbow joint. Galeazzi fracture - not a fracture of the ulna but a displaced fracture of the radius accompanied by a dislocation of the ulna at the wrist, where the radius and ulna come together. Essex-Lopresti fracture – a fracture of the radial head with concomitant dislocation of the distal radio-ulnar joint with disruption of the interosseous membrane. Radial shaft fracture Distal radius fracture Galeazzi fracture – a fracture of the radius with dislocation of the distal radioulnar joint Colles' fracture – a distal fracture of the radius with dorsal (posterior) displacement of the wrist and hand Smith's fracture – a distal fracture of the radius with volar (ventral) displacement of the wrist and hand Barton's fracture – an intra-articular fracture of the distal radius with dislocation of the radiocarpal joint. History The word radius is Latin for \"ray\". In the context of the radius bone, a ray can be thought of rotating around an axis line extending diagonally from center of capitulum to the center of distal ulna. While the ulna is the major contributor to the elbow joint, the radius primarily contributes to the wrist joint. From the time of Hippocrates to the beginning of the nineteenth century, fractures of the distal end of the radius were mistaken for dislocations of the wrist. Clinical observations, anatomic dissections, and experiments on cadavers dispelled this error. It was not, however, until after the discovery of roentgenograms that the variety and complexity of these common injuries could be appreciated. From the large group of fractures of the distal end of the radius, three distinct varieties can be distinguished rather easily, and to them the eponyms of Colles (Pouteau-Colles), Smith, and Barton have been applied. The remainder, which consist of a substantial number, do not fit into any specific category and must be described individually. We report an extremely rare combination of Monteggia equivalent Type 1 lesion (diaphyseal ulna and radial neck fractures without dislocation) with ipsilateral radius shaft and distal radius fractures in a 13-year-old boy. There are only a few cases of Monteggia or Monteggia equivalent injury with ipsilateral forearm fractures in children, and injury pattern being reported by us is not only rare but also the only case reported, thus far to the best of our knowledge. A 13-year-old, right-hand dominant boy presented in casualty with a history of fall 1 day back with pain, swelling and deformity in the left forearm with bleeding from the left forearm, and restriction of movement of fingers and thumb of the left hand. On examination, there was a wound of size 1.5 cm on the upper third-forearm over the ulnar aspect. No neurovascular deficit was present. X-rays were performed, which suggested Type I Monteggia fracture equivalent lesion (diaphyseal ulna and radial neck fractures without dislocation) with ipsilateral distal radius and radial shaft fractures. The patient was operated with toileting, debridement, and close reduction of proximal ulnar fracture with titanium elastic nail (TENS) Distal radius was managed by percutaneous fixation with two K-wires under the guidance of image intensifier, while the shaft of radius fracture was managed by close reduction and internal fixation with elastic TENS nail with a lateral entry point and radial neck fracture was managed by the Metaizeau technique. Follow-up of the patient showed subsequent union of all fractures with good functional outcome. We have highlighted an extremely rare combination of injuries. Early recognition and prompt surgical intervention can lead to a satisfactory outcome, even in these complex injuries. He is reported missing by Donna. Days later, on 8 November 1982 his body is discovered floating in the canal by DCI Gene Hunt on the day he was to have flown to Turkey. The coroner opines that the low volume of water in his lungs suggests that he was killed on dry land, and notes the blunt force trauma to his right frontal lobe. The two facts suggesting murder to DI Alex Drake; while Hunt agrees with the possibility, he offers the alternative theory that Mitchell was drunk, fell, hit his head and fell in the river. Drake and the coroner agree that the scabbing on Mitchell's wrist wounds suggest they were received at the same time as the head wound. A 44-year-old multiple injured patient presented with several fractures including a dislocated, comminuted radial head fracture after a 4 meter fall from a ladder. He was treated with radial head resection. However, at routine follow-up he indicated pain and loss of function of his wrist due to a distal radio-ulnar dislocation with a high position of the ulna, causing loss of pronation and supination. This is also known as the Essex-Lopresti lesion. Operative treatment included reduction and fixation of the distal radio-ulnar joint after resection osteotomy of the distal ulnar shaft according to Sauvé and Kapandji. It is spring and you are meeting for the first time, Eddie, a recently turned 6-year-old boy who moved to the area in September of the previous year and is here for his 6-year-old health maintenance visit. Eddie's mother is concerned that although he is \"only\" in kindergarten, he is not retaining any information at school. His mother reports he knew some of his letters before kindergarten. Currently, when he is trying to write a word, for example, \"daddy\" he will need to ask his mother: \"what letter is the letter D?\" Before kindergarten, he knew his numbers 1 to 10. At times now, Eddie will forget these numbers. For example, \"if he is counting he will forget what comes after 4 and what comes after 9.\" Mother reports he will start crying for no apparent reason and if she asks why, he will say \"I don't know why.\" Mother is worried that Eddie is sad, although she denies suicidal ideation. She reports he used to like making noise with other kids, and now he cannot stand when the children are noisy. Eddie will comment he does not want to go to school because the kids make lots of noise and his head hurts. He complains of headaches as often as 2 to 3 times a month. She next states, \"This was not an issue before his head trauma.\" At this point, she reveals to you that in August, before the family relocated, Eddie fell from a 7-foot deck onto concrete while playing. He struck his head on the left side and lost consciousness for several seconds until shaken awake. He was nauseous and disoriented initially but without emesis or incontinence. He was taken to the local emergency department where he was admitted for 1 day and diagnosed with closed head injury, left frontal epidural hematoma, and question of postconcussive syndrome. Eddie has gone back to see the neurosurgeon twice over the last 6 months for scheduled visits and since the accident has had no further treatment.Eddie's mother reports that before the accident, if she read him a story from a book, he could remember the details from the story. Currently, he does not have good memory recall. Before the trauma, he did not attend a preschool program but stayed home with his mother full time. Eddie's first formal schooling has been kindergarten this year. When they moved, the neurosurgeon recommended he start school at the end of September given his head trauma in August. He had a recent computed tomography completed 3 months ago showing the epidural hematoma had completely resolved and the study was otherwise normal. His mother reports he had an evaluation the spring before the accident for a kindergarten screening test and was reported as \"excellent.\" Eddie's birth and medical history are otherwise unremarkable except for some seasonal allergies. He has not had a loss in language skill, although his mother reports he did not speak during his hospitalization. He would just stare and nod his head if someone would ask him a question. No family history of any learning or behavioral difficulties on either side of the family. Eddie has 2 older brothers, 10 and 7 years of age, with no learning issues.What would you do next? With his feud with Triple H now over, Chris Jericho decided to enter the King of the Ring tournament, with the winner to receive a WWE Undisputed Championship match on August 25 at SummerSlam. Jericho was scheduled to compete against Edge in the first round tournament, but Edge forfeited his match to Jericho due to a legitimate shoulder injury. Jericho advanced as far as the semi-finals, losing to Rob Van Dam. On the May 30 episode of SmackDown!, The Undertaker defeated Randy Orton to retain the WWE Undisputed Championship. Afterward, Triple H assaulted The Undertaker and demanded a title shot. During Triple H's match against Test, The Undertaker interfered, enabling Test to nail Triple H with a big boot for the pin. Afterwards, The Undertaker nailed Triple H with multiple chair shots to his elbow. On the June 6 episode of SmackDown!, Triple H became the number one contender to the WWE Undisputed Championship by defeating Hollywood Hulk Hogan. Triple H faced The Undertaker for the A 7-year-old boy attended the emergency department after falling from a climbing frame onto his outstretched left wrist. On examination, there was mild swelling to the left elbow and tenderness to the antecubital fossa. There was also tenderness diffusely to the distal ulnar and radius. There was no neurovascular deficit. Radiographs revealed a plastic deformation fracture of the left radius and ulna, with dislocations of the ipsilateral radiocapitellar joint and distal radioulnar joint. A diagnosis of combined Monteggia and Galeazzi-type fractures of the left forearm was made. It is rare to find cases of combined Monteggia and Galeazzi fractures to the same forearm. Furthermore, to our knowledge, ipsilateral plastic deformation Monteggia and Galeazzi-type fractures in children have not been reported in the literature. Patients with distal radial fractures will often complain of post-traumatic distal upper extremity pain. DR fractures can also be present as part of a larger multiple trauma presentation. In either case, it is vital not to fixate on an obvious DR injury, and to do a complete evaluation for other possible life-threatening injuries or problems. A systematic approach in trauma situations will prevent a provider from missing occult injuries. Children are also diagnostically difficult as their presentations are often subtle. Children can suffer unwitnessed falls or trauma, and they are often unable to verbalize their symptoms. They can appear well and favoring the uninjured arm may be the only sign of an underlying fracture. [10] [8] We report a case of Type 1 Monteggia equivalent injury with intact radio-capitellar congruity, associated with epiphyseal fracture of distal radius and distal ulna shaft in an 11-year-old boy. There are only a few cases of Monteggia or Monteggia equivalent injury with ipsilateral forearm fractures in children, and injury pattern being reported by us is not only rare but also the only case reported thus far to the best of our knowledge, Sood et al. described Type 1 equivalent with epiphyseal injuries of both radius and ulna Osada et al. also described injury pattern same as Sood et al. with epiphyseal separation in both distal radius and ulna. Our case was slightly different than above two in that distally, there was ulna shaft fracture with Salter Harris Type 2 epiphyseal separation in the radius. An 11-year-old, right-hand dominant boy presented in casualty with a history of fall one day back with pain, swelling and deformity in the left forearm with bleeding from left forearm and loss of movement of fingers and thumb of the left hand. On examination, there was a wound of size one centimeter on mid-forearm over the ulnar aspect. Extension of fingers and thumb at metacarpophalangeal joints was lost with intact sensations suggestive of posterior interosseus nerve involvement. No vascular was deficit was present. X-rays were performed which suggested type two epiphyseal separation proximal radius with fracture shaft ulna with lateral angulation in elbow and proximal forearm. Radiocapitellar joint congruity was maintained in the views performed. X-rays of wrist suggested fracture both bones distal forearm epiphysis in distal radius and distal shaft in ulna. The patient was operated with toileting, debridement, and open reduction of proximal ulnar fracture with K-wire. Proximal radius epiphyseal separation was approached by Kocher approach and fixed with two K-wires, while for distal radius epiphyseal separation open reduction and internal fixation was performed. Follow-up of the patient showed posterior interosseus nerve recovery and subsequent union of all fractures with good functional outcome. This type of lesion is rare in children probably because the annular ligament is relatively lax and the radial head dislocates more easily anteriorly, rather than occurrence of fracture as seen in our case, and associated fracture of distal forearm is a very rare injury. The radiological diagnosis of distal radial fractures is usually easy, but some fractures without displacement cannot be detected at the first examination. In this retrospective study of 626 wrist injuries diagnosed as \"wrist sprain\" we found 39 distal radial fractures which were discovered only after repeated examinations. The incidence of distal radial fractures was much higher than other wrist fractures that were diagnosed after repeated examinations. Repeat standard four-view X-ray examination, as well as other imaging methods, are necessary to diagnose these fractures. Diagnosis Diagnosis may be evident clinically when the distal radius is deformed, but should be confirmed by X-ray. The differential diagnosis includes scaphoid fractures and wrist dislocations, which can also co-exist with a distal radius fracture. Occasionally, fractures may not be seen on X-rays immediately after the injury. Delayed X-rays, X-ray computed tomography (CT scan), or Magnetic resonance imaging (MRI) can confirm the diagnosis. Medical imaging X-ray of the affected wrist is required if a fracture is suspected. Posteroanterior, lateral, and oblique views can be used together to describe the fracture. X-ray of the uninjured wrist should also be taken to determine if any normal anatomic variations exist before surgery. A CT scan is often performed to further investigate the articular anatomy of the fracture, especially for fracture and displacement within the distal radio-ulnar joint. Various kinds of information can be obtained from X-rays of the wrist: Though Sweden was still at war with Denmark a revolution took place in 1568 and King Erik XIV was dethroned by his brothers Johan (John) and Karl (Charles). The situation was chaotic and the brothers didn't know how to dispose of the King. To execute or to expatriate him was far too dangerous, consequently remained to keep him imprisoned. This solution to the problem was not without hazards since Erik had many friends who repeatedly tried to free him. The former king, however, also had many enemies, one of whom was Olof Gustafsson Stenbock a man who was responsible for the guarding of Erik. Olof Gustafsson had himself been sentenced to death by King Erik but been reprieved. His brother Abraham Gustafsson Stenbock was on the other hand executed on the order of the King. On the 19th September 1569 Olof Gustafsson visited the imprisoned king, who rushed to his feet, attacking Olof Gustafsson. Olof retreated, took out his gun and shot the King in his left forearm. The King survived 8 years with a badly wounded arm which probably was of no use to him. In this article I have tried to put together all pieces of evidence to prove that the King really was shot. This includes old tales as well as written evidence and facts brought to light during the latest examination of King Erik's remains. This investigation was done in 1958 by professor Carl-Herman Hjortsjö and his collaborators. At the opening of the sarcophagi a defect healed fracture on the left humerus was still clearly visible. Many facts in this article originate from works by L.-I. Jönsson who in a very thorough and accurate way tried to reconstruct this interesting and exciting historical crime. This case report documents a rare inversion of a closed metacarpal head fracture in the setting of polytrauma. Although rare, hemispherical articular bones can fracture and rotate 180°. Because of the symmetry of the bone and the rarity of an inverted, metacarpal head fracture, a delay in diagnosis and subsequent treatment can occur, which can lead to a poor outcome. This is particularly true in the setting of polytrauma. A 38-year-old male, polytrauma patient presented to the emergency department (ED) after falling off a bridge and being struck by an oncoming vehicle. He presented with multiple surgical fractures of the upper and lower extremities as well as his pelvis. Three days after he was brought to the ED, x-rays were performed of his painful left hand, which revealed an extra-articular third metacarpal head fracture, for which he underwent open reduction of the closed fracture. Both collateral ligaments were intact and the head fragment had inverted within the constraints of these ligaments. Some of the ligament and capsular tissue remained attached to the head fragment along the radial and ulnar margins but was otherwise entirely covered with cartilage. The reduction maneuver was difficult but after the reduction was achieved, the fracture appeared stable and no internal fixation was used. Post reduction, the injury was splinted for 2 weeks and then early motion was allowed. The fracture has since healed, and the patient has attained near-full function of the finger and joint. As with Tommy Tune, Rick Springfield initially signed a one-year contract. Despite becoming the newest victim in EFX long history of performance-related accidents, fracturing his arm and spraining his wrist early on in his run, Springfield renewed his full contract and stayed with the show until it closed permanently on December 31, 2002. The final performances of EFX Alive! were shot with several cameras. The result was a complete DVD video of EFX Alive! (compiling footage from multiple performances) released exclusively by Springfield's Gomer Records as part of a three-disc limited edition of his 2005 studio album, The Day After Yesterday and available only through the official Rick Springfield merchandise site. An original cast album of the Springfield version of EFX was not released. References Monteggia fractures are rare but commonly discussed lesions, with increasing complications due to late diagnosis. This article describes a case of a Monteggia fracture with delayed dislocation of the radial head. Previous radiographs of a 2-year 8-month-old boy show complete fracture of the distal ulna, with no radial head dislocation. The radial head remained well positioned after 4 weeks. Seven years later, he sustained another arm injury. He was diagnosed with a hematoma but was later believed to have nursemaid's elbow. He presented to our institution 5 weeks after the injury, and the radial head was found to be chronically dislocated, indicating a displacement occurring sometime during the past 7 years. After failing conservative treatment, the patient underwent surgical repair. The annular ligament was reconstructed using a harvested triceps fascia band, and an ulnar osteotomy was performed. A review of the literature found few reports of delayed Monteggia fractures, which accounted the delayed dislocations to ulnar angulation. However, our patient showed minimal ulnar angular deformity. We propose that the initial fracture disrupted the annular ligament and the radial head spontaneously relocated prior to being seen, which put the radial head at risk for later dislocation. We present an alternative hypothesis of dislocation after fracture healing and report the longest known period of delay between fracture and dislocation. Elbow dislocations are relatively uncommon in children. Rupture of the brachial artery associated with closed elbow dislocations in children is rare. This is a report of an 8-year-old boy, the youngest patient ever to be reported to have a closed posterior dislocation of the elbow associated with a brachial artery laceration. The boy incurred a closed elbow dislocation after a fall onto his outstretched arm. On physical examination, both radial and ulnar (ulnar) pulses were absent. Radiographs showed a posterolateral dislocation of the right elbow and distal fractures of the radius and ulna. Operative exploration of the antecubital fossa showed complete transection of the brachial artery. Repair of the vessel was performed using an interposition vein graft. The distal forearm fractures were managed by closed reduction. At the two-year postoperative follow-up examination, the patient had a normal neurovascular examination with full range of motion of his elbow and wrist. Surgical treatment should include exploration of the antecubital fossa and reconstruction of the injured vessels. On 3 July 1958, The Bulletin newspaper reported that Dixon was to have an operation that Sunday, quoting him as saying \"A nerve in my right elbow is affecting the hand\". It was \"the result of an injury received in a motorcycle smash when I was a youth.\" The Bulletin reported that \"He wanted to postpone the operation until the end of the season, but doctors have warned him that delay might mean losing the use of the hand\". He returned to the ballroom and its Wurlitzer later in the same month, having made over 2,000 broadcasts. Isolated fracture of the radial diaphysis with dislocation of the radial head is a rare injury, which requires careful evaluation. Combined injuries associated with forearm shaft fractures and elbow dislocations are well recognized. A 35-year-old male presented to our emergency department with a history of fall in ditch under influence of alcohol with swelling of her right elbow and deformity of right upper limb. Roentgenograms showed oblique fracture of the radial shaft and dislocation of radial head posteriorly. He underwent open reduction and internal fixation of fracture with limited contact dynamic compression plate and reduction of radial head and fixing with radiocapitellar wire. After 4 months, the fracture healed fully and he had complete full range of elbow movements. Ipsilateral radial head dislocation and radial shaft fracture are extremely rare injury in a child. A good outcome can be achieved by applying principles of the management of proximal forearm fracture-dislocation. Ipsilateral radial head dislocation and radial shaft fracture is extremely rare injury in a child. A good outcome can be achieved by applying principles of management of proximal forearm fracture-dislocation. Trainer Trainer Ray Hutchins stood by Frank Reys after a horrible two years in which he had suffered a broken shoulder, two pelvis fractures, a broken cheek bone and a broken ankle, and earned himself the nickname \"Autumn Leaves\". Despite these injuries Hutchins entrusted Reys with the ride on the four-year-old gelding Gala Supreme in the 1973 Caulfield Cup, in which Gala Supreme ran second. Hutchins had long before mapped out the Melbourne Cup as his mission, and after the Caulfield Cup second he prepared Gala Supreme for the Cup. We present an unusual case in which a combination of Monteggia and Galeazzi fractures occurred in the same forearm. The patient was a 10-year-old male who climbed up the pole of a basketball net, caught hold of the net, then lost his grip, and fell onto his right hand. On physical examination, a complete paralysis of the radial ulnar and median nerves was recognized. X-rays showed an olecranon fracture and lateral dislocation of the radial head in the elbow joint, a dorsal dislocation of the distal bone fragments due to a fracture of the distal third of the radius, and a palmar dislocation of the distal end of the ulna at the wrist joint. The injuries were diagnosed as a combination of a Bado type III Monteggia fracture and a palmar-type Galeazzi fracture of the same arm. Manual reduction and immobilization in a plaster cast were performed. Three years after the injury, both the distal and proximal radioulnar joints were maintained in the reduction position. Range of motion was reduced minimally in extension at the patient's elbow, and there was complete recovery of all three nerves. A combination of Monteggia and Galeazzi fractures in the same arm has been reported in only two pediatric patients worldwide and in eight cases total when adult patients are included, indicating that this is an extremely rare trauma. It is uncertain when Rhun's reign and life ended. One possibility is that Rhun died in 876, when Causantín seems to have been slain by Vikings. Causantín's death is dated to 876 by the Annals of Ulster. The Chronicle of the Kings of Alba appears to locate his fall in Atholl, whilst several king-lists locate his demise to a place variously called , an otherwise uncertain location that could refer to Inverdovat in Fife. If Causantín indeed enjoyed overlordship of Strathclyde at this date, Rhun could have fallen alongside him as a supporting vassal. It is likewise unknown who succeeded to the kingship of Strathclyde. If Rhun and Causantín both died in 876, Eochaid could well have inherited the British kingship in their absence. Certainly, Causantín's brother, Áed mac Cináeda, succeeded as King of the Picts, and ruled as such upon his death two years later. Whilst it is possible that the Pictish kingship was then assumed by a certain Giric, another possibility is that Eochaid succeeded to\nHere is the question:\nORTHOPEDIC SURGERY AND TRAUMATOLOGY: A 7-year-old boy brought to the emergency department after falling off a swing onto his right hand. He has no history of interest. He presents with fork dorsum deformity of the wrist and functional impotence, with normal distal neurovascular status. What lesion would you expect to find on the urgent x-ray you request?\nHere are the potential choices:\n1. Fracture - dislocation of Monteggia.\n2. Radial head fracture.\n3. Epiphysiolysis of the distal radius.\n4. Fracture in green stem of ulna.\nThe correct answer is: 3. Epiphysiolysis of the distal radius."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Struma ovarii (SO) is usually asymptomatic and only in a few cases it is associated with thyrotoxicosis. The presurgical diagnosis is very uncommon. In the majority of cases a pelvic mass is discovered at physical examination or by abdominal ultrasound. Only the hystopathologic examination is able to reveal the characteristic features of SO, with thyroid cells organized in follicles as the main tumoral tissue constituent. The histologic recognition of malignancy is not easy and usually requires an exhaustive sampling of the lesion to evaluate the extracapsular invasion. We report the case of a 59-year-old woman who came to our observation for the fortuitous finding of elevated serum thyroglobulin (Tg) levels (600-800 ng/mL). Because the thyroid function was normal and the ultrasound showed only a subcentrimetric nodule, the clinical suspicious of a SO was considered. Ultrasound examination of the abdomen showed a solid mass of 2 cm in the left ovary. A (131)I uptake was observed at scintiscan in the site of the solid mass. Three months after the resection of the left ovary serum Tg levels were markedly reduced (106 ng/mL), and its values continued to decrease down to 34 ng/mL at last control. The histology showed that the ovarian mass was mainly constituted of thyroid tissue (98%), with no malignant features. The molecular analysis of several thyroid differentiation gene mRNAs in the SO tissue showed an abundant expression of all genes but pendrin (PDS). A reduced PDS mRNA expression might explain the defective thyroxine (T(4)) production. Despite the absence of malignant features, the expression of RET/PTC3 rearrangement was found, raising the possibility of a potential malignant nature of the tumor. A cancer-free period of 3-4 years, as in our patient, is not long enough to definitively exclude a late onset metastatic disease but, unfortunately, the patient died of nonmedical reasons. In conclusion, we report a case of SO that, to our knowledge, is the first in which the clinical suspicion arose from the inappropriately elevated presurgical serum levels of Tg. A quite exhaustive molecular analysis of thyroid specific genes and oncogenes provided two interesting findings: the low PDS mRNA expression, which may explain the low hormonal production and the absence of thyrotoxicosis and the presence of a RET/PTC3 rearrangement, which prompts the possibility of a late malignant evolution. Mature cystic teratoma is the most common kind of ovarian germ tumor. However, malignant transformation is uncommon, differentiated thyroid carcinoma is even rare. Hyperthyroidism due to coexistence of Graves' disease (GD) and struma ovarii has been reported. Functional teratoma with papillary thyroid carcinoma (PTC) in GD case has never been reported in literature. A 48-year-old woman with GD for 4 years, who visited our hospital with complaints of severe abdominal pain for 1 day. Computed tomography of the abdominal revealed a large fat-containing lesion with dense calcification, measured 8.6 × 7.2 cm in size. Laparotomy right total oophorectomy was performed, and a huge gangrenous right ovary was noted during exploration. The final pathological diagnosis was teratoma with PTC change at right ovary. We performed thyroglobulin, TTF-1 and CK19 staining in the teratoma, the results were positive, suggesting the thyroid-hormone secretion in the PTC tissue. After resection of the ovarian lesion, euthyroidism was achieved. Adjuvant thyroidectomy is not performed for no evidence of thyroid lesion or distant metastases. No GD recurrence in the 2 years after operation. The patient also does not manifest any gynecological disease symptoms, whereas the other ovary, in the follow-up ultrasound examinations, shows normal size and echo structure. PTC can arise within ovarian teratoma and may have thyroid hormone production. Surgeries of unilateral oophorectomy or cystectomy are a reasonable treatment, and follow-up of thyroid image and data is necessary. We report struma ovarii in a case that had hyperthyroidism and was treated with laparoscopic tumor resection. A 40-year-old Japanese woman presented with tachycardia, finger tremor, and weight loss. Although blood examination showed hyperthyroidism, test results for thyroid stimulating hormone receptor antibody and thyroid stimulating antibody were negative, and thyroid scintigraphy showed no abnormal findings. Because she was diagnosed with an ovarian tumor, and whole-body scintigraphy showed that iodine uptake was detected in the pelvic space, we diagnosed her with an ovarian tumor, which caused excessive thyroid hormone secretion. After controlling the thyroid hormone level, we resected the ovarian tumor laparoscopically. The thyroid hormone level was within the normal range postoperatively without any medications. Based on our experience, physicians need to remember that ovarian tumors can cause hyperthyroidism. Controlling the thyroid hormone level preoperatively by using antithyroid drugs and performing minimally invasive laparoscopic surgery is considered useful for preventing thyroid storm. Hyperthyroidism is a state characterized by elevated serum level of thyroid hormones: thyroxine (T4) and triiodothyronine (T3). This is mainly related to the condition and functioning of the thyroid gland. In 60-80% of cases elevation of these hormones are caused by Grave's disease. Thyrotoxicosis is an extreme presentation of hyperthyroidism which can, in rare cases, be caused by excessive synthesis of thyroxine by tumor cells. Struma ovarii is a rare ovarian teratoma composed of thyroid tissue in more than 50%. To present a case of a 30-year-old female patient with a past history of Grave's disease treated by strumectomy 7 years prior; now presenting for the assessment of secondary amenorrhea. Pelvic ultrasound revealed bilateral solid tumors on the left and right ovary, respectively measuring 5 cm and 6 cm in diameter. Her clinical presentation was suggestive of overt hyperthyroidism, and she presented with a significantly elevated CA-125 (152.7 U/mL). The patient subsequently underwent a bilateral oophorectomy in which both masses were excised and histopathological examination confirmed teratoma maturum cysticum. Struma ovarii was noted as a component of the left ovary teratoma. Establishing a proper diagnosis of hyperthyroidism and elucidating its origin is often challenging. Struma ovarii is a rare cause of hyperthyroidism but should always be considered in case of treatment resistant hyperthyroidism. This case-report lends itself as an example of the value in maintaining gynecological-endocrinological knowledge in the setting if clinical gynecology. Subclinical hyperthyroidism, defined as serum thyroid hormone levels in the reference range with low serum TSH concentration, is a well recognized clinical entity, but little information is available concerning the prevalence of the disorders that produce it. We conducted a 24-month retrospective survey of subclinical hyperthyroidism patients referred to a university hospital nuclear medicine service for diagnostic studies. Twenty-four consecutive patients were evaluated (22 outpatients and 2 inpatients). All patients had highly sensitive TSH determination, thyroid hormone levels, radioiodine uptake and scan (except for 2 postpartum women), and, selectively, TSH-receptor antibody (TRAb), serum thyroglobulin, antithyroid antibodies, T3-suppression test, and erythrocyte sedimentation rate. A TSH value of about 0.1 microIU/mL was used as the cutoff. Only one patient in the group had a nonthyroidal disorder. In 14 patients (61%) subclinical hyperthyroidism was self-limited, due to silent thyroiditis (5 patients), iodine-induced hyperthyroidism (3 patients), postpartum thyroiditis (2 patients), subacute thyroiditis (2 patients), and probable hemorrhage into a functioning nodule (2 patients). Of the non-self-limited disorders (39%), Graves' disease accounted for 6 patients and solitary or multinodular goiter for 3. Graves' disease proved difficult to diagnose because the thyroid gland was normal in size in two of the six patients, TRAb was positive in only two of six, and the radioiodine uptake and gradient were normal in all six; the T3-suppression test was positive in two of two patients. We conclude that the causes of subclinical hyperthyroidism are the disorders that commonly produce overt thyrotoxicosis in medical practice, Graves' disease being the most frequent. However, the tests used to diagnose overt Graves' disease often fail in the setting of subclinical hyperthyroidism, except possibly the T3-suppression test. To report an unusual case of hyperthyroidism from Graves' disease that was coexistent with malignant struma ovarii. We summarize the clinical history, physical findings, laboratory data, imaging studies, pathologic features, and treatment in a patient with recurrent hyperthyroidism and discuss the incidence of ovarian tumors of various histologic origins, including thyroid tissue (that is, struma ovarii). Five years after diagnosis of Graves' disease and resolution of symptoms with 1 year of antithyroid drug therapy, a 53-year-old woman had recurrence of palpitations, tremors, and weight loss. Results of thyroid function tests showed high total and free thyroxine levels and a low thyrotropin level. Thyroid radioiodine uptake was high (69% at 24 hours). Abdominal ultrasound studies disclosed a cystic mass in the right adnexal area. Total abdominal hysterectomy and bilateral oophorectomy revealed a 7.5-cm cystic right ovary that contained a 1.0-cm struma ovarii with a 0.4-cm nodule of follicular variant papillary thyroid carcinoma within it. The patient was treated with methimazole and radioiodine ablation of the thyroid. Three months later, a massive myocardial infarction resulted in her death. The concomitant presence of Graves' disease complicates the management of struma ovarii and raises interesting questions about treatment and prognosis. We report two cases of Grave's disease (GD) caracterized by the succession of hypothyroid and hyperthyroid states. Case 1: A 32 years old woman, has presented initially a typical GD with hyperthyroidism. Grave's ophtalmopathy and homogenous goiter. Four months later, she presented a spontaneous hypothyroidism necessiting treatment with thyroxine and a severe myasthenia gravis. More later (6 months), she experienced symptoms of hyperthyroidism after thymectomy. The level of anti-thyrotropin-receptor antibodies (TSab) was very high (141 UI/I, NV &lt; 10). Case 2: A 29 years old woman has been treated by thyroxine (150 microg/day) for a primary hypothyroidism. Ten months later, she presented symptoms of hyperthyroidism even after stoppage of thyroxine. TSH value was decreased (TSH &lt; 0.05 microU/ml) and FT4 level was raised (FT4 = 25.5 pmol/l). The thyroid antibodies were positive. We discuss, after review of the litterature, the physiopathological mecanisms of these changes in the thyroid state, particularly the role of the blocking and stimulating anti-thyrotropin-receptor antibodies. We report a case of 34-year-old clinically asymptomatic woman who had been followed for 6 years for hyperthyroidism with thyroid stimulating hormone &lt;0.006 uIU/mL, free T4 1.98 ng/mL, free T3 5.3 pg/mL, elevated thyroid stimulating immunoglobulin 1.70 IU/L, thyroid peroxidase antibody 38 IU/mL and thyroglobulin antibody 9.3 IU/mL. Radioiodine thyroid scan showed minimal uptake in both thyroid lobes (24-hour uptake was 0.3%). She subsequently underwent evaluation for lower abdominal pain and menstrual irregularities, which revealed a large left ovarian cyst measuring 15.9 cm × 10.8 cm × 13.2 cm and right-sided ovarian cyst measuring 2.7 cm × 3.3 cm × 3.5 cm. Laparoscopic bilateral ovarian cystectomy was performed and the final pathology revealed struma ovarii of the left ovarian cyst with the entire ovarian tumour made up of benign thyroid tissue. Thyroid function tests performed 3 months after surgical removal of struma ovarii showed euthyroidism. We present a rare case with detailed laboratory and immunological data before and after ovarian extirpation with resolution of hyperthyroidism associated with functional struma ovarii. Measuring specific antibodies, such as anti-TSH-receptor antibodies in Graves' disease, or anti-thyroid peroxidase in Hashimoto's thyroiditis—a common cause of hypothyroidism—may also contribute to the diagnosis. The diagnosis of hyperthyroidism is confirmed by blood tests that show a decreased thyroid-stimulating hormone (TSH) level and elevated T4 and T3 levels. TSH is a hormone made by the pituitary gland in the brain that tells the thyroid gland how much hormone to make. When there is too much thyroid hormone, the TSH will be low. A radioactive iodine uptake test and thyroid scan together characterizes or enables radiologists and doctors to determine the cause of hyperthyroidism. The uptake test uses radioactive iodine injected or taken orally on an empty stomach to measure the amount of iodine absorbed by the thyroid gland. Persons with hyperthyroidism absorb much more iodine than healthy persons which includes radioactive iodine which is easy to measure. A thyroid scan An examination of the thyroid will also include observation of the person as a whole, to look for systemic signs such as weight gain or loss, hair loss, and signs in other locations – such as protrusion of the eyes or swelling of the calves in Graves' disease. Tests Thyroid function tests include a battery of blood tests, including the measurement of the thyroid hormones, as well as the measurement of thyroid stimulating hormone (TSH). They may reveal hyperthyroidism (high T3 and T4), hypothyroidism (low T3, T4), or subclinical hyperthyroidism (normal T3 and T4 with a low TSH). The most common type of ovarian germ cell tumor is the teratoma. Thyroid tissue, both benign and malignant, may be a component of an ovarian teratoma. Here we review this topic and illustrate major features by presenting multimodal management of a patient with BRAF-positive disseminated follicular thyroid cancer arising in an ovarian teratoma. Malignant thyroid tissue is often difficult to distinguish from benign thyroid tissue arising in ovarian teratomas. Preoperatively, an elevated thyroglobulin (Tg) level, laboratory or clinical evidence of hyperthyroidism, or ultrasonography appearance of \"struma pearl\" should prompt referral to oncologist for surgical management of a possibly malignant ovarian teratoma. Postoperatively, tumor tissue should be referred to pathologists experienced with differentiating benign from malignant struma ovarii. Once diagnosed, treatment of this rare condition should be handled by a team of specialists with combined treatment modalities. We cared for woman with disseminated thyroid cancer arising in an ovarian teratoma whose history illustrates the complexity of managing ovarian teratomas with malignant thyroid tissue. At age 33 she had an intraoperative rupture of an ovarian cyst, thought to be struma ovarii. During her next pregnancy, pelvic masses were noted; biopsies revealed well-differentiated papillary thyroid carcinoma, follicular variant. She was euthyroid, but had elevated serum Tg levels. Surgical staging demonstrated widely metastatic intraabdominal dissemination. A thyroidectomy revealed no malignancy. A post-(131)I treatment scan revealed diffuse uptake throughout the abdomen. She then developed abdominal pain and, on computed tomography, was found to have multiple intraabdominal foci of disease. Serum Tg was 264 ng/mL while on L-thyroxine for hypothyroidism and to obtain thyrotropin suppression. A 18 fluorodeoxyglucose positron emission tomography scan showed no pathological uptake. The tumor was found to be BRAF mutation positive (K601E). She underwent extensive secondary debulking and a second course of (131)I with lithium pretreatment. Posttreatment scan revealed diffuse abdominal uptake. Six months posttherapy, the patient is asymptomatic with a serum Tg of 18.1 ng/mL. Aggressive multimodal management appears to be the most promising approach for malignant thyroid tissue arising in ovarian teratomas. Struma ovarii (SO) is a rare ovarian teratoma characterized by the presence of thyroid tissue in more than 50% of the tumor. Malignant transformation is rare and the most common associated malignancy is papillary thyroid carcinoma (PTC). Pregnancy may represent a stimulus to differentiated thyroid cancer (DTC) growth in patients with known structural or biochemical evidence of disease, but data about malignant SO evolution during pregnancy are rare. We present the first reported case of a pregnant patient with malignant SO and biochemical evidence of disease. A previously healthy 35-year-old female diagnosed with a suspicious left pelvic mass on routine ultrasound was submitted to laparoscopic oophorectomy which revealed a malignant SO with areas of PTC. A 15-mm thyroid nodule (Bethesda V in the fine-needle aspiration cytology) was detected by palpation and total thyroidectomy was performed. Histology revealed a 15 mm follicular variant of PTC (T1bNxMx). Subsequently, she received 100 mCi of radioactive iodine therapy (RAIT) with the whole-body scan showing only moderate neck uptake. Her suppressed thyroglobulin (Tg) before RAI was 1.1 ng/mL. She maintained biochemical evidence of disease, with serum Tg levels of 7.6 ng/mL. She got pregnant 14 months after RAIT, and during pregnancy, Tg increased to 21.5 ng/mL. After delivery, Tg decreased to 14 ng/mL but, 6 months later, rose again and reached 31.9 ng/mL on the last follow-up visit. TSH was always suppressed during follow-up. At the time of SO diagnosis, a chest computed tomography scan showed 4 bilateral lung micronodules in the upper lobes which were nonspecific, and 9 months after diagnosis, a pelvic MRI revealed a suspicious cystic nodule located on the oophorectomy bed. These lung and pelvic nodules remained stable during follow-up. Neck ultrasonography, abdominal MRI, and fluorodeoxyglucose-positron emission tomography showed no suspicious lesions. As for DTC, pregnancy seems to represent a stimulus to malignant SO growth. This can be caused by the high levels of estrogen during pregnancy that may bind to receptors in malignant cells and/or by the high levels of hCG which is known to stimulate TSH receptors. Graves' disease is the cause of about 50% to 80% of the cases of hyperthyroidism in the United States. Other causes include multinodular goiter, toxic adenoma, inflammation of the thyroid, eating too much iodine, and too much synthetic thyroid hormone. A less common cause is a pituitary adenoma. The diagnosis may be suspected based on signs and symptoms and then confirmed with blood tests. Typically blood tests show a low thyroid stimulating hormone (TSH) and raised T3 or T4. Radioiodine uptake by the thyroid, thyroid scan, and TSI antibodies may help determine the cause. Given the relatively nonspecific symptoms of initial hypothyroidism, Hashimoto's thyroiditis is often misdiagnosed as depression, cyclothymia, premenstrual syndrome, chronic fatigue syndrome, fibromyalgia, and less frequently, as erectile dysfunction or an anxiety disorder. On gross examination, a hard goiter that is not painful to the touch often presents; other symptoms seen with hypothyroidism, such as periorbital myxedema, depend on the current state of progression of the response, especially given the usually gradual development of clinically relevant hypothyroidism. Testing for thyroid-stimulating hormone (TSH), free T3, free T4, and the antithyroglobulin antibodies (anti-Tg), antithyroid peroxidase antibodies (anti-TPO, or TPOAb) and antimicrosomal antibodies can help obtain an accurate diagnosis. Earlier assessment of the person may present with elevated levels of thyroglobulin owing to transient thyrotoxicosis, as inflammation within the thyroid causes damage to the integrity Laboratory Evaluation As depicted in Fig. 405-10, thyroid function tests characteristically evolve through three distinct phases over about 6 months: (1) thyrotoxic phase, (2) hypothyroid phase, and (3) recovery phase. In the thyrotoxic phase, T4 and T3 levels are increased, reflecting their discharge from the damaged thyroid cells, and TSH is suppressed. The T4/T3 ratio is greater than in Graves’ disease or thyroid autonomy, in which T3 is often disproportionately increased. The diagnosis is confirmed by a high ESR and low uptake of radioiodine (<5%) or 99mTc pertechnetate (as compared to salivary gland pertechnetate concentration). The white blood cell count may be increased, and thyroid antibodies are negative. If the diagnosis is in doubt, FNA biopsy may be useful, particularly to distinguish unilateral involvement from bleeding into a cyst or neoplasm. The primary ovarian carcinoid tumor is a very rare ovarian tumor, which accounts for approximately 0.5% to 1.7% of all carcinoids and 1% of ovarian cancer. According to its histopathological features, it can be divided into four categories: insular, trabecular, strumal, and mucinous, among which insular carcinoid is common in Western countries. By comparison, the chain-typed and trabecular carcinoid seem to be common in Asian countries. To date, about 150 cases have been reported in the world, and 40% of them are strumal carcinoid tumor of the ovary (SCTO), which is a highly specialized teratoma differentiated from the monomer, and often characterized by the coexistence of thyroid follicular tissue and carcinoid tissue with the neuroendocrine function. Preoperative diagnosis may be difficult due to the very insidious nature of the disease and its multiple imaging manifestations. We reported the case of a 39-year-old woman with a 5-year clinical history. Gynecologic examination and ultrasonic testing revealed an enlarged ovary with a diameter of about 60 mm, accompanied by a hypoechoic area, which was suspected to be a benign teratoma. Ca-125, AFP, free T4, TSH, and other diagnostic indicators were normal. During the laparoscopic oophorocystectomy of the left ovary, a smooth and solid tumor with the size of 6 × 6 × 5 cm was found in the right ovary. During the operation, a mature cystic teratoma containing a struma was frozen, then the oophorocystectomy of the left ovary was performed. According to the Federation International of Gynecology and Obstetrics (FIGO) in 2014, histopathological examination showed a mature teratoma with thyroid carcinoid stage Ic, and Douglas's cystic hygroma cytopathology was negative. One year after the operation, the patient was tumor-free, with Ca-125, FT4, and TSH being within the normal range. Specific diagnostic tools and serological monitoring of malignant tumors of the ovary have low specificity and sensitivity in the diagnosis of this rare malignant tumor of the ovary. Female patients with habitual constipation, chronic abdominal colic, diarrhea, and endocrine dysfunction also need to be alert to this rare malignant tumor of the ovary. There are multiple sources of extrathyroidal thyroid hormone, including exogenous thyroid hormone ingestion seen in factitious hyperthyroidism, thyroid hormone-producing metastatic thyroid cancer, and struma ovarii, a teratomatous ovarian mass that contains functional thyroid tissue. Another extrathyroidal cause of thyrotoxicosis includes TSH-induced thyrotoxicosis, which is caused by an autonomous TSH secreting pituitary adenoma, the only extrathyroidal cause associated with an elevated RAIU. Clinically, patients can have varying levels of thyrotoxicosis, depending on the level of excretion the exogenous source releases. Factitious hyperthyroidism can often be difficult to diagnose as the patients rarely disclose exogenous thyroid ingestion. Oftentimes the ingested thyroid hormone is T4, which may yield a higher than normal T4 to T3 ratio. Thyroid hormone production from metastatic thyroid malignancy is not very common as it requires a well-differentiated metastatic malignancy, which is usually less efficient at producing and excreting thyroid hormone. These metastases are usually seen in the setting of known thyroid cancer on I-131 imaging. Similar to metastasis, struma ovarii does not efficiently excrete thyroid hormone and rarely produces significant amounts of thyroid hormone. Struma ovarii is often found incidentally when pathology of an ovarian mass returns with thyroid tissue. RAIU of the overall thyroid gland in the neck is decreased, while the lesion may have elevated RAIU. [11] Primary thyrotoxicosis Features of Graves’ diseasea? T3 toxicosis Subclinical hyperthyroidism TSH low, unbound T4 high Measure TSH, unbound T4 Normal Measure unbound T3 TSH normal or increased, high unbound T4 TSH-secreting pituitary adenoma or thyroid hormone resistance syndrome Follow up in 6-12 weeks High TSH low, unbound T4 normal TSH and unbound T4 normal No further tests Graves’ disease Multinodular goiter or toxic adenomab? Yes No Toxic nodular hyperthyroidism Low radionuclide uptake? Yes No Destructive thyroiditis, iodine excess or excess thyroid hormone Rule out other causes including stimulation by chorionic gonadotropin Diagnosis The most common and helpful way to diagnose thyroiditis is first for a physician to palpate the thyroid gland during a physical examination. Laboratory tests allow doctors to evaluate the patient for elevated erythrocyte sedimentation rates, elevated thyroglobulin levels, and depressed radioactive iodine uptake (Mather, 2007). Blood tests also help to determine the kind of thyroiditis and to see how much thyroid stimulating hormone the pituitary gland is producing and what antibodies are present in the body. In some cases, a biopsy may be needed to find out what is attacking the thyroid. Classification Thyroiditis is a group of disorders that all cause thyroidal inflammation. Forms of the disease are Hashimoto's thyroiditis, the most common cause of hypothyroidism in the US, postpartum thyroiditis, subacute thyroiditis, silent thyroiditis, drug-induced thyroiditis, radiation-induced thyroiditis, acute thyroiditis, and Riedel's thyroiditis. Differential Diagnosis Diagnosis of Graves’ disease is straightforward in a patient with biochemically confirmed thyrotoxicosis, diffuse goiter on palpation, ophthalmopathy, and often a personal or family history of autoimmune disorders. For patients with thyrotoxicosis who lack these features, the diagnosis is generally established by a radionuclide (99mTc, 123I, or 131I) scan and uptake of the thyroid, which will distinguish the diffuse, high uptake of Graves’ disease from destructive thyroiditis, ectopic thyroid tissue, and factitious thyrotoxicosis. Scintigraphy is the preferred diagnostic test; however, TRAb measurement can be used to assess autoimmune activity. In secondary hyperthyroidism due to a 2296 TSH-secreting pituitary tumor, there is also a diffuse goiter. The presence of a nonsuppressed TSH level and the finding of a pituitary tumor on CT or magnetic resonance scan (MRI) scan suggest this diagnosis. Clinical features of thyrotoxicosis can mimic certain aspects of other In some types, such as subacute thyroiditis or postpartum thyroiditis, symptoms may go away after a few months and laboratory tests may return to normal. However most types of thyroid disease do not resolve on their own. Common hypothyroid symptoms include fatigue, low energy, weight gain, inability to tolerate the cold, slow heart rate, dry skin and constipation. Common hyperthyroid symptoms include irritability, anxiety, weight loss, fast heartbeat, inability to tolerate the heat, diarrhea, and enlargement of the thyroid. Structural abnormalities may not produce symptoms, however some people may have hyperthyroid or hypothyroid symptoms related to the structural abnormality or notice swelling of the neck. Rarely goiters can cause compression of the airway, compression of the vessels in the neck, or difficulty swallowing. Tumors, often called thyroid nodules, can also have many different symptoms ranging from hyperthyroidism to hypothyroidism to swelling in the neck and compression\nHere is the question:\nENDOCRINOLOGY: A 30-year-old woman comes to the clinic reporting anxiety, weight loss of about 6 kg and a feeling of \"nervousness\" in the last three months. In the physical examination she has tachycardia, hyperreflexia and absence of goiter. In the blood test TSH values are < 0.01 microU/mL, T4 is elevated and thyroglobulin levels are low. A scintigraphy shows an absence of uptake in the thyroid region. What seems to you the most likely diagnosis?\nHere are the potential choices:\n1. Factitious thyrotoxicosis.\n2. Hyperthyroidism due to Graves' disease.\n3. Ovarian teratoma (ovarian stromal tumor).\n4. Subacute thyroiditis.\nThe correct answer is: ",
        "gold_answer": "1 Factitious thyrotoxicosis.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Struma ovarii (SO) is usually asymptomatic and only in a few cases it is associated with thyrotoxicosis. The presurgical diagnosis is very uncommon. In the majority of cases a pelvic mass is discovered at physical examination or by abdominal ultrasound. Only the hystopathologic examination is able to reveal the characteristic features of SO, with thyroid cells organized in follicles as the main tumoral tissue constituent. The histologic recognition of malignancy is not easy and usually requires an exhaustive sampling of the lesion to evaluate the extracapsular invasion. We report the case of a 59-year-old woman who came to our observation for the fortuitous finding of elevated serum thyroglobulin (Tg) levels (600-800 ng/mL). Because the thyroid function was normal and the ultrasound showed only a subcentrimetric nodule, the clinical suspicious of a SO was considered. Ultrasound examination of the abdomen showed a solid mass of 2 cm in the left ovary. A (131)I uptake was observed at scintiscan in the site of the solid mass. Three months after the resection of the left ovary serum Tg levels were markedly reduced (106 ng/mL), and its values continued to decrease down to 34 ng/mL at last control. The histology showed that the ovarian mass was mainly constituted of thyroid tissue (98%), with no malignant features. The molecular analysis of several thyroid differentiation gene mRNAs in the SO tissue showed an abundant expression of all genes but pendrin (PDS). A reduced PDS mRNA expression might explain the defective thyroxine (T(4)) production. Despite the absence of malignant features, the expression of RET/PTC3 rearrangement was found, raising the possibility of a potential malignant nature of the tumor. A cancer-free period of 3-4 years, as in our patient, is not long enough to definitively exclude a late onset metastatic disease but, unfortunately, the patient died of nonmedical reasons. In conclusion, we report a case of SO that, to our knowledge, is the first in which the clinical suspicion arose from the inappropriately elevated presurgical serum levels of Tg. A quite exhaustive molecular analysis of thyroid specific genes and oncogenes provided two interesting findings: the low PDS mRNA expression, which may explain the low hormonal production and the absence of thyrotoxicosis and the presence of a RET/PTC3 rearrangement, which prompts the possibility of a late malignant evolution. Mature cystic teratoma is the most common kind of ovarian germ tumor. However, malignant transformation is uncommon, differentiated thyroid carcinoma is even rare. Hyperthyroidism due to coexistence of Graves' disease (GD) and struma ovarii has been reported. Functional teratoma with papillary thyroid carcinoma (PTC) in GD case has never been reported in literature. A 48-year-old woman with GD for 4 years, who visited our hospital with complaints of severe abdominal pain for 1 day. Computed tomography of the abdominal revealed a large fat-containing lesion with dense calcification, measured 8.6 × 7.2 cm in size. Laparotomy right total oophorectomy was performed, and a huge gangrenous right ovary was noted during exploration. The final pathological diagnosis was teratoma with PTC change at right ovary. We performed thyroglobulin, TTF-1 and CK19 staining in the teratoma, the results were positive, suggesting the thyroid-hormone secretion in the PTC tissue. After resection of the ovarian lesion, euthyroidism was achieved. Adjuvant thyroidectomy is not performed for no evidence of thyroid lesion or distant metastases. No GD recurrence in the 2 years after operation. The patient also does not manifest any gynecological disease symptoms, whereas the other ovary, in the follow-up ultrasound examinations, shows normal size and echo structure. PTC can arise within ovarian teratoma and may have thyroid hormone production. Surgeries of unilateral oophorectomy or cystectomy are a reasonable treatment, and follow-up of thyroid image and data is necessary. We report struma ovarii in a case that had hyperthyroidism and was treated with laparoscopic tumor resection. A 40-year-old Japanese woman presented with tachycardia, finger tremor, and weight loss. Although blood examination showed hyperthyroidism, test results for thyroid stimulating hormone receptor antibody and thyroid stimulating antibody were negative, and thyroid scintigraphy showed no abnormal findings. Because she was diagnosed with an ovarian tumor, and whole-body scintigraphy showed that iodine uptake was detected in the pelvic space, we diagnosed her with an ovarian tumor, which caused excessive thyroid hormone secretion. After controlling the thyroid hormone level, we resected the ovarian tumor laparoscopically. The thyroid hormone level was within the normal range postoperatively without any medications. Based on our experience, physicians need to remember that ovarian tumors can cause hyperthyroidism. Controlling the thyroid hormone level preoperatively by using antithyroid drugs and performing minimally invasive laparoscopic surgery is considered useful for preventing thyroid storm. Hyperthyroidism is a state characterized by elevated serum level of thyroid hormones: thyroxine (T4) and triiodothyronine (T3). This is mainly related to the condition and functioning of the thyroid gland. In 60-80% of cases elevation of these hormones are caused by Grave's disease. Thyrotoxicosis is an extreme presentation of hyperthyroidism which can, in rare cases, be caused by excessive synthesis of thyroxine by tumor cells. Struma ovarii is a rare ovarian teratoma composed of thyroid tissue in more than 50%. To present a case of a 30-year-old female patient with a past history of Grave's disease treated by strumectomy 7 years prior; now presenting for the assessment of secondary amenorrhea. Pelvic ultrasound revealed bilateral solid tumors on the left and right ovary, respectively measuring 5 cm and 6 cm in diameter. Her clinical presentation was suggestive of overt hyperthyroidism, and she presented with a significantly elevated CA-125 (152.7 U/mL). The patient subsequently underwent a bilateral oophorectomy in which both masses were excised and histopathological examination confirmed teratoma maturum cysticum. Struma ovarii was noted as a component of the left ovary teratoma. Establishing a proper diagnosis of hyperthyroidism and elucidating its origin is often challenging. Struma ovarii is a rare cause of hyperthyroidism but should always be considered in case of treatment resistant hyperthyroidism. This case-report lends itself as an example of the value in maintaining gynecological-endocrinological knowledge in the setting if clinical gynecology. Subclinical hyperthyroidism, defined as serum thyroid hormone levels in the reference range with low serum TSH concentration, is a well recognized clinical entity, but little information is available concerning the prevalence of the disorders that produce it. We conducted a 24-month retrospective survey of subclinical hyperthyroidism patients referred to a university hospital nuclear medicine service for diagnostic studies. Twenty-four consecutive patients were evaluated (22 outpatients and 2 inpatients). All patients had highly sensitive TSH determination, thyroid hormone levels, radioiodine uptake and scan (except for 2 postpartum women), and, selectively, TSH-receptor antibody (TRAb), serum thyroglobulin, antithyroid antibodies, T3-suppression test, and erythrocyte sedimentation rate. A TSH value of about 0.1 microIU/mL was used as the cutoff. Only one patient in the group had a nonthyroidal disorder. In 14 patients (61%) subclinical hyperthyroidism was self-limited, due to silent thyroiditis (5 patients), iodine-induced hyperthyroidism (3 patients), postpartum thyroiditis (2 patients), subacute thyroiditis (2 patients), and probable hemorrhage into a functioning nodule (2 patients). Of the non-self-limited disorders (39%), Graves' disease accounted for 6 patients and solitary or multinodular goiter for 3. Graves' disease proved difficult to diagnose because the thyroid gland was normal in size in two of the six patients, TRAb was positive in only two of six, and the radioiodine uptake and gradient were normal in all six; the T3-suppression test was positive in two of two patients. We conclude that the causes of subclinical hyperthyroidism are the disorders that commonly produce overt thyrotoxicosis in medical practice, Graves' disease being the most frequent. However, the tests used to diagnose overt Graves' disease often fail in the setting of subclinical hyperthyroidism, except possibly the T3-suppression test. To report an unusual case of hyperthyroidism from Graves' disease that was coexistent with malignant struma ovarii. We summarize the clinical history, physical findings, laboratory data, imaging studies, pathologic features, and treatment in a patient with recurrent hyperthyroidism and discuss the incidence of ovarian tumors of various histologic origins, including thyroid tissue (that is, struma ovarii). Five years after diagnosis of Graves' disease and resolution of symptoms with 1 year of antithyroid drug therapy, a 53-year-old woman had recurrence of palpitations, tremors, and weight loss. Results of thyroid function tests showed high total and free thyroxine levels and a low thyrotropin level. Thyroid radioiodine uptake was high (69% at 24 hours). Abdominal ultrasound studies disclosed a cystic mass in the right adnexal area. Total abdominal hysterectomy and bilateral oophorectomy revealed a 7.5-cm cystic right ovary that contained a 1.0-cm struma ovarii with a 0.4-cm nodule of follicular variant papillary thyroid carcinoma within it. The patient was treated with methimazole and radioiodine ablation of the thyroid. Three months later, a massive myocardial infarction resulted in her death. The concomitant presence of Graves' disease complicates the management of struma ovarii and raises interesting questions about treatment and prognosis. We report two cases of Grave's disease (GD) caracterized by the succession of hypothyroid and hyperthyroid states. Case 1: A 32 years old woman, has presented initially a typical GD with hyperthyroidism. Grave's ophtalmopathy and homogenous goiter. Four months later, she presented a spontaneous hypothyroidism necessiting treatment with thyroxine and a severe myasthenia gravis. More later (6 months), she experienced symptoms of hyperthyroidism after thymectomy. The level of anti-thyrotropin-receptor antibodies (TSab) was very high (141 UI/I, NV &lt; 10). Case 2: A 29 years old woman has been treated by thyroxine (150 microg/day) for a primary hypothyroidism. Ten months later, she presented symptoms of hyperthyroidism even after stoppage of thyroxine. TSH value was decreased (TSH &lt; 0.05 microU/ml) and FT4 level was raised (FT4 = 25.5 pmol/l). The thyroid antibodies were positive. We discuss, after review of the litterature, the physiopathological mecanisms of these changes in the thyroid state, particularly the role of the blocking and stimulating anti-thyrotropin-receptor antibodies. We report a case of 34-year-old clinically asymptomatic woman who had been followed for 6 years for hyperthyroidism with thyroid stimulating hormone &lt;0.006 uIU/mL, free T4 1.98 ng/mL, free T3 5.3 pg/mL, elevated thyroid stimulating immunoglobulin 1.70 IU/L, thyroid peroxidase antibody 38 IU/mL and thyroglobulin antibody 9.3 IU/mL. Radioiodine thyroid scan showed minimal uptake in both thyroid lobes (24-hour uptake was 0.3%). She subsequently underwent evaluation for lower abdominal pain and menstrual irregularities, which revealed a large left ovarian cyst measuring 15.9 cm × 10.8 cm × 13.2 cm and right-sided ovarian cyst measuring 2.7 cm × 3.3 cm × 3.5 cm. Laparoscopic bilateral ovarian cystectomy was performed and the final pathology revealed struma ovarii of the left ovarian cyst with the entire ovarian tumour made up of benign thyroid tissue. Thyroid function tests performed 3 months after surgical removal of struma ovarii showed euthyroidism. We present a rare case with detailed laboratory and immunological data before and after ovarian extirpation with resolution of hyperthyroidism associated with functional struma ovarii. Measuring specific antibodies, such as anti-TSH-receptor antibodies in Graves' disease, or anti-thyroid peroxidase in Hashimoto's thyroiditis—a common cause of hypothyroidism—may also contribute to the diagnosis. The diagnosis of hyperthyroidism is confirmed by blood tests that show a decreased thyroid-stimulating hormone (TSH) level and elevated T4 and T3 levels. TSH is a hormone made by the pituitary gland in the brain that tells the thyroid gland how much hormone to make. When there is too much thyroid hormone, the TSH will be low. A radioactive iodine uptake test and thyroid scan together characterizes or enables radiologists and doctors to determine the cause of hyperthyroidism. The uptake test uses radioactive iodine injected or taken orally on an empty stomach to measure the amount of iodine absorbed by the thyroid gland. Persons with hyperthyroidism absorb much more iodine than healthy persons which includes radioactive iodine which is easy to measure. A thyroid scan An examination of the thyroid will also include observation of the person as a whole, to look for systemic signs such as weight gain or loss, hair loss, and signs in other locations – such as protrusion of the eyes or swelling of the calves in Graves' disease. Tests Thyroid function tests include a battery of blood tests, including the measurement of the thyroid hormones, as well as the measurement of thyroid stimulating hormone (TSH). They may reveal hyperthyroidism (high T3 and T4), hypothyroidism (low T3, T4), or subclinical hyperthyroidism (normal T3 and T4 with a low TSH). The most common type of ovarian germ cell tumor is the teratoma. Thyroid tissue, both benign and malignant, may be a component of an ovarian teratoma. Here we review this topic and illustrate major features by presenting multimodal management of a patient with BRAF-positive disseminated follicular thyroid cancer arising in an ovarian teratoma. Malignant thyroid tissue is often difficult to distinguish from benign thyroid tissue arising in ovarian teratomas. Preoperatively, an elevated thyroglobulin (Tg) level, laboratory or clinical evidence of hyperthyroidism, or ultrasonography appearance of \"struma pearl\" should prompt referral to oncologist for surgical management of a possibly malignant ovarian teratoma. Postoperatively, tumor tissue should be referred to pathologists experienced with differentiating benign from malignant struma ovarii. Once diagnosed, treatment of this rare condition should be handled by a team of specialists with combined treatment modalities. We cared for woman with disseminated thyroid cancer arising in an ovarian teratoma whose history illustrates the complexity of managing ovarian teratomas with malignant thyroid tissue. At age 33 she had an intraoperative rupture of an ovarian cyst, thought to be struma ovarii. During her next pregnancy, pelvic masses were noted; biopsies revealed well-differentiated papillary thyroid carcinoma, follicular variant. She was euthyroid, but had elevated serum Tg levels. Surgical staging demonstrated widely metastatic intraabdominal dissemination. A thyroidectomy revealed no malignancy. A post-(131)I treatment scan revealed diffuse uptake throughout the abdomen. She then developed abdominal pain and, on computed tomography, was found to have multiple intraabdominal foci of disease. Serum Tg was 264 ng/mL while on L-thyroxine for hypothyroidism and to obtain thyrotropin suppression. A 18 fluorodeoxyglucose positron emission tomography scan showed no pathological uptake. The tumor was found to be BRAF mutation positive (K601E). She underwent extensive secondary debulking and a second course of (131)I with lithium pretreatment. Posttreatment scan revealed diffuse abdominal uptake. Six months posttherapy, the patient is asymptomatic with a serum Tg of 18.1 ng/mL. Aggressive multimodal management appears to be the most promising approach for malignant thyroid tissue arising in ovarian teratomas. Struma ovarii (SO) is a rare ovarian teratoma characterized by the presence of thyroid tissue in more than 50% of the tumor. Malignant transformation is rare and the most common associated malignancy is papillary thyroid carcinoma (PTC). Pregnancy may represent a stimulus to differentiated thyroid cancer (DTC) growth in patients with known structural or biochemical evidence of disease, but data about malignant SO evolution during pregnancy are rare. We present the first reported case of a pregnant patient with malignant SO and biochemical evidence of disease. A previously healthy 35-year-old female diagnosed with a suspicious left pelvic mass on routine ultrasound was submitted to laparoscopic oophorectomy which revealed a malignant SO with areas of PTC. A 15-mm thyroid nodule (Bethesda V in the fine-needle aspiration cytology) was detected by palpation and total thyroidectomy was performed. Histology revealed a 15 mm follicular variant of PTC (T1bNxMx). Subsequently, she received 100 mCi of radioactive iodine therapy (RAIT) with the whole-body scan showing only moderate neck uptake. Her suppressed thyroglobulin (Tg) before RAI was 1.1 ng/mL. She maintained biochemical evidence of disease, with serum Tg levels of 7.6 ng/mL. She got pregnant 14 months after RAIT, and during pregnancy, Tg increased to 21.5 ng/mL. After delivery, Tg decreased to 14 ng/mL but, 6 months later, rose again and reached 31.9 ng/mL on the last follow-up visit. TSH was always suppressed during follow-up. At the time of SO diagnosis, a chest computed tomography scan showed 4 bilateral lung micronodules in the upper lobes which were nonspecific, and 9 months after diagnosis, a pelvic MRI revealed a suspicious cystic nodule located on the oophorectomy bed. These lung and pelvic nodules remained stable during follow-up. Neck ultrasonography, abdominal MRI, and fluorodeoxyglucose-positron emission tomography showed no suspicious lesions. As for DTC, pregnancy seems to represent a stimulus to malignant SO growth. This can be caused by the high levels of estrogen during pregnancy that may bind to receptors in malignant cells and/or by the high levels of hCG which is known to stimulate TSH receptors. Graves' disease is the cause of about 50% to 80% of the cases of hyperthyroidism in the United States. Other causes include multinodular goiter, toxic adenoma, inflammation of the thyroid, eating too much iodine, and too much synthetic thyroid hormone. A less common cause is a pituitary adenoma. The diagnosis may be suspected based on signs and symptoms and then confirmed with blood tests. Typically blood tests show a low thyroid stimulating hormone (TSH) and raised T3 or T4. Radioiodine uptake by the thyroid, thyroid scan, and TSI antibodies may help determine the cause. Given the relatively nonspecific symptoms of initial hypothyroidism, Hashimoto's thyroiditis is often misdiagnosed as depression, cyclothymia, premenstrual syndrome, chronic fatigue syndrome, fibromyalgia, and less frequently, as erectile dysfunction or an anxiety disorder. On gross examination, a hard goiter that is not painful to the touch often presents; other symptoms seen with hypothyroidism, such as periorbital myxedema, depend on the current state of progression of the response, especially given the usually gradual development of clinically relevant hypothyroidism. Testing for thyroid-stimulating hormone (TSH), free T3, free T4, and the antithyroglobulin antibodies (anti-Tg), antithyroid peroxidase antibodies (anti-TPO, or TPOAb) and antimicrosomal antibodies can help obtain an accurate diagnosis. Earlier assessment of the person may present with elevated levels of thyroglobulin owing to transient thyrotoxicosis, as inflammation within the thyroid causes damage to the integrity Laboratory Evaluation As depicted in Fig. 405-10, thyroid function tests characteristically evolve through three distinct phases over about 6 months: (1) thyrotoxic phase, (2) hypothyroid phase, and (3) recovery phase. In the thyrotoxic phase, T4 and T3 levels are increased, reflecting their discharge from the damaged thyroid cells, and TSH is suppressed. The T4/T3 ratio is greater than in Graves’ disease or thyroid autonomy, in which T3 is often disproportionately increased. The diagnosis is confirmed by a high ESR and low uptake of radioiodine (<5%) or 99mTc pertechnetate (as compared to salivary gland pertechnetate concentration). The white blood cell count may be increased, and thyroid antibodies are negative. If the diagnosis is in doubt, FNA biopsy may be useful, particularly to distinguish unilateral involvement from bleeding into a cyst or neoplasm. The primary ovarian carcinoid tumor is a very rare ovarian tumor, which accounts for approximately 0.5% to 1.7% of all carcinoids and 1% of ovarian cancer. According to its histopathological features, it can be divided into four categories: insular, trabecular, strumal, and mucinous, among which insular carcinoid is common in Western countries. By comparison, the chain-typed and trabecular carcinoid seem to be common in Asian countries. To date, about 150 cases have been reported in the world, and 40% of them are strumal carcinoid tumor of the ovary (SCTO), which is a highly specialized teratoma differentiated from the monomer, and often characterized by the coexistence of thyroid follicular tissue and carcinoid tissue with the neuroendocrine function. Preoperative diagnosis may be difficult due to the very insidious nature of the disease and its multiple imaging manifestations. We reported the case of a 39-year-old woman with a 5-year clinical history. Gynecologic examination and ultrasonic testing revealed an enlarged ovary with a diameter of about 60 mm, accompanied by a hypoechoic area, which was suspected to be a benign teratoma. Ca-125, AFP, free T4, TSH, and other diagnostic indicators were normal. During the laparoscopic oophorocystectomy of the left ovary, a smooth and solid tumor with the size of 6 × 6 × 5 cm was found in the right ovary. During the operation, a mature cystic teratoma containing a struma was frozen, then the oophorocystectomy of the left ovary was performed. According to the Federation International of Gynecology and Obstetrics (FIGO) in 2014, histopathological examination showed a mature teratoma with thyroid carcinoid stage Ic, and Douglas's cystic hygroma cytopathology was negative. One year after the operation, the patient was tumor-free, with Ca-125, FT4, and TSH being within the normal range. Specific diagnostic tools and serological monitoring of malignant tumors of the ovary have low specificity and sensitivity in the diagnosis of this rare malignant tumor of the ovary. Female patients with habitual constipation, chronic abdominal colic, diarrhea, and endocrine dysfunction also need to be alert to this rare malignant tumor of the ovary. There are multiple sources of extrathyroidal thyroid hormone, including exogenous thyroid hormone ingestion seen in factitious hyperthyroidism, thyroid hormone-producing metastatic thyroid cancer, and struma ovarii, a teratomatous ovarian mass that contains functional thyroid tissue. Another extrathyroidal cause of thyrotoxicosis includes TSH-induced thyrotoxicosis, which is caused by an autonomous TSH secreting pituitary adenoma, the only extrathyroidal cause associated with an elevated RAIU. Clinically, patients can have varying levels of thyrotoxicosis, depending on the level of excretion the exogenous source releases. Factitious hyperthyroidism can often be difficult to diagnose as the patients rarely disclose exogenous thyroid ingestion. Oftentimes the ingested thyroid hormone is T4, which may yield a higher than normal T4 to T3 ratio. Thyroid hormone production from metastatic thyroid malignancy is not very common as it requires a well-differentiated metastatic malignancy, which is usually less efficient at producing and excreting thyroid hormone. These metastases are usually seen in the setting of known thyroid cancer on I-131 imaging. Similar to metastasis, struma ovarii does not efficiently excrete thyroid hormone and rarely produces significant amounts of thyroid hormone. Struma ovarii is often found incidentally when pathology of an ovarian mass returns with thyroid tissue. RAIU of the overall thyroid gland in the neck is decreased, while the lesion may have elevated RAIU. [11] Primary thyrotoxicosis Features of Graves’ diseasea? T3 toxicosis Subclinical hyperthyroidism TSH low, unbound T4 high Measure TSH, unbound T4 Normal Measure unbound T3 TSH normal or increased, high unbound T4 TSH-secreting pituitary adenoma or thyroid hormone resistance syndrome Follow up in 6-12 weeks High TSH low, unbound T4 normal TSH and unbound T4 normal No further tests Graves’ disease Multinodular goiter or toxic adenomab? Yes No Toxic nodular hyperthyroidism Low radionuclide uptake? Yes No Destructive thyroiditis, iodine excess or excess thyroid hormone Rule out other causes including stimulation by chorionic gonadotropin Diagnosis The most common and helpful way to diagnose thyroiditis is first for a physician to palpate the thyroid gland during a physical examination. Laboratory tests allow doctors to evaluate the patient for elevated erythrocyte sedimentation rates, elevated thyroglobulin levels, and depressed radioactive iodine uptake (Mather, 2007). Blood tests also help to determine the kind of thyroiditis and to see how much thyroid stimulating hormone the pituitary gland is producing and what antibodies are present in the body. In some cases, a biopsy may be needed to find out what is attacking the thyroid. Classification Thyroiditis is a group of disorders that all cause thyroidal inflammation. Forms of the disease are Hashimoto's thyroiditis, the most common cause of hypothyroidism in the US, postpartum thyroiditis, subacute thyroiditis, silent thyroiditis, drug-induced thyroiditis, radiation-induced thyroiditis, acute thyroiditis, and Riedel's thyroiditis. Differential Diagnosis Diagnosis of Graves’ disease is straightforward in a patient with biochemically confirmed thyrotoxicosis, diffuse goiter on palpation, ophthalmopathy, and often a personal or family history of autoimmune disorders. For patients with thyrotoxicosis who lack these features, the diagnosis is generally established by a radionuclide (99mTc, 123I, or 131I) scan and uptake of the thyroid, which will distinguish the diffuse, high uptake of Graves’ disease from destructive thyroiditis, ectopic thyroid tissue, and factitious thyrotoxicosis. Scintigraphy is the preferred diagnostic test; however, TRAb measurement can be used to assess autoimmune activity. In secondary hyperthyroidism due to a 2296 TSH-secreting pituitary tumor, there is also a diffuse goiter. The presence of a nonsuppressed TSH level and the finding of a pituitary tumor on CT or magnetic resonance scan (MRI) scan suggest this diagnosis. Clinical features of thyrotoxicosis can mimic certain aspects of other In some types, such as subacute thyroiditis or postpartum thyroiditis, symptoms may go away after a few months and laboratory tests may return to normal. However most types of thyroid disease do not resolve on their own. Common hypothyroid symptoms include fatigue, low energy, weight gain, inability to tolerate the cold, slow heart rate, dry skin and constipation. Common hyperthyroid symptoms include irritability, anxiety, weight loss, fast heartbeat, inability to tolerate the heat, diarrhea, and enlargement of the thyroid. Structural abnormalities may not produce symptoms, however some people may have hyperthyroid or hypothyroid symptoms related to the structural abnormality or notice swelling of the neck. Rarely goiters can cause compression of the airway, compression of the vessels in the neck, or difficulty swallowing. Tumors, often called thyroid nodules, can also have many different symptoms ranging from hyperthyroidism to hypothyroidism to swelling in the neck and compression\nHere is the question:\nENDOCRINOLOGY: A 30-year-old woman comes to the clinic reporting anxiety, weight loss of about 6 kg and a feeling of \"nervousness\" in the last three months. In the physical examination she has tachycardia, hyperreflexia and absence of goiter. In the blood test TSH values are < 0.01 microU/mL, T4 is elevated and thyroglobulin levels are low. A scintigraphy shows an absence of uptake in the thyroid region. What seems to you the most likely diagnosis?\nHere are the potential choices:\n1. Factitious thyrotoxicosis.\n2. Hyperthyroidism due to Graves' disease.\n3. Ovarian teratoma (ovarian stromal tumor).\n4. Subacute thyroiditis.\nThe correct answer is: 1. Factitious thyrotoxicosis."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The purpose of this article is to draw attention to atypical presentation of medial medullary infarction (MMI). With advanced imaging techniques, small infarctions occurring in the medulla are more easily identified. It is difficult, however, to make a clinical diagnosis of MMI if both hypoglossal nerve palsy and limb weakness are absent, because motor weakness is considered a cardinal manifestation of MMI. We describe here three patients who developed central vestibular dysfunction due to MMI without limb and lingual weakness. Case 1: A 44-year-old, diabetic woman developed vomiting and numbness on her left upper limb. Examination revealed unidirectional horizontal and rotatory nystagmus beating toward the right side. There were no Horner syndrome and hypoglossal nerve palsy. Barré arm and leg signs and limb ataxia were absent. Romberg sign was negative. Hypesthesia was present on her left forearm, hand, and fingers. Thumb-localizing test was normal. Cranial MRI demonstrated an infarction in the right paramedian region of the upper medulla. MR angiography demonstrated irregularity of the basilar and the left vertebral arteries. Case 2: A 69-year-old woman suffered from dizziness and nausea. She showed unidirectional, left-beating horizontal nystagmus. There were no Horner syndrome and hypoglossal nerve palsy, Barré arm and leg signs, and limb ataxia. MRI disclosed an infarction in the left upper medial medulla. Case 3: A 47-year-old man developed vertigo when turning over in bed. He showed left-beating nystagmus without latency, when lying down. Horner syndrome and hypoglossal nerve palsy were absent MRI showed bilateral MMI, with the right lesion being larger than the left. MR angiography demonstrated a stenosis in the distal portion of the left internal carotid artery but not in the vertebral and basilar arteries and their branches. This case represents central positional vertigo. Vestibular syndrome seen in cases 1 and 2 was incomplete and incongruent, suggesting dysfunction of the central vestibular system. There have been only nine cases of MMI with horizontal nystagmus in primary position, including unidirectional horizontorotatory nystagmus. In these cases, horizontal nystagmus beats toward the side of the lesion. In sharp contrast, horizontal nystagmus typically beats away from the lesion side in cases of Wallenberg syndrome, suggesting different underlying mechanism. Unidirectional horizontal and rotatory nystagmus is generally associated with peripheral vestibular dysfunction. There has been no reported case of MMI presenting with vestibular dysfunction preserving motor power. Thus, this \"benign\" form of MMI might have been misdiagnosed as peripheral vestibular dysfunction before the era of MRI. We report a 40-year-old man with hypertension and diabetes mellitus, who had crossed oral-pedal sensory disturbance in lateral medullary infarction. He suddenly developed dysesthesia in the right mount and the left leg. His blood pressure was 150/90 mmHg. Neurological examination showed Horner's sign in the right eye and horizontal nystagmus. Sensory function revealed decreased temperature, hypalgesia and dysesthesia in the right mouth and the left leg. Vibratory and position sense were normal. T1- and T2-weighted images disclosed a low and high signal intensity area in the lateral portion of the right medulla oblongata, respectively. Brain and neck MRA using time-of-flight sequence revealed no obvious abnormal structures. We have diagnosed him as lateral medullary infarction. The unique topography of sensory dysfunction thought to be attributed to a far-lateral lesion in the medulla oblongata. Our patient suggests that lateral medullary infarction causes variable patterns of sensory disturbance. Thus, lateral medullary infarction should be warranted when we encounter patients with miscellaneous distribution of sensory impairment, such as crossed mouth-foot hypalgesia. Lateral medullary syndrome is a neurological disorder causing a range of symptoms due to ischemia in the lateral part of the medulla oblongata in the brainstem. The ischemia is a result of a blockage most commonly in the vertebral artery or the posterior inferior cerebellar artery. Lateral medullary syndrome is also called Wallenberg's syndrome, posterior inferior cerebellar artery (PICA) syndrome and vertebral artery syndrome. Signs and symptoms This syndrome is characterized by sensory deficits that affect the trunk and extremities contralaterally (opposite to the lesion), and sensory deficits of the face and cranial nerves ipsilaterally (same side as the lesion). Specifically a loss of pain and temperature sensation if the lateral spinothalamic tract is involved. The cross body finding is the chief symptom from which a diagnosis can be made. Signs and symptoms: Structures involved 1. Medial medullary syndrome (occlusion of vertebral artery or of branch of vertebral or lower basilar artery) On side of lesion Paralysis with atrophy of one-half half the tongue: Ipsilateral twelfth nerve On side opposite lesion Paralysis of arm and leg, sparing face; impaired tactile and proprioceptive sense over one-half the body: Contralateral pyramidal tract and medial lemniscus 2. Lateral medullary syndrome (occlusion of any of five vessels may be responsible—vertebral, posterior inferior cerebellar, superior, middle, or inferior lateral medullary arteries) On side of lesion Pure Brown-Séquard syndrome is associated with the following: Interruption of the lateral corticospinal tracts: Ipsilateral spastic paralysis below the level of the lesion Babinski sign ipsilateral to lesion Abnormal reflexes and Babinski sign may not be present in acute injury Interruption of posterior white column: Ipsilateral loss of tactile discrimination, vibratory, and position sensation below the level of the lesion Interruption of lateral spinothalamic tracts: Contralateral loss of pain and temperature sensation. This usually occurs 2–3 segments below the level of the lesion. Treatment Treatment is directed at the pathology causing the paralysis. If the syndrome is caused by a spinal fracture, this should be identified and treated appropriately. Although steroids may be used to decrease cord swelling and inflammation, the usual therapy for spinal cord injury is expectant. A 68-year-old man presented with right eye pain and vertigo. Thereafter, he gradually leaned rightward, then laid down. He felt nausea and vomited. His right upper eyelid drooped and he felt dysethesia of the right hand. On neurological examination, ptosis of his right eye with slightly miotic right pupil, paresis of the right soft palate and hoarseness were noted. Arm deviation test demonstrated rightward deviation. He presented sensory ataxia of the right upper and lower extremities: finger nose test showed mild dysmetria of the right upper extremity, heel knee test demonstrated dysmetria of right lower extremity and these findings worsened when he closed his eyes. He showed mild bending of his bilateral ring and little fingers when he did rapid alternative movement. He leaned rightward when he sat and closed his eyes. Position sense of his right upper and lower extremities was decreased and sometimes he could not answer correctly when asked on which direction his finger pointed. Pinprick sensation was mildly decreased on the left side not including the face. Touch and vibration sense were normal. SEP findings on upper and lower extremity stimulation were normal. MRI of the brain showed T2 high intensity and partially T1 low intensity lesion at the right medulla (Figure). MR angiography showed no apparent lesion of major arteries such as dissection of the vertebral arteries. He complained and presented with hiccup initially. On MRI, the lesion was thought to involve the spinothalamic tract, medial lemniscus and inferior olivary nucleus. Ambiguus nucleus was in the lesion and solitary nucleus near the lesion. There is no report that seems to describe clinical features of a lesion like that in this case. Intermediate medullary infarction may present dissociated sensory disturbance like Brown-Sequard syndrome and position sensory disturbance without disturbance of vibration sense. We have experienced a case of myeloneuropathy following habitual abuse of nitrous oxide. We report clinical and pathological findings of this case with review of literatures. A 36-year-old dentist was first admitted to our hospital on August 17, 1983 because of numbness of both lower legs and unsteady gait. He had recreationally inhaled nitrous oxide 30 to 60 minutes everyday since a year ago. Neurological examination showed ataxic broad-based gait, moderate loss of pain and touch sensation in the lower limbs up to patella. Position and vibratory senses were more severely impaired. Deep tendon reflexes increased in the upper extremities and at the knees, but diminished at ankle jerks. Muscle strength was normal. Prominent Lhermitte's sign was present. Except for reduced serum vitamin B12 level, laboratory results were normal. Needle electromyography showed high amplitude and long duration NMU in the right quadriceps and anterior tibial muscles. Motor nerve conduction velocity was 34 m/sec at the right posterior tibial nerve and could not be detected at the left. Sural nerve biopsy was performed. The density of the myelinated fibre measured on transverse section was in normal range but degenerated fibres were occasionally recognized. Single teased nerve fibre showed various degree of myelin ovoid along the fibre. Myelin loss was shown to occur in some parts of the fibre. Electron microscopy showed myelin splitting and formation of intramyelinic vacuoles containing myelin debris. Axon was almost normal at least in the early stage of degeneration. Later, axon disappeared with destruction of myelin sheath. These nerve changes largely demonstrated demyelination but it was occasionally accompanied with axonal degeneration.(ABSTRACT TRUNCATED AT 250 WORDS) be more rapid or more leisurely. The initial disturbance may be of motor or sensory function and the distribution may be asymmetrical. High cervical or foramen magnum lesions produce special clinical syndromes, as described in Chap. 3 and below. With thoracic lesions, one leg usually becomes weak and stiff before the other one. Subjective sensory symptoms of the dorsal column type (tingling paresthesias) assume similar distributions. Pain and thermal senses are more likely to be affected than tactile, vibration, and position senses. Nevertheless, the posterior columns are frequently involved as the process progresses. Initially, the sensory disturbance is contralateral to the maximum motor weakness, but a sharply defined Brown-Séquard hemicord syndrome is rarely observed. The bladder and bowel usually become paralyzed coincident with paralysis of the legs. If the compression is relieved, there is recovery from these sensory and motor symptoms, often in the reverse order of their Among cases with terminal syringomyelia, 25% are associated with tethered cord syndrome. As it can be difficult to determine whether the neurological deficits are attributable to a syrinx or to a coexisting occult spinal dysraphism, it is not easy to determine the correct surgical strategy. We report a 19-month-old girl with an underdeveloped right leg and pes varus detected when she was 1 month old; lumbosacral magnetic resonance imaging (MRI) revealed syringomyelia. She developed recurrent urinary tract infections and consulted our department with a diagnosis of congenital neurogenic bladder. She presented with clubbed equine position, wore a short brace on her underdeveloped right leg, and exhibited limping gait due to shortening of the right leg. There was no anal reflex. The skin on her lower back was normal. MRI study showed that the lower end of the conus medullaris existed at the L3/4 level; central-type syringomyelia was recognized in the conus medullaris at the T12/L1-L2/L3 level. Computed tomography myelography detected no trabeculae causing tethering effects or influx of contrast medium into the syrinx. There was no comorbid disease like hydrocephalus or Chiari malformation. We performed syringo-subarachnoidal shunt by L1-L2 hemilaminectomy. Postoperative MRI confirmed shrinkage of the syrinx. One year later, although her perianal sensory loss and bowel and bladder dysfunction remained, her right leg had caught up with the left and at 1 year and 9 months after the procedure there is no discrepancy in her legs and she is able to run without limping. A modified H-reflex, known as R-1 response, was recorded in healthy subjects by averaging 200 responses from the moderately contracting tibialis anterior muscle (TA) after repetitive submaximal stimulation of common peroneal nerve. Physiological changes to different modes of stimulation and recording were studied and normative data obtained at the most reliable parameters. Subsequently, the test is applied to 36 patients with clinical and myelographic evidences of L5 or L4-L5 radicular compression (with or without S1 radicular compression). Increasing the force of muscle contraction resulted in increase in amplitude up to a certain limit, with no change in latency. Increasing the current from subliminal to submaximal stimulation caused initial increase and subsequent fall in the amplitude without change in the latency. The change in the stimulus frequency from 0.5 to 3 Hz did not alter latency or amplitude but the higher frequencies sometimes did. On changing the position of the foot from plantarflexed to dorsiflexed, an increase in amplitude and reduction in duration of the response was noted. Fifty subjects were studied using stimulus intensity just enough to produce 200-400 microV M-response, stimulus duration of 1.0 msec, stimulus rate of 3 Hz and the muscle force sufficient to keep the foot in complete dorsiflexion. The tibialis anterior R-1 response (TAR-1) could be recorded reliably from both legs in all the subjects. The take-off point was sharp and in no subject was there any difficulty in measuring the latency to onset point. On repeating the test, the onset point of the response was superimposable. Latency showed linear correlation with height and age. Among the patients, 21 out of 25 cases of unilateral (84.0%) and 10 out of 11 cases of bilateral (90.9%) radicular compression had abnormal findings. Abnormalities included significant a right-left latency difference within the normal range of absolute latencies, unilateral or bilateral prolongation of latency to onset point and attenuation or absence of the response. It was concluded that the TAR-1 is an important and reliable test for the study of functional integrity of L4-L5 spinal segments in lumbo-sacral sensorimotor root lesions. Fig. 10-3) and between the fourth and fifth lumbar vertebrae (compressing the L5 root). Lesions of the fifth lumbar root (L5) produce pain in the region of the hip and posterolateral thigh (i.e., sciatica) and, in more than half such cases, lateral calf (to the lateral malleolus), and less often, the dorsal surface of the foot and the first or second and third toes. Pain is elicited by the straight-leg raising test or one of its variants, and protective nocifensive reflexes come into play, limiting further elevation of the leg. Paresthesia may be felt in the entire territory or only in its distal parts. The tenderness is in the lateral gluteal region and near the head of the femur. Weakness, if present, involves the extensors of the big toe and foot and the foot invertors (a distinguishing feature of foot drop originating from peroneal nerve damage, which spares inversion because it is a tibial nerve function). The ankle jerk may be diminished (more often it is normal), but the knee Clinical significance Trigeminal neuralgia Cluster headache Migraine Wallenberg syndrome Wallenberg syndrome (lateral medullary syndrome) is a clinical demonstration of the anatomy of the trigeminal nerve, summarizing how it processes sensory information. A stroke usually affects only one side of the body; loss of sensation due to a stroke will be lateralized to the right or the left side of the body. The only exceptions to this rule are certain spinal-cord lesions and the medullary syndromes, of which Wallenberg syndrome is the best-known example. In this syndrome, a stroke causes a loss of pain-temperature sensation from one side of the face and the other side of the body. We report a 64-year-old man with recurrent bouts of blurred vision who died after developing an abdominal mass. He was well until June of 1985 when he was 59-years-old when he had an acute onset of loss of vision in his right eye. He was treated by prednisolone with a complete remission. In August of 1986, he had another bout of blurring of vision in his left eye. Once he lost his left vision completely, from which he showed slow recovery. In January of 1987, he developed blurring of his right eye and loss of pain and touch sensation in his right leg. Since then he repeated loss of vision in his right or left eye five times, and he was admitted to our hospital in May of 1990. On admission, he was alert and oriented. General physical examination was unremarkable. Neurologic examination revealed bilateral optic nerve atrophy. He could not discriminate light or dark by either eye. Other cranial nerves were unremarkable. He could walk in a wide-base only with support; spasticity was noted in his left leg. Muscle strength was preserved. Deep reflexes were exaggerated in both legs with extensor plantar reflex bilaterally. Pain and touch sensation was decreased in the left leg by 30%, and vibration was diminished in both feet. Position sense was preserved. Routine blood counts and chemistries were unremarkable. Cranial MRI scans revealed multiple high-signal intensity lesions in both pontine bases, basal ganglia, thalami, and in the deep cerebral white matters. He was treated with oral prednisolone, plasmapheresis, lymphocytapheresis, and then immuran. His vision showed only slight recovery to discriminate light and dark. In October of 1990, slight weakness appeared in his both legs. In December of that year, he developed nausea, and a fiber colonoscopic study revealed a stenosis in the transverse colon. In March of 1991, he developed anemia and liver dysfunction. In July of that year, jaundice appeared, and his serum bilirubin was increased. In October, his leg weakness became more prominent, and his cranial CT scans at that time revealed a low density change in the right cerebellum in the right superior cerebellar artery territory; in addition, multiple low density spots were scattered to be seen in both cerebral hemispheres including the basal ganglia and thalamic areas with ventricular dilatation and cortical atrophy.(ABSTRACT TRUNCATED AT 400 WORDS) The aim of this study was to analyze the contribution of the cerebellum in the performance of the lower limb withdrawal reflexes. This has been accomplished by comparing the electrically evoked responses in cerebellar patients (CBL) with those in sex- and age-matched healthy control subjects (CTRL). The stimulus was applied to the subjects' medial plantar nerve in four blocks of ten trials each with switching the stimulus from one leg to the other after each block. Responses of the main muscle groups (tibial muscle: TA; gastrocnemius muscle: GA; rectus femoris muscle: RF; biceps femoris muscle: BI) of both legs were recorded during each stimulus. The group of CBL patients consisted of both focally lesioned patients (CBLf) and patients presenting a diffuse degenerative pathology (CBLd). (1) For the withdrawal reflex in CTRL subjects, responses were observed in distal and proximal muscles of the ipsilateral side and corresponding concomitant responses on the side contralateral to the stimulation, whereas in CBL patients responses were restricted primarily to distal muscles, particularly the TA of the ipsilateral, i.e. the stimulated, side. (2) The sequence of activation of the different distal and proximal muscles ipsilateral to the stimulation, derived from latencies and times-to-peak, was for the CTRL group: TA-GA-BI-RF. This sequence was found also in the CBLf patients on their unaffected side. However, on their affected side CBLf patients showed very early GA activation, almost simultaneously with TA and RF activations and before BI activation. RF activation before BI activation was also found in CBLd. In the latter group, GA was activated after RF but before BI with all responses typically delayed. (3) The general pattern of the electrically evoked lower limb reflex consisted of an early, excitatory F1 component and a later, excitatory F2 component of larger amplitude observed in the CTRL subjects and the CBLd patients. In contrast to this pattern CBLf patients exhibited large F1 components followed by small F2 components. (4) The characteristic differences in the withdrawal reflex responses of cerebellar patients depended on the type of the lesion, providing evidence for an important involvement of the cerebellum in the control of the performance of withdrawal reflexes. We report a 38-year-old man systemic lupus erythematosus who presented with an acute onset of paraplegia and urinary retention. The man had a 12-year history of nodular cutaneous mucinosis and arthralgia. In 1994, he was admitted to our hospital with a sudden onset of weakness and numbness of the right leg followed by an emergence of similar symptoms in the left leg. His elder sister had died at 16 years of age after suffering from systemic lupus erythematosus for 6 years. On examination, the patient had skin rash on his chest, back, head, forehead, and extremities. The neurological examination revealed that his tongue deviated to the right on protrusion. The muscle power was reduced to 2-3/5 in the right leg and to 4/5 in the left leg. The sensory disturbance was noted in the lower extremities with predominant involvement of the right leg. Reflexes were increased in the right biceps, triceps, both patellas, and Achilles tendons. Babinski sign was noted bilaterally. Urinary retention and constipation were also noted. The results of the blood cell count and hepatic and renal function tests were normal. Serum levels of C-reactive protein and complements (C3, C4, CH50) were also normal. Serological examinations showed increased anti-DNA antibody (14 U/ml, [normal, &lt; 6]). Antinuclear antibody was positive at a titer of 1:1380. CSF study showed an increased protein concentration of 83 mg/dl and an IgG level of 14 mg/dl with a normal number of cells. MR images revealed a T1-low, T2-high signal lesion at the upper part of the left ventral medulla. MR images of the brain and spinal cord were normal. The patient was diagnosed as having SLE. High-dose intravenous methylprednisolone (1 g/day) pulse treatment that was started 25 days after the onset of neurological symptoms, produced partial relief. Our case presented with paraplegia with a focal lesion in the left upper ventral part of the medulla on MR images. The incidence of male SLE is low, and paraplegia is a rare complication of SLE. Thus, the medullary lesion in SLE observed in our case appears to be rare. SLE should be considered as a cause of acute onset paraplegia or myelopathy. Conus medullaris syndrome (CMS) is a rare pathology. The conus medullaris is located at the end of the spinal cord and continues to the cauda equina. Conus medullaris lesions can cause variable symptoms and neurological deficits, usually involving the lower extremities; CMS that does not affect the lower limbs is extremely rare. No reports have described isolated CMS caused by intradural disc herniation (IDH). This report describes a case of CMS without lower extremity involvement associated with IDH at L1/2. A 52-year-old man with a 10-year history of lower back pain complained of dysuria and lumbago with no leg symptoms at his first visit to the urology department. Neurological examination revealed mild perineal hypoalgesia; however, motor function and lower extremity sensation were normal with except for left ankle dorsiflexion weakness (manual muscle test, 4/5). Magnetic resonance imaging revealed conus medullaris compression by a mass, continuous with the L1/2 disc, and severe spinal canal stenosis at vertebral levels L3/4 and L4/5. Postmyelographic computed tomography indicated direct conus medullaris compression by an intradural and extramedullary mass continuous with the L1/2 disc. Without recovery of his dysuria, the patient underwent surgery, including partial laminectomy of the L1/2, incision of the dura mater, and removal of the herniated disc. Immediately after surgery, his dysuria completely resolved. More than one year postoperatively, the patient remained active with no change in his neurological condition. Although CMS without lower limb symptoms is extremely rare, we experienced an isolated case of CMS associated with IDH causing direct conus medullaris compression. Without lower extremity involvement, the CMS diagnosis was relatively easy. Surgical treatment for CMS without lower extremity involvement caused by IDH was effective. Physical examination may be normal in mild cases. Bruises may be seen in cases of trauma. A straight leg raise test is positive in more than half of the patients. Asymmetric lower limb muscle weakness may be seen with asymmetrically absent or reduced deep tendon reflexes. Knee jerk reflex is affected in lumbar plexopathy and ankle jerk is affected in sacral plexopathy. Muscle weakness in hip flexion, knee extension, or adduction suggests a possible injury to the lumbar plexus. Sensory loss may be present in a dermatomal pattern in cases of proximal LS plexopathy involving the roots, or in the nerve distribution. Sensory changes to the medial thigh, anterior thigh, and medial leg can suggest lumbar plexus involvement; posterior thigh, dorsum of the foot, and perineum are likely related to sacral plexus involvement. Spinal point tenderness may be present, especially in cases of sacral fracture or infection. A rectal exam should be performed to assess rectal tone. Saddle anesthesia and bowel or bladder incontinence are rare and may be present, making it difficult to differentiate from cauda equina and conus medullaris syndromes. The inguinal region should also be palpated for suspected hematomas. We report a 74-year-old man with a lung cancer, who developed right leg weakness, neurogenic bladder, and multiple cranial nerve palsies. The patient was well until December of 1992, when he was 74-year-old, when he noted transient double vision; in February of 1993, he noted numb sensation and weakness in his right leg. Later in the same month, he developed overflow incontinence of urine and weakness in his right face. He also noted deafness in his left ear (he had a marked loss of hearing in his right ear since childhood because of otitis media). His weakness in his right leg had progressed, and he was admitted to our service on March 19, 1993. On admission, he was afebrile and BP was 130/50 mmHg. General physical examination was unremarkable. On neurologic examination, he was alert and oriented to all spheres; no dementia was noted nor were detected aphasia, apraxia, and agnosia. His optic fundi were unremarkable; ocular movement appeared normal, however, he complained of diplopia in far vision. Sensation of the face was intact. He had right facial palsy of peripheral type; he was unable to close his right eye, and Bell's phenomenon was observed on attempted eye closure. On the left side, he had facial spasm. He had marked bilateral deafness. He had no dysarthria or dysphagia. The remaining of the cranial nerves were intact. Motor wise, he was unable to stand or walk alone; weakness did not appear to account for his difficulty in gait; manual muscle testing revealed 4/5 weakness in his tibialis anterior muscle, 1/5 in the peroneus longus, 0/5 in his extensor hallucis longus and extensor digitorum longus, all on the right side. Brachioradial and quadriceps femoris reflexes were increased to 3/4; plantar response was equivocal on the right side, and flexor on the left. Sensory examination revealed loss of touch and pain sensation in the L5 and S1 distributions in his right leg: vibration and position sensations were also diminished in his right foot. He had overflow urinary incontinence with loss of bladder sensation. Marked nuchal stiffness was noted, however, no Kernig's sign or eye ball tenderness was present. Pertinent laboratory findings were as allows; WBC 8,100/microliters, Ht 42.5%, platelet 326,000/microliters, TP 6.8 g/dl, BUN 16 mg/dl, creatinine 0.54 mg/dl, glucose 95 mg/dl, Na 136 mEq/l, K 4.4 mEq/l, Cl 100 mEq/l; liver profile was normal; CEA 436.6 ng/ml, CA19-93 U/ml; urinalysis was normal.(ABSTRACT TRUNCATED AT 400 WORDS)\nHere is the question:\nNEUROSURGERY: A man presents on neurological examination with a thermoalgesic sensory deficit in the left leg associated with a loss of vibratory and positional sensitivity in the right leg. At the same time he presents with clumsiness and loss of distal strength in the right leg and a right plantar cutaneous reflex in extension. Which of the following statements is correct:\nHere are the potential choices:\n1. It is a centromedullary syndrome type syringomyelia.\n2. It is a hemimedullary syndrome.\n3. It is a pattern of transverse medullary lesion.\n4. It is a pattern of lateral bulbar lesion.\nThe correct answer is: ",
        "gold_answer": "2 It is a hemimedullary syndrome.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The purpose of this article is to draw attention to atypical presentation of medial medullary infarction (MMI). With advanced imaging techniques, small infarctions occurring in the medulla are more easily identified. It is difficult, however, to make a clinical diagnosis of MMI if both hypoglossal nerve palsy and limb weakness are absent, because motor weakness is considered a cardinal manifestation of MMI. We describe here three patients who developed central vestibular dysfunction due to MMI without limb and lingual weakness. Case 1: A 44-year-old, diabetic woman developed vomiting and numbness on her left upper limb. Examination revealed unidirectional horizontal and rotatory nystagmus beating toward the right side. There were no Horner syndrome and hypoglossal nerve palsy. Barré arm and leg signs and limb ataxia were absent. Romberg sign was negative. Hypesthesia was present on her left forearm, hand, and fingers. Thumb-localizing test was normal. Cranial MRI demonstrated an infarction in the right paramedian region of the upper medulla. MR angiography demonstrated irregularity of the basilar and the left vertebral arteries. Case 2: A 69-year-old woman suffered from dizziness and nausea. She showed unidirectional, left-beating horizontal nystagmus. There were no Horner syndrome and hypoglossal nerve palsy, Barré arm and leg signs, and limb ataxia. MRI disclosed an infarction in the left upper medial medulla. Case 3: A 47-year-old man developed vertigo when turning over in bed. He showed left-beating nystagmus without latency, when lying down. Horner syndrome and hypoglossal nerve palsy were absent MRI showed bilateral MMI, with the right lesion being larger than the left. MR angiography demonstrated a stenosis in the distal portion of the left internal carotid artery but not in the vertebral and basilar arteries and their branches. This case represents central positional vertigo. Vestibular syndrome seen in cases 1 and 2 was incomplete and incongruent, suggesting dysfunction of the central vestibular system. There have been only nine cases of MMI with horizontal nystagmus in primary position, including unidirectional horizontorotatory nystagmus. In these cases, horizontal nystagmus beats toward the side of the lesion. In sharp contrast, horizontal nystagmus typically beats away from the lesion side in cases of Wallenberg syndrome, suggesting different underlying mechanism. Unidirectional horizontal and rotatory nystagmus is generally associated with peripheral vestibular dysfunction. There has been no reported case of MMI presenting with vestibular dysfunction preserving motor power. Thus, this \"benign\" form of MMI might have been misdiagnosed as peripheral vestibular dysfunction before the era of MRI. We report a 40-year-old man with hypertension and diabetes mellitus, who had crossed oral-pedal sensory disturbance in lateral medullary infarction. He suddenly developed dysesthesia in the right mount and the left leg. His blood pressure was 150/90 mmHg. Neurological examination showed Horner's sign in the right eye and horizontal nystagmus. Sensory function revealed decreased temperature, hypalgesia and dysesthesia in the right mouth and the left leg. Vibratory and position sense were normal. T1- and T2-weighted images disclosed a low and high signal intensity area in the lateral portion of the right medulla oblongata, respectively. Brain and neck MRA using time-of-flight sequence revealed no obvious abnormal structures. We have diagnosed him as lateral medullary infarction. The unique topography of sensory dysfunction thought to be attributed to a far-lateral lesion in the medulla oblongata. Our patient suggests that lateral medullary infarction causes variable patterns of sensory disturbance. Thus, lateral medullary infarction should be warranted when we encounter patients with miscellaneous distribution of sensory impairment, such as crossed mouth-foot hypalgesia. Lateral medullary syndrome is a neurological disorder causing a range of symptoms due to ischemia in the lateral part of the medulla oblongata in the brainstem. The ischemia is a result of a blockage most commonly in the vertebral artery or the posterior inferior cerebellar artery. Lateral medullary syndrome is also called Wallenberg's syndrome, posterior inferior cerebellar artery (PICA) syndrome and vertebral artery syndrome. Signs and symptoms This syndrome is characterized by sensory deficits that affect the trunk and extremities contralaterally (opposite to the lesion), and sensory deficits of the face and cranial nerves ipsilaterally (same side as the lesion). Specifically a loss of pain and temperature sensation if the lateral spinothalamic tract is involved. The cross body finding is the chief symptom from which a diagnosis can be made. Signs and symptoms: Structures involved 1. Medial medullary syndrome (occlusion of vertebral artery or of branch of vertebral or lower basilar artery) On side of lesion Paralysis with atrophy of one-half half the tongue: Ipsilateral twelfth nerve On side opposite lesion Paralysis of arm and leg, sparing face; impaired tactile and proprioceptive sense over one-half the body: Contralateral pyramidal tract and medial lemniscus 2. Lateral medullary syndrome (occlusion of any of five vessels may be responsible—vertebral, posterior inferior cerebellar, superior, middle, or inferior lateral medullary arteries) On side of lesion Pure Brown-Séquard syndrome is associated with the following: Interruption of the lateral corticospinal tracts: Ipsilateral spastic paralysis below the level of the lesion Babinski sign ipsilateral to lesion Abnormal reflexes and Babinski sign may not be present in acute injury Interruption of posterior white column: Ipsilateral loss of tactile discrimination, vibratory, and position sensation below the level of the lesion Interruption of lateral spinothalamic tracts: Contralateral loss of pain and temperature sensation. This usually occurs 2–3 segments below the level of the lesion. Treatment Treatment is directed at the pathology causing the paralysis. If the syndrome is caused by a spinal fracture, this should be identified and treated appropriately. Although steroids may be used to decrease cord swelling and inflammation, the usual therapy for spinal cord injury is expectant. A 68-year-old man presented with right eye pain and vertigo. Thereafter, he gradually leaned rightward, then laid down. He felt nausea and vomited. His right upper eyelid drooped and he felt dysethesia of the right hand. On neurological examination, ptosis of his right eye with slightly miotic right pupil, paresis of the right soft palate and hoarseness were noted. Arm deviation test demonstrated rightward deviation. He presented sensory ataxia of the right upper and lower extremities: finger nose test showed mild dysmetria of the right upper extremity, heel knee test demonstrated dysmetria of right lower extremity and these findings worsened when he closed his eyes. He showed mild bending of his bilateral ring and little fingers when he did rapid alternative movement. He leaned rightward when he sat and closed his eyes. Position sense of his right upper and lower extremities was decreased and sometimes he could not answer correctly when asked on which direction his finger pointed. Pinprick sensation was mildly decreased on the left side not including the face. Touch and vibration sense were normal. SEP findings on upper and lower extremity stimulation were normal. MRI of the brain showed T2 high intensity and partially T1 low intensity lesion at the right medulla (Figure). MR angiography showed no apparent lesion of major arteries such as dissection of the vertebral arteries. He complained and presented with hiccup initially. On MRI, the lesion was thought to involve the spinothalamic tract, medial lemniscus and inferior olivary nucleus. Ambiguus nucleus was in the lesion and solitary nucleus near the lesion. There is no report that seems to describe clinical features of a lesion like that in this case. Intermediate medullary infarction may present dissociated sensory disturbance like Brown-Sequard syndrome and position sensory disturbance without disturbance of vibration sense. We have experienced a case of myeloneuropathy following habitual abuse of nitrous oxide. We report clinical and pathological findings of this case with review of literatures. A 36-year-old dentist was first admitted to our hospital on August 17, 1983 because of numbness of both lower legs and unsteady gait. He had recreationally inhaled nitrous oxide 30 to 60 minutes everyday since a year ago. Neurological examination showed ataxic broad-based gait, moderate loss of pain and touch sensation in the lower limbs up to patella. Position and vibratory senses were more severely impaired. Deep tendon reflexes increased in the upper extremities and at the knees, but diminished at ankle jerks. Muscle strength was normal. Prominent Lhermitte's sign was present. Except for reduced serum vitamin B12 level, laboratory results were normal. Needle electromyography showed high amplitude and long duration NMU in the right quadriceps and anterior tibial muscles. Motor nerve conduction velocity was 34 m/sec at the right posterior tibial nerve and could not be detected at the left. Sural nerve biopsy was performed. The density of the myelinated fibre measured on transverse section was in normal range but degenerated fibres were occasionally recognized. Single teased nerve fibre showed various degree of myelin ovoid along the fibre. Myelin loss was shown to occur in some parts of the fibre. Electron microscopy showed myelin splitting and formation of intramyelinic vacuoles containing myelin debris. Axon was almost normal at least in the early stage of degeneration. Later, axon disappeared with destruction of myelin sheath. These nerve changes largely demonstrated demyelination but it was occasionally accompanied with axonal degeneration.(ABSTRACT TRUNCATED AT 250 WORDS) be more rapid or more leisurely. The initial disturbance may be of motor or sensory function and the distribution may be asymmetrical. High cervical or foramen magnum lesions produce special clinical syndromes, as described in Chap. 3 and below. With thoracic lesions, one leg usually becomes weak and stiff before the other one. Subjective sensory symptoms of the dorsal column type (tingling paresthesias) assume similar distributions. Pain and thermal senses are more likely to be affected than tactile, vibration, and position senses. Nevertheless, the posterior columns are frequently involved as the process progresses. Initially, the sensory disturbance is contralateral to the maximum motor weakness, but a sharply defined Brown-Séquard hemicord syndrome is rarely observed. The bladder and bowel usually become paralyzed coincident with paralysis of the legs. If the compression is relieved, there is recovery from these sensory and motor symptoms, often in the reverse order of their Among cases with terminal syringomyelia, 25% are associated with tethered cord syndrome. As it can be difficult to determine whether the neurological deficits are attributable to a syrinx or to a coexisting occult spinal dysraphism, it is not easy to determine the correct surgical strategy. We report a 19-month-old girl with an underdeveloped right leg and pes varus detected when she was 1 month old; lumbosacral magnetic resonance imaging (MRI) revealed syringomyelia. She developed recurrent urinary tract infections and consulted our department with a diagnosis of congenital neurogenic bladder. She presented with clubbed equine position, wore a short brace on her underdeveloped right leg, and exhibited limping gait due to shortening of the right leg. There was no anal reflex. The skin on her lower back was normal. MRI study showed that the lower end of the conus medullaris existed at the L3/4 level; central-type syringomyelia was recognized in the conus medullaris at the T12/L1-L2/L3 level. Computed tomography myelography detected no trabeculae causing tethering effects or influx of contrast medium into the syrinx. There was no comorbid disease like hydrocephalus or Chiari malformation. We performed syringo-subarachnoidal shunt by L1-L2 hemilaminectomy. Postoperative MRI confirmed shrinkage of the syrinx. One year later, although her perianal sensory loss and bowel and bladder dysfunction remained, her right leg had caught up with the left and at 1 year and 9 months after the procedure there is no discrepancy in her legs and she is able to run without limping. A modified H-reflex, known as R-1 response, was recorded in healthy subjects by averaging 200 responses from the moderately contracting tibialis anterior muscle (TA) after repetitive submaximal stimulation of common peroneal nerve. Physiological changes to different modes of stimulation and recording were studied and normative data obtained at the most reliable parameters. Subsequently, the test is applied to 36 patients with clinical and myelographic evidences of L5 or L4-L5 radicular compression (with or without S1 radicular compression). Increasing the force of muscle contraction resulted in increase in amplitude up to a certain limit, with no change in latency. Increasing the current from subliminal to submaximal stimulation caused initial increase and subsequent fall in the amplitude without change in the latency. The change in the stimulus frequency from 0.5 to 3 Hz did not alter latency or amplitude but the higher frequencies sometimes did. On changing the position of the foot from plantarflexed to dorsiflexed, an increase in amplitude and reduction in duration of the response was noted. Fifty subjects were studied using stimulus intensity just enough to produce 200-400 microV M-response, stimulus duration of 1.0 msec, stimulus rate of 3 Hz and the muscle force sufficient to keep the foot in complete dorsiflexion. The tibialis anterior R-1 response (TAR-1) could be recorded reliably from both legs in all the subjects. The take-off point was sharp and in no subject was there any difficulty in measuring the latency to onset point. On repeating the test, the onset point of the response was superimposable. Latency showed linear correlation with height and age. Among the patients, 21 out of 25 cases of unilateral (84.0%) and 10 out of 11 cases of bilateral (90.9%) radicular compression had abnormal findings. Abnormalities included significant a right-left latency difference within the normal range of absolute latencies, unilateral or bilateral prolongation of latency to onset point and attenuation or absence of the response. It was concluded that the TAR-1 is an important and reliable test for the study of functional integrity of L4-L5 spinal segments in lumbo-sacral sensorimotor root lesions. Fig. 10-3) and between the fourth and fifth lumbar vertebrae (compressing the L5 root). Lesions of the fifth lumbar root (L5) produce pain in the region of the hip and posterolateral thigh (i.e., sciatica) and, in more than half such cases, lateral calf (to the lateral malleolus), and less often, the dorsal surface of the foot and the first or second and third toes. Pain is elicited by the straight-leg raising test or one of its variants, and protective nocifensive reflexes come into play, limiting further elevation of the leg. Paresthesia may be felt in the entire territory or only in its distal parts. The tenderness is in the lateral gluteal region and near the head of the femur. Weakness, if present, involves the extensors of the big toe and foot and the foot invertors (a distinguishing feature of foot drop originating from peroneal nerve damage, which spares inversion because it is a tibial nerve function). The ankle jerk may be diminished (more often it is normal), but the knee Clinical significance Trigeminal neuralgia Cluster headache Migraine Wallenberg syndrome Wallenberg syndrome (lateral medullary syndrome) is a clinical demonstration of the anatomy of the trigeminal nerve, summarizing how it processes sensory information. A stroke usually affects only one side of the body; loss of sensation due to a stroke will be lateralized to the right or the left side of the body. The only exceptions to this rule are certain spinal-cord lesions and the medullary syndromes, of which Wallenberg syndrome is the best-known example. In this syndrome, a stroke causes a loss of pain-temperature sensation from one side of the face and the other side of the body. We report a 64-year-old man with recurrent bouts of blurred vision who died after developing an abdominal mass. He was well until June of 1985 when he was 59-years-old when he had an acute onset of loss of vision in his right eye. He was treated by prednisolone with a complete remission. In August of 1986, he had another bout of blurring of vision in his left eye. Once he lost his left vision completely, from which he showed slow recovery. In January of 1987, he developed blurring of his right eye and loss of pain and touch sensation in his right leg. Since then he repeated loss of vision in his right or left eye five times, and he was admitted to our hospital in May of 1990. On admission, he was alert and oriented. General physical examination was unremarkable. Neurologic examination revealed bilateral optic nerve atrophy. He could not discriminate light or dark by either eye. Other cranial nerves were unremarkable. He could walk in a wide-base only with support; spasticity was noted in his left leg. Muscle strength was preserved. Deep reflexes were exaggerated in both legs with extensor plantar reflex bilaterally. Pain and touch sensation was decreased in the left leg by 30%, and vibration was diminished in both feet. Position sense was preserved. Routine blood counts and chemistries were unremarkable. Cranial MRI scans revealed multiple high-signal intensity lesions in both pontine bases, basal ganglia, thalami, and in the deep cerebral white matters. He was treated with oral prednisolone, plasmapheresis, lymphocytapheresis, and then immuran. His vision showed only slight recovery to discriminate light and dark. In October of 1990, slight weakness appeared in his both legs. In December of that year, he developed nausea, and a fiber colonoscopic study revealed a stenosis in the transverse colon. In March of 1991, he developed anemia and liver dysfunction. In July of that year, jaundice appeared, and his serum bilirubin was increased. In October, his leg weakness became more prominent, and his cranial CT scans at that time revealed a low density change in the right cerebellum in the right superior cerebellar artery territory; in addition, multiple low density spots were scattered to be seen in both cerebral hemispheres including the basal ganglia and thalamic areas with ventricular dilatation and cortical atrophy.(ABSTRACT TRUNCATED AT 400 WORDS) The aim of this study was to analyze the contribution of the cerebellum in the performance of the lower limb withdrawal reflexes. This has been accomplished by comparing the electrically evoked responses in cerebellar patients (CBL) with those in sex- and age-matched healthy control subjects (CTRL). The stimulus was applied to the subjects' medial plantar nerve in four blocks of ten trials each with switching the stimulus from one leg to the other after each block. Responses of the main muscle groups (tibial muscle: TA; gastrocnemius muscle: GA; rectus femoris muscle: RF; biceps femoris muscle: BI) of both legs were recorded during each stimulus. The group of CBL patients consisted of both focally lesioned patients (CBLf) and patients presenting a diffuse degenerative pathology (CBLd). (1) For the withdrawal reflex in CTRL subjects, responses were observed in distal and proximal muscles of the ipsilateral side and corresponding concomitant responses on the side contralateral to the stimulation, whereas in CBL patients responses were restricted primarily to distal muscles, particularly the TA of the ipsilateral, i.e. the stimulated, side. (2) The sequence of activation of the different distal and proximal muscles ipsilateral to the stimulation, derived from latencies and times-to-peak, was for the CTRL group: TA-GA-BI-RF. This sequence was found also in the CBLf patients on their unaffected side. However, on their affected side CBLf patients showed very early GA activation, almost simultaneously with TA and RF activations and before BI activation. RF activation before BI activation was also found in CBLd. In the latter group, GA was activated after RF but before BI with all responses typically delayed. (3) The general pattern of the electrically evoked lower limb reflex consisted of an early, excitatory F1 component and a later, excitatory F2 component of larger amplitude observed in the CTRL subjects and the CBLd patients. In contrast to this pattern CBLf patients exhibited large F1 components followed by small F2 components. (4) The characteristic differences in the withdrawal reflex responses of cerebellar patients depended on the type of the lesion, providing evidence for an important involvement of the cerebellum in the control of the performance of withdrawal reflexes. We report a 38-year-old man systemic lupus erythematosus who presented with an acute onset of paraplegia and urinary retention. The man had a 12-year history of nodular cutaneous mucinosis and arthralgia. In 1994, he was admitted to our hospital with a sudden onset of weakness and numbness of the right leg followed by an emergence of similar symptoms in the left leg. His elder sister had died at 16 years of age after suffering from systemic lupus erythematosus for 6 years. On examination, the patient had skin rash on his chest, back, head, forehead, and extremities. The neurological examination revealed that his tongue deviated to the right on protrusion. The muscle power was reduced to 2-3/5 in the right leg and to 4/5 in the left leg. The sensory disturbance was noted in the lower extremities with predominant involvement of the right leg. Reflexes were increased in the right biceps, triceps, both patellas, and Achilles tendons. Babinski sign was noted bilaterally. Urinary retention and constipation were also noted. The results of the blood cell count and hepatic and renal function tests were normal. Serum levels of C-reactive protein and complements (C3, C4, CH50) were also normal. Serological examinations showed increased anti-DNA antibody (14 U/ml, [normal, &lt; 6]). Antinuclear antibody was positive at a titer of 1:1380. CSF study showed an increased protein concentration of 83 mg/dl and an IgG level of 14 mg/dl with a normal number of cells. MR images revealed a T1-low, T2-high signal lesion at the upper part of the left ventral medulla. MR images of the brain and spinal cord were normal. The patient was diagnosed as having SLE. High-dose intravenous methylprednisolone (1 g/day) pulse treatment that was started 25 days after the onset of neurological symptoms, produced partial relief. Our case presented with paraplegia with a focal lesion in the left upper ventral part of the medulla on MR images. The incidence of male SLE is low, and paraplegia is a rare complication of SLE. Thus, the medullary lesion in SLE observed in our case appears to be rare. SLE should be considered as a cause of acute onset paraplegia or myelopathy. Conus medullaris syndrome (CMS) is a rare pathology. The conus medullaris is located at the end of the spinal cord and continues to the cauda equina. Conus medullaris lesions can cause variable symptoms and neurological deficits, usually involving the lower extremities; CMS that does not affect the lower limbs is extremely rare. No reports have described isolated CMS caused by intradural disc herniation (IDH). This report describes a case of CMS without lower extremity involvement associated with IDH at L1/2. A 52-year-old man with a 10-year history of lower back pain complained of dysuria and lumbago with no leg symptoms at his first visit to the urology department. Neurological examination revealed mild perineal hypoalgesia; however, motor function and lower extremity sensation were normal with except for left ankle dorsiflexion weakness (manual muscle test, 4/5). Magnetic resonance imaging revealed conus medullaris compression by a mass, continuous with the L1/2 disc, and severe spinal canal stenosis at vertebral levels L3/4 and L4/5. Postmyelographic computed tomography indicated direct conus medullaris compression by an intradural and extramedullary mass continuous with the L1/2 disc. Without recovery of his dysuria, the patient underwent surgery, including partial laminectomy of the L1/2, incision of the dura mater, and removal of the herniated disc. Immediately after surgery, his dysuria completely resolved. More than one year postoperatively, the patient remained active with no change in his neurological condition. Although CMS without lower limb symptoms is extremely rare, we experienced an isolated case of CMS associated with IDH causing direct conus medullaris compression. Without lower extremity involvement, the CMS diagnosis was relatively easy. Surgical treatment for CMS without lower extremity involvement caused by IDH was effective. Physical examination may be normal in mild cases. Bruises may be seen in cases of trauma. A straight leg raise test is positive in more than half of the patients. Asymmetric lower limb muscle weakness may be seen with asymmetrically absent or reduced deep tendon reflexes. Knee jerk reflex is affected in lumbar plexopathy and ankle jerk is affected in sacral plexopathy. Muscle weakness in hip flexion, knee extension, or adduction suggests a possible injury to the lumbar plexus. Sensory loss may be present in a dermatomal pattern in cases of proximal LS plexopathy involving the roots, or in the nerve distribution. Sensory changes to the medial thigh, anterior thigh, and medial leg can suggest lumbar plexus involvement; posterior thigh, dorsum of the foot, and perineum are likely related to sacral plexus involvement. Spinal point tenderness may be present, especially in cases of sacral fracture or infection. A rectal exam should be performed to assess rectal tone. Saddle anesthesia and bowel or bladder incontinence are rare and may be present, making it difficult to differentiate from cauda equina and conus medullaris syndromes. The inguinal region should also be palpated for suspected hematomas. We report a 74-year-old man with a lung cancer, who developed right leg weakness, neurogenic bladder, and multiple cranial nerve palsies. The patient was well until December of 1992, when he was 74-year-old, when he noted transient double vision; in February of 1993, he noted numb sensation and weakness in his right leg. Later in the same month, he developed overflow incontinence of urine and weakness in his right face. He also noted deafness in his left ear (he had a marked loss of hearing in his right ear since childhood because of otitis media). His weakness in his right leg had progressed, and he was admitted to our service on March 19, 1993. On admission, he was afebrile and BP was 130/50 mmHg. General physical examination was unremarkable. On neurologic examination, he was alert and oriented to all spheres; no dementia was noted nor were detected aphasia, apraxia, and agnosia. His optic fundi were unremarkable; ocular movement appeared normal, however, he complained of diplopia in far vision. Sensation of the face was intact. He had right facial palsy of peripheral type; he was unable to close his right eye, and Bell's phenomenon was observed on attempted eye closure. On the left side, he had facial spasm. He had marked bilateral deafness. He had no dysarthria or dysphagia. The remaining of the cranial nerves were intact. Motor wise, he was unable to stand or walk alone; weakness did not appear to account for his difficulty in gait; manual muscle testing revealed 4/5 weakness in his tibialis anterior muscle, 1/5 in the peroneus longus, 0/5 in his extensor hallucis longus and extensor digitorum longus, all on the right side. Brachioradial and quadriceps femoris reflexes were increased to 3/4; plantar response was equivocal on the right side, and flexor on the left. Sensory examination revealed loss of touch and pain sensation in the L5 and S1 distributions in his right leg: vibration and position sensations were also diminished in his right foot. He had overflow urinary incontinence with loss of bladder sensation. Marked nuchal stiffness was noted, however, no Kernig's sign or eye ball tenderness was present. Pertinent laboratory findings were as allows; WBC 8,100/microliters, Ht 42.5%, platelet 326,000/microliters, TP 6.8 g/dl, BUN 16 mg/dl, creatinine 0.54 mg/dl, glucose 95 mg/dl, Na 136 mEq/l, K 4.4 mEq/l, Cl 100 mEq/l; liver profile was normal; CEA 436.6 ng/ml, CA19-93 U/ml; urinalysis was normal.(ABSTRACT TRUNCATED AT 400 WORDS)\nHere is the question:\nNEUROSURGERY: A man presents on neurological examination with a thermoalgesic sensory deficit in the left leg associated with a loss of vibratory and positional sensitivity in the right leg. At the same time he presents with clumsiness and loss of distal strength in the right leg and a right plantar cutaneous reflex in extension. Which of the following statements is correct:\nHere are the potential choices:\n1. It is a centromedullary syndrome type syringomyelia.\n2. It is a hemimedullary syndrome.\n3. It is a pattern of transverse medullary lesion.\n4. It is a pattern of lateral bulbar lesion.\nThe correct answer is: 1. It is a centromedullary syndrome type syringomyelia."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A large number of diagnostic procedures (e.g., ultrasound, computed tomography [CT] scan, fine-needle aspiration [FNA], angiography, endoscopic retrograde cholangiopancreatography [ERCP], and laparoscopy), are available to the clinician as he/she pursues the workup of patients who are thought to have a pancreatic (periampullary) malignancy. Not all of these procedures should be used in every patient and some have been overused. Based on a current literature review and their own experience, the authors describe the rationale of the diagnostic workup in patients with suspected pancreatic carcinoma in a single institution (a university medical center). Helical CT scan provides the best overall assessment of patients with periampullary malignancies, and it is often the only test required. If the patient's history and blood test abnormalities suggest pancreatic carcinoma and the helical CT scan shows a mass in the head of the pancreas that appears to be resectable, the patient should be prepared for surgery. If no mass is apparent on the helical CT scan, a diagnostic ERCP is indicated. If microscopic proof of the diagnosis will avoid surgery, then an FNA for cytology should be performed. When unresectability appears likely and cannot be confirmed in less invasive ways, laparoscopy is indicated. In patients with periampullary malignancies, helical CT scan provides the best overall assessment. Guidelines are presented for the selective use of ultrasound, FNA, ERCP, and laparoscopy, which are important for the most cost-effective workup of these patients. to assess the clinical value of ultrasonographic methods and computed tomography in diagnosing and staging pancreatic carcinoma. prospective clinical trial of 140 patients (64 women and 77 men; mean age 59,6) operated on for pancreatic carcinoma between 2000 and 2004. In each case helical CT, routine-, color- and power Doppler and 3-D USG were performed to detect and stage cancer. Analyses of accuracy, sensitivity, specificity, PPV and NPV of ultrasonographic methods and CT were made. 3-D USG showed the best accuracy of local staging (T): 95.6%. CT was the most accurate in lymph node assessment: 91.3%. The accuracy of CT, 3-D USG and power-Doppler at detecting vascular infiltration was 93.1%. diagnostic accuracy of modern ultrasound techniques is comparable to helical CT in detecting and staging pancreatic carcinoma. USG is recommended due to the relatively low cost, non-invasiveness and availability of the procedure. Diagnostic imaging The insulinoma might be localized by noninvasive means, using ultrasound, CT scan, or MRI techniques. An indium-111 pentetreotide scan is more sensitive than ultrasound, CT, or MRI for detection of somatostatin receptor positive tumors, but not a good diagnostic tool for insulinomas. An endoscopic ultrasound has a sensitivity of 40-93% (depending on the location of the tumor) for detecting insulinomas. Sometimes, angiography with percutaneous transhepatic pancreatic vein catheterization to sample the blood for insulin levels is required. Calcium can be injected into selected arteries to stimulate insulin release from various parts of the pancreas, which can be measured by sampling blood from their respective veins. The use of calcium stimulation improves the specificity of this test. Diagnosis Techniques for the diagnosis of Page kidney are all imaging based, including abdominal x-ray, intravenous pyelography, angiography, renal doppler ultrasound, CT scan, and Magnetic resonance imaging (MRI). X-ray and pyelography may add in diagnosis, but are non-diagnostic when used alone. Additionally, pyelograms use potentially nephrotoxic contrast agents, further limiting their utility. Diagnosis is primarily made using ultrasound and CT. CT and MRI imaging can show the space occupying lesions but doppler ultrasound is needed to display the hemodynamic changes occurring in the kidney. Ultrasound is often the initial diagnostic test of choice but due to its low resolution further imaging may be necessary. Treatment The principal value of CT imaging to the treating clinician is the capacity to identify devitalised areas of the pancreas which have become necrotic due to ischaemia. Pancreatic necrosis can be reliably identified by intravenous contrast-enhanced CT imaging, and is of value if infection occurs and surgical or percutaneous debridement is indicated. Magnetic resonance imaging While computed tomography is considered the gold standard in diagnostic imaging for acute pancreatitis, magnetic resonance imaging (MRI) has become increasingly valuable as a tool for the visualization of the pancreas, particularly of pancreatic fluid collections and necrotized debris. Additional utility of MRI includes its indication for imaging of patients with an allergy to CT's contrast material, and an overall greater sensitivity to hemorrhage, vascular complications, pseudoaneurysms, and venous thrombosis. Diagnostic radiology () Diagnostic radiology () Soft tissue x-ray of thorax () Other x-ray of thorax () X-ray of urinary system () Computerized axial tomography of kidney CAT scan of kidney () Other nephrotomogram () Intravenous pyelogram Diuretic infusion pyelogram () Retrograde pyelogram () Percutaneous pyelogram () Retrograde cystourethrogram () Other cystogram () Ileal conduitogram () Other x-ray of the urinary system KUB x-ray () Other diagnostic radiology and related techniques () Soft tissue x-ray of abdomen () Other x-ray of abdomen () Skeletal x-ray of extremities and pelvis () Other x-ray () Arteriography using contrast material () Angiocardiography using contrast material () Phlebography () Diagnostic ultrasound () Thermography () Other diagnostic imaging () Diagnostic imaging, not elsewhere classified () Magnetic resonance imaging of brain and brain stem () Magnetic resonance imaging of chest and myocardium Mesenteric angiography is commonly employed in the modern-day investigation of gastro-intestinal bleeding if the bleeding sites cannot be identified by endoscopic means. Angiography is optimally sensitive in the presence of active bleeding. However, vasospasm may occasionally account for a negative study shortly after bleeding. A 70-year-old lady with inoperable carcinoma of the pancreas presented with gastro-intestinal bleeding. Although upper endoscopy visualised active bleeding from the tumour, which had invaded into the duodenum, haemostasis could not be achieved endoscopically. Therefore, mesenteric angiography was arranged. The initial angiography failed to demonstrate the bleeding site, which only became obvious on a repeat study, when embolisation was performed to achieve haemostasis. Vasospasm probably accounted for the initial negative study, as the second angiography was able to demonstrate contrast extravasation without the use of any anticoagulant or thrombolytic agent. It is not our routine to give pharmacological agents to provoke bleeding after a negative angiography, but for selected patients this manoeuvre may turn out to be more cost-effective. Fractures represent up to 80% of the missed diagnoses in the emergency department. Failure to recognize the subtle signs of osseous injury is one of the reasons behind this major diagnostic challenge. While occult fractures present no radiographic findings, radiographically subtle fractures are easily overlooked on initial radiographs. In both cases, a negative radiographic diagnosis with prominent clinical suspicion of osseous injury will prompt advanced imaging examination such as CT scan, magnetic resonance imaging, ultrasound, and nuclear medicine to confirm or exclude the clinically suspected diagnosis. The burden entailed in missing these fractures includes prolonged pain with a loss of function, and disability. Early detection, on the other hand, enables more effective treatment, a shorter hospitalization period if necessary, and decreased medical costs in the long run. It will also prevent inherent complications such as nonunion, malunion, premature osteoarthritis, and The objective of this study was to evaluate how the introduction of radiologic studies affected the diagnostic workup for pancreatic cancer, from 1955 through 1979. For 961 patients diagnosed as having pancreatic cancer at three teaching hospitals, we reviewed medical records, autopsy reports, and death certificates for results from all radiologic studies, surgical and pathologic procedures, and for the final diagnosis. The number of radiologic studies per patient increased as new studies were introduced; 1.6 for 1955-1959, 3.5 for 1975-1979 (P less than 0.0001). Depending on the cutoff level chosen, the sensitivity of the overall radiologic diagnosis increased over time, 0.17-0.43 for 1955-1959, to 0.54-0.78 for 1975-1979; CT, US, and ERCP accounted for much of the increase. As newer radiologic studies are introduced, continued use of previously accepted studies should be carefully evaluated. Diagnostic images Bioluminescence imaging Dermatoscopy Diffuse optical tomography Gamma camera Computed tomography Infrared imaging of the body Magnetic resonance elastography Magnetic resonance imaging Magnetic resonance spectroscopy Optical coherence tomography Posturography Radiography, fluoroscopy Ultrasonography and echocardiography Diagnostic signals Electrocardiography Electroencephalography Electromyography Photoplethysmograph Electrical impedance tomography Electroneuronography Electroretinography Electronystagmography Magnetoencephalography Evoked potentials Impedance phlebography Nuclear magnetic resonance Therapy Epidermal radioisotope therapy Radiation therapy Brachytherapy Lithotripsy Defibrillation Biofeedback Oxygen therapy Non-invasive ventilation VPAP BIPAP Neurally adjusted ventilatory assist Biphasic cuirass ventilation Therapeutic ultrasound See also Minimally invasive procedures References Medical procedures A case of biliopancreatic pathology studied with traditional (the old algorithm) and the latest (new algorithm) diagnostic techniques is examined. A comparative analysis reveals the second to be simpler, less expensive and less dangerous to the patient. The hope is expressed that doctors will become better informed of the diagnostic criteria to employ for the purpose of cost reduction. Diagnostic procedures : Diagnostic procedures : physical examination : study of individual body systems : biopsy without incision : biopsy with incision : diagnostic endoscopy : function tests : exploratory diagnostic measures : Other diagnostic measures Radiology : Radiology : ultrasound : projection radiography : computed tomography (CT) : optical techniques : representation of the vascular system : nuclear medicine diagnostic procedure : scintigraphy : single-photon emission computed tomography (SPECT) : single-photon emission computed tomography with computed tomography (SPECT / CT) : positron emission tomography (PET) with full-ring scanner : positron emission tomography with computed tomography (PET / CT) : probe measurements and incorporation : magnetic resonance imaging (MRI) : other imaging techniques : additional information on imaging techniques Few pancreatic carcinomas (5-22%) are resectable at the time of diagnosis because this lesion is seldom diagnosed in an early stage. A considerable improvement in the rate of survival is described only for resectable tumors: it is extremely necessary to find an imaging technique for early diagnosis and for accurate staging of pancreatic carcinoma to discern operable from inoperable cancer. The sensitivity of CT in predicting that pancreatic carcinoma is unresectable has been described as approaching 100%. However the reverse is not true. More than one third of the tumors revealed with CT and interpreted as resectable cannot be excised. The major reason for errors with CT are failure to detected liver metastases, peritoneal implants, lymph node involvement and encasement of the great vessels by tumor. Significant progress has recently been made to improve the detection of these details with the recent introduction of helical CT with infusion of a bolus of contrast material and thin section collimation. Traditionally, when a single sequence of images was acquired during abdominal CT, the time of the acquisition was dominated by the requirement to scan during maximal hepatic enhancement, which unfortunately may not be optimal for evaluation of the pancreas. With the advent of helical CT, the acquisition of two sets of images after infusion of contrast material is now possible; the first one takes place during the arterial enhancement; it is useful to detect tumor vascular encasement and the maximum difference of tissue attenuation between normal greater pancreatic enhancement and hypodense pancreatic mass, less vascularizated. It appears that the peak parenchymal enhancement achieved with helical CT may improve the sensitivity of CT scanning in detecting pancreatic carcinoma, especially small tumors confined within the organ. The second phase takes place during the venous or portal enhancement and provides useful information about venous encasement and hepatic metastasis. Extraglandular extension with invasion of adjacent major arterial (celiac axis or its branches, superior mesenteric artery) and venous (portal, splenic, superior mesenteric) appear as soft-tissue attenuation thickening obscuring the perivascular fat, with deformity, thrombosis or occlusion of the vessels. In cases of venous occlusion, collateral vein can be identified. Dilatation of the small veins that surround the head of the pancreas might be used as an additional criterion of extrapancreatic extension of neoplasia. With the features of spiral CT (contrast material optimization and continuous scanning), the detection of small lesions in the liver and peritoneal implants has been increased. Helical CT seems not to detect anything else about lymph node involvement than conventional CT, limited by the same morphologic criteria. The only CT means of detection of node involvement by pancreatic carcinoma is the pathologic enlargement of lymph nodes without specificity for neoplastic or not neoplastic ones. In many cases 2D, 3D and MIP imaging are helpful to evaluate vasculature encasement, especially for visualization of vessels which lie in oblique, coronal or sagittal plane. Consequently helical CT has the potential to become an alternative angiographic technique. Many studies have been done to evaluate spiral CT potential impact and to compare the value of this technique with other ones in the initial diagnosis and staging of pancreatic carcinoma. One of these studies compares dual-phase helical CT and endoscopic endo-sonography. The Authors observe that the two techniques do not differ significant statistically in detecting pancreatic carcinoma, except endoscopic sonography is more sensitive than helical CT for tumors smaller than 15-20 mm. They found the accuracy to predict unresectable carcinoma is 100% for dual-phase helical CT and less for endoscopic endosonography (86%). (ABSTRACT TRUNCATED) Services Inpatient services provided include: birthing rooms, adult heart catheterization and diagnostics, hospice, pain management, cancer treatment, and psychiatric emergency services. Outpatient services include: chemotherapy, trauma center, Chiropractic treatment, dentistry care, kidney dialysis, physical rehabilitation, substance abuse treatment, and urgent care. Diagnostic equipment available include: CT scanner, a diagnostic radioisotope facility, Magnetic resonance imaging, Multislice spiral CT, Single photon emission CT, and ultrasound. References Buildings and structures in Blue Earth County, Minnesota Mankato, Minnesota Hospitals in Minnesota Hospitals established in 1898 Hospitals established in 1996 Mayo Clinic Forty-six patients, including 33 with proved pancreatic carcinoma, were studied with computerized tomography (CT), ultrasound (US), and radionuclide (RN) scanning. The results of each scanning procedure were compared with the surgical and clinical findings. The detection rate was 82% for CT, and 92% with US. A mass is the most important finding in the diagnosis of pancreatic carcinoma. Measurements of the pancreas with CT and US were similar, with visualization of all parts of the pancreas routinely better with CT scans. Radionuclide scans were abnormal in 96% of the patients with pancreatic carcinoma as well as in 75% of patients without pancreatic disease. A rational approach to examination of a patient with suspected pancreatic carcinoma should begin with US scan with available, because the detection rate with this method is equal to that with CT and its cost per procedure and for equipment is substantially less. Medical ultrasound is an ultrasound-based diagnostic medical imaging technique used to visualize muscles, tendons, and many internal organs to capture their size, structure and any pathological lesions with real time tomographic images. Ultrasound has been used by radiologists and sonographers to image the human body for at least 50 years and has become a widely used diagnostic tool. The technology is relatively inexpensive and portable, especially when compared with other techniques, such as magnetic resonance imaging (MRI) and computed tomography (CT). Ultrasound is also used to visualize fetuses during routine and emergency prenatal care. Such diagnostic applications used during pregnancy are referred to as obstetric sonography. As currently applied in the medical field, properly performed ultrasound poses no known risks to the patient. Sonography does not use ionizing radiation, and the power levels used for imaging are too low to cause adverse heating or pressure effects in Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, and is considered uniformly fatal when patients present with unresectable, advanced-stage disease at the time of diagnosis. Long-term survival of patients with advanced-stage pancreatic adenocarcinoma remains rare, despite advances in adjuvant chemoradiation protocols. A 73-year-old male presented to our emergency department with abdominal pain and a history of biopsy-proven, stage III pancreatic adenocarcinoma. His initial staging CT scan and trans-duodenal ultrasound had demonstrated a stage IIa (T3, N0, Mx) lesion. On surgical exploration, he was up-staged to stage III (T4, N0, Mx), noting encasement of the superior mesenteric vessels and involvement of the portal vein. He underwent palliative choledochojejunostomy and was treated with 4 months of oxaliplatin and capecitabine, with concurrent radiation therapy (50.4 Gy), followed by 4 months of gemcitabine. After 7 months, the patient withdrew from therapy due to treatment intolerance. He then turned to self-medication with non-traditional herbal therapies. After 3 years of surveillance, he was lost to follow-up until presenting to our facility with abdominal pain 8 years after his initial diagnosis. On diagnostic CT scan during his current presentation for abdominal pain, he was found to have no evidence of pancreatic cancer. Based on our review of the literature, we present the longest known survival of a patient with surgically unresectable pancreatic adenocarcinoma. Further study of this patient's phenotypic or genotypic characteristics may provide insight into better therapeutic agents, or a predictive subset of patients who will benefit from specific chemotherapeutic options. Computed tomography (CT) or magnetic resonance imaging (MRI) are diagnostic imaging tests that allow physicians to better visualize the appearance of the brain. MRI imaging test uses magnetic fields and radio waves to help create images of the brain. CT scan uses x-rays and computers to create a detailed image of the brain's tissues and structures. Both diagnostic imaging tests can help reveal brain areas that are decaying, or atrophic, in persons with NCL. Measurement of enzyme activity specific to Batten disease may help confirm certain diagnoses caused by different mutations. Elevated levels of palmitoyl-protein thioesterase is involved in CLN1. Acid protease is involved in CLN2. Cathepsin D is involved in CLN10. Spiral CT allows for a noninvasive evaluation of the mesenteric arterial and venous vessels. This test can be performed quicker, with less expense, and with a reduced radiation and contrast load than angiography. Comparison studies of angiography and spiral CT are needed in patients with pancreatic cancer to determine the best method of evaluating possible vessel involvement. Preoperative imaging of patients with pancreatic cancer is crucial in determining resectability and planning management. Computed tomography (CT) remains the diagnostic procedure of choice for the evaluation of the primary tumor and angiography is the gold standard to evaluate vessel encasement. This case evaluates the usefulness of spiral computed tomography in determining vessel encasement. A 53-yr-old female presented with vague abdominal complaints and evaluation revealed a mass in the pancreas. CT suggested portal vein involvement and collateralization was noted in the upper abdomen. Spiral CT revealed normal arterial anatomy and near complete obstruction of the portal vein at the superior mesenteric vein (SMV) splenic vein (SV) confluence. Operative findings confirmed the involvement of the portal vein at the confluence of the SMV and SV. Pancreatico-duodenectomy with portal vein resection and primary anastomosis was performed. The patient's postoperative course was uneventful and she was discharged home on the 13th postoperative day. Follow up guidelines Cysts from 1–5 mm on CT or ultrasound are typically too small to characterize and considered benign. No further imaging follow-up is recommended for these lesions. Cysts from 6–9 mm require a single follow-up in 2–3 years, preferably with magnetic resonance cholangiopancreatography (MRCP) to better evaluate the pancreatic duct. If stable at follow-up, no further imaging follow-up is recommended. For cysts from 1–1.9 cm follow-up is suggested with MRCP or multiphasic CT in 1–2 years. If stable at follow-up, the interval of imaging follow-up is increased to 2–3 years. Cysts from 2–2.9 cm have more malignant potential, and a baseline endoscopic ultrasound is suggested, followed by MRCP or multiphasic CT in 6–12 months. If patients are young, surgery may be considered to avoid the need for prolonged surveillance. If these cysts are stable at follow-up, interval imaging follow-up can be done in 1–2 years. References External links Pancreas disorders Cysts Thin slice table incremental CE-CT was performed on 18 patients considered to have pancreatic carcinoma, 13 patients with chronic pancreatitis, and 19 patients with a normal pancreas. Each patient underwent precontrast CT scanning and delayed scanning. Computed tomography was performed with a high-speed scanner, a TCT 900s. First, precontrast CT scanning was initiated at the level of the top of the right diaphragm, and the scan sequence was performed to include the liver and pancreas at contiguous 10 mm intervals. Second, a bolus of 50-60 mL of 300 mgI/mL iopamidol was delivered intravenously by hand injection via a peripheral arm vein, and subsequent injections were administered during table incrementation with 2-second interscan delay, and the scan sequence was obtained at contiguous 5 mm intervals with a scan speed of 1-second. Delayed scanning was performed 1-2 minutes later after 12 images had been obtained by thin slice table incremental CE-CT scanning. The average CT numbers were calculated for each lesion by precontrast CT scanning, thin slice table incremental CE-CT scanning, and delayed scanning. For the patients with pancreatic carcinoma, the average CT numbers were 41.6HU +/- 6.4HU, 69.6HU +/- 10.4HU, and 86.2HU +/- 14.7HU by precontrast CT scanning, thin slice table incremental CE-CT scanning, and delayed scanning, respectively. While for the patients with chronic pancreatitis, the average CT numbers were 50.0HU +/- 5.0HU, 94.3HU +/- 13.3HU, and 82.5HU +/- 11.6HU, respectively, and for those with a normal pancreas, the average CT numbers were 51.3HU +/- 5.7HU, 93.5HU +/- 7.6HU, and 82.0HU +/- 11.6HU, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) Diagnosis Nutcracker syndrome is diagnosed through imaging such as doppler ultrasound (DUS), computed tomography (CT), magnetic resonance imaging (MRI), and venography. The selection of the imaging modality is a step-wise process. DUS is the initial choice after clinical suspicion based on symptoms. CT and MRI are used to follow up afterwards, and if further confirmation is necessary, venography is used to confirm. Doppler Ultrasound Although its ability to detect renal vein compression is dependent on how a patient is positioned during imaging, DUS is recommended as an initial screening tool as it has a high sensitivity (69–90%) and specificity (89–100%). DUS measures the anteroposterior diameter, and a peak systolic velocity at least four times as fast as an uncompressed vein is indicative of NCS. There is no study establishing time trends for the diagnostic and therapeutic approaches to pancreatic cancer based on population data. The data of the Registry of Digestive Tumors of Côte-d'Or (France) were used to this end in 544 cancers diagnosed between 1976 and 1988. The proportion of the histologically confirmed cases increased annually by 13.4% (P &lt; 0.001). This was mainly due to progress in percutaneous biopsy (+25.7% per year between 1983 and 1988, P &lt; 0.001). As regards the diagnosis, ultrasonography was used more frequently (+21.9% per year, P &lt; 0.001) as well as CT scan since its introduction in 1983 (+19.6% per year, P &lt; 0.001). Pancreatic cancer was diagnosed by sonography in 16.7% of the cases in 1976 and 70.6% in 1988 (mean annual variation: +5.7%, P &lt; 0.001). The proportions for CT scan were 12.8% in 1983 and 23.5% in 1988 (mean annual variation: +3.5%, NS). There was no significant change in the use of retrograde cholangiopancreatography over time. Other diagnosis criteria were less frequently used: laparoscopy was no longer used after 1983 and intraoperative diagnosis was made less frequently (-2.5% per year, P &lt; 0.001). Endoscopy or radiographic data were rarely used as a diagnosis criterion. These changes in approaches to the diagnosis of pancreatic cancer were not accompanied by any progress in diagnosis stage, therapeutic approach or survival suggesting that when clinical symptoms become evident, pancreatic cancer is already advanced. Therapeutic advances, early diagnosis in patient at risk or identification or reasons for pancreatic cancer are the only means of progress in this problem. In some hospitals, they are measured by laboratories after a form is completed showing the probability score and only if the probability score is low or intermediate. This reduces the need for unnecessary tests in those who are high-probability. Performing the D-dimer test first can avoid a significant proportion of imaging tests and is less invasive. Since the D-dimer can exclude the need for imaging, specialty professional organizations recommend that physicians use D-dimer testing as an initial diagnostic. Interpretation Reference ranges The following are reference ranges for D-dimer: D-dimer increases with age. It has therefore been suggested to use a cutoff equal to patient’s age in years × 10 µg/L (or x 0.056 nmol/L) for patients aged over 50 years for the suspicion of venous thromboembolism (VTE), as it decreases the false positive rate without substantially increasing the false negative rate. The most effective way to localize the mostly small ( &lt; 2 cm), benign and solitary insulinomas is still under discussion. Especially the evaluation of the different preoperative localization methods is not clarified. The aim of our study was to support the ongoing discussion in that matter. In total 25 patients have been included in our study since 1987. All showed sporadic insulinomas and underwent surgery. The following preoperative localization methods had been used: ultrasonography (US): 25 patients, computed tomography (CT): 23 patients, somatostatin receptor scintigraphy (SRS): four patients since 1990, angiography: six patients, endosonography (ES): five patients since 1995, selective portal venous sampling (PVS): two patients, magnetic resonance imaging (MRI): four patients since 1993. All 25 patients underwent a bidigital palpation in combination with intraoperative ultrasonography (IOUS). Four of the 25 patients were reoperated and had a prior unsuccessful operation elsewhere. Preoperatively 19 of 25 insulinomas were localized (76%). The following sensitivity rates had been found: ultrasonography: 56%, computed tomography: 43%, endosonography: 100%, angiography: 66%, magnetic resonance imaging: 25%, selective portal venous sampling: 100%, somatostatin receptor scintigraphy: 0%. All 25 insulinomas were detected during operation, 100% by palpation in combination with intraoperative ultrasonography and 92% by palpation on its own. After an insulinoma is biochemically proven and after exclusion of a malignant metastasizing tumor by ultrasonography, all patients should be operated on. Intraoperative ultrasonography should be performed in any case. As other preoperative localization methods did not prove a convincing cost-utility-relation, one should not consider the usage of these methods before the initial operations. Before re-operations one should consider the use of costly pre-operative methods to localize insulinomas. Here endosonography and selective portal venous sampling are recommended as the first procedures of choice. The genome determination helps to distinguish other congenital muscular dystrophies before and after birth. However, only some laboratories provide prenatal genetic test to screen for MEB. Medical imaging MEB can be diagnosed with medical imaging by the shared patterns of brain structural abnormalities. Common practice includes magnetic resonance imaging (MRI) and computerized tomography (CT). They can show the enlargement of ventricle, absence or degeneration of septum pellucidum, pachygyric symptoms, abnormalities in corpus collosum, lissencephaly. Fetal MRI and ultrasound are used as a prenatal diagnostic tool if needed to screen for the disease. Observation like general structural malformation in the third trimester suggests congenital muscular dystrophy. Further diagnostic test is required to make confirmation.\nHere is the question:\nPNEUMOLOGY: 65-year-old man with a history of pancreatic neoplasm undergoing chemotherapy. What diagnostic test is more cost-effective to confirm the diagnostic suspicion?\nHere are the potential choices:\n1. D-dimer.\n2. Magnetic resonance imaging.\n3. Phlebography.\n4. Venous Doppler ultrasound.\n5. Helical CT.\nThe correct answer is: ",
        "gold_answer": "4 Venous Doppler ultrasound.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A large number of diagnostic procedures (e.g., ultrasound, computed tomography [CT] scan, fine-needle aspiration [FNA], angiography, endoscopic retrograde cholangiopancreatography [ERCP], and laparoscopy), are available to the clinician as he/she pursues the workup of patients who are thought to have a pancreatic (periampullary) malignancy. Not all of these procedures should be used in every patient and some have been overused. Based on a current literature review and their own experience, the authors describe the rationale of the diagnostic workup in patients with suspected pancreatic carcinoma in a single institution (a university medical center). Helical CT scan provides the best overall assessment of patients with periampullary malignancies, and it is often the only test required. If the patient's history and blood test abnormalities suggest pancreatic carcinoma and the helical CT scan shows a mass in the head of the pancreas that appears to be resectable, the patient should be prepared for surgery. If no mass is apparent on the helical CT scan, a diagnostic ERCP is indicated. If microscopic proof of the diagnosis will avoid surgery, then an FNA for cytology should be performed. When unresectability appears likely and cannot be confirmed in less invasive ways, laparoscopy is indicated. In patients with periampullary malignancies, helical CT scan provides the best overall assessment. Guidelines are presented for the selective use of ultrasound, FNA, ERCP, and laparoscopy, which are important for the most cost-effective workup of these patients. to assess the clinical value of ultrasonographic methods and computed tomography in diagnosing and staging pancreatic carcinoma. prospective clinical trial of 140 patients (64 women and 77 men; mean age 59,6) operated on for pancreatic carcinoma between 2000 and 2004. In each case helical CT, routine-, color- and power Doppler and 3-D USG were performed to detect and stage cancer. Analyses of accuracy, sensitivity, specificity, PPV and NPV of ultrasonographic methods and CT were made. 3-D USG showed the best accuracy of local staging (T): 95.6%. CT was the most accurate in lymph node assessment: 91.3%. The accuracy of CT, 3-D USG and power-Doppler at detecting vascular infiltration was 93.1%. diagnostic accuracy of modern ultrasound techniques is comparable to helical CT in detecting and staging pancreatic carcinoma. USG is recommended due to the relatively low cost, non-invasiveness and availability of the procedure. Diagnostic imaging The insulinoma might be localized by noninvasive means, using ultrasound, CT scan, or MRI techniques. An indium-111 pentetreotide scan is more sensitive than ultrasound, CT, or MRI for detection of somatostatin receptor positive tumors, but not a good diagnostic tool for insulinomas. An endoscopic ultrasound has a sensitivity of 40-93% (depending on the location of the tumor) for detecting insulinomas. Sometimes, angiography with percutaneous transhepatic pancreatic vein catheterization to sample the blood for insulin levels is required. Calcium can be injected into selected arteries to stimulate insulin release from various parts of the pancreas, which can be measured by sampling blood from their respective veins. The use of calcium stimulation improves the specificity of this test. Diagnosis Techniques for the diagnosis of Page kidney are all imaging based, including abdominal x-ray, intravenous pyelography, angiography, renal doppler ultrasound, CT scan, and Magnetic resonance imaging (MRI). X-ray and pyelography may add in diagnosis, but are non-diagnostic when used alone. Additionally, pyelograms use potentially nephrotoxic contrast agents, further limiting their utility. Diagnosis is primarily made using ultrasound and CT. CT and MRI imaging can show the space occupying lesions but doppler ultrasound is needed to display the hemodynamic changes occurring in the kidney. Ultrasound is often the initial diagnostic test of choice but due to its low resolution further imaging may be necessary. Treatment The principal value of CT imaging to the treating clinician is the capacity to identify devitalised areas of the pancreas which have become necrotic due to ischaemia. Pancreatic necrosis can be reliably identified by intravenous contrast-enhanced CT imaging, and is of value if infection occurs and surgical or percutaneous debridement is indicated. Magnetic resonance imaging While computed tomography is considered the gold standard in diagnostic imaging for acute pancreatitis, magnetic resonance imaging (MRI) has become increasingly valuable as a tool for the visualization of the pancreas, particularly of pancreatic fluid collections and necrotized debris. Additional utility of MRI includes its indication for imaging of patients with an allergy to CT's contrast material, and an overall greater sensitivity to hemorrhage, vascular complications, pseudoaneurysms, and venous thrombosis. Diagnostic radiology () Diagnostic radiology () Soft tissue x-ray of thorax () Other x-ray of thorax () X-ray of urinary system () Computerized axial tomography of kidney CAT scan of kidney () Other nephrotomogram () Intravenous pyelogram Diuretic infusion pyelogram () Retrograde pyelogram () Percutaneous pyelogram () Retrograde cystourethrogram () Other cystogram () Ileal conduitogram () Other x-ray of the urinary system KUB x-ray () Other diagnostic radiology and related techniques () Soft tissue x-ray of abdomen () Other x-ray of abdomen () Skeletal x-ray of extremities and pelvis () Other x-ray () Arteriography using contrast material () Angiocardiography using contrast material () Phlebography () Diagnostic ultrasound () Thermography () Other diagnostic imaging () Diagnostic imaging, not elsewhere classified () Magnetic resonance imaging of brain and brain stem () Magnetic resonance imaging of chest and myocardium Mesenteric angiography is commonly employed in the modern-day investigation of gastro-intestinal bleeding if the bleeding sites cannot be identified by endoscopic means. Angiography is optimally sensitive in the presence of active bleeding. However, vasospasm may occasionally account for a negative study shortly after bleeding. A 70-year-old lady with inoperable carcinoma of the pancreas presented with gastro-intestinal bleeding. Although upper endoscopy visualised active bleeding from the tumour, which had invaded into the duodenum, haemostasis could not be achieved endoscopically. Therefore, mesenteric angiography was arranged. The initial angiography failed to demonstrate the bleeding site, which only became obvious on a repeat study, when embolisation was performed to achieve haemostasis. Vasospasm probably accounted for the initial negative study, as the second angiography was able to demonstrate contrast extravasation without the use of any anticoagulant or thrombolytic agent. It is not our routine to give pharmacological agents to provoke bleeding after a negative angiography, but for selected patients this manoeuvre may turn out to be more cost-effective. Fractures represent up to 80% of the missed diagnoses in the emergency department. Failure to recognize the subtle signs of osseous injury is one of the reasons behind this major diagnostic challenge. While occult fractures present no radiographic findings, radiographically subtle fractures are easily overlooked on initial radiographs. In both cases, a negative radiographic diagnosis with prominent clinical suspicion of osseous injury will prompt advanced imaging examination such as CT scan, magnetic resonance imaging, ultrasound, and nuclear medicine to confirm or exclude the clinically suspected diagnosis. The burden entailed in missing these fractures includes prolonged pain with a loss of function, and disability. Early detection, on the other hand, enables more effective treatment, a shorter hospitalization period if necessary, and decreased medical costs in the long run. It will also prevent inherent complications such as nonunion, malunion, premature osteoarthritis, and The objective of this study was to evaluate how the introduction of radiologic studies affected the diagnostic workup for pancreatic cancer, from 1955 through 1979. For 961 patients diagnosed as having pancreatic cancer at three teaching hospitals, we reviewed medical records, autopsy reports, and death certificates for results from all radiologic studies, surgical and pathologic procedures, and for the final diagnosis. The number of radiologic studies per patient increased as new studies were introduced; 1.6 for 1955-1959, 3.5 for 1975-1979 (P less than 0.0001). Depending on the cutoff level chosen, the sensitivity of the overall radiologic diagnosis increased over time, 0.17-0.43 for 1955-1959, to 0.54-0.78 for 1975-1979; CT, US, and ERCP accounted for much of the increase. As newer radiologic studies are introduced, continued use of previously accepted studies should be carefully evaluated. Diagnostic images Bioluminescence imaging Dermatoscopy Diffuse optical tomography Gamma camera Computed tomography Infrared imaging of the body Magnetic resonance elastography Magnetic resonance imaging Magnetic resonance spectroscopy Optical coherence tomography Posturography Radiography, fluoroscopy Ultrasonography and echocardiography Diagnostic signals Electrocardiography Electroencephalography Electromyography Photoplethysmograph Electrical impedance tomography Electroneuronography Electroretinography Electronystagmography Magnetoencephalography Evoked potentials Impedance phlebography Nuclear magnetic resonance Therapy Epidermal radioisotope therapy Radiation therapy Brachytherapy Lithotripsy Defibrillation Biofeedback Oxygen therapy Non-invasive ventilation VPAP BIPAP Neurally adjusted ventilatory assist Biphasic cuirass ventilation Therapeutic ultrasound See also Minimally invasive procedures References Medical procedures A case of biliopancreatic pathology studied with traditional (the old algorithm) and the latest (new algorithm) diagnostic techniques is examined. A comparative analysis reveals the second to be simpler, less expensive and less dangerous to the patient. The hope is expressed that doctors will become better informed of the diagnostic criteria to employ for the purpose of cost reduction. Diagnostic procedures : Diagnostic procedures : physical examination : study of individual body systems : biopsy without incision : biopsy with incision : diagnostic endoscopy : function tests : exploratory diagnostic measures : Other diagnostic measures Radiology : Radiology : ultrasound : projection radiography : computed tomography (CT) : optical techniques : representation of the vascular system : nuclear medicine diagnostic procedure : scintigraphy : single-photon emission computed tomography (SPECT) : single-photon emission computed tomography with computed tomography (SPECT / CT) : positron emission tomography (PET) with full-ring scanner : positron emission tomography with computed tomography (PET / CT) : probe measurements and incorporation : magnetic resonance imaging (MRI) : other imaging techniques : additional information on imaging techniques Few pancreatic carcinomas (5-22%) are resectable at the time of diagnosis because this lesion is seldom diagnosed in an early stage. A considerable improvement in the rate of survival is described only for resectable tumors: it is extremely necessary to find an imaging technique for early diagnosis and for accurate staging of pancreatic carcinoma to discern operable from inoperable cancer. The sensitivity of CT in predicting that pancreatic carcinoma is unresectable has been described as approaching 100%. However the reverse is not true. More than one third of the tumors revealed with CT and interpreted as resectable cannot be excised. The major reason for errors with CT are failure to detected liver metastases, peritoneal implants, lymph node involvement and encasement of the great vessels by tumor. Significant progress has recently been made to improve the detection of these details with the recent introduction of helical CT with infusion of a bolus of contrast material and thin section collimation. Traditionally, when a single sequence of images was acquired during abdominal CT, the time of the acquisition was dominated by the requirement to scan during maximal hepatic enhancement, which unfortunately may not be optimal for evaluation of the pancreas. With the advent of helical CT, the acquisition of two sets of images after infusion of contrast material is now possible; the first one takes place during the arterial enhancement; it is useful to detect tumor vascular encasement and the maximum difference of tissue attenuation between normal greater pancreatic enhancement and hypodense pancreatic mass, less vascularizated. It appears that the peak parenchymal enhancement achieved with helical CT may improve the sensitivity of CT scanning in detecting pancreatic carcinoma, especially small tumors confined within the organ. The second phase takes place during the venous or portal enhancement and provides useful information about venous encasement and hepatic metastasis. Extraglandular extension with invasion of adjacent major arterial (celiac axis or its branches, superior mesenteric artery) and venous (portal, splenic, superior mesenteric) appear as soft-tissue attenuation thickening obscuring the perivascular fat, with deformity, thrombosis or occlusion of the vessels. In cases of venous occlusion, collateral vein can be identified. Dilatation of the small veins that surround the head of the pancreas might be used as an additional criterion of extrapancreatic extension of neoplasia. With the features of spiral CT (contrast material optimization and continuous scanning), the detection of small lesions in the liver and peritoneal implants has been increased. Helical CT seems not to detect anything else about lymph node involvement than conventional CT, limited by the same morphologic criteria. The only CT means of detection of node involvement by pancreatic carcinoma is the pathologic enlargement of lymph nodes without specificity for neoplastic or not neoplastic ones. In many cases 2D, 3D and MIP imaging are helpful to evaluate vasculature encasement, especially for visualization of vessels which lie in oblique, coronal or sagittal plane. Consequently helical CT has the potential to become an alternative angiographic technique. Many studies have been done to evaluate spiral CT potential impact and to compare the value of this technique with other ones in the initial diagnosis and staging of pancreatic carcinoma. One of these studies compares dual-phase helical CT and endoscopic endo-sonography. The Authors observe that the two techniques do not differ significant statistically in detecting pancreatic carcinoma, except endoscopic sonography is more sensitive than helical CT for tumors smaller than 15-20 mm. They found the accuracy to predict unresectable carcinoma is 100% for dual-phase helical CT and less for endoscopic endosonography (86%). (ABSTRACT TRUNCATED) Services Inpatient services provided include: birthing rooms, adult heart catheterization and diagnostics, hospice, pain management, cancer treatment, and psychiatric emergency services. Outpatient services include: chemotherapy, trauma center, Chiropractic treatment, dentistry care, kidney dialysis, physical rehabilitation, substance abuse treatment, and urgent care. Diagnostic equipment available include: CT scanner, a diagnostic radioisotope facility, Magnetic resonance imaging, Multislice spiral CT, Single photon emission CT, and ultrasound. References Buildings and structures in Blue Earth County, Minnesota Mankato, Minnesota Hospitals in Minnesota Hospitals established in 1898 Hospitals established in 1996 Mayo Clinic Forty-six patients, including 33 with proved pancreatic carcinoma, were studied with computerized tomography (CT), ultrasound (US), and radionuclide (RN) scanning. The results of each scanning procedure were compared with the surgical and clinical findings. The detection rate was 82% for CT, and 92% with US. A mass is the most important finding in the diagnosis of pancreatic carcinoma. Measurements of the pancreas with CT and US were similar, with visualization of all parts of the pancreas routinely better with CT scans. Radionuclide scans were abnormal in 96% of the patients with pancreatic carcinoma as well as in 75% of patients without pancreatic disease. A rational approach to examination of a patient with suspected pancreatic carcinoma should begin with US scan with available, because the detection rate with this method is equal to that with CT and its cost per procedure and for equipment is substantially less. Medical ultrasound is an ultrasound-based diagnostic medical imaging technique used to visualize muscles, tendons, and many internal organs to capture their size, structure and any pathological lesions with real time tomographic images. Ultrasound has been used by radiologists and sonographers to image the human body for at least 50 years and has become a widely used diagnostic tool. The technology is relatively inexpensive and portable, especially when compared with other techniques, such as magnetic resonance imaging (MRI) and computed tomography (CT). Ultrasound is also used to visualize fetuses during routine and emergency prenatal care. Such diagnostic applications used during pregnancy are referred to as obstetric sonography. As currently applied in the medical field, properly performed ultrasound poses no known risks to the patient. Sonography does not use ionizing radiation, and the power levels used for imaging are too low to cause adverse heating or pressure effects in Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, and is considered uniformly fatal when patients present with unresectable, advanced-stage disease at the time of diagnosis. Long-term survival of patients with advanced-stage pancreatic adenocarcinoma remains rare, despite advances in adjuvant chemoradiation protocols. A 73-year-old male presented to our emergency department with abdominal pain and a history of biopsy-proven, stage III pancreatic adenocarcinoma. His initial staging CT scan and trans-duodenal ultrasound had demonstrated a stage IIa (T3, N0, Mx) lesion. On surgical exploration, he was up-staged to stage III (T4, N0, Mx), noting encasement of the superior mesenteric vessels and involvement of the portal vein. He underwent palliative choledochojejunostomy and was treated with 4 months of oxaliplatin and capecitabine, with concurrent radiation therapy (50.4 Gy), followed by 4 months of gemcitabine. After 7 months, the patient withdrew from therapy due to treatment intolerance. He then turned to self-medication with non-traditional herbal therapies. After 3 years of surveillance, he was lost to follow-up until presenting to our facility with abdominal pain 8 years after his initial diagnosis. On diagnostic CT scan during his current presentation for abdominal pain, he was found to have no evidence of pancreatic cancer. Based on our review of the literature, we present the longest known survival of a patient with surgically unresectable pancreatic adenocarcinoma. Further study of this patient's phenotypic or genotypic characteristics may provide insight into better therapeutic agents, or a predictive subset of patients who will benefit from specific chemotherapeutic options. Computed tomography (CT) or magnetic resonance imaging (MRI) are diagnostic imaging tests that allow physicians to better visualize the appearance of the brain. MRI imaging test uses magnetic fields and radio waves to help create images of the brain. CT scan uses x-rays and computers to create a detailed image of the brain's tissues and structures. Both diagnostic imaging tests can help reveal brain areas that are decaying, or atrophic, in persons with NCL. Measurement of enzyme activity specific to Batten disease may help confirm certain diagnoses caused by different mutations. Elevated levels of palmitoyl-protein thioesterase is involved in CLN1. Acid protease is involved in CLN2. Cathepsin D is involved in CLN10. Spiral CT allows for a noninvasive evaluation of the mesenteric arterial and venous vessels. This test can be performed quicker, with less expense, and with a reduced radiation and contrast load than angiography. Comparison studies of angiography and spiral CT are needed in patients with pancreatic cancer to determine the best method of evaluating possible vessel involvement. Preoperative imaging of patients with pancreatic cancer is crucial in determining resectability and planning management. Computed tomography (CT) remains the diagnostic procedure of choice for the evaluation of the primary tumor and angiography is the gold standard to evaluate vessel encasement. This case evaluates the usefulness of spiral computed tomography in determining vessel encasement. A 53-yr-old female presented with vague abdominal complaints and evaluation revealed a mass in the pancreas. CT suggested portal vein involvement and collateralization was noted in the upper abdomen. Spiral CT revealed normal arterial anatomy and near complete obstruction of the portal vein at the superior mesenteric vein (SMV) splenic vein (SV) confluence. Operative findings confirmed the involvement of the portal vein at the confluence of the SMV and SV. Pancreatico-duodenectomy with portal vein resection and primary anastomosis was performed. The patient's postoperative course was uneventful and she was discharged home on the 13th postoperative day. Follow up guidelines Cysts from 1–5 mm on CT or ultrasound are typically too small to characterize and considered benign. No further imaging follow-up is recommended for these lesions. Cysts from 6–9 mm require a single follow-up in 2–3 years, preferably with magnetic resonance cholangiopancreatography (MRCP) to better evaluate the pancreatic duct. If stable at follow-up, no further imaging follow-up is recommended. For cysts from 1–1.9 cm follow-up is suggested with MRCP or multiphasic CT in 1–2 years. If stable at follow-up, the interval of imaging follow-up is increased to 2–3 years. Cysts from 2–2.9 cm have more malignant potential, and a baseline endoscopic ultrasound is suggested, followed by MRCP or multiphasic CT in 6–12 months. If patients are young, surgery may be considered to avoid the need for prolonged surveillance. If these cysts are stable at follow-up, interval imaging follow-up can be done in 1–2 years. References External links Pancreas disorders Cysts Thin slice table incremental CE-CT was performed on 18 patients considered to have pancreatic carcinoma, 13 patients with chronic pancreatitis, and 19 patients with a normal pancreas. Each patient underwent precontrast CT scanning and delayed scanning. Computed tomography was performed with a high-speed scanner, a TCT 900s. First, precontrast CT scanning was initiated at the level of the top of the right diaphragm, and the scan sequence was performed to include the liver and pancreas at contiguous 10 mm intervals. Second, a bolus of 50-60 mL of 300 mgI/mL iopamidol was delivered intravenously by hand injection via a peripheral arm vein, and subsequent injections were administered during table incrementation with 2-second interscan delay, and the scan sequence was obtained at contiguous 5 mm intervals with a scan speed of 1-second. Delayed scanning was performed 1-2 minutes later after 12 images had been obtained by thin slice table incremental CE-CT scanning. The average CT numbers were calculated for each lesion by precontrast CT scanning, thin slice table incremental CE-CT scanning, and delayed scanning. For the patients with pancreatic carcinoma, the average CT numbers were 41.6HU +/- 6.4HU, 69.6HU +/- 10.4HU, and 86.2HU +/- 14.7HU by precontrast CT scanning, thin slice table incremental CE-CT scanning, and delayed scanning, respectively. While for the patients with chronic pancreatitis, the average CT numbers were 50.0HU +/- 5.0HU, 94.3HU +/- 13.3HU, and 82.5HU +/- 11.6HU, respectively, and for those with a normal pancreas, the average CT numbers were 51.3HU +/- 5.7HU, 93.5HU +/- 7.6HU, and 82.0HU +/- 11.6HU, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) Diagnosis Nutcracker syndrome is diagnosed through imaging such as doppler ultrasound (DUS), computed tomography (CT), magnetic resonance imaging (MRI), and venography. The selection of the imaging modality is a step-wise process. DUS is the initial choice after clinical suspicion based on symptoms. CT and MRI are used to follow up afterwards, and if further confirmation is necessary, venography is used to confirm. Doppler Ultrasound Although its ability to detect renal vein compression is dependent on how a patient is positioned during imaging, DUS is recommended as an initial screening tool as it has a high sensitivity (69–90%) and specificity (89–100%). DUS measures the anteroposterior diameter, and a peak systolic velocity at least four times as fast as an uncompressed vein is indicative of NCS. There is no study establishing time trends for the diagnostic and therapeutic approaches to pancreatic cancer based on population data. The data of the Registry of Digestive Tumors of Côte-d'Or (France) were used to this end in 544 cancers diagnosed between 1976 and 1988. The proportion of the histologically confirmed cases increased annually by 13.4% (P &lt; 0.001). This was mainly due to progress in percutaneous biopsy (+25.7% per year between 1983 and 1988, P &lt; 0.001). As regards the diagnosis, ultrasonography was used more frequently (+21.9% per year, P &lt; 0.001) as well as CT scan since its introduction in 1983 (+19.6% per year, P &lt; 0.001). Pancreatic cancer was diagnosed by sonography in 16.7% of the cases in 1976 and 70.6% in 1988 (mean annual variation: +5.7%, P &lt; 0.001). The proportions for CT scan were 12.8% in 1983 and 23.5% in 1988 (mean annual variation: +3.5%, NS). There was no significant change in the use of retrograde cholangiopancreatography over time. Other diagnosis criteria were less frequently used: laparoscopy was no longer used after 1983 and intraoperative diagnosis was made less frequently (-2.5% per year, P &lt; 0.001). Endoscopy or radiographic data were rarely used as a diagnosis criterion. These changes in approaches to the diagnosis of pancreatic cancer were not accompanied by any progress in diagnosis stage, therapeutic approach or survival suggesting that when clinical symptoms become evident, pancreatic cancer is already advanced. Therapeutic advances, early diagnosis in patient at risk or identification or reasons for pancreatic cancer are the only means of progress in this problem. In some hospitals, they are measured by laboratories after a form is completed showing the probability score and only if the probability score is low or intermediate. This reduces the need for unnecessary tests in those who are high-probability. Performing the D-dimer test first can avoid a significant proportion of imaging tests and is less invasive. Since the D-dimer can exclude the need for imaging, specialty professional organizations recommend that physicians use D-dimer testing as an initial diagnostic. Interpretation Reference ranges The following are reference ranges for D-dimer: D-dimer increases with age. It has therefore been suggested to use a cutoff equal to patient’s age in years × 10 µg/L (or x 0.056 nmol/L) for patients aged over 50 years for the suspicion of venous thromboembolism (VTE), as it decreases the false positive rate without substantially increasing the false negative rate. The most effective way to localize the mostly small ( &lt; 2 cm), benign and solitary insulinomas is still under discussion. Especially the evaluation of the different preoperative localization methods is not clarified. The aim of our study was to support the ongoing discussion in that matter. In total 25 patients have been included in our study since 1987. All showed sporadic insulinomas and underwent surgery. The following preoperative localization methods had been used: ultrasonography (US): 25 patients, computed tomography (CT): 23 patients, somatostatin receptor scintigraphy (SRS): four patients since 1990, angiography: six patients, endosonography (ES): five patients since 1995, selective portal venous sampling (PVS): two patients, magnetic resonance imaging (MRI): four patients since 1993. All 25 patients underwent a bidigital palpation in combination with intraoperative ultrasonography (IOUS). Four of the 25 patients were reoperated and had a prior unsuccessful operation elsewhere. Preoperatively 19 of 25 insulinomas were localized (76%). The following sensitivity rates had been found: ultrasonography: 56%, computed tomography: 43%, endosonography: 100%, angiography: 66%, magnetic resonance imaging: 25%, selective portal venous sampling: 100%, somatostatin receptor scintigraphy: 0%. All 25 insulinomas were detected during operation, 100% by palpation in combination with intraoperative ultrasonography and 92% by palpation on its own. After an insulinoma is biochemically proven and after exclusion of a malignant metastasizing tumor by ultrasonography, all patients should be operated on. Intraoperative ultrasonography should be performed in any case. As other preoperative localization methods did not prove a convincing cost-utility-relation, one should not consider the usage of these methods before the initial operations. Before re-operations one should consider the use of costly pre-operative methods to localize insulinomas. Here endosonography and selective portal venous sampling are recommended as the first procedures of choice. The genome determination helps to distinguish other congenital muscular dystrophies before and after birth. However, only some laboratories provide prenatal genetic test to screen for MEB. Medical imaging MEB can be diagnosed with medical imaging by the shared patterns of brain structural abnormalities. Common practice includes magnetic resonance imaging (MRI) and computerized tomography (CT). They can show the enlargement of ventricle, absence or degeneration of septum pellucidum, pachygyric symptoms, abnormalities in corpus collosum, lissencephaly. Fetal MRI and ultrasound are used as a prenatal diagnostic tool if needed to screen for the disease. Observation like general structural malformation in the third trimester suggests congenital muscular dystrophy. Further diagnostic test is required to make confirmation.\nHere is the question:\nPNEUMOLOGY: 65-year-old man with a history of pancreatic neoplasm undergoing chemotherapy. What diagnostic test is more cost-effective to confirm the diagnostic suspicion?\nHere are the potential choices:\n1. D-dimer.\n2. Magnetic resonance imaging.\n3. Phlebography.\n4. Venous Doppler ultrasound.\n5. Helical CT.\nThe correct answer is: 4. Venous Doppler ultrasound."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Electroencephalographic epileptic status during sleep (ESES--according to Electrical Status Epilepticus in Sleep) is characterized with paroxysmal attacks of 1.5-3.5 (even to 5) Hz/s spikes and waves during NREM. A case is presented of a 7-year-old boy who had normal development until 3 years of age when epileptic attacks started. First to appear were left-sided, hemifacial twitches with orofacio-lingual deficits. Despite treatment with various types and combinations of antiepileptic medications, the attacks persisted and became more frequent. About a year after the onset of the disease, the spectrum of epileptic attacks had expanded (left-sided tonic-clonic, atonic-astatic, myoclonic, atypical absences, and then drop attacks and negative myoclonic seizures became dominant). The boy appeared mentally retarded. During the course of the disease, the diagnoses varied: hemifacial twitches, partial epilepsy, left-sided partial epilepsy, atypical benign epilepsy, Landau-Kleffner syndrome, myoclonic-astatic epilepsy. A year and a half after the onset of the disease EEG (polysomnographic whole-night recording) revealed electrical status epilepticus in sleep (ESES) with spike-wave index &gt; 85%. It appeared that this was continuous spike and wave during slow wave sleep syndrome (CSWS) with characteristic attacks, bifrontal atrophies on brain CT and right frontotemporal EEG focus. Treatment with valproate and ethosuximide combined with vigabatrin and clonazepam seemed to be effective. In the last 20 months ESES is rare and transitory, mental and neuropsychological functions have improved, but he still has several hemifacial twitches daily. The two brain MRI scans were normal. Differential diagnosis can be atypical benign epilepsy (suspected familial diagnosis). Family history of atopy, 'persistent' colds and obstructive bronchitis in the boy and treatment with antiepileptic medications (especially carbamazepine, phenobarbital and phenytoin) could have been provoking or modulating factors of the epileptic disease. So far we have not identified an epileptic syndrome because it seems that multiple clinical pictures overlap. ESES could be diagnosed using polysomnographic whole-night recording with calculated spike-wave index. Follow-up of the spike-wave index could be useful in differentiation, but not in precise diagnosis of epileptic syndrome. Clinical course could be modulated by different factors. Continuous following over a long period could be helpful in the classification of epilepsy. EEG typically shows 10-Hz activity during the tonic phase and slow waves during the clonic phase. Protect the airway. Treat the underlying cause if known. 1° generalized tonic-clonic seizures: Phenytoin, fosphenytoin, or valproate constitutes first-line therapy. Lamotrigine or topiramate may be used as adjunctive therapy. Secondarily generalized tonic-clonic seizures: Treatment is the same as that for partial seizures. Begin in childhood; subside before adulthood. Often familial. Hx/PE: Present with brief (5to 10-second), often unnoticeable episodes of impaired consciousness occurring up to hundreds of times per day. Patients are amnestic during and immediately after seizures and may appear to be daydreaming or staring. Eye fluttering or lip smacking is common. Dx: EEG shows classic three-per-second spike-and-wave discharges. Tx: Ethosuximide is the first-line agent. We present the clinical and video-EEG data on an epileptic boy whose absence seizures with marked perioral movements had started at the age of 1.5 years. From age 12 years, he experienced frequent episodes of typical absence status epilepticus (ASE) lasting 1-2 hours with marked perioral myoclonia and moderate confusion. Initial therapy with carbamazepine was substituted by valproate because of worsening of the absence seizures. At the age of 17, the patient was admitted to our clinic with his usual, but long lasting ASE attack, accompanied by 2 generalized tonic-clonic convulsions. ASE was confirmed with the EEG which showed continuous 3 Hz spike and wave paroxysms with occasional normal intervals of 1-5 seconds. IV injection of clonazepam improved the clinical and EEG findings immediately. Video- EEG examination performed after a few weeks demonstrated typical absence seizures with perioral myoclonia. Based on the characteristics of seizure semiology, other clinical data and EEG findings, the patient was diagnosed as having the syndrome of \"perioral myoclonia with absence seizures\" described by Panayiotopoulos. A 5-year-old girl exhibited daily episodes of repetitive blinking lasting 5-10 s. Electroencephalography (EEG) revealed marked photoparoxysmal responses (PPR) at 3-20 Hz of photic stimulation and diffuse spike-wave bursts during sleep. A 24-h video EEG identified 11 episodes of repetitive blinking, 3 of which resulted in widespread spike-wave discharges. These suggested that the behavior of the patient represented self-induction of PPR. Valproate sodium was ineffective in decreasing PPR, as revealed by EEG, and the frequency of blinking episodes, but clonazepam attenuated PPR and significantly decreased the blinking behavior. (1) The standard treatment for partial epilepsy in children is carbamazepine. The efficacy of other antiepileptics has also been documented, either alone (phenobarbital, oxcarbazepine, valproate sodium, phenytoin), or in drug combinations (lamotrigine, topiramate). (2) A licence extension has been granted in France for gabapentin in partial epilepsy in children aged 3 to 12 years, in combination with other antiepileptics. (3) The clinical file contains no data from trials comparing gabapentin with other antiepileptics. (4) The main double-blind trial involved 247 children who were treated either with their usual treatment + gabapentin or usual treatment + placebo. Gabapentin was only moderately effective, and the overall number of responders did not differ significantly between the gabapentin and placebo groups. (5) In this trial the main adverse effects among the children on their usual treatment + gabapentin were behavioural disorders (hostility and mood swings). (6) In practice, the licensing of gabapentin for children with partial epilepsy aged between 3 and 12 years changes nothing in their practical management. A patient of pyridoxine dependent seizures was reported. He was born at 34 weeks' gestation and weighted 2,760 g. Apgar scores were 6 and 9 at 1 and 5 minutes, respectively. He showed the first seizure 2 hours after his birth. Phenobarbital, phenytoin, sodium valproate, diazepam and clonazepam were not effective. Pyridoxal phosphate (50 mg) was given intravenously, resulting in suppression of convulsions. However, muscle tonus was severely depressed. In EEG, a discontinuous pattern was found in quiet and indeterminate sleep on the 2nd day of life. At 5th week multifocal spikes were found, and the discontinuous pattern persisted. Ictal discharges at 13th week showed generalized, continuous, irregular and high voltage slow waves with multifocal spikes. At 27th week of life, high voltage slow waves disappeared and multifocal spike discharges decreased. At 2 years and 10 months of age, the patient was suffering from athetotic cerebral palsy and severe mental retardation. Pyridoxal phosphate at the doses of 35-40 mg/kg/day had been administered. Irritability sometimes occurred and additional 50 mg of pyridoxal phosphate controlled this irritability effectively. A 7-year-old female with benign childhood epilepsy with centrotemporal spikes developed epileptic negative myoclonus (ENM) seizures during carbamazepine (CBZ) treatment. She had experienced nocturnal partial seizures since 5 years of age. Interictal electroencephalography demonstrated typical rolandic discharges. Valproate was first initiated at 6 years of age, but the seizures were uncontrollable. Carbamazepine was added and valproate withdrawn. The frequency of partial seizures did not decrease. Moreover, she had brief episodes of tone loss in each or both arms and eye blinking several weeks after CBZ introduction. Unilateral loss of arm tone corresponded to spike-and-wave discharges in the contralateral centrotemporal region, and a loss of tone in arms was associated with bilateral synchronous discharges. Eye blinking was also related to bilateral synchronous discharges and classified as a myoclonic seizure. The ENM and myoclonic seizures disappeared soon after CBZ withdrawal. Therefore the authors concluded that CBZ induced the ENM and myoclonic seizures in this patient. CBZ sometimes induces generalized seizures in the treatment of partial epilepsy and generalized epilepsy. CBZ-induced ENM seizures should be considered when a brief lapse of tone appears during CBZ treatment. We evaluated with clinical interviews and polysomnographic examinations 10 adults with the complaint of sleepwalking, often accompanied by violent behavior or self-injury. During the polysomnographic studies, 8 patients had 47 distinct somnambulistic episodes. All episodes occurred in non-REM sleep, with 91% occurring in slow-wave sleep. Contrary to previous reports, episodes were not confined to the 1st 3rd of the night. Clinical EEGs were normal in 5 of 6 patients. In the 7 patients tried on 1 or more treatment regimens, clonazepam effectively suppressed the somnambulism in 5 of 6 patients in whom it was tried, carbamazepine in 1 of 3, flurazepam in 2 of 2, and a combination of clonazepam and phenytoin in one. Treatment Given the benign nature of the condition and the low seizure frequency, treatment is often unnecessary. If treatment is warranted or preferred by the child and his or her family, antiepileptic drugs can usually control the seizures easily. Carbamazepine is the most frequently used first-line drug, but many other antiepileptic drugs, including valproate, phenytoin, gabapentin, levetiracetam and sultiame have been found effective as well. Bedtime dosing is advised by some. Treatment can be short and drugs can almost certainly be discontinued after two years without seizures and with normal EEG findings, perhaps even earlier. Parental education about Rolandic epilepsy is the cornerstone of correct management. The traumatizing, sometimes long-lasting effect on parents is significant. It is unclear if there are any benefits to clobazam over other seizure medications. Carbamazepine is effective in 70 to 80 percent of patients (600 to 1,200 mg/d), but half become tolerant over a period of several years. Other antiepileptic drugs such as phenytoin (300 to 400 mg/d), valproic acid (800 to 1,200 mg/d), clonazepam (2 to 6 mg/d), gabapentin (300 to 900 mg/d or more), pregabalin (150 to 300 mg/d), and carbamazepine in combination with other medications, suppress or shorten the duration and severity of the attacks in most patients for varying times. Baclofen may be useful in patients who cannot tolerate carbamazepine or gabapentin, but it is most effective as an adjunct to one of the anticonvulsant drugs. Capsaicin applied locally to the trigger zones or the topical instillation in the eye of an anesthetic has been helpful in some patients. By temporizing and using these drugs, one may permit a spontaneous remission to occur in perhaps 1 in 5 patients over a year or two. Long-term follow-up studies indicate a low remission rate in idiopathic generalised epilepsies (IGE) (Martinez-Juarez et al., 2006), suggesting they may persist to an advanced age. However there are few estimates of IGE frequency in the elderly. EEGs of 700 patients aged over 70 years, recorded between January 2006 and March 2007, were reviewed for anomalies consistent with IGE. We then examined the clinical history of patients with these anomalies. A persistent IGE was identified in four female patients (mean age: 79 years); in two cases it was a juvenile myoclonic epilepsy (JME) and in two an epilepsy with grand mal seizures. Seizures in three patients had begun in childhood or adolescence and in one at 40 years. Before hospitalization, few or no seizures were reported and IGE had not been diagnosed. IGE was revealed in each patient by a relatively severe event: an absence status (AS), subcontinuous myoclonic seizures or repeated convulsive generalised seizures (CGS). These events were not situation-related but in one patient the relapse of simple convulsive seizures, may have been related to the withdrawal of anti-epileptic drugs (AED) several months previously. EEG records showed generalised spikes or polyspikes and waves organised in a status epilepticus or in interictal rhythmic discharges. In one case they were evident only from a 24 hours recording. Clonazepam injection was used to suppress the AS episode and the subintrant myoclonia. After the AS, interictal generalised epileptic discharges persisted. Two of the four patients had familial history of epilepsy or febrile seizures but in no case was an epileptogenic lesion evident in brain CT scan or MRI. Clinical exams and biologic parameters were normal. All of the patients had worked and were married with children. Appropriate therapies were followed after the diagnosis of IGE. One patient with JME had been treated by Valproate which was discontinued by the general practitioner because of lethargy and replaced by Carbamazepine; seizures were aggravated under both Carbamazepine and then Lamotrigine and until the patient became seizure-free on Levetiracetam. The antiepiletic treatment was also modified in a second patient, while the two others responded well to Valproate. IGE can exacerbate in the elderly, as different types of seizures including AS, subintrant myoclonia or repeated CGS. Our data suggest persistent IGE are quite frequent in an aged population and may be underestimated due to difficulties in diagnosis. Correctly diagnosed, adjustment of AED may offer substantial clinical improvements in IGE of the elderly. At the age of 2 years, a girl had an autonomic status epilepticus during sleep. This was characterized by pallor, progressive impairment of consciousness, and vomiting that lasted 45 minutes. A second episode occurred after 11 months, during sleep, and consisted of impairment of consciousness, hypotonia, deviation of the eyes to the right, hypersalivation, and right-sided clonic convulsions. It was terminated after 45 minutes with rectal diazepam. Treatment with carbamazepine was initiated. After 6 months, she had a third episode similar to the previous ones, but shorter. At the age of 4 years 9 months, during an ambulatory EEG, she had another autonomic seizure with marked ictal EEG abnormalities, but again, the interictal did not show any spikes. Carbamazepine was replaced with phenobarbital. All 12 interictal EEGs during the active seizure period, 6 of them during sleep, were normal. At last follow-up at the age of 16 years, she was well, a good student, unmedicated, and We studied 15 children with complex partial seizures in whom one or more seizure type was exacerbated during treatment with carbamazepine. The most common seizure type that was exacerbated was generalized atypical absence (11 patients). Four patients had more frequent and severe generalized convulsive seizures. Monitoring with video-electroencephalographic telemetry suggested that the electroencephalogram can be used to predict the risk of seizure exacerbation with carbamazepine. A bilaterally synchronous spike-and-wave discharge of 2.5 to 3 cycles per second is predictive of increased atypical absence seizures with carbamazepine, whereas generalized bursts of spikes and slow waves of 1 to 2 cycles per second suggest a risk of increased generalized convulsive seizures. Carbamazepine should be used with caution in children with a mixed seizure disorder, particularly those with a generalized bilaterally synchronous discharge of 2.5 to 3 cycles per second on the electroencephalogram. The drug should be considered a possible precipitating factor in any child with an increased frequency of generalized convulsive or generalized absence seizures concomitant with administration of this anticonvulsant agent. Cross reactivity between phenytoin, carbamazepine, and oxcarbazepine is reported. An 8 year old boy with partial seizures developed maculopapular rashes with itching on day 15 of carbamazepine therapy. After stopping carbamazepine, phenytoin 100 mg daily was prescribed two days later. On the 12th day of phenytoin therapy he developed cervical and axillary lymphadenopathy with fever. Lymph nodes revealed reactive hyperplasia. Oxcarbazepine 75 mg twice daily also resulted in oral and mucosa ulceration. The seizures were controlled without any side effects with sodium valproate 200 mg three times a day and gabapentin 300 mg twice a day. Due to the cross reactivity of aromatic anticonvulsants (phenytoin, carbamazepine, and oxcarbazepine), valproate or newer anticonvulsants should be used if a patient has sensitivity to these drugs. Management Based on anecdotal evidence, the drugs of choice are those used for other idiopathic generalized epilepsies. Valproate alone, or most probably in combination with clonazepam, levetiracetam, lamotrigine or ethosuximide, appears to be the most effective regimen. The choice of the second drug depends on the main seizure type. Clonazepam is highly efficacious in eyelid myoclonia and myoclonic jerks. Of the newer antiepileptic drugs, levetiracetam may be the most effective, because of its anti myoclonic and anti photosensitive properties. Lamotrigine is very effective in absence seizures but may exaggerate myoclonic jerks. Contra-indicated drugs are: Carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine and vigabatrin. We report one of the youngest and most intensively studied cases of Landau-Kleffner syndrome, with a follow-up of 5 years. The boy developed normally until the age of 18 months when he had two attacks, possibly epileptic. Electroencephalogram (EEG) was normal. Over the next 5 months he lost his six to ten words, did not engage with other children and became mute. When he was 34 months old a child-psychiatrist suggested a diagnosis of pervasive developmental disorder or developmental dysphasia. An EEG 3 months later showed abnormalities typical of Landau-Kleffner syndrome. His non-verbal abilities were normal as well as his neurological examination and brain magnetic resonance imaging (MRI). A trial of clobazam and vigabatrin was unsuccessful. When he was 4 years and 9 months old he was treated with corticosteroids and within 3 months his vocabulary increased from the standard for 1 1/2 years of age to that for 2 1/2 years of age. His language abilities continued to improve slowly until a stagnation period at the age of 6 years and 9 months. A second course of corticosteroids improved his comprehension and vocabulary to an almost normal level, and his EEG normalized. A total of 11 EEGs were obtained; all included sleep, but continuous spike and wave during slow sleep was never documented. This report illustrates that Landau-Kleffner syndrome should be considered as an alternative diagnosis in children diagnosed with developmental dysphasia. An EEG including sleep should be considered, and in the presence of abnormalities a trial of anti-epileptic drugs or corticosteroids should be undertaken. (1) Gabapentin is now licensed for first-line or replacement monotherapy of partial epilepsy, in patients over 12 years of age.  (2) The assessment file concurs with current recommendations of medicines agencies.  (3) One comparative trial of first-line monotherapy showed a similar efficacy/adverse effects ratio of gabapentin and carbamazepine. Gabapentin has not been compared with valproate sodium.  (4) In one trial, involving patients with refractory epilepsy, various doses of gabapentin were added to an ongoing inadequately effective treatment, which was then gradually stopped.  Gabapentin monotherapy was considered satisfactory in a minority of patients.  (5) The adverse effects of gabapentin are limited to neuropsychological disorders, namely dizzy spells, drowsiness, fatigue and headache.  The risk of interactions is also limited.  (6) The optimal dose regimen of gabapentin is not yet established. Rolandic discharge (RD), noted in the electroencephalography (EEG) of patients with benign epilepsy in childhood with centrotemporal spikes (BECCT) has several unique features. One feature is that the amount or frequency of RDs does not correlate well with the incidence of seizures in BECCT although it is a key finding in the diagnosis of this epileptic syndrome. In this study, we examined the efficacy of antiepileptic drugs focusing on the disappearance of RDs in relationship with seizure control. Forty patients with BECCT who were not medically treated prior to this study were randomly sorted into three groups. Twenty patients were assigned for clonazepam (CZP) treatment, 10 patients for valproate (VPA) and the remaining 10 patients for carbamazepine (CBZ). Each drug was administered for 4 consecutive weeks. EEGs were recorded twice during the study, before and 4 weeks after the medication trial. The effects of each treatment on RDs were assessed. RDs disappeared in 15 of the 20 cases treated with CZP (75%) within 4 weeks while the same was observed in only one of the 10 cases treated with VPA (10%). CBZ failed to demonstrate any effect on RD. In the group treated with CZP, there were no differences in seizure incidence, seizure type and blood concentration of CZP between the patients whose RDs disappeared and those whose RDs remained. BACKGROUND Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs) commonly occur in critically ill patients and can be distinguished from spontaneous epileptic seizures by continuous electroencephalogram (CEEG) monitoring. There are no current treatment guidelines for SIRPIDs. This report is of a 73-year-old woman with respiratory failure and without any detectable gross brain lesions. She had developed SIRPIDs, which were diagnosed through CEEG monitoring. She responded well to valproate, carbamazepine, and clonazepam. CASE REPORT A 73-year-old woman was admitted to the intensive care unit (ICU) with a chest infection. After 3 days, this infection was complicated by respiratory failure and coma, for which she was intubated. After that, recurrent brief episodes of abnormal head and right upper limb jerky movements with right gaze deviation occurred. Nurses noticed that these episodes occurred exclusively upon physical interaction with the patient, and lasted up to 3 minutes. No focal findings were noted on neurological examination. The brain computed tomography (CT) scan revealed no acute brain insult. CEEG revealed SIRPIDs, which abated with midazolam boluses, followed by infusion at 15 mg/hour. Later, they were controlled by valproate, carbamazepine, and clonazepam in succession, guided by CEEG data. CONCLUSIONS This report shows the importance of CEEG monitoring to diagnose SIRPIDs and monitor treatment response. It also suggests that SIRPIDs can occur even in the absence of gross brain pathology. Although there are no current treatment guidelines for SIRPIDs, the use of valproate, carbamazepine, and clonazepam can help control them, as evidenced in this case. Benign myoclonic epilepsy of childhood is a rare syndrome which appears at between 4 months and 3 years of age. The prognosis is good if diagnosed and treated early. It is characterized by many short crises (usually of 3 seconds and not more than 5-10 seconds long), proximal and cephalic jerking movements without falling to the ground, and at no particular time of the day. In the EEG polygraph background activity continues and crises coincide with generalized spike and wave or multiple spike and wave discharges of 1 to 2 seconds, accompanied by isolated myoclonic movements in the neck and deltoid muscles, which persist during NREM sleep. Benign epilepsy of childhood usually responds to monotherapy with valproic acid. In our case photosensitivity appeared at 7 years of age with persistence of generalized spikes and waves during sleep. We suggest that photosensitivity may be used as an index of the clinical course, and that treatment should continue to be given until photosensitivity disappears. We report the case of a 39-year-old woman with onset of daily epigastric sensations associated with brief episodes of unresponsive blank stare, which have been interpreted as complex partial seizures with occasional secondary generalisation. Phenytoin as monotherapy and in combination with valproate had not been effective. During video-EEG we recorded typical absences with brief 3 second spike, and slow-wave discharges of up to 5 seconds, which were recognized by the patient herself. All absences were preceded by epigastric sensations. There was no indication of focal epilepsy. Monotherapy with valproate substantially decreased the frequency of the absences. In conclusion, this case is peculiar for several reasons: 1) late onset of absence epilepsy, 2) epigastric sensation at onset of absence seizures, 3) recognition of brief \"phantom\" absences and 4) presumable adverse effects of phenytoin. In the present paper the clinical symptomatology and treatment of childhood mania that was first seen in a child at 5 years of age and which re-emerged at age 7, is reported. The patient presented at the child and adolescent psychiatric outpatient clinic of Istanbul Medical University with the typical symptoms of mania such of hyperactivity, euphoria, irritability, dangerous and risky behavior, decreased sleep, and age-inappropriate sexual behavior. He was treated with carbamazepine safely and effectively without any major side-effects. Clinical phenomenology and treatment of the condition are discussed with relevant literature. Vagoglossopharyngeal neuralgia (VGPN) is a very rare condition. VGPN with convulsive like attack is even rarer All of the cases had their head turned to the opposite side of facial pain. Hemifacial spasm occurring concurrently with VGPN has never been reported. Herein, we present the first case of VGPN that had ipsilateral hemifacial spasm and versive seizure-like movement to the same side of facial pain. We reported a 71-year-old man presenting with multiple episodes of intermittent sharp shooting pain arising on the right middle neck, followed by hemifacial spasm on right face. Then the patient became syncope while his head and gaze turned to the same side of the painful neck. Electrocardiography showed sinus arrest. Interictal Electroencephalography was normal. This patient initially responded to pregabalin for two weeks, then the symptoms became worse. Microvascular decompression and carbamazepine resulted in the complete remission of all symptoms after six months of follow-up. We could not explain the pathophysiology of unilateral versive seizure like movement. We present a 4-year-old girl with stereotyped episodes of inability to speak and dystonic posturing of the face and extremities lasting 20 minutes. An older brother and mother had similar spells in childhood. Routine and video-EEG during events were normal. The diagnosis was non-kinesigenic paroxysmal dystonic choreoathetosis since the episodes were not exacerbated by movement. Gabapentin 10 mg/kg/d eliminated most attacks. Provocation of various seizure types including epileptic negative myoclonus and generalised atonic seizures is rarely observed in children treated with carbamazepine (CBZ). Provocation of the latter seizure types by oxcarbazepine (OXC) is not described in the literature. We report a four year-old boy with symptomatic epilepsy caused by left-sided cerebral atrophy of unknown origin who developed numerous daily drop attacks when exposed to OXC. Polygraphic analysis revealed secondary generalised precentral sharp-slow waves frequently associated with a silent period lasting for 100-150 ms in the electromyogram recorded from the deltoid and neck muscles. These seizures stopped promptly within 36 hours after discontinuation of OXC. This case demonstrates that OXC, similar to CBZ, can provoke epileptic negative myoclonus in some children with focal epilepsies. [Published with videosequences]. We report two cases of unusual movement disorders associated with the use of gabapentin (GBP) in patients being treated for epilepsy who were otherwise neurologically intact. We describe two cases of unusual movement disorders associated with the use of GBP. There were significant differences in the clinical findings between the two cases. In the first case, movements were very pronounced and the patient was in oculogyric crisis. Movements in the second case were quite subtle but nonetheless problematic for the patient. In each case, discontinuation of GBP led to rapid resolution of the movements, although a single dose of lorazepam was used in the first case. Although formal electrophysiologic studies have not been performed, the movements associated with GBP use appear to be dystonic or myoclonic. Discontinuation of GBP led to rapid resolution of the movements. In severe cases, as in patients with oculogyric crisis, small doses of a benzodiazepine (BZD) appear to be efficacious and safe.\nHere is the question:\nPEDIATRICS: A 10-year-old boy with brief episodes of distractions (< 1 minute) in which he does not respond to calls and blinks. An EEG shows spike-wave discharges at 3 cycles per second. First-line elective treatment would with:\nHere are the potential choices:\n1. Valproate.\n2. Carbamazepine.\n3. Phenytoin.\n4. Gabapentin.\n5. Clonazepam.\nThe correct answer is: ",
        "gold_answer": "1 Valproate.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Electroencephalographic epileptic status during sleep (ESES--according to Electrical Status Epilepticus in Sleep) is characterized with paroxysmal attacks of 1.5-3.5 (even to 5) Hz/s spikes and waves during NREM. A case is presented of a 7-year-old boy who had normal development until 3 years of age when epileptic attacks started. First to appear were left-sided, hemifacial twitches with orofacio-lingual deficits. Despite treatment with various types and combinations of antiepileptic medications, the attacks persisted and became more frequent. About a year after the onset of the disease, the spectrum of epileptic attacks had expanded (left-sided tonic-clonic, atonic-astatic, myoclonic, atypical absences, and then drop attacks and negative myoclonic seizures became dominant). The boy appeared mentally retarded. During the course of the disease, the diagnoses varied: hemifacial twitches, partial epilepsy, left-sided partial epilepsy, atypical benign epilepsy, Landau-Kleffner syndrome, myoclonic-astatic epilepsy. A year and a half after the onset of the disease EEG (polysomnographic whole-night recording) revealed electrical status epilepticus in sleep (ESES) with spike-wave index &gt; 85%. It appeared that this was continuous spike and wave during slow wave sleep syndrome (CSWS) with characteristic attacks, bifrontal atrophies on brain CT and right frontotemporal EEG focus. Treatment with valproate and ethosuximide combined with vigabatrin and clonazepam seemed to be effective. In the last 20 months ESES is rare and transitory, mental and neuropsychological functions have improved, but he still has several hemifacial twitches daily. The two brain MRI scans were normal. Differential diagnosis can be atypical benign epilepsy (suspected familial diagnosis). Family history of atopy, 'persistent' colds and obstructive bronchitis in the boy and treatment with antiepileptic medications (especially carbamazepine, phenobarbital and phenytoin) could have been provoking or modulating factors of the epileptic disease. So far we have not identified an epileptic syndrome because it seems that multiple clinical pictures overlap. ESES could be diagnosed using polysomnographic whole-night recording with calculated spike-wave index. Follow-up of the spike-wave index could be useful in differentiation, but not in precise diagnosis of epileptic syndrome. Clinical course could be modulated by different factors. Continuous following over a long period could be helpful in the classification of epilepsy. EEG typically shows 10-Hz activity during the tonic phase and slow waves during the clonic phase. Protect the airway. Treat the underlying cause if known. 1° generalized tonic-clonic seizures: Phenytoin, fosphenytoin, or valproate constitutes first-line therapy. Lamotrigine or topiramate may be used as adjunctive therapy. Secondarily generalized tonic-clonic seizures: Treatment is the same as that for partial seizures. Begin in childhood; subside before adulthood. Often familial. Hx/PE: Present with brief (5to 10-second), often unnoticeable episodes of impaired consciousness occurring up to hundreds of times per day. Patients are amnestic during and immediately after seizures and may appear to be daydreaming or staring. Eye fluttering or lip smacking is common. Dx: EEG shows classic three-per-second spike-and-wave discharges. Tx: Ethosuximide is the first-line agent. We present the clinical and video-EEG data on an epileptic boy whose absence seizures with marked perioral movements had started at the age of 1.5 years. From age 12 years, he experienced frequent episodes of typical absence status epilepticus (ASE) lasting 1-2 hours with marked perioral myoclonia and moderate confusion. Initial therapy with carbamazepine was substituted by valproate because of worsening of the absence seizures. At the age of 17, the patient was admitted to our clinic with his usual, but long lasting ASE attack, accompanied by 2 generalized tonic-clonic convulsions. ASE was confirmed with the EEG which showed continuous 3 Hz spike and wave paroxysms with occasional normal intervals of 1-5 seconds. IV injection of clonazepam improved the clinical and EEG findings immediately. Video- EEG examination performed after a few weeks demonstrated typical absence seizures with perioral myoclonia. Based on the characteristics of seizure semiology, other clinical data and EEG findings, the patient was diagnosed as having the syndrome of \"perioral myoclonia with absence seizures\" described by Panayiotopoulos. A 5-year-old girl exhibited daily episodes of repetitive blinking lasting 5-10 s. Electroencephalography (EEG) revealed marked photoparoxysmal responses (PPR) at 3-20 Hz of photic stimulation and diffuse spike-wave bursts during sleep. A 24-h video EEG identified 11 episodes of repetitive blinking, 3 of which resulted in widespread spike-wave discharges. These suggested that the behavior of the patient represented self-induction of PPR. Valproate sodium was ineffective in decreasing PPR, as revealed by EEG, and the frequency of blinking episodes, but clonazepam attenuated PPR and significantly decreased the blinking behavior. (1) The standard treatment for partial epilepsy in children is carbamazepine. The efficacy of other antiepileptics has also been documented, either alone (phenobarbital, oxcarbazepine, valproate sodium, phenytoin), or in drug combinations (lamotrigine, topiramate). (2) A licence extension has been granted in France for gabapentin in partial epilepsy in children aged 3 to 12 years, in combination with other antiepileptics. (3) The clinical file contains no data from trials comparing gabapentin with other antiepileptics. (4) The main double-blind trial involved 247 children who were treated either with their usual treatment + gabapentin or usual treatment + placebo. Gabapentin was only moderately effective, and the overall number of responders did not differ significantly between the gabapentin and placebo groups. (5) In this trial the main adverse effects among the children on their usual treatment + gabapentin were behavioural disorders (hostility and mood swings). (6) In practice, the licensing of gabapentin for children with partial epilepsy aged between 3 and 12 years changes nothing in their practical management. A patient of pyridoxine dependent seizures was reported. He was born at 34 weeks' gestation and weighted 2,760 g. Apgar scores were 6 and 9 at 1 and 5 minutes, respectively. He showed the first seizure 2 hours after his birth. Phenobarbital, phenytoin, sodium valproate, diazepam and clonazepam were not effective. Pyridoxal phosphate (50 mg) was given intravenously, resulting in suppression of convulsions. However, muscle tonus was severely depressed. In EEG, a discontinuous pattern was found in quiet and indeterminate sleep on the 2nd day of life. At 5th week multifocal spikes were found, and the discontinuous pattern persisted. Ictal discharges at 13th week showed generalized, continuous, irregular and high voltage slow waves with multifocal spikes. At 27th week of life, high voltage slow waves disappeared and multifocal spike discharges decreased. At 2 years and 10 months of age, the patient was suffering from athetotic cerebral palsy and severe mental retardation. Pyridoxal phosphate at the doses of 35-40 mg/kg/day had been administered. Irritability sometimes occurred and additional 50 mg of pyridoxal phosphate controlled this irritability effectively. A 7-year-old female with benign childhood epilepsy with centrotemporal spikes developed epileptic negative myoclonus (ENM) seizures during carbamazepine (CBZ) treatment. She had experienced nocturnal partial seizures since 5 years of age. Interictal electroencephalography demonstrated typical rolandic discharges. Valproate was first initiated at 6 years of age, but the seizures were uncontrollable. Carbamazepine was added and valproate withdrawn. The frequency of partial seizures did not decrease. Moreover, she had brief episodes of tone loss in each or both arms and eye blinking several weeks after CBZ introduction. Unilateral loss of arm tone corresponded to spike-and-wave discharges in the contralateral centrotemporal region, and a loss of tone in arms was associated with bilateral synchronous discharges. Eye blinking was also related to bilateral synchronous discharges and classified as a myoclonic seizure. The ENM and myoclonic seizures disappeared soon after CBZ withdrawal. Therefore the authors concluded that CBZ induced the ENM and myoclonic seizures in this patient. CBZ sometimes induces generalized seizures in the treatment of partial epilepsy and generalized epilepsy. CBZ-induced ENM seizures should be considered when a brief lapse of tone appears during CBZ treatment. We evaluated with clinical interviews and polysomnographic examinations 10 adults with the complaint of sleepwalking, often accompanied by violent behavior or self-injury. During the polysomnographic studies, 8 patients had 47 distinct somnambulistic episodes. All episodes occurred in non-REM sleep, with 91% occurring in slow-wave sleep. Contrary to previous reports, episodes were not confined to the 1st 3rd of the night. Clinical EEGs were normal in 5 of 6 patients. In the 7 patients tried on 1 or more treatment regimens, clonazepam effectively suppressed the somnambulism in 5 of 6 patients in whom it was tried, carbamazepine in 1 of 3, flurazepam in 2 of 2, and a combination of clonazepam and phenytoin in one. Treatment Given the benign nature of the condition and the low seizure frequency, treatment is often unnecessary. If treatment is warranted or preferred by the child and his or her family, antiepileptic drugs can usually control the seizures easily. Carbamazepine is the most frequently used first-line drug, but many other antiepileptic drugs, including valproate, phenytoin, gabapentin, levetiracetam and sultiame have been found effective as well. Bedtime dosing is advised by some. Treatment can be short and drugs can almost certainly be discontinued after two years without seizures and with normal EEG findings, perhaps even earlier. Parental education about Rolandic epilepsy is the cornerstone of correct management. The traumatizing, sometimes long-lasting effect on parents is significant. It is unclear if there are any benefits to clobazam over other seizure medications. Carbamazepine is effective in 70 to 80 percent of patients (600 to 1,200 mg/d), but half become tolerant over a period of several years. Other antiepileptic drugs such as phenytoin (300 to 400 mg/d), valproic acid (800 to 1,200 mg/d), clonazepam (2 to 6 mg/d), gabapentin (300 to 900 mg/d or more), pregabalin (150 to 300 mg/d), and carbamazepine in combination with other medications, suppress or shorten the duration and severity of the attacks in most patients for varying times. Baclofen may be useful in patients who cannot tolerate carbamazepine or gabapentin, but it is most effective as an adjunct to one of the anticonvulsant drugs. Capsaicin applied locally to the trigger zones or the topical instillation in the eye of an anesthetic has been helpful in some patients. By temporizing and using these drugs, one may permit a spontaneous remission to occur in perhaps 1 in 5 patients over a year or two. Long-term follow-up studies indicate a low remission rate in idiopathic generalised epilepsies (IGE) (Martinez-Juarez et al., 2006), suggesting they may persist to an advanced age. However there are few estimates of IGE frequency in the elderly. EEGs of 700 patients aged over 70 years, recorded between January 2006 and March 2007, were reviewed for anomalies consistent with IGE. We then examined the clinical history of patients with these anomalies. A persistent IGE was identified in four female patients (mean age: 79 years); in two cases it was a juvenile myoclonic epilepsy (JME) and in two an epilepsy with grand mal seizures. Seizures in three patients had begun in childhood or adolescence and in one at 40 years. Before hospitalization, few or no seizures were reported and IGE had not been diagnosed. IGE was revealed in each patient by a relatively severe event: an absence status (AS), subcontinuous myoclonic seizures or repeated convulsive generalised seizures (CGS). These events were not situation-related but in one patient the relapse of simple convulsive seizures, may have been related to the withdrawal of anti-epileptic drugs (AED) several months previously. EEG records showed generalised spikes or polyspikes and waves organised in a status epilepticus or in interictal rhythmic discharges. In one case they were evident only from a 24 hours recording. Clonazepam injection was used to suppress the AS episode and the subintrant myoclonia. After the AS, interictal generalised epileptic discharges persisted. Two of the four patients had familial history of epilepsy or febrile seizures but in no case was an epileptogenic lesion evident in brain CT scan or MRI. Clinical exams and biologic parameters were normal. All of the patients had worked and were married with children. Appropriate therapies were followed after the diagnosis of IGE. One patient with JME had been treated by Valproate which was discontinued by the general practitioner because of lethargy and replaced by Carbamazepine; seizures were aggravated under both Carbamazepine and then Lamotrigine and until the patient became seizure-free on Levetiracetam. The antiepiletic treatment was also modified in a second patient, while the two others responded well to Valproate. IGE can exacerbate in the elderly, as different types of seizures including AS, subintrant myoclonia or repeated CGS. Our data suggest persistent IGE are quite frequent in an aged population and may be underestimated due to difficulties in diagnosis. Correctly diagnosed, adjustment of AED may offer substantial clinical improvements in IGE of the elderly. At the age of 2 years, a girl had an autonomic status epilepticus during sleep. This was characterized by pallor, progressive impairment of consciousness, and vomiting that lasted 45 minutes. A second episode occurred after 11 months, during sleep, and consisted of impairment of consciousness, hypotonia, deviation of the eyes to the right, hypersalivation, and right-sided clonic convulsions. It was terminated after 45 minutes with rectal diazepam. Treatment with carbamazepine was initiated. After 6 months, she had a third episode similar to the previous ones, but shorter. At the age of 4 years 9 months, during an ambulatory EEG, she had another autonomic seizure with marked ictal EEG abnormalities, but again, the interictal did not show any spikes. Carbamazepine was replaced with phenobarbital. All 12 interictal EEGs during the active seizure period, 6 of them during sleep, were normal. At last follow-up at the age of 16 years, she was well, a good student, unmedicated, and We studied 15 children with complex partial seizures in whom one or more seizure type was exacerbated during treatment with carbamazepine. The most common seizure type that was exacerbated was generalized atypical absence (11 patients). Four patients had more frequent and severe generalized convulsive seizures. Monitoring with video-electroencephalographic telemetry suggested that the electroencephalogram can be used to predict the risk of seizure exacerbation with carbamazepine. A bilaterally synchronous spike-and-wave discharge of 2.5 to 3 cycles per second is predictive of increased atypical absence seizures with carbamazepine, whereas generalized bursts of spikes and slow waves of 1 to 2 cycles per second suggest a risk of increased generalized convulsive seizures. Carbamazepine should be used with caution in children with a mixed seizure disorder, particularly those with a generalized bilaterally synchronous discharge of 2.5 to 3 cycles per second on the electroencephalogram. The drug should be considered a possible precipitating factor in any child with an increased frequency of generalized convulsive or generalized absence seizures concomitant with administration of this anticonvulsant agent. Cross reactivity between phenytoin, carbamazepine, and oxcarbazepine is reported. An 8 year old boy with partial seizures developed maculopapular rashes with itching on day 15 of carbamazepine therapy. After stopping carbamazepine, phenytoin 100 mg daily was prescribed two days later. On the 12th day of phenytoin therapy he developed cervical and axillary lymphadenopathy with fever. Lymph nodes revealed reactive hyperplasia. Oxcarbazepine 75 mg twice daily also resulted in oral and mucosa ulceration. The seizures were controlled without any side effects with sodium valproate 200 mg three times a day and gabapentin 300 mg twice a day. Due to the cross reactivity of aromatic anticonvulsants (phenytoin, carbamazepine, and oxcarbazepine), valproate or newer anticonvulsants should be used if a patient has sensitivity to these drugs. Management Based on anecdotal evidence, the drugs of choice are those used for other idiopathic generalized epilepsies. Valproate alone, or most probably in combination with clonazepam, levetiracetam, lamotrigine or ethosuximide, appears to be the most effective regimen. The choice of the second drug depends on the main seizure type. Clonazepam is highly efficacious in eyelid myoclonia and myoclonic jerks. Of the newer antiepileptic drugs, levetiracetam may be the most effective, because of its anti myoclonic and anti photosensitive properties. Lamotrigine is very effective in absence seizures but may exaggerate myoclonic jerks. Contra-indicated drugs are: Carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine and vigabatrin. We report one of the youngest and most intensively studied cases of Landau-Kleffner syndrome, with a follow-up of 5 years. The boy developed normally until the age of 18 months when he had two attacks, possibly epileptic. Electroencephalogram (EEG) was normal. Over the next 5 months he lost his six to ten words, did not engage with other children and became mute. When he was 34 months old a child-psychiatrist suggested a diagnosis of pervasive developmental disorder or developmental dysphasia. An EEG 3 months later showed abnormalities typical of Landau-Kleffner syndrome. His non-verbal abilities were normal as well as his neurological examination and brain magnetic resonance imaging (MRI). A trial of clobazam and vigabatrin was unsuccessful. When he was 4 years and 9 months old he was treated with corticosteroids and within 3 months his vocabulary increased from the standard for 1 1/2 years of age to that for 2 1/2 years of age. His language abilities continued to improve slowly until a stagnation period at the age of 6 years and 9 months. A second course of corticosteroids improved his comprehension and vocabulary to an almost normal level, and his EEG normalized. A total of 11 EEGs were obtained; all included sleep, but continuous spike and wave during slow sleep was never documented. This report illustrates that Landau-Kleffner syndrome should be considered as an alternative diagnosis in children diagnosed with developmental dysphasia. An EEG including sleep should be considered, and in the presence of abnormalities a trial of anti-epileptic drugs or corticosteroids should be undertaken. (1) Gabapentin is now licensed for first-line or replacement monotherapy of partial epilepsy, in patients over 12 years of age.  (2) The assessment file concurs with current recommendations of medicines agencies.  (3) One comparative trial of first-line monotherapy showed a similar efficacy/adverse effects ratio of gabapentin and carbamazepine. Gabapentin has not been compared with valproate sodium.  (4) In one trial, involving patients with refractory epilepsy, various doses of gabapentin were added to an ongoing inadequately effective treatment, which was then gradually stopped.  Gabapentin monotherapy was considered satisfactory in a minority of patients.  (5) The adverse effects of gabapentin are limited to neuropsychological disorders, namely dizzy spells, drowsiness, fatigue and headache.  The risk of interactions is also limited.  (6) The optimal dose regimen of gabapentin is not yet established. Rolandic discharge (RD), noted in the electroencephalography (EEG) of patients with benign epilepsy in childhood with centrotemporal spikes (BECCT) has several unique features. One feature is that the amount or frequency of RDs does not correlate well with the incidence of seizures in BECCT although it is a key finding in the diagnosis of this epileptic syndrome. In this study, we examined the efficacy of antiepileptic drugs focusing on the disappearance of RDs in relationship with seizure control. Forty patients with BECCT who were not medically treated prior to this study were randomly sorted into three groups. Twenty patients were assigned for clonazepam (CZP) treatment, 10 patients for valproate (VPA) and the remaining 10 patients for carbamazepine (CBZ). Each drug was administered for 4 consecutive weeks. EEGs were recorded twice during the study, before and 4 weeks after the medication trial. The effects of each treatment on RDs were assessed. RDs disappeared in 15 of the 20 cases treated with CZP (75%) within 4 weeks while the same was observed in only one of the 10 cases treated with VPA (10%). CBZ failed to demonstrate any effect on RD. In the group treated with CZP, there were no differences in seizure incidence, seizure type and blood concentration of CZP between the patients whose RDs disappeared and those whose RDs remained. BACKGROUND Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs) commonly occur in critically ill patients and can be distinguished from spontaneous epileptic seizures by continuous electroencephalogram (CEEG) monitoring. There are no current treatment guidelines for SIRPIDs. This report is of a 73-year-old woman with respiratory failure and without any detectable gross brain lesions. She had developed SIRPIDs, which were diagnosed through CEEG monitoring. She responded well to valproate, carbamazepine, and clonazepam. CASE REPORT A 73-year-old woman was admitted to the intensive care unit (ICU) with a chest infection. After 3 days, this infection was complicated by respiratory failure and coma, for which she was intubated. After that, recurrent brief episodes of abnormal head and right upper limb jerky movements with right gaze deviation occurred. Nurses noticed that these episodes occurred exclusively upon physical interaction with the patient, and lasted up to 3 minutes. No focal findings were noted on neurological examination. The brain computed tomography (CT) scan revealed no acute brain insult. CEEG revealed SIRPIDs, which abated with midazolam boluses, followed by infusion at 15 mg/hour. Later, they were controlled by valproate, carbamazepine, and clonazepam in succession, guided by CEEG data. CONCLUSIONS This report shows the importance of CEEG monitoring to diagnose SIRPIDs and monitor treatment response. It also suggests that SIRPIDs can occur even in the absence of gross brain pathology. Although there are no current treatment guidelines for SIRPIDs, the use of valproate, carbamazepine, and clonazepam can help control them, as evidenced in this case. Benign myoclonic epilepsy of childhood is a rare syndrome which appears at between 4 months and 3 years of age. The prognosis is good if diagnosed and treated early. It is characterized by many short crises (usually of 3 seconds and not more than 5-10 seconds long), proximal and cephalic jerking movements without falling to the ground, and at no particular time of the day. In the EEG polygraph background activity continues and crises coincide with generalized spike and wave or multiple spike and wave discharges of 1 to 2 seconds, accompanied by isolated myoclonic movements in the neck and deltoid muscles, which persist during NREM sleep. Benign epilepsy of childhood usually responds to monotherapy with valproic acid. In our case photosensitivity appeared at 7 years of age with persistence of generalized spikes and waves during sleep. We suggest that photosensitivity may be used as an index of the clinical course, and that treatment should continue to be given until photosensitivity disappears. We report the case of a 39-year-old woman with onset of daily epigastric sensations associated with brief episodes of unresponsive blank stare, which have been interpreted as complex partial seizures with occasional secondary generalisation. Phenytoin as monotherapy and in combination with valproate had not been effective. During video-EEG we recorded typical absences with brief 3 second spike, and slow-wave discharges of up to 5 seconds, which were recognized by the patient herself. All absences were preceded by epigastric sensations. There was no indication of focal epilepsy. Monotherapy with valproate substantially decreased the frequency of the absences. In conclusion, this case is peculiar for several reasons: 1) late onset of absence epilepsy, 2) epigastric sensation at onset of absence seizures, 3) recognition of brief \"phantom\" absences and 4) presumable adverse effects of phenytoin. In the present paper the clinical symptomatology and treatment of childhood mania that was first seen in a child at 5 years of age and which re-emerged at age 7, is reported. The patient presented at the child and adolescent psychiatric outpatient clinic of Istanbul Medical University with the typical symptoms of mania such of hyperactivity, euphoria, irritability, dangerous and risky behavior, decreased sleep, and age-inappropriate sexual behavior. He was treated with carbamazepine safely and effectively without any major side-effects. Clinical phenomenology and treatment of the condition are discussed with relevant literature. Vagoglossopharyngeal neuralgia (VGPN) is a very rare condition. VGPN with convulsive like attack is even rarer All of the cases had their head turned to the opposite side of facial pain. Hemifacial spasm occurring concurrently with VGPN has never been reported. Herein, we present the first case of VGPN that had ipsilateral hemifacial spasm and versive seizure-like movement to the same side of facial pain. We reported a 71-year-old man presenting with multiple episodes of intermittent sharp shooting pain arising on the right middle neck, followed by hemifacial spasm on right face. Then the patient became syncope while his head and gaze turned to the same side of the painful neck. Electrocardiography showed sinus arrest. Interictal Electroencephalography was normal. This patient initially responded to pregabalin for two weeks, then the symptoms became worse. Microvascular decompression and carbamazepine resulted in the complete remission of all symptoms after six months of follow-up. We could not explain the pathophysiology of unilateral versive seizure like movement. We present a 4-year-old girl with stereotyped episodes of inability to speak and dystonic posturing of the face and extremities lasting 20 minutes. An older brother and mother had similar spells in childhood. Routine and video-EEG during events were normal. The diagnosis was non-kinesigenic paroxysmal dystonic choreoathetosis since the episodes were not exacerbated by movement. Gabapentin 10 mg/kg/d eliminated most attacks. Provocation of various seizure types including epileptic negative myoclonus and generalised atonic seizures is rarely observed in children treated with carbamazepine (CBZ). Provocation of the latter seizure types by oxcarbazepine (OXC) is not described in the literature. We report a four year-old boy with symptomatic epilepsy caused by left-sided cerebral atrophy of unknown origin who developed numerous daily drop attacks when exposed to OXC. Polygraphic analysis revealed secondary generalised precentral sharp-slow waves frequently associated with a silent period lasting for 100-150 ms in the electromyogram recorded from the deltoid and neck muscles. These seizures stopped promptly within 36 hours after discontinuation of OXC. This case demonstrates that OXC, similar to CBZ, can provoke epileptic negative myoclonus in some children with focal epilepsies. [Published with videosequences]. We report two cases of unusual movement disorders associated with the use of gabapentin (GBP) in patients being treated for epilepsy who were otherwise neurologically intact. We describe two cases of unusual movement disorders associated with the use of GBP. There were significant differences in the clinical findings between the two cases. In the first case, movements were very pronounced and the patient was in oculogyric crisis. Movements in the second case were quite subtle but nonetheless problematic for the patient. In each case, discontinuation of GBP led to rapid resolution of the movements, although a single dose of lorazepam was used in the first case. Although formal electrophysiologic studies have not been performed, the movements associated with GBP use appear to be dystonic or myoclonic. Discontinuation of GBP led to rapid resolution of the movements. In severe cases, as in patients with oculogyric crisis, small doses of a benzodiazepine (BZD) appear to be efficacious and safe.\nHere is the question:\nPEDIATRICS: A 10-year-old boy with brief episodes of distractions (< 1 minute) in which he does not respond to calls and blinks. An EEG shows spike-wave discharges at 3 cycles per second. First-line elective treatment would with:\nHere are the potential choices:\n1. Valproate.\n2. Carbamazepine.\n3. Phenytoin.\n4. Gabapentin.\n5. Clonazepam.\nThe correct answer is: 1. Valproate."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Multiple cysts and benign cystadenomas of the pancreas have been documented occasionally in von Hippel-Lindau syndrome (HLS); however, the malignant involvement of the pancreas in HLS is very rare. We report a case of HLS in which metastatic tumors from renal cell carcinoma (RCC) coexisted with multiple cysts in the pancreas. A 22-year-old woman with a history of HLS had undergone a partial resection of the left kidney for RCC 3 years earlier, at which time a solid mass in the pancreatic tail and multiple pancreatic cysts were also incidentally detected by computed tomography. Over the following 3 years, the mass enlarged slightly, thus raising suspicions that it might be a primary neoplasm of the pancreas. She was referred to the Department of Surgery and Surgical Basic Science to undergo surgery. In addition to the tumor in the pancreatic tail, however, further tumors in the pancreatic head were also disclosed by preoperative celiac arteriography and intraoperative palpation and ultrasonography. A distal pancreatectomy was performed, because the enucleation of all the tumors in the pancreatic head was technically impossible and because the patient declined a total pancreatectomy. A histologic examination of the mass in the pancreatic tail revealed metastatic RCC. This case emphasizes that metastatic disease should be included in the differential diagnosis when evaluating the pancreas in a patient with HLS. Autosomal dominant polycystic kidney disease, the most frequent inherited polycystic disease, is a systemic disorder characterised by the development of numerous and bilateral kidney cysts leading to chronic renal failure. Extrarenal cysts are located mainly in the liver but also in various organs including the pancreas. To our knowledge, complications of pancreatic cysts in this disease have never been reported. The first case of painful chronic obstructive pancreatitis due to a true pancreatic cyst in a patient with autosomal dominant polycystic kidney disease is reported. Abdominal transparietal and endoscopic ultrasonography, computed tomography, and endoscopic retrograde cholangiopancreatography showed a cystic lesion in the body of the pancreas associated with upstream dilatation of the main pancreatic duct. Intraoperative ultrasonography before and after cyst fluid aspiration, and pancreatography and pathological examination of the resected distal pancreas confirmed that both main pancreatic duct enlargement and chronic pancreatitis were caused by a benign cyst. Chronic obstructive pancreatitis should be added to the extrarenal complications of autosomal dominant polycystic kidney disease. von Hippel-Lindau (VHL) syndrome is an inherited neoplastic syndrome caused by abnormity of the VHL gene found on the short arm of the chromosome 3. We reported a case of VHL disease diagnosed by the detection of multiple pancreatic endocrine tumors and renal tumor 13 years after bilateral adrenalectomy. A 40-year-old man presented with multiple pancreas tumors (maximum size 42 mm in diameter) detected by screening abdominal ultrasonography. A 23 mm renal tumor was detected by contrast computed tomography scan at that time. His past history included left retinal angioma (age 15) and bilateral adrenal pheochromocytoma (age 27). VHL was diagnosed by genetic testing. Endoscopic ultrasound-guided fine-needle aspiration biopsy of the pancreas tumor was performed, and tumor was diagnosed as an endocrine tumor. After diagnosis, distal pancreatectomy (body-tail) was performed. This was a didactic case indicating that we should suspect VHL syndrome based on past history and family history and follow such cases up strictly. Cystic neoplasms of the pancreas are rare, accounting for about 9 to 10% of cystic pancreatic lesions. A 63-year-old man, who had been receiving chronic hemodialysis due to diabetic chronic renal failure, was admitted after the discovery of cystic masses in the pancreatic tail. Abdominal ultrasonography and computed tomography revealed multiloculated cystic tumors. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated findings consistent with malignant tumors. Preoperatively, he was thought to have a cystadenocarcinoma in the pancreatic tail for which he underwent a distal pancreatectomy and splenectomy. Histologic analysis of the resected mass established the diagnosis mucinous cystadenoma. To our knowledge, pancreatic mucinous cystadenoma occurring in a patient receiving chronic hemodialysis has not been previously reported. Therefore, we present a novel case in this report. The pancreas is an infrequent site of hydatid disease. This study aims at giving better insight into the diagnostic and managerial approach to the disease. Six patients with hydatid cysts of the pancreas. Retrospective review of the clinical records. The six patients (four men, two women) ranged in age from 18 to 68 years. Five of the cysts were primary while one had an associated cyst in the liver. Abdominal pain, vomiting, abdominal mass and dyspeptic symptoms were seen in cysts involving the body and tail. Two patients having cysts in the head of the pancreas presented with obstructive jaundice. An indirect hemagglutination test and an enzyme-linked immunoabsorbent assay were positive for the presence of specific hydatid antibodies in four patients. Abdominal ultrasonography, computed tomography and magnetic resonance cholangiopancreatography (MRCP) successfully imaged the cysts and also defined the relationship of the lesion with the pancreatic duct. All patients underwent surgical exploration. Three patients had intraoperative fine needle aspiration cytology of the cystic lesion for microscopic and electrolyte analysis. A preoperative diagnosis was possible in two patients and, in the other four, the diagnosis was made intraoperatively and confirmed on histopathological examination. with cysts located in the tail underwent a distal pancreatectomy with a splenectomy while those with cysts in the body had a pericystectomy or central pancreatectomy. Cysts of the head were treated with evacuation, partial cystectomy and tube drainage. There were no postoperative complications, and no evidence of cyst recurrence was observed during the follow-up period. All the patients were followed up at three-month intervals with a mean follow-up time of 58.7 months (rang: 4-120 months); no patient had cyst recurrence or dissemination. A hydatid cyst is an uncommon cause of cystic lesions in the pancreas and should be included in the differential diagnosis of cystic lesions of the pancreas, especially in endemic areas. Intraoperative fine needle aspirate for microscopic and electrolyte estimation seems to be an effective method for establishing a proper diagnosis. MRCP, which can depict the communication of the cystic lesion with the pancreatic duct, helps in defining the type of surgical treatment. Cysts in body and tail are best treated by resectional methods whereas, for those in the head region, a cystectomy with simple drainage is a simple, quick and effective solution. We describe here a case of von Hippel-Lindau (VHL) disease with a serous cystic neoplasm of the whole pancreas. The patient was a 35-year-old woman suffering from a palpable abdominal tumor. She had a history of hemangioblastomas of the cerebellum. CT revealed large solid tumors in the pancreatic head and body, and multiple cystic lesions in the whole pancreas as well as a right renal tumor. When endoscopic retrograde cholangiopancreatography (ERCP) was performed, bleeding from the duodenal papilla was detected. Since she had some distinguishing clinical features, the diagnosis of VHL disease was made. The preoperative diagnosis of the pancreatic lesion was serous cystic neoplasms with hemosuccus pancreaticus and total pancreatectomy was performed. Histological examination of the specimen revealed serous cystic neoplasms which occupied the entire pancreas. VHL cases operated on for serous cystic neoplasms of the entire pancreas are very rare. Cystic lesions of the pancreas are a group of pancreatic lesions characterized by a cystic appearance. They can be benign or malignant. Cystic lesions are found in 20.6% of all pancreatectomy specimens. Among this heterogeneous group, benign neoplasms predominate, particularly those with mucinous lining. Age at presentation, gender, location and tumor size are highly variable, with the exception of solid pseudopapillary tumor. Types Pancreatic intraductal papillary mucinous tumors (most common diagnosis - 52.6%) Pancreatic serous cystic tumors (20.6%) Pancreatic serous cystadenoma Pancreatic serous cystadenocarcinoma Pancreatic mucinous cystic tumors (13.4%) Pancreatic mucinous cystadenoma Pancreatic mucinous cystadenocarcinoma References Digestive system neoplasia Pancreas Pathology Treatment These lesions rarely require surgery unless they are symptomatic or the diagnosis is in question. Since these lesions do not have malignant potential, long-term observation with imaging surveillance is unnecessary. Surgery can include the removal of the head of the pancreas (a pancreaticoduodenectomy), removal of the body and tail of the pancreas (a distal pancreatectomy), or rarely removal of the entire pancreas (a total pancreatectomy). In selected cases the surgery can be performed using minimally invasive techniques such as laparoscopy. Epidemiology Serous cystadenomas of the pancreas are more common in women. SCAs are usually diagnosed in people 50-60 years of age. See also Ovarian serous cystadenoma Pancreatic mucinous cystadenoma Solid pseudopapillary neoplasm References External links Digestive system neoplasia Pancreas disorders () Repair of liver () Other operations on liver () Operations on gallbladder and biliary tract () Cholecystotomy and cholecystostomy () Diagnostic procedures on biliary tract () Endoscopic retrograde cholangiopancreatography (ERCP) () Cholecystectomy () Anastomosis of gallbladder or bile duct () Incision of bile duct for relief of obstruction () Other incision of bile duct () Local excision or destruction of lesion or tissue of biliary ducts and sphincter of Oddi () Repair of bile ducts () Other operations on biliary ducts and sphincter of Oddi () Other operations on biliary tract () Operations on pancreas () Pancreatotomy () Diagnostic procedures on pancreas () Local excision or destruction of pancreas and pancreatic duct () Marsupialization of pancreatic cyst () Internal drainage of pancreatic cyst () Partial pancreatectomy () Total pancreatectomy () Radical pancreaticoduodenectomy () Transplant of pancreas () Other operations on pancreas Deciding on the benign or malignant nature of the renal mass on the basis of its localized size is an issue as renal cell carcinoma may also be cystic. As there are several benign cystic renal lesions (simple renal cyst, haemorrhagic renal cyst, multilocular cystic nephroma, polycystic kidney disease), it may occasionally be difficult for the radiologist to differentiate a benign cystic lesion from a malignant one. The Bosniak classification system for cystic renal lesions classifies them into groups that are benign and those that need surgical resection, based on specific imaging features. The pancreas is an uncommon site of metastasis from renal cell carcinoma. Three observations are described in this review which is aimed at reporting recent data on diagnosis, prognosis and therapeutic features of this kind of metastasis 0: The average space of time between nephrectomy and the diagnosis of the metastasis was 16 years. They have been fortuitously discovered in 2 cases, in patients who did not complain of any pancreatic symptom, during abdominal ultrasonography done for another reason. In the third case, pancreatic symptoms led to the diagnosis. Endoscopic ultrasonography (EUS) was useful to diagnose multiple lesions misdiagnosed on CT-scan or MRI imaging. EUS patterns are characteristic, but histological and cytological examinations of EUS-guided needle biopsies are difficult to study according to the hypervascularized character of these metastasis. The diagnosis of pancreatic metastasis must be suggested for patients suffering from a pancreatic mass with a previous medical history of late renal cell carcinoma. According to their hypervascularized character, the negativity of EUS-guided needle biopsies could strongly direct the diagnosis. When surgery is possible, the survival rate is better than in primary pancreatic adenocarcinoma and is even better than in pancreatic metastasis from other sites. Diagnosis The gold standard for diagnosing solid pseudopapillary tumour of the pancreas is endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) of the lesion. Management In most cases, solid pseudopapillary tumours should be resected surgically, as there is a risk of malignancy (cancer). See also Pancreatic cancer Pancreatic mucinous cystic neoplasm Serous cystadenoma of the pancreas References Digestive system neoplasia Pancreatic cancer Determining whether a pancreatic mass is a primary or secondary neoplasm is necessary for appropriate treatment. We reviewed our experience using endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for diagnosis of pancreatic tumors to identify clinical and cytopathologic characteristics of metastatic disease. We reviewed all cases of tumors metastatic to the pancreas evaluated at The University of Texas MD Anderson Cancer Center and The Methodist Hospital in Houston, Texas during the period from 2002 to 2012. The review included cytologic specimens, clinical history, radiologic findings, primary tumor type, and clinical follow-up. We identified 66 patients with disease metastatic to the pancreas for which cytologic material was available: 38 (58%) men and 28 (42%) women, with an average age of 63 years (range, 40-89 years). Most metastases (98%) were single lesions, and nearly half were located in the head of the pancreas (30/66). The most common site of origin for these metastases was kidney (27 [41%] cases). Follow-up information was available for 65 (98%) patients, and duration of follow-up ranged from &lt;1 to 10 years (mean, 2.3 years). Thirty-three patients (50%) were alive at the time of the most recent follow-up contact. Of the 25 patients with metastatic renal cell carcinoma, clear cell type, 19 (76%) were alive at the time of the most recent follow-up. It was concluded that metastases may mimic primary pancreatic carcinomas both clinically and cytologically. Ancillary studies in conjunction with clinical history are necessary for the accurate diagnosis of FNAs of secondary pancreatic tumors. Macroscopy Microscopy Types Pancreatic Pancreatic mucinous cystadenoma or mucinous cystadenoma of the pancreas (MCN) are a type of mucinous cystic neoplasm of the pancreas. The cure rate is very high in cases on benign cystic lesions, but the case changes if malignant changes ensue. Benign cystadenomas are the most common cystic tumors of the pancreas accounting for 75% of the cases. On an average, mucinous accounts for 40%-50% of cystic tumors, and serous cytadenoma accounts for 30% of it. Mucinous cystadenomas are in the dital pancreas in about 80% of the cases and distal pancreatectomy is needed for resection. In 20% of the cases it is in the head of the pancreas. Earlier it was believed that MCN occurs exclusively in females who are middle aged. However, occasional occurrence in men have been reported, especially those who are 45 years of age or above. The patient was a 79-year-old man, who underwent left nephrectomy for left renal cell carcinoma in 2007. In March 2015, he complained ofthirst, polydipsia, and polyuria. A slight elevation ofamylase levels was detected following laboratory testing. Abdominal CT revealed well-enhanced tumors in the pancreatic head and tail. MPD was dilated in the pancreatic body and tail. Endoscopic ultrasound-guided fine-needle aspiration(EUS-FNA)was used to obtain additional pathological findings. We diagnosed multiple pancreatic metastases from renal cell carcinoma using cell block sections from EUS-FNA ofthe pancreatic head tumor. We also identified worsening of diabetes control due to pancreatic disease. A subtotal stomachsparing pancreaticoduodenectomy and a distal pancreatectomy were performed in June 2015. Histological examination confirmed clear cell carcinoma metastases from RCC in both tumors. The patient remains alive without recurrence approximately 1 year after surgery. Glycemic control has improved with a decrease in insulin levels. Cell block sections from EUS-FNA are useful in the diagnosis of pancreatic disease. Although postoperative follow-up ofthe remnant pancreas is important, preservation ofthe pancreas should be considered for multiple pancreatic metastases when complete tumor removal is possible. von Hippel-Lindau disease is a dominantly inherited multi-system syndrome with neoplastic hallmarks. Pancreatic lesions associated with von Hippel-Lindau include serous cystic neoplasms, simple cysts, and neuroendocrine tumors. The combination of pancreatic neuroendocrine tumors and serous cystic neoplasms is relatively rare, and the surgical treatment of these lesions must consider both preservation of pancreatic function and oncological clearance. We report a patient with von Hippel-Lindau disease successfully treated with pancreas-sparing resection of a pancreatic neuroendocrine tumor where the pancreas had been completely replaced by serous cystic neoplasms, in which pancreatic function was preserved. A 39-year-old female with von Hippel-Lindau disease was referred to our institution for treatment of a pancreatic neuroendocrine tumor. Abdominal computed tomography demonstrated a well-enhanced mass, 4 cm in diameter in the tail of the pancreas, and two multilocular tumors with several calcifications, 5 cm in diameter, in the head of the pancreas. There was complete replacement of the pancreas by multiple cystic lesions with diameters ranging from 1 to 3 cm. Magnetic resonance cholangiopancreatography showed innumerable cystic lesions on the whole pancreas and no detectable main pancreatic duct. Endoscopic ultrasound-guided fine-needle aspiration of the mass in the pancreatic tail showed characteristic features of a neuroendocrine tumor. A diagnosis of pancreatic neuroendocrine tumor in the tail of the pancreas and mixed-type serous cystic neoplasms replacing the whole pancreas was made and she underwent distal pancreatectomy while avoiding total pancreatectomy. The stump of the pancreas was sutured as firm as possible using a fish-mouth closure. The patient made a good recovery and was discharged on postoperative day 9. She is currently alive and well with no symptoms of endocrine or exocrine pancreatic insufficiency 8 months after surgery. A pancreas-sparing resection should be considered for patients with pancreatic neuroendocrine tumors and complete cystic replacement of the pancreas to preserve quality of life after surgery. Two cases of operated pancreatic serous cystadenoma were reported with radiological findings. A 67-year-old man was admitted to our hospital complaining of pain in the left upper quadrant. Ultrasonography revealed a mass having a mixed hypoechoic and echogenic pattern at the body of the pancreas. Computed tomography showed a honeycomb appearance. Angiogram showed hypervascularity and ERCP finding showed narrowing of the main pancreatic duct at the body of the pancreas. A 73-year-old man was detected incidentally to have a low density mass with central satellite appearance by computed tomography at the tail of the pancreas during the examination for the renal tumor. The mass showed hypervascularity and A-V shunt angiographically and narrowing of the main pancreatic duct at the tail of the pancreas by ERCP. Both patients underwent distal pancreatectomy. Histopathological findings showed microcystic pattern with single lining epithelial cells which were low cuboidal or flattened and contained intracytoplasmic glycogen. Pancreas divisum is an embryologic anomaly of the pancreas that is characterized by a lack of fusion of the dorsal and ventral pancreatic ducts. It is rarely associated with pancreatic neoplasms. We report herein a rare association of pancreas divisum and serous cystadenoma of the pancreas. A 46-year-old Japanese woman presented with epigastralgia. Ultrasonography, computed tomography (CT) and magnetic resonance cholangiopancreatography revealed a multilocular cystic mass, measuring 7 cm in diameter, with a central stellate scar, in the body and tail of the pancreas. Angiography demonstrated a relatively hypervascular mass, suppressing the splenic vein. No arterial encasement was evident. Endoscopic retrograde pancreatography through the major papilla demonstrated only the duct of Wirsung; cannulation into the minor papilla was unsuccessful. In addition, CT showed a mildly dilated main pancreatic duct draining into the minor papilla. Distal pancreatectomy and splenectomy were performed, with the tentative diagnosis being serous cystic neoplasm of the pancreas, possibly malignant, and pancreas divisum. The cut surface of the resected specimen had a honeycomb-like appearance and the specimen consisted of multiple cysts of various sizes. Histopathological examination showed multiple cysts lined by a single layer of flat or cuboidal epithelial cells with glycogen in the cytoplasm. There was no evidence of malignancy. The histopathological diagnosis was serous cystadenoma of the pancreas. To the best of our knowledge, only three cases of serous cystadenoma of the pancreas associated with pancreas divisum have been reported. We report the fourth case of such an association, and briefly review the literature. Pancreatic metastasis from renal cell carcinoma (RCC) is a rare event and has not been reported in our country. We report a series of 3 patients with metastatic RCC to the pancreas after radical nephrectomy at our institution. The published reports in the literature were reviewed, and the diagnosis, treatment as well as prognosis of this rare event were discussed. The data of 3 RCC patients with metastasis to the pancreas were reviewed retrospectively, including radical nephrectomy, metastatic interval, the second and third surgical removal. Survival of the three patients was analyzed and the reports in the literature were compared as well. The average interval from radical nephrectectomy to the comfirmed pancreatic metastasis was 6.6 years (range, 1.2 to 12 years). The pathological stage revealed T2N0M0 (n = 2) or T3N0M0 (n = 1), with right-sided tumor in 2 patients and left side in 1. One patient was asymptomatic, while the other two cases were symptomatic at presentation, including upper abdominal pain, weight loss, slight xanthochromia of the skin and titillation, clay stool (n = 1); irregular fever, weight loss and jaundice (n = 1). All pancreatic metastases were hypervascular on arterial stage of CT imaging. One patient had only a solitary pancreatic metastasis (n = 1), the another showed two metastatic lesions (n = 1), the third one had multiple lesions (n = 1). Surgical removal was accomplished in 2 patients: including pylorus-preserving pancreaticoduodenectomy in one, and pylorus-preserving pancreaticoduodenectomy together with partial tail resection in another one. The third one only received interventional therapy due to widespread extrapancreatic metastasis, and died of disseminated disease 11 months after the therapy. One of the above two surgically treated patients underwent the second removal due to local recurrence 2.5 years after the first removal of pancreatic metastasis. These two patients were still alive after follow-up of 8.6 years and 16.1 years, respectively. Renal cell carcinoma is an unpredictable tumor that may demonstrate very delayed metastasis even from early-stage of the disease. The pancreas is a rare site of metastasis from renal cell carcinoma. We advocate careful long-term follow-up of patients with a history of RCC. Aggressive surgical management of pancreatic metastatic lesions may provide a chance of long-term survival. Solid pseudopapillary tumor of the pancreas, otherwise known as solid and cystic tumor or Frantz tumor, is an unusual form of pancreatic carcinoma, with unknown etiopathogenesis, that accounts for 0.2 to 2.7% of all pancreatic tumors. It is defined as an exocrine pancreatic neoplasia that mainly affects women between the second and third decade of life, and its management is not well defined. Endoscopic ultrasound offers a key anatomical advantage in accessing the pancreas and endoscopic ultrasound fine-needle aspiration has become the gold standard method for the diagnosis of pancreatic lesions. Case 1: A 31-year-old white Hispanic woman presented with epigastric pain for 5 months. An abdominal ultrasound revealed a single 2 cm nodule in the uncinate process of her pancreas. Endoscopic ultrasound showed a regular, well-defined solid lesion with alternating cystic areas at the uncinate process of her pancreas, measuring 1.7 × 1.4 cm; endoscopic ultrasound fine-needle aspiration was then performed with cytopathological analysis compatible with solid pseudopapillary tumor. Body computed tomography confirmed the absence of metastases and she underwent conventional duodenopancreatectomy. However, she died 4 days after surgery due to postoperative surgical complications. Case 2: A 35-year-old Hispanic woman presented with left upper quadrant abdominal pain for 3 months, associated with a palpable mass at this region. A computed tomography scan showed a solitary nodule in the pancreatic body. Endoscopic ultrasound showed a regular, well-defined, homogeneous lesion with small anechoic (cystic) areas, measuring 2 × 2 cm, in between the pancreatic body and neck. Endoscopic ultrasound fine-needle aspiration was performed and cytopathological analysis was suggestive of a pseudopapillary solid tumor. She underwent a body-tail laparoscopic pancreatectomy with splenectomy. Nine months after the diagnosis, she remains asymptomatic, continuing regular follow-up in the oncology out-patient clinic. Solid pseudopapillary tumor is a rare pancreatic malignancy. Endoscopic ultrasound fine-needle aspiration is the gold standard method to characterize and diagnose this type of pancreatic lesion, making this an invaluable tool to help guide clinical management and improve the preoperative diagnostic yield. A 78-year-old man was admitted to Ogikubo Hospital for pancreatic tumors detected by computed tomography (CT). The patient had undergone right nephrectomy for renal cell carcinoma (RCC) 27 years previously. Dynamic CT revealed a hypervascular mass in the pancreatic head and a cystic mass in the pancreatic body that were approximately 35 mm and 20 mm in size, respectively. Total pancreatectomy and splenectomy were performed. Histological examination of the resected specimens revealed metastatic tumors from RCC and they were diagnosed as clear cell type. Metastatic carcinoma of the pancreas is uncommon. Pancreatic metastasis from RCC is rare; however, it could occur many years after the initial diagnosis and treatment of the primary tumor. A long and careful follow-up that includes examination of the pancreas is mandatory after nephrectomy for RCC. In this paper, we discuss a case of RCC metastasis to the pancreas and report it in the literature. \nHere is the question:\nDIGESTIVE: A 72-year-old woman with no past history of interest. After a complicated renal colic, a 2 cm cystic lesion in the tail of the pancreas, together with multiple bilateral renal cystic lesions, is found by chance in the abdominal CT scan. Endoscopic ultrasonography shows a polycystic lesion formed by multiple vesicles with central calcification in the tail of the pancreas with no connection to the duct of Wirsung. Fluid analysis is compatible with a serous cystadenoma. Of the following, which is the most correct attitude regarding the management of this patient:\nHere are the potential choices:\n1. Surgical resection (corporocaudal pancreatectomy).\n2. Endoscopic ultrasonography-guided puncture and ethanolization of the puncture.\n3. Follow-up of the lesion by MRI.\n4. Kidney-pancreas transplant.\nThe correct answer is: ",
        "gold_answer": "3 Follow-up of the lesion by MRI.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Multiple cysts and benign cystadenomas of the pancreas have been documented occasionally in von Hippel-Lindau syndrome (HLS); however, the malignant involvement of the pancreas in HLS is very rare. We report a case of HLS in which metastatic tumors from renal cell carcinoma (RCC) coexisted with multiple cysts in the pancreas. A 22-year-old woman with a history of HLS had undergone a partial resection of the left kidney for RCC 3 years earlier, at which time a solid mass in the pancreatic tail and multiple pancreatic cysts were also incidentally detected by computed tomography. Over the following 3 years, the mass enlarged slightly, thus raising suspicions that it might be a primary neoplasm of the pancreas. She was referred to the Department of Surgery and Surgical Basic Science to undergo surgery. In addition to the tumor in the pancreatic tail, however, further tumors in the pancreatic head were also disclosed by preoperative celiac arteriography and intraoperative palpation and ultrasonography. A distal pancreatectomy was performed, because the enucleation of all the tumors in the pancreatic head was technically impossible and because the patient declined a total pancreatectomy. A histologic examination of the mass in the pancreatic tail revealed metastatic RCC. This case emphasizes that metastatic disease should be included in the differential diagnosis when evaluating the pancreas in a patient with HLS. Autosomal dominant polycystic kidney disease, the most frequent inherited polycystic disease, is a systemic disorder characterised by the development of numerous and bilateral kidney cysts leading to chronic renal failure. Extrarenal cysts are located mainly in the liver but also in various organs including the pancreas. To our knowledge, complications of pancreatic cysts in this disease have never been reported. The first case of painful chronic obstructive pancreatitis due to a true pancreatic cyst in a patient with autosomal dominant polycystic kidney disease is reported. Abdominal transparietal and endoscopic ultrasonography, computed tomography, and endoscopic retrograde cholangiopancreatography showed a cystic lesion in the body of the pancreas associated with upstream dilatation of the main pancreatic duct. Intraoperative ultrasonography before and after cyst fluid aspiration, and pancreatography and pathological examination of the resected distal pancreas confirmed that both main pancreatic duct enlargement and chronic pancreatitis were caused by a benign cyst. Chronic obstructive pancreatitis should be added to the extrarenal complications of autosomal dominant polycystic kidney disease. von Hippel-Lindau (VHL) syndrome is an inherited neoplastic syndrome caused by abnormity of the VHL gene found on the short arm of the chromosome 3. We reported a case of VHL disease diagnosed by the detection of multiple pancreatic endocrine tumors and renal tumor 13 years after bilateral adrenalectomy. A 40-year-old man presented with multiple pancreas tumors (maximum size 42 mm in diameter) detected by screening abdominal ultrasonography. A 23 mm renal tumor was detected by contrast computed tomography scan at that time. His past history included left retinal angioma (age 15) and bilateral adrenal pheochromocytoma (age 27). VHL was diagnosed by genetic testing. Endoscopic ultrasound-guided fine-needle aspiration biopsy of the pancreas tumor was performed, and tumor was diagnosed as an endocrine tumor. After diagnosis, distal pancreatectomy (body-tail) was performed. This was a didactic case indicating that we should suspect VHL syndrome based on past history and family history and follow such cases up strictly. Cystic neoplasms of the pancreas are rare, accounting for about 9 to 10% of cystic pancreatic lesions. A 63-year-old man, who had been receiving chronic hemodialysis due to diabetic chronic renal failure, was admitted after the discovery of cystic masses in the pancreatic tail. Abdominal ultrasonography and computed tomography revealed multiloculated cystic tumors. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated findings consistent with malignant tumors. Preoperatively, he was thought to have a cystadenocarcinoma in the pancreatic tail for which he underwent a distal pancreatectomy and splenectomy. Histologic analysis of the resected mass established the diagnosis mucinous cystadenoma. To our knowledge, pancreatic mucinous cystadenoma occurring in a patient receiving chronic hemodialysis has not been previously reported. Therefore, we present a novel case in this report. The pancreas is an infrequent site of hydatid disease. This study aims at giving better insight into the diagnostic and managerial approach to the disease. Six patients with hydatid cysts of the pancreas. Retrospective review of the clinical records. The six patients (four men, two women) ranged in age from 18 to 68 years. Five of the cysts were primary while one had an associated cyst in the liver. Abdominal pain, vomiting, abdominal mass and dyspeptic symptoms were seen in cysts involving the body and tail. Two patients having cysts in the head of the pancreas presented with obstructive jaundice. An indirect hemagglutination test and an enzyme-linked immunoabsorbent assay were positive for the presence of specific hydatid antibodies in four patients. Abdominal ultrasonography, computed tomography and magnetic resonance cholangiopancreatography (MRCP) successfully imaged the cysts and also defined the relationship of the lesion with the pancreatic duct. All patients underwent surgical exploration. Three patients had intraoperative fine needle aspiration cytology of the cystic lesion for microscopic and electrolyte analysis. A preoperative diagnosis was possible in two patients and, in the other four, the diagnosis was made intraoperatively and confirmed on histopathological examination. with cysts located in the tail underwent a distal pancreatectomy with a splenectomy while those with cysts in the body had a pericystectomy or central pancreatectomy. Cysts of the head were treated with evacuation, partial cystectomy and tube drainage. There were no postoperative complications, and no evidence of cyst recurrence was observed during the follow-up period. All the patients were followed up at three-month intervals with a mean follow-up time of 58.7 months (rang: 4-120 months); no patient had cyst recurrence or dissemination. A hydatid cyst is an uncommon cause of cystic lesions in the pancreas and should be included in the differential diagnosis of cystic lesions of the pancreas, especially in endemic areas. Intraoperative fine needle aspirate for microscopic and electrolyte estimation seems to be an effective method for establishing a proper diagnosis. MRCP, which can depict the communication of the cystic lesion with the pancreatic duct, helps in defining the type of surgical treatment. Cysts in body and tail are best treated by resectional methods whereas, for those in the head region, a cystectomy with simple drainage is a simple, quick and effective solution. We describe here a case of von Hippel-Lindau (VHL) disease with a serous cystic neoplasm of the whole pancreas. The patient was a 35-year-old woman suffering from a palpable abdominal tumor. She had a history of hemangioblastomas of the cerebellum. CT revealed large solid tumors in the pancreatic head and body, and multiple cystic lesions in the whole pancreas as well as a right renal tumor. When endoscopic retrograde cholangiopancreatography (ERCP) was performed, bleeding from the duodenal papilla was detected. Since she had some distinguishing clinical features, the diagnosis of VHL disease was made. The preoperative diagnosis of the pancreatic lesion was serous cystic neoplasms with hemosuccus pancreaticus and total pancreatectomy was performed. Histological examination of the specimen revealed serous cystic neoplasms which occupied the entire pancreas. VHL cases operated on for serous cystic neoplasms of the entire pancreas are very rare. Cystic lesions of the pancreas are a group of pancreatic lesions characterized by a cystic appearance. They can be benign or malignant. Cystic lesions are found in 20.6% of all pancreatectomy specimens. Among this heterogeneous group, benign neoplasms predominate, particularly those with mucinous lining. Age at presentation, gender, location and tumor size are highly variable, with the exception of solid pseudopapillary tumor. Types Pancreatic intraductal papillary mucinous tumors (most common diagnosis - 52.6%) Pancreatic serous cystic tumors (20.6%) Pancreatic serous cystadenoma Pancreatic serous cystadenocarcinoma Pancreatic mucinous cystic tumors (13.4%) Pancreatic mucinous cystadenoma Pancreatic mucinous cystadenocarcinoma References Digestive system neoplasia Pancreas Pathology Treatment These lesions rarely require surgery unless they are symptomatic or the diagnosis is in question. Since these lesions do not have malignant potential, long-term observation with imaging surveillance is unnecessary. Surgery can include the removal of the head of the pancreas (a pancreaticoduodenectomy), removal of the body and tail of the pancreas (a distal pancreatectomy), or rarely removal of the entire pancreas (a total pancreatectomy). In selected cases the surgery can be performed using minimally invasive techniques such as laparoscopy. Epidemiology Serous cystadenomas of the pancreas are more common in women. SCAs are usually diagnosed in people 50-60 years of age. See also Ovarian serous cystadenoma Pancreatic mucinous cystadenoma Solid pseudopapillary neoplasm References External links Digestive system neoplasia Pancreas disorders () Repair of liver () Other operations on liver () Operations on gallbladder and biliary tract () Cholecystotomy and cholecystostomy () Diagnostic procedures on biliary tract () Endoscopic retrograde cholangiopancreatography (ERCP) () Cholecystectomy () Anastomosis of gallbladder or bile duct () Incision of bile duct for relief of obstruction () Other incision of bile duct () Local excision or destruction of lesion or tissue of biliary ducts and sphincter of Oddi () Repair of bile ducts () Other operations on biliary ducts and sphincter of Oddi () Other operations on biliary tract () Operations on pancreas () Pancreatotomy () Diagnostic procedures on pancreas () Local excision or destruction of pancreas and pancreatic duct () Marsupialization of pancreatic cyst () Internal drainage of pancreatic cyst () Partial pancreatectomy () Total pancreatectomy () Radical pancreaticoduodenectomy () Transplant of pancreas () Other operations on pancreas Deciding on the benign or malignant nature of the renal mass on the basis of its localized size is an issue as renal cell carcinoma may also be cystic. As there are several benign cystic renal lesions (simple renal cyst, haemorrhagic renal cyst, multilocular cystic nephroma, polycystic kidney disease), it may occasionally be difficult for the radiologist to differentiate a benign cystic lesion from a malignant one. The Bosniak classification system for cystic renal lesions classifies them into groups that are benign and those that need surgical resection, based on specific imaging features. The pancreas is an uncommon site of metastasis from renal cell carcinoma. Three observations are described in this review which is aimed at reporting recent data on diagnosis, prognosis and therapeutic features of this kind of metastasis 0: The average space of time between nephrectomy and the diagnosis of the metastasis was 16 years. They have been fortuitously discovered in 2 cases, in patients who did not complain of any pancreatic symptom, during abdominal ultrasonography done for another reason. In the third case, pancreatic symptoms led to the diagnosis. Endoscopic ultrasonography (EUS) was useful to diagnose multiple lesions misdiagnosed on CT-scan or MRI imaging. EUS patterns are characteristic, but histological and cytological examinations of EUS-guided needle biopsies are difficult to study according to the hypervascularized character of these metastasis. The diagnosis of pancreatic metastasis must be suggested for patients suffering from a pancreatic mass with a previous medical history of late renal cell carcinoma. According to their hypervascularized character, the negativity of EUS-guided needle biopsies could strongly direct the diagnosis. When surgery is possible, the survival rate is better than in primary pancreatic adenocarcinoma and is even better than in pancreatic metastasis from other sites. Diagnosis The gold standard for diagnosing solid pseudopapillary tumour of the pancreas is endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) of the lesion. Management In most cases, solid pseudopapillary tumours should be resected surgically, as there is a risk of malignancy (cancer). See also Pancreatic cancer Pancreatic mucinous cystic neoplasm Serous cystadenoma of the pancreas References Digestive system neoplasia Pancreatic cancer Determining whether a pancreatic mass is a primary or secondary neoplasm is necessary for appropriate treatment. We reviewed our experience using endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for diagnosis of pancreatic tumors to identify clinical and cytopathologic characteristics of metastatic disease. We reviewed all cases of tumors metastatic to the pancreas evaluated at The University of Texas MD Anderson Cancer Center and The Methodist Hospital in Houston, Texas during the period from 2002 to 2012. The review included cytologic specimens, clinical history, radiologic findings, primary tumor type, and clinical follow-up. We identified 66 patients with disease metastatic to the pancreas for which cytologic material was available: 38 (58%) men and 28 (42%) women, with an average age of 63 years (range, 40-89 years). Most metastases (98%) were single lesions, and nearly half were located in the head of the pancreas (30/66). The most common site of origin for these metastases was kidney (27 [41%] cases). Follow-up information was available for 65 (98%) patients, and duration of follow-up ranged from &lt;1 to 10 years (mean, 2.3 years). Thirty-three patients (50%) were alive at the time of the most recent follow-up contact. Of the 25 patients with metastatic renal cell carcinoma, clear cell type, 19 (76%) were alive at the time of the most recent follow-up. It was concluded that metastases may mimic primary pancreatic carcinomas both clinically and cytologically. Ancillary studies in conjunction with clinical history are necessary for the accurate diagnosis of FNAs of secondary pancreatic tumors. Macroscopy Microscopy Types Pancreatic Pancreatic mucinous cystadenoma or mucinous cystadenoma of the pancreas (MCN) are a type of mucinous cystic neoplasm of the pancreas. The cure rate is very high in cases on benign cystic lesions, but the case changes if malignant changes ensue. Benign cystadenomas are the most common cystic tumors of the pancreas accounting for 75% of the cases. On an average, mucinous accounts for 40%-50% of cystic tumors, and serous cytadenoma accounts for 30% of it. Mucinous cystadenomas are in the dital pancreas in about 80% of the cases and distal pancreatectomy is needed for resection. In 20% of the cases it is in the head of the pancreas. Earlier it was believed that MCN occurs exclusively in females who are middle aged. However, occasional occurrence in men have been reported, especially those who are 45 years of age or above. The patient was a 79-year-old man, who underwent left nephrectomy for left renal cell carcinoma in 2007. In March 2015, he complained ofthirst, polydipsia, and polyuria. A slight elevation ofamylase levels was detected following laboratory testing. Abdominal CT revealed well-enhanced tumors in the pancreatic head and tail. MPD was dilated in the pancreatic body and tail. Endoscopic ultrasound-guided fine-needle aspiration(EUS-FNA)was used to obtain additional pathological findings. We diagnosed multiple pancreatic metastases from renal cell carcinoma using cell block sections from EUS-FNA ofthe pancreatic head tumor. We also identified worsening of diabetes control due to pancreatic disease. A subtotal stomachsparing pancreaticoduodenectomy and a distal pancreatectomy were performed in June 2015. Histological examination confirmed clear cell carcinoma metastases from RCC in both tumors. The patient remains alive without recurrence approximately 1 year after surgery. Glycemic control has improved with a decrease in insulin levels. Cell block sections from EUS-FNA are useful in the diagnosis of pancreatic disease. Although postoperative follow-up ofthe remnant pancreas is important, preservation ofthe pancreas should be considered for multiple pancreatic metastases when complete tumor removal is possible. von Hippel-Lindau disease is a dominantly inherited multi-system syndrome with neoplastic hallmarks. Pancreatic lesions associated with von Hippel-Lindau include serous cystic neoplasms, simple cysts, and neuroendocrine tumors. The combination of pancreatic neuroendocrine tumors and serous cystic neoplasms is relatively rare, and the surgical treatment of these lesions must consider both preservation of pancreatic function and oncological clearance. We report a patient with von Hippel-Lindau disease successfully treated with pancreas-sparing resection of a pancreatic neuroendocrine tumor where the pancreas had been completely replaced by serous cystic neoplasms, in which pancreatic function was preserved. A 39-year-old female with von Hippel-Lindau disease was referred to our institution for treatment of a pancreatic neuroendocrine tumor. Abdominal computed tomography demonstrated a well-enhanced mass, 4 cm in diameter in the tail of the pancreas, and two multilocular tumors with several calcifications, 5 cm in diameter, in the head of the pancreas. There was complete replacement of the pancreas by multiple cystic lesions with diameters ranging from 1 to 3 cm. Magnetic resonance cholangiopancreatography showed innumerable cystic lesions on the whole pancreas and no detectable main pancreatic duct. Endoscopic ultrasound-guided fine-needle aspiration of the mass in the pancreatic tail showed characteristic features of a neuroendocrine tumor. A diagnosis of pancreatic neuroendocrine tumor in the tail of the pancreas and mixed-type serous cystic neoplasms replacing the whole pancreas was made and she underwent distal pancreatectomy while avoiding total pancreatectomy. The stump of the pancreas was sutured as firm as possible using a fish-mouth closure. The patient made a good recovery and was discharged on postoperative day 9. She is currently alive and well with no symptoms of endocrine or exocrine pancreatic insufficiency 8 months after surgery. A pancreas-sparing resection should be considered for patients with pancreatic neuroendocrine tumors and complete cystic replacement of the pancreas to preserve quality of life after surgery. Two cases of operated pancreatic serous cystadenoma were reported with radiological findings. A 67-year-old man was admitted to our hospital complaining of pain in the left upper quadrant. Ultrasonography revealed a mass having a mixed hypoechoic and echogenic pattern at the body of the pancreas. Computed tomography showed a honeycomb appearance. Angiogram showed hypervascularity and ERCP finding showed narrowing of the main pancreatic duct at the body of the pancreas. A 73-year-old man was detected incidentally to have a low density mass with central satellite appearance by computed tomography at the tail of the pancreas during the examination for the renal tumor. The mass showed hypervascularity and A-V shunt angiographically and narrowing of the main pancreatic duct at the tail of the pancreas by ERCP. Both patients underwent distal pancreatectomy. Histopathological findings showed microcystic pattern with single lining epithelial cells which were low cuboidal or flattened and contained intracytoplasmic glycogen. Pancreas divisum is an embryologic anomaly of the pancreas that is characterized by a lack of fusion of the dorsal and ventral pancreatic ducts. It is rarely associated with pancreatic neoplasms. We report herein a rare association of pancreas divisum and serous cystadenoma of the pancreas. A 46-year-old Japanese woman presented with epigastralgia. Ultrasonography, computed tomography (CT) and magnetic resonance cholangiopancreatography revealed a multilocular cystic mass, measuring 7 cm in diameter, with a central stellate scar, in the body and tail of the pancreas. Angiography demonstrated a relatively hypervascular mass, suppressing the splenic vein. No arterial encasement was evident. Endoscopic retrograde pancreatography through the major papilla demonstrated only the duct of Wirsung; cannulation into the minor papilla was unsuccessful. In addition, CT showed a mildly dilated main pancreatic duct draining into the minor papilla. Distal pancreatectomy and splenectomy were performed, with the tentative diagnosis being serous cystic neoplasm of the pancreas, possibly malignant, and pancreas divisum. The cut surface of the resected specimen had a honeycomb-like appearance and the specimen consisted of multiple cysts of various sizes. Histopathological examination showed multiple cysts lined by a single layer of flat or cuboidal epithelial cells with glycogen in the cytoplasm. There was no evidence of malignancy. The histopathological diagnosis was serous cystadenoma of the pancreas. To the best of our knowledge, only three cases of serous cystadenoma of the pancreas associated with pancreas divisum have been reported. We report the fourth case of such an association, and briefly review the literature. Pancreatic metastasis from renal cell carcinoma (RCC) is a rare event and has not been reported in our country. We report a series of 3 patients with metastatic RCC to the pancreas after radical nephrectomy at our institution. The published reports in the literature were reviewed, and the diagnosis, treatment as well as prognosis of this rare event were discussed. The data of 3 RCC patients with metastasis to the pancreas were reviewed retrospectively, including radical nephrectomy, metastatic interval, the second and third surgical removal. Survival of the three patients was analyzed and the reports in the literature were compared as well. The average interval from radical nephrectectomy to the comfirmed pancreatic metastasis was 6.6 years (range, 1.2 to 12 years). The pathological stage revealed T2N0M0 (n = 2) or T3N0M0 (n = 1), with right-sided tumor in 2 patients and left side in 1. One patient was asymptomatic, while the other two cases were symptomatic at presentation, including upper abdominal pain, weight loss, slight xanthochromia of the skin and titillation, clay stool (n = 1); irregular fever, weight loss and jaundice (n = 1). All pancreatic metastases were hypervascular on arterial stage of CT imaging. One patient had only a solitary pancreatic metastasis (n = 1), the another showed two metastatic lesions (n = 1), the third one had multiple lesions (n = 1). Surgical removal was accomplished in 2 patients: including pylorus-preserving pancreaticoduodenectomy in one, and pylorus-preserving pancreaticoduodenectomy together with partial tail resection in another one. The third one only received interventional therapy due to widespread extrapancreatic metastasis, and died of disseminated disease 11 months after the therapy. One of the above two surgically treated patients underwent the second removal due to local recurrence 2.5 years after the first removal of pancreatic metastasis. These two patients were still alive after follow-up of 8.6 years and 16.1 years, respectively. Renal cell carcinoma is an unpredictable tumor that may demonstrate very delayed metastasis even from early-stage of the disease. The pancreas is a rare site of metastasis from renal cell carcinoma. We advocate careful long-term follow-up of patients with a history of RCC. Aggressive surgical management of pancreatic metastatic lesions may provide a chance of long-term survival. Solid pseudopapillary tumor of the pancreas, otherwise known as solid and cystic tumor or Frantz tumor, is an unusual form of pancreatic carcinoma, with unknown etiopathogenesis, that accounts for 0.2 to 2.7% of all pancreatic tumors. It is defined as an exocrine pancreatic neoplasia that mainly affects women between the second and third decade of life, and its management is not well defined. Endoscopic ultrasound offers a key anatomical advantage in accessing the pancreas and endoscopic ultrasound fine-needle aspiration has become the gold standard method for the diagnosis of pancreatic lesions. Case 1: A 31-year-old white Hispanic woman presented with epigastric pain for 5 months. An abdominal ultrasound revealed a single 2 cm nodule in the uncinate process of her pancreas. Endoscopic ultrasound showed a regular, well-defined solid lesion with alternating cystic areas at the uncinate process of her pancreas, measuring 1.7 × 1.4 cm; endoscopic ultrasound fine-needle aspiration was then performed with cytopathological analysis compatible with solid pseudopapillary tumor. Body computed tomography confirmed the absence of metastases and she underwent conventional duodenopancreatectomy. However, she died 4 days after surgery due to postoperative surgical complications. Case 2: A 35-year-old Hispanic woman presented with left upper quadrant abdominal pain for 3 months, associated with a palpable mass at this region. A computed tomography scan showed a solitary nodule in the pancreatic body. Endoscopic ultrasound showed a regular, well-defined, homogeneous lesion with small anechoic (cystic) areas, measuring 2 × 2 cm, in between the pancreatic body and neck. Endoscopic ultrasound fine-needle aspiration was performed and cytopathological analysis was suggestive of a pseudopapillary solid tumor. She underwent a body-tail laparoscopic pancreatectomy with splenectomy. Nine months after the diagnosis, she remains asymptomatic, continuing regular follow-up in the oncology out-patient clinic. Solid pseudopapillary tumor is a rare pancreatic malignancy. Endoscopic ultrasound fine-needle aspiration is the gold standard method to characterize and diagnose this type of pancreatic lesion, making this an invaluable tool to help guide clinical management and improve the preoperative diagnostic yield. A 78-year-old man was admitted to Ogikubo Hospital for pancreatic tumors detected by computed tomography (CT). The patient had undergone right nephrectomy for renal cell carcinoma (RCC) 27 years previously. Dynamic CT revealed a hypervascular mass in the pancreatic head and a cystic mass in the pancreatic body that were approximately 35 mm and 20 mm in size, respectively. Total pancreatectomy and splenectomy were performed. Histological examination of the resected specimens revealed metastatic tumors from RCC and they were diagnosed as clear cell type. Metastatic carcinoma of the pancreas is uncommon. Pancreatic metastasis from RCC is rare; however, it could occur many years after the initial diagnosis and treatment of the primary tumor. A long and careful follow-up that includes examination of the pancreas is mandatory after nephrectomy for RCC. In this paper, we discuss a case of RCC metastasis to the pancreas and report it in the literature. \nHere is the question:\nDIGESTIVE: A 72-year-old woman with no past history of interest. After a complicated renal colic, a 2 cm cystic lesion in the tail of the pancreas, together with multiple bilateral renal cystic lesions, is found by chance in the abdominal CT scan. Endoscopic ultrasonography shows a polycystic lesion formed by multiple vesicles with central calcification in the tail of the pancreas with no connection to the duct of Wirsung. Fluid analysis is compatible with a serous cystadenoma. Of the following, which is the most correct attitude regarding the management of this patient:\nHere are the potential choices:\n1. Surgical resection (corporocaudal pancreatectomy).\n2. Endoscopic ultrasonography-guided puncture and ethanolization of the puncture.\n3. Follow-up of the lesion by MRI.\n4. Kidney-pancreas transplant.\nThe correct answer is: 3. Follow-up of the lesion by MRI."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n An elderly case of systemic lupus erythematosus (SLE) with suspected hemolytic anemia was experienced. A 70 year-old female was admitted to our hospital on December 31 with complaints of herpetic eruption. She complained of arthralgia since 3 month prior to her admission. The positive findings on examination were skin eruption in the left chest, a systolic heart murmur and a palpable elastic hard liver. Laboratory data showed raised erythrocyte sedimentation rate of 149 mm per hour, decreased Hb (10.1 g/dl), decreased hematocrit (30.0%), increased reticulocytes (33%1000), decreased thrombocytes (73,000/mm3), increased gamma-globulin (33%) and positive rheumatoid factor. During admission, she developed anemia. A stool test for occult blood was negative. The haptoglobin was 38.8 mg/dl and bone marrow aspiration showed increased erythropoiesis, suggesting features of immune hemolytic anemia, except she was negative on Coomb'test. Eye fundi were similar to case of typical bleeding observed in SLE. Concerning immunological findings, the antinuclear factor was x 1280 and the anti-dsDNA antibody was x 80, on which a diagnosis of SLE was based. She experienced numbness of the left arm and developed left hemiparesis 2 days later. Therapy with 15 mg/day prednisone obtained a good response and anemia, abnormal immunological findings and hemiparesis disappeared. BACKGROUND Patients with late-onset systemic lupus erythematosus (SLE) do not present with typical SLE symptoms or serology, and this can lead to a major delay in diagnosis. We report a complex case of an older woman who developed autoimmune hemolytic anemia and sixth cranial nerve palsy that posed considerable challenges in diagnosing late-onset SLE. CASE REPORT A 78-year-old Japanese woman presented with polyarthritis associated with generalized fatigue for 2 months, who later developed diplopia. Physical examination revealed conjunctival pallor, polyarthritis, and subsequent development of sixth cranial nerve palsy. Laboratory data revealed a decreased white blood cell count; macrocytic anemia; elevated levels of lactate dehydrogenase, indirect bilirubin, and erythrocyte sedimentation rate; hypocomplementemia; positive Coombs test; antinuclear antibodies (ANAs, 1: 40); and positive anti-double-strand DNA antibodies. Lymphoma, cerebral venous sinus thrombosis, and varicella-zoster virus infection were unlikely based on head computed tomography, brain magnetic resonance imaging, and cerebrospinal fluid analysis. She was diagnosed with late-onset SLE associated with autoimmune hemolytic anemia and sixth cranial nerve palsy. The patient was successfully treated with prednisone and hydroxychloroquine. CONCLUSIONS The difficulty in diagnosing late-onset SLE with atypical presentations and uncommon complications must be recognized. SLE cannot be excluded based on a low titer of ANA in a particular subgroup such as the elderly, and the prozone effect should be considered responsible for low ANA titers. In this case, late-onset SLE was diagnosed by considering multisystem pathologies despite low ANA titers. Fever >38.3°C (101°F) on at least two occasions 2. Illness duration of ≥3 weeks 3. 4. Diagnosis that remains uncertain after a thorough history-taking, physical examination, and the following obligatory investigations: determination of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level; platelet count; leukocyte count and differential; measurement of levels of hemoglobin, electrolytes, creatinine, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, ferritin, antinuclear antibodies, and rheumatoid factor; protein electrophoresis; urinalysis; blood cultures (n = 3); urine culture; chest x-ray; abdominal ultrasonography; and tuberculin skin test (TST). The range of FUO etiologies has evolved over time as a result of changes in the spectrum of diseases causing FUO, the widespread Percentage of Cases Due to Indicated Cause History A 46-year-old woman with known mixed connective tissue disease with clinical features of scleroderma and polymyositis and who was not on specific medications was referred to our institution to assess for interstitial lung disease due to her predisposing condition. She was a nonsmoker, had no respiratory symptoms, and enjoyed good exercise tolerance. She did not have any cutaneous lesions or renal disease. There was no family history of pulmonary or systemic disease. Her routine blood test results revealed a white blood cell count of 4.6 × 10<sup9</sup/L (normal range, [4.4-10.1] × 10<sup9</sup/L), a hemoglobin level of 7.76 mmol/L (normal range, 7.26-9.18 mmol/L), a platelet count of 189 × 10<sup9</sup/L (normal range, [170-380] × 10<sup9</sup/L), a bilirubin level of 8 μmol/L (7-19 μmol/L), and a creatinine level of 63 μmol/L (45-82 μmol/L), all within normal limits. Lung function tests at presentation yielded normal results, with a diffusing capacity for carbon monoxide of 95% and a forced vital capacity of 2.29 (98% predicted value). However, this patient had an elevated serum globulin level of 47 g/L (normal range, 26-32 g/L) and an erythrocyte sedimentation rate of 36 mm/h (normal range, 0-20 mm/h), while C-reactive protein level was normal at less than 0.35 mg/dL. She was seropositive for antinuclear (titer &gt;1/720), anti-Ro, anti-La, and anti-extractable nuclear antigen antibodies. Chest radiography and CT were performed at presentation (Figs 1, 2) and 14-year follow-up (Figs 3, 4). PET/CT was performed at 7- (Fig 5, <iA</i and <iB</i) and 13-year follow-up (Fig 5, <iC</i and <iD</i). Throughout this 14-year follow-up period, she remained completely free of respiratory symptoms and continued to go for a brisk walk every day. At 14-year follow-up, there was no substantial change in serum laboratory values, but a lung function test revealed her diffusing capacity for carbon monoxide had decreased to 52%, while her forced vital capacity remained good at 95%; these findings were suggestive of interval development of restrictive lung function. Fever ˜38.3° C (101° F) and illness lasting ˜3 weeks and no known immunocompromised state History and physical examination Stop antibiotic treatment and glucocorticoids Obligatory investigations: ESR and CRP, hemoglobin, platelet count, leukocyte count and differential, electrolytes, creatinine, total protein, protein electrophoresis, alkaline phosphatase, AST, ALT, LDH, creatine kinase, antinuclear antibodies, rheumatoid factor, urinalysis, blood cultures (n=3), urine culture, chest x-ray, abdominal ultrasonography, and tuberculin skin test A 49-year-old woman with type 2 diabetes mellitus (T2DM) presented to the emergency department. Her examination showed marked pallor, exhaustion, lethargy, yellowish eyes, anorexia, nausea and vomiting. Hematuria; negative standard direct antiglobulin test (DAT); normal glucose 6 phosphate dehydrogenase (G6PD); hemoglobin (Hb), 4.8 g/dl; Mean cell volume (MCV), 91fl; platelet count, 233 × 10<sup6</sup/L; Total bilirubin, 7.0 mg/dl; Glucose, 316 mg/dl; lactate dehydrogenase (LDH), 1750U/L. Undoubtedly, therapeutic panel should have been used for hemolytic anemia. Intravenous (IV) fluids and 2 units of packed cell were transfused. Methylprednisolone with rituximab were started for the patient. After 3 weeks of the patient admission, she was discharged home with stable vital signs and Hb, 10 g/dl. We concluded in the cases that presented along with a severe drop in Hb and evidence of hemolysis which non immune hemolytic anemia is excluded in spite of negative standard DAT limited transfusion besides corticosteroids combined with rituximab, could be helpful in saving the patient. The by far most common clinical test for ACPAs is the anti-cyclic citrullinated peptide (anti CCP) ELISA. In 2008 a serological point-of-care test for the early detection of RA combined the detection of RF and anti-MCV with a sensitivity of 72% and specificity of 99.7%. Other blood tests are usually done to differentiate from other causes of arthritis, like the erythrocyte sedimentation rate (ESR), C-reactive protein, full blood count, kidney function, liver enzymes and other immunological tests (e.g., antinuclear antibody/ANA) are all performed at this stage. Elevated ferritin levels can reveal hemochromatosis, a mimic of RA, or be a sign of Still's disease, a seronegative, usually juvenile, variant of rheumatoid arthritis. Classification criteria In 2010, the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria were introduced. Although severe vitamin B12 deficiency is rare in the United States, recent increases in the adoption of vegan lifestyles have led to a significant rise in the rates of B12 deficiency, along with its hematologic and neurologic sequelae, the latter of which is often irreversible. We describe a case of a 39-year-old male who presented with a several-month history of progressively worsening word-finding difficulties, shortness of breath, and a four-day history of bilateral hand numbness and tingling. Laboratory data revealed pancytopenia with profound anemia. Markers of hemolysis were positive, including elevated indirect bilirubin, disproportionately elevated lactate dehydrogenase (LDH), low haptoglobin, negative direct anticoagulant test, and hypoproliferative reticulocyte index. Blood smear revealed hypersegmented neutrophils and macrocytosis. Vitamin B12 levels were undetectable, and anti-intrinsic factor and parietal cell antibodies were negative. A thorough history revealed a 20-year history of strict veganism without B12 supplementation. He was transfused with packed red blood cells and started on subcutaneous B12 injections with rapid improvement of his symptoms. Early recognition of B12 deficiency causing the constellation of pancytopenia, hemolytic anemia, and neurologic symptoms is vital in preventing irreversible neurologic sequelae. This case also highlights the importance of accurate history taking to aid in early diagnosis of B12 deficiency, especially in the context of rising rates of veganism in the United States. A 67-year-old woman was admitted to our hospital with a fever. She had been experiencing arthralgia for about one month. On admission, she had a fever of 38.5 degrees C, was anemic and was experiencing tenderness in the joints of both hands, elbows and feet. Laboratory data revealed proteinuria, urinary cylinders, pancytopenia (WBC 900/mm3, Hb 9.5 g/dl, Plt 7.8 x 10(4)/mm3), liver dysfunction (GOT 414 IU/l, GPT 140 IU/l), and hyper-gamma globulinemia. Antibiotics and granulocyte-colony stimulating factor were administered intravenously. Bone marrow aspiration was unsuccessful, but a bone marrow biopsy revealed bone marrow fibrosis. Immunological examinations were positive for antinuclear antibodies, anti-deoxyribonucleic acid (DNA) antibodies, anti-double stranded anti- DNA antibodies, as well as a decreased level of serum complement and an increased level of serum immune complexes. Tests for viral antigens and antibodies known to cause hepatitis were negative. Based on these findings, a diagnosis of SLE accompanied by liver dysfunction and bone marrow fibrosis was made. Steroid pulse therapy was initiated, but her liver function deteriorated on the first day of steroid therapy, and she died three days later. SLE accompanied by myelofibrosis is extremely rare, and only 17 and cases have been reported to date. Among these reports, the present case is the second oldest subject and the first SLE patient to suffer from both myelofibrosis and severe liver dysfunction. Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology. It is characterized by fever, skin rash, polyarthralgias or polyarthritis, sore throat, hepatosplenomegaly, lymphadenopathy, leukocytosis, liver enzyme elevation, and high serum level of ferritin. Several kinds of skin lesions have been reported in this condition. The aim of this study was to assess the clinical and laboratory aspects of 28 patients with AOSD in central Iran. According to the diagnostic criteria of AOSD, we identified 28 patients between 2002 and 2007. We intended to describe the clinical characteristics, treatment, and outcome of our patients with AOSD. Of 28 patients with AOSD, 21 (75%) were female, 7 (25%) were male. Fever (100%), sore throat (92%), Arthralgia (92%), dermatographism (92%), typical rash (85%) and arthritis (60%) were the most common findings. The mean values of laboratory findings were as follows; C-reactive protein (CRP) level of 14.4 mg/dl, erythrocyte sedimentation rate (ESR) of 91.5 mm/h, leukocyte count of 15744.4/microl. Abnormal levels of aspartate aminotransferase and alanine aminotransferase were observed in 25 (89%) patients. Twenty patients (71%) had high ferritin values (&gt;500 ng/ml). The clinical characteristics were similar to previous series. A febrile polyarthritis was the most frequent presentation form. Dermatographism was frequently encountered phenomenon in our patients with AOSD. Being that dermatographism is a simple inducible skin reaction, along with its sensitivity in active disease, we suggest more controlled studies to validate accuracy and positive predictive value of it in convenient clinical setting in the diagnosis of AOSD and to consider including it in diagnostic criteria. Laboratory investigations are carried out to determine the etiology of the disease. Following confirmation of hemolysis (seen with laboratory markers of low hemoglobin, elevated LDH, decreased haptoglobin, and elevated unconjugated bilirubin), a direct antiglobulin test (DAT)(also known as a Coomb's test) is done to show auto-immune pathogenesis with antibodies, compliment or both on the erythrocyte surface. This is followed by a monospecific DAT that identifies the specific antibody and compliment types on the erythrocyte surface. In cold agglutinin disease, the monospecific DAT is by definition positive for the compliment molecule C3d but IgM may be negative as the molecule may detach at the time of testing. The diagnosis of cold agglutinin disease is confirmed with an elevated cold agglutinin titer. A bone marrow biopsy is used in AIHA to identify a possible underlying lymphoproliferative disorder. There is no single test or clinical presentation which is suggestive of viral arthritis. The diagnosis is mainly clinical, supported by other tests, including inflammatory markers, autoantibodies, and serology. A viral etiology should be suspected in a patient presenting with acute onset of arthralgias or polyarticular symptoms, especially if the duration of symptomatology has been less than six weeks. The presence of extra-articular symptoms, viz rash or lymphadenopathy, should be noted. Testing for antinuclear antibodies (ANA), rheumatoid factor (RF), and anti-citrullinated protein antibodies (ACPA) could be helpful if the features of inflammatory arthritis persist. In suspected cases of viral arthritis, the serum should be collected for serology. Serologic testing, however, must be directed against the specific viruses suspected based upon both epidemiologic and clinical data. As a general rule with serology, an IgM antibody response would be indicative of acute infection and would be converted to an IgG isotype after a few weeks. Due to the high rate of infections in the general population, for example, with EBV and hepatitis, positive IgG antibodies, especially if stable in titers, are non-diagnostic. Other laboratory features are related to the specific viral syndromes. For example, the detection of positive HBsAg elevated aminotransferases and IgM anti-HBc antibodies in a patient with recent-onset polyarthritis could provide the clue to the diagnosis of HBV-associated polyarthritis. Isolation of virus from the joint itself or viral cultures is not useful except in rare circumstances. A 33-year-old man presented malar rash in April, 1992. The rash had gradually developed and he was admitted to our hospital in February, 1994. Laboratory findings showed proteinuria of 0.5-0.8 g/ day, thrombocytopenia (4.8 x 10(4)/mm3), false positive serologic test for syphilis, anti-nuclear antibody with a speckled type at a titer of 1 : 80. Activated partial thromboplastin time was prolonged (41.3 s), and anti-beta 2-GPI antibody was strongly positive (56.6 U/ml on enzyme linked immunosorbent assay). The diagnosis of systemic lupus erythematosus with antiphospholipid syndrome was made and prednisolone 60 mg/day improved his manifestations. He could be discharged in July, 1994. Nine months after the discharge he developed dyspnea, and he was admitted to our hospital again. On admission the blood pressure was 212/170 mmHg, Levine III/VI systolic murmur was noted at the apex of heart. Significant laboratory findings showed as follows: WBC 15, 110/mm3 (Neu 73%, Lym 18%), RBC 380 x 10(4)/mm3, Hb 10.2 g/dl, Plt 20.0 x 10(4)/mm3, GOT 23 IU/l, GPT 21. Diagnosis Blood tests in PNH show changes consistent with intravascular hemolytic anemia: low hemoglobin, raised lactate dehydrogenase, raised bilirubin (a breakdown product of hemoglobin), and decreased levels of haptoglobin; there can be raised reticulocytes (immature red cells released by the bone marrow to replace the destroyed cells) if there is no iron deficiency present. The direct antiglobulin test (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by antibodies. If the PNH occurs in the setting of known (or suspected) aplastic anemia, abnormal white blood cell counts and decreased platelet counts may be seen at this. In this case, anemia may be caused by insufficient red blood cell production in addition to the hemolysis. Meningococcal infections are important health problems causing high morbidity and mortality. Neisseria meningitidis have 13 serogroups. A, B, C, Y and W135 are the most common causes of invasive disease among those serogroups. The distribution of the serogroups differs according to the geographical regions and the age groups. In this case report, two cases of meningococcemia infected with serogroup C and Y of N.meningitidis rarely seen in our country were presented. First case was a two and a half year-old female patient who has admitted to our pediatric emergency unit with fever and rash spreading from lower extremities to her body. The patient had diffuse purpuric rash with generalized weakness and tendency to sleep at admission. The patient has been suspected as meningococcemia because of the skin rash, tendency to sleep and hypotension. Antibiotics treatment was started immediately and lumber puncture was performed. In blood tests, leukocyte count: 3600/mm3 (61% neutrophils), hemoglobin: 11.1 g/ dl, platelet count: 127.000/mm3 , C-reactive protein: 10 mg/dl, erythrocyte sedimentation rate: 6 mm/ hour, prothrombin time: 28.8 seconds (normal value= 11-16), prothrombin activity: 36%, international normalized ratio (INR): 2.13 (normal value= 1-1.5), activated partial thromboplastin time: 57.7 seconds (normal value= 25-35 sec), fibrinogen: 246 mg/dl (normal value= 200-400 mg/dl) and in cerebrospinal fluid protein: 21 mg/dl and glucose: 62 mg/dl were found. There were eight cells in the microscopic examination. Skin rashes were increased and the patient became hypotensive. No microorganisms were isolated in blood and cerebrospinal cultures. N.meningitidis serogroup C was isolated from the cerebrospinal fluid of the patient using polymerase chain reaction (PCR). The patient suffered from immune-mediated arthritis in the sixth day of treatment and nonsteroidal anti-inflammatory drugs were given. The patient has recovered with antibiotics, fresh frozen plasma and inotropic treatment. Second case was a 13 year-old male patient who has admitted three days after the first case with a pre-diagnosis of malignancy because of pancytopenia and fever. The patient had generalized weakness and a few petechial purpuric rashes at the facial region at admission. After the admission general status of the patient has worsened rapidly and he has died as a result of cardiovascular arrest. Blood tests in admission showed leukocyte count: 6000/mm3 (79% neutrophils), hemoglobin: 17.3 mg/dl, platelet count: 16.000/mm3 , C-reactive protein: 8.63 mg/dl, prothrombin time: 92.6 seconds, prothrombin activity: 10%, INR: 6.78, activated partial thromboplastin time: 231.5 seconds. Cerebrospinal fluid obtained from postmortem lumbar puncture showed no growth (protein: 95 mg/dl, glucose: 35 mg/dl) and N.meningitidis serogroup Y was detected by PCR. Two meningococcemia cases caused by two different serogroups which are rarely seen in our region in recent years were presented at the same time period in the same hospital. This case report pointed out that surveillance has a great importance in such diseases. A 52-year-old male with no significant past medical history reports increasing generalized fatigue and weakness for the past 2 weeks. Physical examination reveals jaundice and pallor without organomegaly or lymphadenopathy. His hemoglobin was 5.9 g/dL with a mean corpuscular volume of 87.1 fL and elevated red blood cell distribution width of 30.7%. His liver function test was normal except for elevated total bilirubin of 3.7 mg/dL. Serum LDH was 701 IU/L, and serum haptoglobin was undetectable. Further investigation revealed serum vitamin B12 of &lt;30 pg/mL with elevated methylmalonic acid and homocysteine level. In addition, serum ferritin and transferrin saturation were low. The patient was diagnosed with hemolytic anemia secondary to vitamin B12 deficiency with concomitant iron deficiency anemia.  A 70-year-old woman was admitted to our hospital in November 1992 for evaluation of anemia. Physical examination revealed anemia, jaundice, swelling of axial and inguinal lymph nodes, and splenomegaly. Abnormal hematological findings were as follows: Hb of 3.9 g/dl, reticulocyte count of 58.2% (61.7 x 10(4)/microliters), hyperplasia of normal erythroblasts in bone marrow, and eosinophilia (21.0%, 2352/microliters) in peripheral blood. Routine laboratory examinations revealed polycolonal hypergammaglobulinemia 3.0 g/dl, a high level of serum LDH (797 IU/I) and a total bilirubin of 2.4 mg/dl (indirect, 1.6 mg/dl). The serum haptoglobin level was very low (&lt; 5 mg/dl). Results of serological examinations were as follows: IgG of 3366 mg/dl, CH50 of 16.0 U/ml, positive Coombs test 2+, and positive tests for antinuclear antibody, rheumatoid factor, and cold agglutinin. CRP was negative. PHA-stimulated lymphocyte blast formation, NK activity, and ADCC activity were found to be suppressed, and the percentage of CD4-positive lymphocytes in peripheral blood was also low. An axillary lymph node biopsy revealed reactive lymphadenitis. No signs or history suggested allergy, collagen disease, or parasitic infection. Autoimmune hemolytic anemia (AIHA) complicated by immunologic abnormalities and eosinophilia was diagnosed. Oral prednisolone markedly reduced the hemolytic anemia, eosinophilia, lymph node swelling, and splenomegaly, but NK activity remained low.\nHere is the question:\nRHEUMATOLOGY: A 25-year-old female patient with a history of skin rash after sun exposure and occasional polyarthritis in the joints of the hands, controlled with non-steroidal anti-inflammatory drugs, presents with general malaise, progressive feeling of generalized weakness and pallor for the last 15 days. Laboratory tests showed hemoglobin 7 g/dL, MCV 108 mm/h, 150,000 platelets/mm3, 3000 leukocytes/mm3, elevated LDH, undetectable haptoglobin. In the case of choosing a single diagnostic test indicate which of the following determinations should be performed first:\nHere are the potential choices:\n1. Direct Coombs test.\n2. Antinuclear antibodies (ANA).\n3. Vitamin B12.\n4. Ferritin.\n5. Folic acid.\nThe correct answer is: ",
        "gold_answer": "1 Direct Coombs test.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n An elderly case of systemic lupus erythematosus (SLE) with suspected hemolytic anemia was experienced. A 70 year-old female was admitted to our hospital on December 31 with complaints of herpetic eruption. She complained of arthralgia since 3 month prior to her admission. The positive findings on examination were skin eruption in the left chest, a systolic heart murmur and a palpable elastic hard liver. Laboratory data showed raised erythrocyte sedimentation rate of 149 mm per hour, decreased Hb (10.1 g/dl), decreased hematocrit (30.0%), increased reticulocytes (33%1000), decreased thrombocytes (73,000/mm3), increased gamma-globulin (33%) and positive rheumatoid factor. During admission, she developed anemia. A stool test for occult blood was negative. The haptoglobin was 38.8 mg/dl and bone marrow aspiration showed increased erythropoiesis, suggesting features of immune hemolytic anemia, except she was negative on Coomb'test. Eye fundi were similar to case of typical bleeding observed in SLE. Concerning immunological findings, the antinuclear factor was x 1280 and the anti-dsDNA antibody was x 80, on which a diagnosis of SLE was based. She experienced numbness of the left arm and developed left hemiparesis 2 days later. Therapy with 15 mg/day prednisone obtained a good response and anemia, abnormal immunological findings and hemiparesis disappeared. BACKGROUND Patients with late-onset systemic lupus erythematosus (SLE) do not present with typical SLE symptoms or serology, and this can lead to a major delay in diagnosis. We report a complex case of an older woman who developed autoimmune hemolytic anemia and sixth cranial nerve palsy that posed considerable challenges in diagnosing late-onset SLE. CASE REPORT A 78-year-old Japanese woman presented with polyarthritis associated with generalized fatigue for 2 months, who later developed diplopia. Physical examination revealed conjunctival pallor, polyarthritis, and subsequent development of sixth cranial nerve palsy. Laboratory data revealed a decreased white blood cell count; macrocytic anemia; elevated levels of lactate dehydrogenase, indirect bilirubin, and erythrocyte sedimentation rate; hypocomplementemia; positive Coombs test; antinuclear antibodies (ANAs, 1: 40); and positive anti-double-strand DNA antibodies. Lymphoma, cerebral venous sinus thrombosis, and varicella-zoster virus infection were unlikely based on head computed tomography, brain magnetic resonance imaging, and cerebrospinal fluid analysis. She was diagnosed with late-onset SLE associated with autoimmune hemolytic anemia and sixth cranial nerve palsy. The patient was successfully treated with prednisone and hydroxychloroquine. CONCLUSIONS The difficulty in diagnosing late-onset SLE with atypical presentations and uncommon complications must be recognized. SLE cannot be excluded based on a low titer of ANA in a particular subgroup such as the elderly, and the prozone effect should be considered responsible for low ANA titers. In this case, late-onset SLE was diagnosed by considering multisystem pathologies despite low ANA titers. Fever >38.3°C (101°F) on at least two occasions 2. Illness duration of ≥3 weeks 3. 4. Diagnosis that remains uncertain after a thorough history-taking, physical examination, and the following obligatory investigations: determination of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level; platelet count; leukocyte count and differential; measurement of levels of hemoglobin, electrolytes, creatinine, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, ferritin, antinuclear antibodies, and rheumatoid factor; protein electrophoresis; urinalysis; blood cultures (n = 3); urine culture; chest x-ray; abdominal ultrasonography; and tuberculin skin test (TST). The range of FUO etiologies has evolved over time as a result of changes in the spectrum of diseases causing FUO, the widespread Percentage of Cases Due to Indicated Cause History A 46-year-old woman with known mixed connective tissue disease with clinical features of scleroderma and polymyositis and who was not on specific medications was referred to our institution to assess for interstitial lung disease due to her predisposing condition. She was a nonsmoker, had no respiratory symptoms, and enjoyed good exercise tolerance. She did not have any cutaneous lesions or renal disease. There was no family history of pulmonary or systemic disease. Her routine blood test results revealed a white blood cell count of 4.6 × 10<sup9</sup/L (normal range, [4.4-10.1] × 10<sup9</sup/L), a hemoglobin level of 7.76 mmol/L (normal range, 7.26-9.18 mmol/L), a platelet count of 189 × 10<sup9</sup/L (normal range, [170-380] × 10<sup9</sup/L), a bilirubin level of 8 μmol/L (7-19 μmol/L), and a creatinine level of 63 μmol/L (45-82 μmol/L), all within normal limits. Lung function tests at presentation yielded normal results, with a diffusing capacity for carbon monoxide of 95% and a forced vital capacity of 2.29 (98% predicted value). However, this patient had an elevated serum globulin level of 47 g/L (normal range, 26-32 g/L) and an erythrocyte sedimentation rate of 36 mm/h (normal range, 0-20 mm/h), while C-reactive protein level was normal at less than 0.35 mg/dL. She was seropositive for antinuclear (titer &gt;1/720), anti-Ro, anti-La, and anti-extractable nuclear antigen antibodies. Chest radiography and CT were performed at presentation (Figs 1, 2) and 14-year follow-up (Figs 3, 4). PET/CT was performed at 7- (Fig 5, <iA</i and <iB</i) and 13-year follow-up (Fig 5, <iC</i and <iD</i). Throughout this 14-year follow-up period, she remained completely free of respiratory symptoms and continued to go for a brisk walk every day. At 14-year follow-up, there was no substantial change in serum laboratory values, but a lung function test revealed her diffusing capacity for carbon monoxide had decreased to 52%, while her forced vital capacity remained good at 95%; these findings were suggestive of interval development of restrictive lung function. Fever ˜38.3° C (101° F) and illness lasting ˜3 weeks and no known immunocompromised state History and physical examination Stop antibiotic treatment and glucocorticoids Obligatory investigations: ESR and CRP, hemoglobin, platelet count, leukocyte count and differential, electrolytes, creatinine, total protein, protein electrophoresis, alkaline phosphatase, AST, ALT, LDH, creatine kinase, antinuclear antibodies, rheumatoid factor, urinalysis, blood cultures (n=3), urine culture, chest x-ray, abdominal ultrasonography, and tuberculin skin test A 49-year-old woman with type 2 diabetes mellitus (T2DM) presented to the emergency department. Her examination showed marked pallor, exhaustion, lethargy, yellowish eyes, anorexia, nausea and vomiting. Hematuria; negative standard direct antiglobulin test (DAT); normal glucose 6 phosphate dehydrogenase (G6PD); hemoglobin (Hb), 4.8 g/dl; Mean cell volume (MCV), 91fl; platelet count, 233 × 10<sup6</sup/L; Total bilirubin, 7.0 mg/dl; Glucose, 316 mg/dl; lactate dehydrogenase (LDH), 1750U/L. Undoubtedly, therapeutic panel should have been used for hemolytic anemia. Intravenous (IV) fluids and 2 units of packed cell were transfused. Methylprednisolone with rituximab were started for the patient. After 3 weeks of the patient admission, she was discharged home with stable vital signs and Hb, 10 g/dl. We concluded in the cases that presented along with a severe drop in Hb and evidence of hemolysis which non immune hemolytic anemia is excluded in spite of negative standard DAT limited transfusion besides corticosteroids combined with rituximab, could be helpful in saving the patient. The by far most common clinical test for ACPAs is the anti-cyclic citrullinated peptide (anti CCP) ELISA. In 2008 a serological point-of-care test for the early detection of RA combined the detection of RF and anti-MCV with a sensitivity of 72% and specificity of 99.7%. Other blood tests are usually done to differentiate from other causes of arthritis, like the erythrocyte sedimentation rate (ESR), C-reactive protein, full blood count, kidney function, liver enzymes and other immunological tests (e.g., antinuclear antibody/ANA) are all performed at this stage. Elevated ferritin levels can reveal hemochromatosis, a mimic of RA, or be a sign of Still's disease, a seronegative, usually juvenile, variant of rheumatoid arthritis. Classification criteria In 2010, the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria were introduced. Although severe vitamin B12 deficiency is rare in the United States, recent increases in the adoption of vegan lifestyles have led to a significant rise in the rates of B12 deficiency, along with its hematologic and neurologic sequelae, the latter of which is often irreversible. We describe a case of a 39-year-old male who presented with a several-month history of progressively worsening word-finding difficulties, shortness of breath, and a four-day history of bilateral hand numbness and tingling. Laboratory data revealed pancytopenia with profound anemia. Markers of hemolysis were positive, including elevated indirect bilirubin, disproportionately elevated lactate dehydrogenase (LDH), low haptoglobin, negative direct anticoagulant test, and hypoproliferative reticulocyte index. Blood smear revealed hypersegmented neutrophils and macrocytosis. Vitamin B12 levels were undetectable, and anti-intrinsic factor and parietal cell antibodies were negative. A thorough history revealed a 20-year history of strict veganism without B12 supplementation. He was transfused with packed red blood cells and started on subcutaneous B12 injections with rapid improvement of his symptoms. Early recognition of B12 deficiency causing the constellation of pancytopenia, hemolytic anemia, and neurologic symptoms is vital in preventing irreversible neurologic sequelae. This case also highlights the importance of accurate history taking to aid in early diagnosis of B12 deficiency, especially in the context of rising rates of veganism in the United States. A 67-year-old woman was admitted to our hospital with a fever. She had been experiencing arthralgia for about one month. On admission, she had a fever of 38.5 degrees C, was anemic and was experiencing tenderness in the joints of both hands, elbows and feet. Laboratory data revealed proteinuria, urinary cylinders, pancytopenia (WBC 900/mm3, Hb 9.5 g/dl, Plt 7.8 x 10(4)/mm3), liver dysfunction (GOT 414 IU/l, GPT 140 IU/l), and hyper-gamma globulinemia. Antibiotics and granulocyte-colony stimulating factor were administered intravenously. Bone marrow aspiration was unsuccessful, but a bone marrow biopsy revealed bone marrow fibrosis. Immunological examinations were positive for antinuclear antibodies, anti-deoxyribonucleic acid (DNA) antibodies, anti-double stranded anti- DNA antibodies, as well as a decreased level of serum complement and an increased level of serum immune complexes. Tests for viral antigens and antibodies known to cause hepatitis were negative. Based on these findings, a diagnosis of SLE accompanied by liver dysfunction and bone marrow fibrosis was made. Steroid pulse therapy was initiated, but her liver function deteriorated on the first day of steroid therapy, and she died three days later. SLE accompanied by myelofibrosis is extremely rare, and only 17 and cases have been reported to date. Among these reports, the present case is the second oldest subject and the first SLE patient to suffer from both myelofibrosis and severe liver dysfunction. Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology. It is characterized by fever, skin rash, polyarthralgias or polyarthritis, sore throat, hepatosplenomegaly, lymphadenopathy, leukocytosis, liver enzyme elevation, and high serum level of ferritin. Several kinds of skin lesions have been reported in this condition. The aim of this study was to assess the clinical and laboratory aspects of 28 patients with AOSD in central Iran. According to the diagnostic criteria of AOSD, we identified 28 patients between 2002 and 2007. We intended to describe the clinical characteristics, treatment, and outcome of our patients with AOSD. Of 28 patients with AOSD, 21 (75%) were female, 7 (25%) were male. Fever (100%), sore throat (92%), Arthralgia (92%), dermatographism (92%), typical rash (85%) and arthritis (60%) were the most common findings. The mean values of laboratory findings were as follows; C-reactive protein (CRP) level of 14.4 mg/dl, erythrocyte sedimentation rate (ESR) of 91.5 mm/h, leukocyte count of 15744.4/microl. Abnormal levels of aspartate aminotransferase and alanine aminotransferase were observed in 25 (89%) patients. Twenty patients (71%) had high ferritin values (&gt;500 ng/ml). The clinical characteristics were similar to previous series. A febrile polyarthritis was the most frequent presentation form. Dermatographism was frequently encountered phenomenon in our patients with AOSD. Being that dermatographism is a simple inducible skin reaction, along with its sensitivity in active disease, we suggest more controlled studies to validate accuracy and positive predictive value of it in convenient clinical setting in the diagnosis of AOSD and to consider including it in diagnostic criteria. Laboratory investigations are carried out to determine the etiology of the disease. Following confirmation of hemolysis (seen with laboratory markers of low hemoglobin, elevated LDH, decreased haptoglobin, and elevated unconjugated bilirubin), a direct antiglobulin test (DAT)(also known as a Coomb's test) is done to show auto-immune pathogenesis with antibodies, compliment or both on the erythrocyte surface. This is followed by a monospecific DAT that identifies the specific antibody and compliment types on the erythrocyte surface. In cold agglutinin disease, the monospecific DAT is by definition positive for the compliment molecule C3d but IgM may be negative as the molecule may detach at the time of testing. The diagnosis of cold agglutinin disease is confirmed with an elevated cold agglutinin titer. A bone marrow biopsy is used in AIHA to identify a possible underlying lymphoproliferative disorder. There is no single test or clinical presentation which is suggestive of viral arthritis. The diagnosis is mainly clinical, supported by other tests, including inflammatory markers, autoantibodies, and serology. A viral etiology should be suspected in a patient presenting with acute onset of arthralgias or polyarticular symptoms, especially if the duration of symptomatology has been less than six weeks. The presence of extra-articular symptoms, viz rash or lymphadenopathy, should be noted. Testing for antinuclear antibodies (ANA), rheumatoid factor (RF), and anti-citrullinated protein antibodies (ACPA) could be helpful if the features of inflammatory arthritis persist. In suspected cases of viral arthritis, the serum should be collected for serology. Serologic testing, however, must be directed against the specific viruses suspected based upon both epidemiologic and clinical data. As a general rule with serology, an IgM antibody response would be indicative of acute infection and would be converted to an IgG isotype after a few weeks. Due to the high rate of infections in the general population, for example, with EBV and hepatitis, positive IgG antibodies, especially if stable in titers, are non-diagnostic. Other laboratory features are related to the specific viral syndromes. For example, the detection of positive HBsAg elevated aminotransferases and IgM anti-HBc antibodies in a patient with recent-onset polyarthritis could provide the clue to the diagnosis of HBV-associated polyarthritis. Isolation of virus from the joint itself or viral cultures is not useful except in rare circumstances. A 33-year-old man presented malar rash in April, 1992. The rash had gradually developed and he was admitted to our hospital in February, 1994. Laboratory findings showed proteinuria of 0.5-0.8 g/ day, thrombocytopenia (4.8 x 10(4)/mm3), false positive serologic test for syphilis, anti-nuclear antibody with a speckled type at a titer of 1 : 80. Activated partial thromboplastin time was prolonged (41.3 s), and anti-beta 2-GPI antibody was strongly positive (56.6 U/ml on enzyme linked immunosorbent assay). The diagnosis of systemic lupus erythematosus with antiphospholipid syndrome was made and prednisolone 60 mg/day improved his manifestations. He could be discharged in July, 1994. Nine months after the discharge he developed dyspnea, and he was admitted to our hospital again. On admission the blood pressure was 212/170 mmHg, Levine III/VI systolic murmur was noted at the apex of heart. Significant laboratory findings showed as follows: WBC 15, 110/mm3 (Neu 73%, Lym 18%), RBC 380 x 10(4)/mm3, Hb 10.2 g/dl, Plt 20.0 x 10(4)/mm3, GOT 23 IU/l, GPT 21. Diagnosis Blood tests in PNH show changes consistent with intravascular hemolytic anemia: low hemoglobin, raised lactate dehydrogenase, raised bilirubin (a breakdown product of hemoglobin), and decreased levels of haptoglobin; there can be raised reticulocytes (immature red cells released by the bone marrow to replace the destroyed cells) if there is no iron deficiency present. The direct antiglobulin test (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by antibodies. If the PNH occurs in the setting of known (or suspected) aplastic anemia, abnormal white blood cell counts and decreased platelet counts may be seen at this. In this case, anemia may be caused by insufficient red blood cell production in addition to the hemolysis. Meningococcal infections are important health problems causing high morbidity and mortality. Neisseria meningitidis have 13 serogroups. A, B, C, Y and W135 are the most common causes of invasive disease among those serogroups. The distribution of the serogroups differs according to the geographical regions and the age groups. In this case report, two cases of meningococcemia infected with serogroup C and Y of N.meningitidis rarely seen in our country were presented. First case was a two and a half year-old female patient who has admitted to our pediatric emergency unit with fever and rash spreading from lower extremities to her body. The patient had diffuse purpuric rash with generalized weakness and tendency to sleep at admission. The patient has been suspected as meningococcemia because of the skin rash, tendency to sleep and hypotension. Antibiotics treatment was started immediately and lumber puncture was performed. In blood tests, leukocyte count: 3600/mm3 (61% neutrophils), hemoglobin: 11.1 g/ dl, platelet count: 127.000/mm3 , C-reactive protein: 10 mg/dl, erythrocyte sedimentation rate: 6 mm/ hour, prothrombin time: 28.8 seconds (normal value= 11-16), prothrombin activity: 36%, international normalized ratio (INR): 2.13 (normal value= 1-1.5), activated partial thromboplastin time: 57.7 seconds (normal value= 25-35 sec), fibrinogen: 246 mg/dl (normal value= 200-400 mg/dl) and in cerebrospinal fluid protein: 21 mg/dl and glucose: 62 mg/dl were found. There were eight cells in the microscopic examination. Skin rashes were increased and the patient became hypotensive. No microorganisms were isolated in blood and cerebrospinal cultures. N.meningitidis serogroup C was isolated from the cerebrospinal fluid of the patient using polymerase chain reaction (PCR). The patient suffered from immune-mediated arthritis in the sixth day of treatment and nonsteroidal anti-inflammatory drugs were given. The patient has recovered with antibiotics, fresh frozen plasma and inotropic treatment. Second case was a 13 year-old male patient who has admitted three days after the first case with a pre-diagnosis of malignancy because of pancytopenia and fever. The patient had generalized weakness and a few petechial purpuric rashes at the facial region at admission. After the admission general status of the patient has worsened rapidly and he has died as a result of cardiovascular arrest. Blood tests in admission showed leukocyte count: 6000/mm3 (79% neutrophils), hemoglobin: 17.3 mg/dl, platelet count: 16.000/mm3 , C-reactive protein: 8.63 mg/dl, prothrombin time: 92.6 seconds, prothrombin activity: 10%, INR: 6.78, activated partial thromboplastin time: 231.5 seconds. Cerebrospinal fluid obtained from postmortem lumbar puncture showed no growth (protein: 95 mg/dl, glucose: 35 mg/dl) and N.meningitidis serogroup Y was detected by PCR. Two meningococcemia cases caused by two different serogroups which are rarely seen in our region in recent years were presented at the same time period in the same hospital. This case report pointed out that surveillance has a great importance in such diseases. A 52-year-old male with no significant past medical history reports increasing generalized fatigue and weakness for the past 2 weeks. Physical examination reveals jaundice and pallor without organomegaly or lymphadenopathy. His hemoglobin was 5.9 g/dL with a mean corpuscular volume of 87.1 fL and elevated red blood cell distribution width of 30.7%. His liver function test was normal except for elevated total bilirubin of 3.7 mg/dL. Serum LDH was 701 IU/L, and serum haptoglobin was undetectable. Further investigation revealed serum vitamin B12 of &lt;30 pg/mL with elevated methylmalonic acid and homocysteine level. In addition, serum ferritin and transferrin saturation were low. The patient was diagnosed with hemolytic anemia secondary to vitamin B12 deficiency with concomitant iron deficiency anemia.  A 70-year-old woman was admitted to our hospital in November 1992 for evaluation of anemia. Physical examination revealed anemia, jaundice, swelling of axial and inguinal lymph nodes, and splenomegaly. Abnormal hematological findings were as follows: Hb of 3.9 g/dl, reticulocyte count of 58.2% (61.7 x 10(4)/microliters), hyperplasia of normal erythroblasts in bone marrow, and eosinophilia (21.0%, 2352/microliters) in peripheral blood. Routine laboratory examinations revealed polycolonal hypergammaglobulinemia 3.0 g/dl, a high level of serum LDH (797 IU/I) and a total bilirubin of 2.4 mg/dl (indirect, 1.6 mg/dl). The serum haptoglobin level was very low (&lt; 5 mg/dl). Results of serological examinations were as follows: IgG of 3366 mg/dl, CH50 of 16.0 U/ml, positive Coombs test 2+, and positive tests for antinuclear antibody, rheumatoid factor, and cold agglutinin. CRP was negative. PHA-stimulated lymphocyte blast formation, NK activity, and ADCC activity were found to be suppressed, and the percentage of CD4-positive lymphocytes in peripheral blood was also low. An axillary lymph node biopsy revealed reactive lymphadenitis. No signs or history suggested allergy, collagen disease, or parasitic infection. Autoimmune hemolytic anemia (AIHA) complicated by immunologic abnormalities and eosinophilia was diagnosed. Oral prednisolone markedly reduced the hemolytic anemia, eosinophilia, lymph node swelling, and splenomegaly, but NK activity remained low.\nHere is the question:\nRHEUMATOLOGY: A 25-year-old female patient with a history of skin rash after sun exposure and occasional polyarthritis in the joints of the hands, controlled with non-steroidal anti-inflammatory drugs, presents with general malaise, progressive feeling of generalized weakness and pallor for the last 15 days. Laboratory tests showed hemoglobin 7 g/dL, MCV 108 mm/h, 150,000 platelets/mm3, 3000 leukocytes/mm3, elevated LDH, undetectable haptoglobin. In the case of choosing a single diagnostic test indicate which of the following determinations should be performed first:\nHere are the potential choices:\n1. Direct Coombs test.\n2. Antinuclear antibodies (ANA).\n3. Vitamin B12.\n4. Ferritin.\n5. Folic acid.\nThe correct answer is: 1. Direct Coombs test."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 37-year-old woman experienced painless, progressive vision loss to no light perception in the left eye over the course of 3 days. The right eye was unaffected. On examination, the only other abnormal finding was a +4 left afferent pupillary defect. She was initially diagnosed with retrobulbar optic neuritis and admitted for treatment with intravenous methylprednisolone. Neuro-imaging revealed a large right anterior cerebral artery aneurysm that crossed the midline to compress the left optic nerve. The aneurysm was treated with coil embolization, which was technically successful but which did not lead to significant improvement in vision. A 75-year-old Caucasian woman presented with sudden-onset multifocal scotomas in her right eye's central vision for 1 day. There were subtle white intraretinal foveal lesions that correlated with patchy inner retinal hyperreflectivity on optical coherence tomography, suggestive of paracentral acute middle maculopathy. Initial cerebrovascular work-up was negative. Review of systems was positive for lethargy and jaw claudication. The sedimentation rate and c-reactive protein were elevated, but platelet count was normal. The patient was started on 60 mg oral prednisone daily and underwent bilateral temporal artery that confirmed the diagnosis of giant cell arteritis. A careful neurologic examination is an essential first step in the evaluation. In most cases, patients with an abnormal examination or a history of recent-onset headache should be evaluated by a computed tomography (CT) or magnetic resonance imaging (MRI) study. As an initial screening procedure for intracranial pathology in this setting, CT and MRI methods appear to be equally sensitive. In some circumstances, a lumbar puncture (LP) is also required, unless a benign etiology can be otherwise established. A general evaluation of acute headache might include cranial arteries by palpation; cervical spine by Pain induced by bending, lifting, cough Pain associated with local tenderness, e.g., region of temporal artery the effect of passive movement of the head and by imaging; the investigation of cardiovascular and renal status by blood pressure monitoring and urine examination; and eyes by funduscopy, intraocular pressure measurement, and refraction. Giant cell arteritis Giant cell arteritis should be considered in an older person with jaw claudication, temporal pain, and tiredness. Placing the person on steroids might save both their vision and decrease their risk of stroke. Without treatment a person can quickly go blind in both eyes. Vascular occlusions Central retinal artery occlusion: CRAO is characterized by painless, acute vision loss in one eye. Central retinal vein occlusion: CRVO causes sudden, painless vision loss that can be mild to severe. Branch retinal vein occlusion: sudden painless vision loss or visual field defect are the main symptom of BRVO. Branch retinal artery occlusion: BRAO may also cause acute painless loss of vision. Vitreous hemorrhage It is one of the most common causes of acute or subacute decrease in vision. Hyphema Blood in the anterior chamber of the eye is known as hyphema. Severe hyphema covering pupillary area can cause sudden decrease in vision. References Blindness Magnetic resonance angiography (MRA) or CT angiography (CTA) can be used to examine cerebral blood vessels and to rule out vascular abnormalities, such as an aneurysm. In cases where intracranial vascular lesions, for example, subarachnoid hemorrhage cannot be completely ruled out after performing MRA or CTA, physicians may consider using traditional digital subtraction angiography (DSA) for more detailed investigation. Laboratory tests Lumbar punctures and blood tests might be performed on those with RPON to identify other possible causes of cranial neuropathy, including diabetes, inflammatory diseases, infections, tumors, and other systemic diseases that involve either the central nervous system or the peripheral nervous system. The detection of abnormalities in these tests suggests that RPON is highly unlikely to be the culprit in cranial neuropathy, and more diagnostic tests should be done to find out the underlying condition. The purpose is to report a patient with primary open-angle glaucoma that developed sudden painless unilateral vision loss, a sequential ophthalmoscopic appearance with features of both central retinal artery and later central retinal vein occlusion, and objective visual system dysfunction in the form of a relative afferent pupil defect, who spontaneously recovered vision along with complete resolution of the pupillary defect over several weeks. A 50-year-old woman with a long-standing history of glaucoma presented with acute, painless vision loss in one eye, a pallid retina with a cherry red macula, diffuse retinal hemorrhages, and a relative afferent pupil defect. Spectral domain optical coherence tomography and fluorescein angiography were essentially normal with neither retinal edema nor retinal ischemia to account for the visual dysfunction. Over the course of 2 months, the patient regained vision and the relative afferent pupil defect, typically a permanent manifestation of retinal destruction, resolved. Not all retinal vaso-occlusive phenomena can be completely attributed to a central retinal vein or artery occlusion. In the patient presented, there was no objective diagnostic testing that revealed a cause for the patient's vision loss or relative afferent pupillary defect. This combined with the complete recovery of vision and resolution of the relative afferent pupillary defect underscores a lack of comprehensive understanding of retinal vaso-occlusive disease. A 71-year-old man visited our clinic with a 3-day history of severe throbbing headache and 1-day history of horizontal diplopia. He had had jaw claudication and pain in the neck and shoulder several days previously. His right eye was slightly esotropic and did not move laterally. There was no blepharoptosis, proptosis, lid edema, or conjunctival injection. The pupils were unremarkable. The remainder of the cranial nerve functions was intact. There was no limb weakness or sensory impairment. Superficial temporal arteries were swollen and tender on both sides. Laboratory examination showed elevated CRP level and high erythrocyte sedimentation rate. Cranial MR images were unremarkable. The cerebrospinal fluid was acellular with 45 mg/dl of protein. A diagnosis of temporal arteritis was made. Treatment with 50 mg of prednisolone brought about prompt disappearance of the headache. Right ocular movement fully recovered in 10 days. Temporal artery biopsy findings and response to corticosteroid were consistent with temporal arteritis. The motility pattern of the right eye was consistent with complete abducens nerve palsy, which is a rare manifestation of temporal arteritis. Although temporal arteritis is a rare cause of ophthalmoplegia in the elderly patients, swift diagnosis and treatment is necessary to avoid blindness. One recommended diagnostic approach is as follows. If any urgent red flags are present such as visual loss, new seizures, new weakness, new confusion, further workup with imaging and possibly a lumbar puncture should be done (see red flags section for more details). If the headache is sudden onset (thunderclap headache), a computed tomography test to look for a brain bleed (subarachnoid hemorrhage) should be done. If the CT scan does not show a bleed, a lumbar puncture should be done to look for blood in the CSF, as the CT scan can be falsely negative and subarachnoid hemorrhages can be fatal. If there are signs of infection such as fever, rash, or stiff neck, a lumbar puncture to look for meningitis should be considered. If there is jaw claudication and scalp tenderness in an older person, a temporal artery biopsy to look for temporal arteritis should be performed and immediate treatment should be started. Neuroimaging Leber hereditary optic neuropathy (LHON) is an inherited mitochondrial disease characterized by painless vision loss affecting both eyes. The disease usually develops in both eyes within weeks to months of onset. We report a case of LHON who presented with unilateral vision loss in childhood with an interval of more than 30 years between vision loss in the two eyes. A 43-year-old man presented with a 1-month history of vision loss in his right eye. At 9 years of age, his visual acuity in the left eye declined, and he had been treated with glaucoma eyedrops bilaterally at his eye clinic. At his first visit to our hospital, his BCVA was 0.15 in the right eye and 0.1 in the left eye, and critical flicker frequency was 16 Hz in the right eye and 15 Hz in the left eye, and he was negative for a relative afferent pupillary defect. The Goldman visual field showed central scotoma in both eyes. Fundus examination revealed slight redness of the right optic disc with meandering retinal small vessels, and the left optic disc had a slight pallor. Fluorescein angiography could not be performed because of liver dysfunction. OCT showed prominent bilateral thinning of the RNFL and retinal ganglion cell layer. Enhancement of the optic nerve was not apparent on orbital gadolinium-enhanced magnetic resonance imaging. Hematologic analysis revealed macrocytic anemia and low levels of vitamin B12 and folate. His mother had a presumptive diagnosis of LHON but did not receive genetic testing. A male cousin also had severe vision loss. Based on the likely family history of LHON, we performed genetic testing, which revealed the 11778 mitochondrial point mutation associated with this condition. We report a case of LHON with 34 years interval in vision loss in the fellow eye. LHON may develop in the second eye decades after its onset in the first. Detailed medical interviews and scrutiny, such as examination of family history, are warranted in consideration of LHON. If a 20-year-old female develops headaches after drinking red wine, think migraine. Associated symptoms/signs: Significant findings include fever or rash (consider meningitis or other infectious causes), jaw claudication (specific for temporal arteritis), or constitutional symptoms such as weight loss (associated with neoplastic, inflammatory, or infectious conditions). Photophobia, nausea, and vomiting are associated with migraine, aneurysmal SAH, and meningitis, but neck stiffness is more likely to accompany the latter two. Neurologic sequelae: Look for diplopia, mental status changes or associated symptoms (numbness, weakness, dizziness, ataxia, visual disturbances), papilledema, or pupillary abnormalities (partial CN III palsy or Horner’s syndrome). Patient risk factors: High-risk patients are > 50 years of age, immunocompromised, or with preexisting malignancy. If SAH is suspected, obtain a head CT without contrast. If CT is , LP is mandatory. Obtain a CBC. Optic neuritis is a common cause of subacute unilateral vision loss, occurring in 1-5 per 100,000 persons per year. It is more common in Caucasians, women, and those from countries with northern latitudes. Those aged 20-49 years are at greatest risk. The condition arises due to inflammation of the optic nerve. Inflammation may occur due to systemic inflammatory disorders, most commonly multiple sclerosis. A 21-year-old African-American male presented to our emergency department with a complaint of painful unilateral vision loss. On examination he was found to have a relative afferent pupillary defect and red desaturation. A bedside ultrasound suggested pseudopapilledema suggestive of optic neuritis. He was admitted to Neurology for confirmation of and treatment for optic neuritis. Magnetic resonance imaging confirmed optic neuritis. The patient was treated with i.v. steroids and discharged after improvement in visual function. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Optic neuritis is a clinical diagnosis. The subtle historical components and examination findings make it a diagnostic challenge for the busy emergency physician. Early diagnosis may improve visual outcomes. Discovery of pseudopapilledema on bedside ultrasound may be seen in optic neuritis, and is another finding that emergency physicians may assess for in patient presenting with unilateral vision loss. We report a 62-year-old man who developed coma and died in a fulminant course. The patient was well until May 1, 1996 when he noted chillness, tenderness in his shoulders, and he went to bed without having his lunch and dinner. In the early morning of May 2, his families found him unresponsive and snoring; he was brought into the ER of our hospital. He had histories of hypertension, gout, and hyperlipidemia since 42 years of the age. On admission, his blood pressure was 120/70, heart rate 102 and regular, and body temperature 36.3 degrees C. His respiration was regular and he was not cyanotic. Low pitch rhonchi was heard in his right lower lung field. Otherwise general physical examination was unremarkable. Neurologic examination revealed that he was somnolent and he was only able to respond to simple questions such as opening eyes and grasping the examiner's hand, but he was unable to respond verbally. The optic discs were flat; the right pupil was slightly larger than the left, but both reacted to light. He showed ptosis on the left side, conjugate deviation of eyes to the left, and right facial paresis. The oculocephalic response and the corneal reflex were present. His right extremities were paralyzed and did not respond to pain Deep tendon reflexes were exaggerated on the right side and the plantar response was extensor on the right. No meningeal signs were present. Laboratory examination revealed the following abnormalities; WBC 18,400/ml, GOT 131 IU/l GPT 50 IU/l, CK616 IU/l, BUN 30 mg/dl, Cr 2.1 mg/ dl, glucose 339 mg/dl, and CRP 27.4 mg/dl. ECG showed sinus tachycardia and ST elevation in II, III and a VF leads and abnormal q waves in I, V5, and V6 leads. Chest X-ray revealed cardiac enlargement but the lung fields were clear. Cranial CT scan revealed low density areas in the left middle cerebral and left posterior cerebral artery territories. The patient was treated with intravenous glycerol infusion and other supportive measures. At 2: 10 AM on May 3, he developed sudden hypotension and cardiopulmonary arrest. He was pronounced dead at 3:45 AM. The patient was discussed in a neurological CPC, and the chief discussant arrived at the conclusion that the patient had acute myocardial infarction involving the inferior and the true posterior walls and left internal carotid embolism from a mural thrombus. Post mortem examination revealed occlusion of the circumflex branch of the left coronary artery due to atherom plaque rupture and myocardial infarction involving the posterior and the lateral wall with a rupture in the postero-lateral wall. Marked atheromatous changes were seen in the left internal carotid, the middle cerebral and the basilar arteries; the left internal carotid and the middle cerebral arteries were almost occluded by thrombi and blood coagulate. The territories of the left middle cerebral and the occipital arteries were infarcted; but the left thalamic area was spared. The neuropathologist concluded that the infarction was thrombotic origin not an embolic one as the atherosclerotic changes were severe. Cardiac rupture appeared to be the cause of terminal sudden hypotension and cardiopulmonary arrest. It appears likely that a vegetation which had been attached to the aortic valve induced thromboembolic occlusion of the left internal carotid artery which had already been markedly sclerotic by atherosclerosis. It is also possible that the vegetations in the aortic valve came from mural thrombi at the site of acute myocardial infarction, as no bacteria were found in those vegetations. To report the case and multimodal imaging findings of a healthy young woman who developed paracentral acute middle maculopathy (PAMM) 9 weeks after COVID-19 disease. Case report. Ultra-widefield fundus photography, macular spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), and OCT-angiography (OCT-A) were performed. A 36-year-old woman who developed PAMM 9 weeks after SARS-CoV-2 infection. A 36-year-old woman went to the emergency department (ED) with sudden, painless, left eye (LE) vision loss. The only relevant past medical history was COVID-19 disease 9 weeks before. Best corrected visual acuity (BCVA) was 20/200, a LE relative afferent pupillary defect (RAPD) was present and superficial hemorrhages throughout the macular area and peripheral retina were found. Nearly four hours after admission, LE BCVA recovered to 20/20 without RAPD. Five days after presentation in the ED, the patient returned with recurrent LE vision loss, with spontaneous recovery within 12 hours. Macular SD-OCT revealed hyperreflectivity of the inner plexiform and inner nuclear layers and the diagnosis of PAMM was established. The patient started oral acetylsalicylic acid and oral prednisolone. The patient did not report any new episodes of vision loss and there was a progressive resolution of abnormal fundus findings. SARS-CoV-2 infection increases the risk of vascular thrombotic events with possible involvement of the retinal circulation, and PAMM may present as a possible complication. Ophthalmologists should be able to recognize it promptly through multimodal imaging findings. In anterior ischemic optic neuropathy (AION), it is important not to miss the diagnosis of giant cell arteritis (GCA) because this requires immediate steroid treatment to prevent involvement of the second eye and possible blindness. A missed diagnosis also might lead to fatal systemic complications. Observational case report. A 79-year-old woman noticed decreased visual and visual field loss in the right eye. At presentation, right visual acuity was 10/20 (ETDRS chart 2000). There was a right relative afferent pupillary defect of 0.6 log units. Asked for symptoms of GCA she complained about temporal and occipital headache, jaw claudication combined with malaise, and myalgia of the upper limbs. Laboratory tests showed normal inflammatory markers. Repeated tests confirmed ESR and CRP to be within the normal range. GCA being suspected, ultrasound of the superficial temporal arteries and temporal artery biopsy were performed unilaterally on the right side. Histology showed a chronic inflammatory cell infiltrate consistent with active GCA. The patient was treated with high-dose corticosteroids (250 mg methylprednisolone, three times/day, initially) and symptoms rapidly resolved, but visual loss remained unchanged. The case presented here proves that GCA with typical related visual loss (AION) is possible even when both ESR and CRP are in the normal range. Therefore, in the presence of typical symptoms, the clinician must not rely solely on laboratory testing, but start steroid therapy immediately and order a temporal artery biopsy. Cancer should be suspected if there is previous history of it, unexplained weight loss, or unremitting pain. Spinal epidural abscess is more common among those with diabetes mellitus or immunocompromised or who had spinal surgery, injection or catheter; it typically causes fever, leukocytosis and increased erythrocyte sedimentation rate. If cancer or spinal epidural abscess are suspected, urgent magnetic resonance imaging is recommended for confirmation. Proximal diabetic neuropathy typically affects middle aged and older people with well-controlled type-2 diabetes mellitus; onset is sudden causing pain usually in multiple dermatomes quickly followed by weakness. Diagnosis typically involves electromyography and lumbar puncture. Shingles is more common among the elderly and immunocompromised; usually (but not always) pain is followed by appearance of a rash with small blisters along a single dermatome. Acute Lyme radiculopathy may follow a history of outdoor activities during warmer Giant cell arteritis (GCA) is an important condition to suspect and treat early, as failure to do so can result in anterior ischaemic optic neuropathy and subsequent permanent visual loss.A 71-year-old woman presented to her local emergency department with a 1-week history of constant, moderate-severe global headache associated with intermittent periorbital pain. Two weeks later she developed sudden horizontal diplopia. Examination demonstrated right oculomotor nerve palsy. Her erythrocyte sedimentation rate (ESR) was 9 mm/hr. Repeat blood tests 1 month later showed an ESR of 67 mm/hr. Temporal artery biopsy was positive.A review from a cohort of 764 patients with suspected GCA who underwent biopsy found the sensitivity of an elevated ESR and c-reactive protein was 84% and 86%, respectively, but the specificity was only 30%. Therefore, inflammatory markers should only act as a guide, and caution should be taken in their interpretation especially with respect to the time of sampling in the disease evolution.Isolated oculomotor nerve palsy in association with GCA is rare. The first case series was described by miller fisher in 1959 who observed two patients presenting with diplopia, ptosis and ocular palsies. In anyone over the age of 50 who develops a new, refractory headache and cranial neuropathy, GCA should be the first consideration. A 70-year-old woman presented with new onset of left eye and facial pain. Ophthalmic and neurological examinations, magnetic resonance imaging brain, erythrocyte sedimentation rate, and C-reactive protein were unrevealing. A few days later, she developed vision loss in her left eye. Examination revealed decreased visual acuity with a relative afferent pupillary defect in the left eye and a diffuse mild swelling of the left optic nerve head. Repeat magnetic resonance imaging showed T2 hyperintensity and enhancement of the intraorbital optic nerve and surrounding tissues with no other intracranial abnormalities. Serum studies showed elevated myelin oligodendrocyte glycoprotein IgG titer. She was treated with IV methylprednisolone 1000 mg daily for 3 days and was discharged on prolonged prednisone taper with return of vision to baseline. A 71-year-old male presented with a history of sudden partial visual loss in the right eye with an inferior visual field defect over the past 3-4 days. He had no history of headache or of facial pain. Clinical examination confirmed that vision on the right side was reduced to 6/18 and on the left to 6/12. The right eye showed a relative afferent pupillary defect. There was no other abnormality of the anterior segment of either eye. The right retina showed a pale swollen optic disc and a provisional diagnosis of anterior ischaemic optic neuropathy (AION) was made. An urgent erythrocyte sedimentation rate (ESR) was ordered and the patient was asked to return to the eye clinic in one month. However, 16 days later--when it was first recognised that his ESR was elevated to 75 mm in the first hour--the patient was recalled immediately in order to commence systemic steroid treatment; but regrettably, by this time, his right eye had become totally blind. In this case, although the attending doctor made a correct clinical diagnosis on presentation, he failed to act upon the result of the blood test. Leber hereditary optic neuropathy (LHON) is an optic neuropathy of mitochondrial inheritance. Childhood-onset disease is relatively rare and there are limited data on this important patient subgroup. We present 3 particular presentations of LHON. Patient 1 was an 8-year-old boy admitted to the emergency department reporting a progressive bilateral visual loss and intermittent headaches. Neuro-ophthalmological examination revealed a bilateral pseudopapilledema. Lumbar puncture identified intracranial hypertension and the brain and orbits magnetic resonance imaging showed T2 hyperintensity in the posterior region of the left optic nerve and the optic chiasm. Patient 2 was a 12-year-old boy admitted to the emergency department reporting painless, progressive central vision loss in the right eye. Fundus examination revealed a hyperemic disc and vascular network papillary and peripapillary vascular microdilations. Three months later, the left eye presented visual loss. Patient 3 was a 6-year-old female child referred to the neuro-ophthalmology specialist due to painless central visual loss in both eyes. Her BCVA was 1/10 and counting fingers in right and left eye, respectively, and fundus examination revealed a pallor optic disc in the temporal sector. The phenotype of childhood-onset disease may present itself distinct from classical adult-onset LHON. The absence of classical clinical features could lead to initial misdiagnosis. There should exist a high index of suspicion in children presenting unexplained subnormal vision in order to avoid potential diagnostic delays. Giant cell arteritis (GCA) is a polysymptomatic disease which constitutes an ophthalmic emergency because early recognition and management can prevent blindness. There is conflicting information in the literature on the validity, sensitivity, and specificity of various systemic symptoms and signs of GCA. This paper presents a review of our prospective studies on the subject, and our findings are particularly relevant to dentists. We investigated 363 patients in a prospective study. Positive temporal artery biopsy was seen in 106 patients and negative in 257 referred for diagnosis of GCA. Systemic symptoms and signs of GCA and erythrocyte sedimentation rate (Westergren-ESR) and C-reactive protein (CRP) levels were compared in these two groups of patients. The odds of having a positive temporal artery biopsy (i.e., GCA) were 9.1 times greater with jaw claudication (pain in masticatory muscles on eating), 3.4 times with neck pain, 3.2 times with CRP &gt; 2.45 mg/dL, 2.0 times with ESR 47.107 mm/hr, 2.7 times with ESR &gt; 107 mm/hr, and 2.0 times when the patients were aged &gt; or = 75 years. Other signs and symptoms did not show a significant association with a positive biopsy. Our study showed that \"normal\" ESR values do not rule out GCA but that CRP is a more useful test than ESR. Since jaw claudication is one of the most important symptoms of GCA, dentists should keep this possibility in mind when older patients come complaining of jaw pain while eating. Defective light perception in one eye causes an asymmetrical pupillary constriction reflex called the afferent pupillary defect (APD). Arteritic PION A-PION most commonly affects Caucasian women, with an average age of 73. At onset vision loss is unilateral, but without treatment it rapidly progresses to involve both eyes. Vision loss is usually severe, ranging from counting fingers to no light perception. Associated symptoms are jaw pain exacerbated by chewing, scalp tenderness, shoulder and hip pain, headache and fatigue. Perioperative PION Vision loss is usually apparent upon waking from general anesthesia. Signs observable to a bystander include long surgery duration and facial swelling. Vision loss is usually bilateral and severe, ranging from counting fingers to no light perception. Cause Panarteritis nodosa (PAN) is a systemic vasculitis affecting small and medium-sized arteries. Neuro-ophthalmological complications of PAN are rare but numerous, and may affect the eye, the visual and the oculomotor pathways. Such complications occur mainly in patients previously diagnosed with PAN. A 51-year-old woman presented with an isolated right trochlear (IV) palsy, in the setting of headaches and fluctuating fever of unknown etiology. Erythrocyte sedimentation rate was 13 mm and full blood cell count was normal. Previous chest X-ray and blood studies were negative for an infection or inflammation. Orbital and cerebral CT scan was normal. Spontaneous recovery of diplopia ensued over four days. Two days later, paresthesia and sensory paresis of the dorsal portion of the left foot were present. Lumbar puncture revealed 14 leucocytes (76 percent lymphocytes) with elevated proteins, but blood studies and serologies were negative. A diagnosis of undetermined meningo-myelo-radiculoneuritis was made. Because of a possible tick bite six weeks previously the patient was empirically treated with 2 g intravenous ceftriaxone for 3 weeks. Fever rapidly dropped. Six weeks after the onset of diplopia, acute onset of blindness in her right eye, diffuse arthralgias and fever motivated a new hospitalization. There was a central retinal artery occlusion of the right eye. Blood studies now revealed signs of systemic inflammation (ESR 30 mm, CRP 12 mg/L, ANA 1/80, pANCA 1/40, leucocytosis 12.4 G/L, Hb 111 g/L, Ht 33 percent). Biopsy of the left sural nerve revealed arterial fibrinoid necrosis. A diagnosis of PAN was made. Transient diplopia can be the heralding symptom of a systemic vasculitis such as PAN, giant cell arteritis and Wegener granulomatosis. In this patient the presence of accompanying systemic symptoms raised a suspicion of systemic inflammation, but the absence of serologic and imaging abnormalities precluded a specific diagnosis initially. A few weeks later, the presence of a second ischemic event (retinal) and positive blood studies led to a further diagnostic procedure. Oculomotor and abducens palsies have rarely been reported in association with PAN. We report the first case of trochlear nerve paresis as the inaugural neurological sign of PAN. This case highlights the importance of considering inflammatory systemic disorders in patients with acute diplopia particularly when they are young, lack vascular risk factors or cause, and complain of associated systemic symptoms. These diagnostic criteria include: Inflammatory back pain:Chronic, inflammatory back pain is defined when at least four out of five of the following parameters are present: (1) Age of onset below 40 years old, (2) insidious onset, (3) improvement with exercise, (4) no improvement with rest, and (5) pain at night (with improvement upon getting up) Past history of inflammation in the joints, heels, or tendon-bone attachments Family history for axial spondyloarthritis or other associated rheumatic/autoimmune conditions Positive for the biomarker HLA-B27 Good response to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) Signs of elevated inflammation (C-reactive protein and erythrocyte sedimentation rate) Manifestation of psoriasis, inflammatory bowel disease, or inflammation of the eye (uveitis) If these criteria still do not give a compelling diagnosis magnetic resonance imaging (MRI) may be useful. MRI can show inflammation of the sacroiliac joint. Imaging\nHere is the question:\nOPHTHALMOLOGY (ECTOPIC): A 70-year-old woman with a history of anorexia, weight loss, discomfort in the musculature and proximal joints plus pain in the temporomandibular region who comes to the emergency department for unilateral loss of vision (hand movement), sudden and painless onset (afferent pupillary defect). What test would you request first for diagnostic purposes?\nHere are the potential choices:\n1. Lumbar puncture.\n2. C-reactive protein.\n3. Magnetic Resonance Angiography.\n4. Carotid ultrasound.\nThe correct answer is: ",
        "gold_answer": "2 C-reactive protein.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 37-year-old woman experienced painless, progressive vision loss to no light perception in the left eye over the course of 3 days. The right eye was unaffected. On examination, the only other abnormal finding was a +4 left afferent pupillary defect. She was initially diagnosed with retrobulbar optic neuritis and admitted for treatment with intravenous methylprednisolone. Neuro-imaging revealed a large right anterior cerebral artery aneurysm that crossed the midline to compress the left optic nerve. The aneurysm was treated with coil embolization, which was technically successful but which did not lead to significant improvement in vision. A 75-year-old Caucasian woman presented with sudden-onset multifocal scotomas in her right eye's central vision for 1 day. There were subtle white intraretinal foveal lesions that correlated with patchy inner retinal hyperreflectivity on optical coherence tomography, suggestive of paracentral acute middle maculopathy. Initial cerebrovascular work-up was negative. Review of systems was positive for lethargy and jaw claudication. The sedimentation rate and c-reactive protein were elevated, but platelet count was normal. The patient was started on 60 mg oral prednisone daily and underwent bilateral temporal artery that confirmed the diagnosis of giant cell arteritis. A careful neurologic examination is an essential first step in the evaluation. In most cases, patients with an abnormal examination or a history of recent-onset headache should be evaluated by a computed tomography (CT) or magnetic resonance imaging (MRI) study. As an initial screening procedure for intracranial pathology in this setting, CT and MRI methods appear to be equally sensitive. In some circumstances, a lumbar puncture (LP) is also required, unless a benign etiology can be otherwise established. A general evaluation of acute headache might include cranial arteries by palpation; cervical spine by Pain induced by bending, lifting, cough Pain associated with local tenderness, e.g., region of temporal artery the effect of passive movement of the head and by imaging; the investigation of cardiovascular and renal status by blood pressure monitoring and urine examination; and eyes by funduscopy, intraocular pressure measurement, and refraction. Giant cell arteritis Giant cell arteritis should be considered in an older person with jaw claudication, temporal pain, and tiredness. Placing the person on steroids might save both their vision and decrease their risk of stroke. Without treatment a person can quickly go blind in both eyes. Vascular occlusions Central retinal artery occlusion: CRAO is characterized by painless, acute vision loss in one eye. Central retinal vein occlusion: CRVO causes sudden, painless vision loss that can be mild to severe. Branch retinal vein occlusion: sudden painless vision loss or visual field defect are the main symptom of BRVO. Branch retinal artery occlusion: BRAO may also cause acute painless loss of vision. Vitreous hemorrhage It is one of the most common causes of acute or subacute decrease in vision. Hyphema Blood in the anterior chamber of the eye is known as hyphema. Severe hyphema covering pupillary area can cause sudden decrease in vision. References Blindness Magnetic resonance angiography (MRA) or CT angiography (CTA) can be used to examine cerebral blood vessels and to rule out vascular abnormalities, such as an aneurysm. In cases where intracranial vascular lesions, for example, subarachnoid hemorrhage cannot be completely ruled out after performing MRA or CTA, physicians may consider using traditional digital subtraction angiography (DSA) for more detailed investigation. Laboratory tests Lumbar punctures and blood tests might be performed on those with RPON to identify other possible causes of cranial neuropathy, including diabetes, inflammatory diseases, infections, tumors, and other systemic diseases that involve either the central nervous system or the peripheral nervous system. The detection of abnormalities in these tests suggests that RPON is highly unlikely to be the culprit in cranial neuropathy, and more diagnostic tests should be done to find out the underlying condition. The purpose is to report a patient with primary open-angle glaucoma that developed sudden painless unilateral vision loss, a sequential ophthalmoscopic appearance with features of both central retinal artery and later central retinal vein occlusion, and objective visual system dysfunction in the form of a relative afferent pupil defect, who spontaneously recovered vision along with complete resolution of the pupillary defect over several weeks. A 50-year-old woman with a long-standing history of glaucoma presented with acute, painless vision loss in one eye, a pallid retina with a cherry red macula, diffuse retinal hemorrhages, and a relative afferent pupil defect. Spectral domain optical coherence tomography and fluorescein angiography were essentially normal with neither retinal edema nor retinal ischemia to account for the visual dysfunction. Over the course of 2 months, the patient regained vision and the relative afferent pupil defect, typically a permanent manifestation of retinal destruction, resolved. Not all retinal vaso-occlusive phenomena can be completely attributed to a central retinal vein or artery occlusion. In the patient presented, there was no objective diagnostic testing that revealed a cause for the patient's vision loss or relative afferent pupillary defect. This combined with the complete recovery of vision and resolution of the relative afferent pupillary defect underscores a lack of comprehensive understanding of retinal vaso-occlusive disease. A 71-year-old man visited our clinic with a 3-day history of severe throbbing headache and 1-day history of horizontal diplopia. He had had jaw claudication and pain in the neck and shoulder several days previously. His right eye was slightly esotropic and did not move laterally. There was no blepharoptosis, proptosis, lid edema, or conjunctival injection. The pupils were unremarkable. The remainder of the cranial nerve functions was intact. There was no limb weakness or sensory impairment. Superficial temporal arteries were swollen and tender on both sides. Laboratory examination showed elevated CRP level and high erythrocyte sedimentation rate. Cranial MR images were unremarkable. The cerebrospinal fluid was acellular with 45 mg/dl of protein. A diagnosis of temporal arteritis was made. Treatment with 50 mg of prednisolone brought about prompt disappearance of the headache. Right ocular movement fully recovered in 10 days. Temporal artery biopsy findings and response to corticosteroid were consistent with temporal arteritis. The motility pattern of the right eye was consistent with complete abducens nerve palsy, which is a rare manifestation of temporal arteritis. Although temporal arteritis is a rare cause of ophthalmoplegia in the elderly patients, swift diagnosis and treatment is necessary to avoid blindness. One recommended diagnostic approach is as follows. If any urgent red flags are present such as visual loss, new seizures, new weakness, new confusion, further workup with imaging and possibly a lumbar puncture should be done (see red flags section for more details). If the headache is sudden onset (thunderclap headache), a computed tomography test to look for a brain bleed (subarachnoid hemorrhage) should be done. If the CT scan does not show a bleed, a lumbar puncture should be done to look for blood in the CSF, as the CT scan can be falsely negative and subarachnoid hemorrhages can be fatal. If there are signs of infection such as fever, rash, or stiff neck, a lumbar puncture to look for meningitis should be considered. If there is jaw claudication and scalp tenderness in an older person, a temporal artery biopsy to look for temporal arteritis should be performed and immediate treatment should be started. Neuroimaging Leber hereditary optic neuropathy (LHON) is an inherited mitochondrial disease characterized by painless vision loss affecting both eyes. The disease usually develops in both eyes within weeks to months of onset. We report a case of LHON who presented with unilateral vision loss in childhood with an interval of more than 30 years between vision loss in the two eyes. A 43-year-old man presented with a 1-month history of vision loss in his right eye. At 9 years of age, his visual acuity in the left eye declined, and he had been treated with glaucoma eyedrops bilaterally at his eye clinic. At his first visit to our hospital, his BCVA was 0.15 in the right eye and 0.1 in the left eye, and critical flicker frequency was 16 Hz in the right eye and 15 Hz in the left eye, and he was negative for a relative afferent pupillary defect. The Goldman visual field showed central scotoma in both eyes. Fundus examination revealed slight redness of the right optic disc with meandering retinal small vessels, and the left optic disc had a slight pallor. Fluorescein angiography could not be performed because of liver dysfunction. OCT showed prominent bilateral thinning of the RNFL and retinal ganglion cell layer. Enhancement of the optic nerve was not apparent on orbital gadolinium-enhanced magnetic resonance imaging. Hematologic analysis revealed macrocytic anemia and low levels of vitamin B12 and folate. His mother had a presumptive diagnosis of LHON but did not receive genetic testing. A male cousin also had severe vision loss. Based on the likely family history of LHON, we performed genetic testing, which revealed the 11778 mitochondrial point mutation associated with this condition. We report a case of LHON with 34 years interval in vision loss in the fellow eye. LHON may develop in the second eye decades after its onset in the first. Detailed medical interviews and scrutiny, such as examination of family history, are warranted in consideration of LHON. If a 20-year-old female develops headaches after drinking red wine, think migraine. Associated symptoms/signs: Significant findings include fever or rash (consider meningitis or other infectious causes), jaw claudication (specific for temporal arteritis), or constitutional symptoms such as weight loss (associated with neoplastic, inflammatory, or infectious conditions). Photophobia, nausea, and vomiting are associated with migraine, aneurysmal SAH, and meningitis, but neck stiffness is more likely to accompany the latter two. Neurologic sequelae: Look for diplopia, mental status changes or associated symptoms (numbness, weakness, dizziness, ataxia, visual disturbances), papilledema, or pupillary abnormalities (partial CN III palsy or Horner’s syndrome). Patient risk factors: High-risk patients are > 50 years of age, immunocompromised, or with preexisting malignancy. If SAH is suspected, obtain a head CT without contrast. If CT is , LP is mandatory. Obtain a CBC. Optic neuritis is a common cause of subacute unilateral vision loss, occurring in 1-5 per 100,000 persons per year. It is more common in Caucasians, women, and those from countries with northern latitudes. Those aged 20-49 years are at greatest risk. The condition arises due to inflammation of the optic nerve. Inflammation may occur due to systemic inflammatory disorders, most commonly multiple sclerosis. A 21-year-old African-American male presented to our emergency department with a complaint of painful unilateral vision loss. On examination he was found to have a relative afferent pupillary defect and red desaturation. A bedside ultrasound suggested pseudopapilledema suggestive of optic neuritis. He was admitted to Neurology for confirmation of and treatment for optic neuritis. Magnetic resonance imaging confirmed optic neuritis. The patient was treated with i.v. steroids and discharged after improvement in visual function. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Optic neuritis is a clinical diagnosis. The subtle historical components and examination findings make it a diagnostic challenge for the busy emergency physician. Early diagnosis may improve visual outcomes. Discovery of pseudopapilledema on bedside ultrasound may be seen in optic neuritis, and is another finding that emergency physicians may assess for in patient presenting with unilateral vision loss. We report a 62-year-old man who developed coma and died in a fulminant course. The patient was well until May 1, 1996 when he noted chillness, tenderness in his shoulders, and he went to bed without having his lunch and dinner. In the early morning of May 2, his families found him unresponsive and snoring; he was brought into the ER of our hospital. He had histories of hypertension, gout, and hyperlipidemia since 42 years of the age. On admission, his blood pressure was 120/70, heart rate 102 and regular, and body temperature 36.3 degrees C. His respiration was regular and he was not cyanotic. Low pitch rhonchi was heard in his right lower lung field. Otherwise general physical examination was unremarkable. Neurologic examination revealed that he was somnolent and he was only able to respond to simple questions such as opening eyes and grasping the examiner's hand, but he was unable to respond verbally. The optic discs were flat; the right pupil was slightly larger than the left, but both reacted to light. He showed ptosis on the left side, conjugate deviation of eyes to the left, and right facial paresis. The oculocephalic response and the corneal reflex were present. His right extremities were paralyzed and did not respond to pain Deep tendon reflexes were exaggerated on the right side and the plantar response was extensor on the right. No meningeal signs were present. Laboratory examination revealed the following abnormalities; WBC 18,400/ml, GOT 131 IU/l GPT 50 IU/l, CK616 IU/l, BUN 30 mg/dl, Cr 2.1 mg/ dl, glucose 339 mg/dl, and CRP 27.4 mg/dl. ECG showed sinus tachycardia and ST elevation in II, III and a VF leads and abnormal q waves in I, V5, and V6 leads. Chest X-ray revealed cardiac enlargement but the lung fields were clear. Cranial CT scan revealed low density areas in the left middle cerebral and left posterior cerebral artery territories. The patient was treated with intravenous glycerol infusion and other supportive measures. At 2: 10 AM on May 3, he developed sudden hypotension and cardiopulmonary arrest. He was pronounced dead at 3:45 AM. The patient was discussed in a neurological CPC, and the chief discussant arrived at the conclusion that the patient had acute myocardial infarction involving the inferior and the true posterior walls and left internal carotid embolism from a mural thrombus. Post mortem examination revealed occlusion of the circumflex branch of the left coronary artery due to atherom plaque rupture and myocardial infarction involving the posterior and the lateral wall with a rupture in the postero-lateral wall. Marked atheromatous changes were seen in the left internal carotid, the middle cerebral and the basilar arteries; the left internal carotid and the middle cerebral arteries were almost occluded by thrombi and blood coagulate. The territories of the left middle cerebral and the occipital arteries were infarcted; but the left thalamic area was spared. The neuropathologist concluded that the infarction was thrombotic origin not an embolic one as the atherosclerotic changes were severe. Cardiac rupture appeared to be the cause of terminal sudden hypotension and cardiopulmonary arrest. It appears likely that a vegetation which had been attached to the aortic valve induced thromboembolic occlusion of the left internal carotid artery which had already been markedly sclerotic by atherosclerosis. It is also possible that the vegetations in the aortic valve came from mural thrombi at the site of acute myocardial infarction, as no bacteria were found in those vegetations. To report the case and multimodal imaging findings of a healthy young woman who developed paracentral acute middle maculopathy (PAMM) 9 weeks after COVID-19 disease. Case report. Ultra-widefield fundus photography, macular spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography (FA), and OCT-angiography (OCT-A) were performed. A 36-year-old woman who developed PAMM 9 weeks after SARS-CoV-2 infection. A 36-year-old woman went to the emergency department (ED) with sudden, painless, left eye (LE) vision loss. The only relevant past medical history was COVID-19 disease 9 weeks before. Best corrected visual acuity (BCVA) was 20/200, a LE relative afferent pupillary defect (RAPD) was present and superficial hemorrhages throughout the macular area and peripheral retina were found. Nearly four hours after admission, LE BCVA recovered to 20/20 without RAPD. Five days after presentation in the ED, the patient returned with recurrent LE vision loss, with spontaneous recovery within 12 hours. Macular SD-OCT revealed hyperreflectivity of the inner plexiform and inner nuclear layers and the diagnosis of PAMM was established. The patient started oral acetylsalicylic acid and oral prednisolone. The patient did not report any new episodes of vision loss and there was a progressive resolution of abnormal fundus findings. SARS-CoV-2 infection increases the risk of vascular thrombotic events with possible involvement of the retinal circulation, and PAMM may present as a possible complication. Ophthalmologists should be able to recognize it promptly through multimodal imaging findings. In anterior ischemic optic neuropathy (AION), it is important not to miss the diagnosis of giant cell arteritis (GCA) because this requires immediate steroid treatment to prevent involvement of the second eye and possible blindness. A missed diagnosis also might lead to fatal systemic complications. Observational case report. A 79-year-old woman noticed decreased visual and visual field loss in the right eye. At presentation, right visual acuity was 10/20 (ETDRS chart 2000). There was a right relative afferent pupillary defect of 0.6 log units. Asked for symptoms of GCA she complained about temporal and occipital headache, jaw claudication combined with malaise, and myalgia of the upper limbs. Laboratory tests showed normal inflammatory markers. Repeated tests confirmed ESR and CRP to be within the normal range. GCA being suspected, ultrasound of the superficial temporal arteries and temporal artery biopsy were performed unilaterally on the right side. Histology showed a chronic inflammatory cell infiltrate consistent with active GCA. The patient was treated with high-dose corticosteroids (250 mg methylprednisolone, three times/day, initially) and symptoms rapidly resolved, but visual loss remained unchanged. The case presented here proves that GCA with typical related visual loss (AION) is possible even when both ESR and CRP are in the normal range. Therefore, in the presence of typical symptoms, the clinician must not rely solely on laboratory testing, but start steroid therapy immediately and order a temporal artery biopsy. Cancer should be suspected if there is previous history of it, unexplained weight loss, or unremitting pain. Spinal epidural abscess is more common among those with diabetes mellitus or immunocompromised or who had spinal surgery, injection or catheter; it typically causes fever, leukocytosis and increased erythrocyte sedimentation rate. If cancer or spinal epidural abscess are suspected, urgent magnetic resonance imaging is recommended for confirmation. Proximal diabetic neuropathy typically affects middle aged and older people with well-controlled type-2 diabetes mellitus; onset is sudden causing pain usually in multiple dermatomes quickly followed by weakness. Diagnosis typically involves electromyography and lumbar puncture. Shingles is more common among the elderly and immunocompromised; usually (but not always) pain is followed by appearance of a rash with small blisters along a single dermatome. Acute Lyme radiculopathy may follow a history of outdoor activities during warmer Giant cell arteritis (GCA) is an important condition to suspect and treat early, as failure to do so can result in anterior ischaemic optic neuropathy and subsequent permanent visual loss.A 71-year-old woman presented to her local emergency department with a 1-week history of constant, moderate-severe global headache associated with intermittent periorbital pain. Two weeks later she developed sudden horizontal diplopia. Examination demonstrated right oculomotor nerve palsy. Her erythrocyte sedimentation rate (ESR) was 9 mm/hr. Repeat blood tests 1 month later showed an ESR of 67 mm/hr. Temporal artery biopsy was positive.A review from a cohort of 764 patients with suspected GCA who underwent biopsy found the sensitivity of an elevated ESR and c-reactive protein was 84% and 86%, respectively, but the specificity was only 30%. Therefore, inflammatory markers should only act as a guide, and caution should be taken in their interpretation especially with respect to the time of sampling in the disease evolution.Isolated oculomotor nerve palsy in association with GCA is rare. The first case series was described by miller fisher in 1959 who observed two patients presenting with diplopia, ptosis and ocular palsies. In anyone over the age of 50 who develops a new, refractory headache and cranial neuropathy, GCA should be the first consideration. A 70-year-old woman presented with new onset of left eye and facial pain. Ophthalmic and neurological examinations, magnetic resonance imaging brain, erythrocyte sedimentation rate, and C-reactive protein were unrevealing. A few days later, she developed vision loss in her left eye. Examination revealed decreased visual acuity with a relative afferent pupillary defect in the left eye and a diffuse mild swelling of the left optic nerve head. Repeat magnetic resonance imaging showed T2 hyperintensity and enhancement of the intraorbital optic nerve and surrounding tissues with no other intracranial abnormalities. Serum studies showed elevated myelin oligodendrocyte glycoprotein IgG titer. She was treated with IV methylprednisolone 1000 mg daily for 3 days and was discharged on prolonged prednisone taper with return of vision to baseline. A 71-year-old male presented with a history of sudden partial visual loss in the right eye with an inferior visual field defect over the past 3-4 days. He had no history of headache or of facial pain. Clinical examination confirmed that vision on the right side was reduced to 6/18 and on the left to 6/12. The right eye showed a relative afferent pupillary defect. There was no other abnormality of the anterior segment of either eye. The right retina showed a pale swollen optic disc and a provisional diagnosis of anterior ischaemic optic neuropathy (AION) was made. An urgent erythrocyte sedimentation rate (ESR) was ordered and the patient was asked to return to the eye clinic in one month. However, 16 days later--when it was first recognised that his ESR was elevated to 75 mm in the first hour--the patient was recalled immediately in order to commence systemic steroid treatment; but regrettably, by this time, his right eye had become totally blind. In this case, although the attending doctor made a correct clinical diagnosis on presentation, he failed to act upon the result of the blood test. Leber hereditary optic neuropathy (LHON) is an optic neuropathy of mitochondrial inheritance. Childhood-onset disease is relatively rare and there are limited data on this important patient subgroup. We present 3 particular presentations of LHON. Patient 1 was an 8-year-old boy admitted to the emergency department reporting a progressive bilateral visual loss and intermittent headaches. Neuro-ophthalmological examination revealed a bilateral pseudopapilledema. Lumbar puncture identified intracranial hypertension and the brain and orbits magnetic resonance imaging showed T2 hyperintensity in the posterior region of the left optic nerve and the optic chiasm. Patient 2 was a 12-year-old boy admitted to the emergency department reporting painless, progressive central vision loss in the right eye. Fundus examination revealed a hyperemic disc and vascular network papillary and peripapillary vascular microdilations. Three months later, the left eye presented visual loss. Patient 3 was a 6-year-old female child referred to the neuro-ophthalmology specialist due to painless central visual loss in both eyes. Her BCVA was 1/10 and counting fingers in right and left eye, respectively, and fundus examination revealed a pallor optic disc in the temporal sector. The phenotype of childhood-onset disease may present itself distinct from classical adult-onset LHON. The absence of classical clinical features could lead to initial misdiagnosis. There should exist a high index of suspicion in children presenting unexplained subnormal vision in order to avoid potential diagnostic delays. Giant cell arteritis (GCA) is a polysymptomatic disease which constitutes an ophthalmic emergency because early recognition and management can prevent blindness. There is conflicting information in the literature on the validity, sensitivity, and specificity of various systemic symptoms and signs of GCA. This paper presents a review of our prospective studies on the subject, and our findings are particularly relevant to dentists. We investigated 363 patients in a prospective study. Positive temporal artery biopsy was seen in 106 patients and negative in 257 referred for diagnosis of GCA. Systemic symptoms and signs of GCA and erythrocyte sedimentation rate (Westergren-ESR) and C-reactive protein (CRP) levels were compared in these two groups of patients. The odds of having a positive temporal artery biopsy (i.e., GCA) were 9.1 times greater with jaw claudication (pain in masticatory muscles on eating), 3.4 times with neck pain, 3.2 times with CRP &gt; 2.45 mg/dL, 2.0 times with ESR 47.107 mm/hr, 2.7 times with ESR &gt; 107 mm/hr, and 2.0 times when the patients were aged &gt; or = 75 years. Other signs and symptoms did not show a significant association with a positive biopsy. Our study showed that \"normal\" ESR values do not rule out GCA but that CRP is a more useful test than ESR. Since jaw claudication is one of the most important symptoms of GCA, dentists should keep this possibility in mind when older patients come complaining of jaw pain while eating. Defective light perception in one eye causes an asymmetrical pupillary constriction reflex called the afferent pupillary defect (APD). Arteritic PION A-PION most commonly affects Caucasian women, with an average age of 73. At onset vision loss is unilateral, but without treatment it rapidly progresses to involve both eyes. Vision loss is usually severe, ranging from counting fingers to no light perception. Associated symptoms are jaw pain exacerbated by chewing, scalp tenderness, shoulder and hip pain, headache and fatigue. Perioperative PION Vision loss is usually apparent upon waking from general anesthesia. Signs observable to a bystander include long surgery duration and facial swelling. Vision loss is usually bilateral and severe, ranging from counting fingers to no light perception. Cause Panarteritis nodosa (PAN) is a systemic vasculitis affecting small and medium-sized arteries. Neuro-ophthalmological complications of PAN are rare but numerous, and may affect the eye, the visual and the oculomotor pathways. Such complications occur mainly in patients previously diagnosed with PAN. A 51-year-old woman presented with an isolated right trochlear (IV) palsy, in the setting of headaches and fluctuating fever of unknown etiology. Erythrocyte sedimentation rate was 13 mm and full blood cell count was normal. Previous chest X-ray and blood studies were negative for an infection or inflammation. Orbital and cerebral CT scan was normal. Spontaneous recovery of diplopia ensued over four days. Two days later, paresthesia and sensory paresis of the dorsal portion of the left foot were present. Lumbar puncture revealed 14 leucocytes (76 percent lymphocytes) with elevated proteins, but blood studies and serologies were negative. A diagnosis of undetermined meningo-myelo-radiculoneuritis was made. Because of a possible tick bite six weeks previously the patient was empirically treated with 2 g intravenous ceftriaxone for 3 weeks. Fever rapidly dropped. Six weeks after the onset of diplopia, acute onset of blindness in her right eye, diffuse arthralgias and fever motivated a new hospitalization. There was a central retinal artery occlusion of the right eye. Blood studies now revealed signs of systemic inflammation (ESR 30 mm, CRP 12 mg/L, ANA 1/80, pANCA 1/40, leucocytosis 12.4 G/L, Hb 111 g/L, Ht 33 percent). Biopsy of the left sural nerve revealed arterial fibrinoid necrosis. A diagnosis of PAN was made. Transient diplopia can be the heralding symptom of a systemic vasculitis such as PAN, giant cell arteritis and Wegener granulomatosis. In this patient the presence of accompanying systemic symptoms raised a suspicion of systemic inflammation, but the absence of serologic and imaging abnormalities precluded a specific diagnosis initially. A few weeks later, the presence of a second ischemic event (retinal) and positive blood studies led to a further diagnostic procedure. Oculomotor and abducens palsies have rarely been reported in association with PAN. We report the first case of trochlear nerve paresis as the inaugural neurological sign of PAN. This case highlights the importance of considering inflammatory systemic disorders in patients with acute diplopia particularly when they are young, lack vascular risk factors or cause, and complain of associated systemic symptoms. These diagnostic criteria include: Inflammatory back pain:Chronic, inflammatory back pain is defined when at least four out of five of the following parameters are present: (1) Age of onset below 40 years old, (2) insidious onset, (3) improvement with exercise, (4) no improvement with rest, and (5) pain at night (with improvement upon getting up) Past history of inflammation in the joints, heels, or tendon-bone attachments Family history for axial spondyloarthritis or other associated rheumatic/autoimmune conditions Positive for the biomarker HLA-B27 Good response to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) Signs of elevated inflammation (C-reactive protein and erythrocyte sedimentation rate) Manifestation of psoriasis, inflammatory bowel disease, or inflammation of the eye (uveitis) If these criteria still do not give a compelling diagnosis magnetic resonance imaging (MRI) may be useful. MRI can show inflammation of the sacroiliac joint. Imaging\nHere is the question:\nOPHTHALMOLOGY (ECTOPIC): A 70-year-old woman with a history of anorexia, weight loss, discomfort in the musculature and proximal joints plus pain in the temporomandibular region who comes to the emergency department for unilateral loss of vision (hand movement), sudden and painless onset (afferent pupillary defect). What test would you request first for diagnostic purposes?\nHere are the potential choices:\n1. Lumbar puncture.\n2. C-reactive protein.\n3. Magnetic Resonance Angiography.\n4. Carotid ultrasound.\nThe correct answer is: 2. C-reactive protein."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 43-year-old man was admitted to our hospital because of legs edema and periorbital edema in Dec. 1983. Laboratory findings showed massive proteinuria (3.7 g/day), Bence Jones protein (BJP) in urine, and hypoproteinemia. Peripheral blood examinations were normal and a bone marrow aspiration showed hypocellularity with slight increase of monocytes and plasma cells. Serum immunoelectrophoresis showed two M-components (IgG kappa, IgA lambda). Serum IgG was 1,690 mg/dl, IgA 379 mg/dl and IgM 160 mg/dl. No remarkable findings were obtained in bone survey, Ga-scintigraphy and rectal biopsy, and a diagnosis of diclonal gammopathy with nephrotic syndrome was made. In Aug. 1986, serum IgA started to increase rapidly with concomitant decrease IgG. He died of pneumonia due to pancytopenia in Dec. 1986, when serum IgG was 450 mg/dl, IgA 1,014 mg/dl, and IgM less than 39 mg/dl. Immunoelectrophoresis showed two M-components (IgG kappa, IgA lambda) in serum and BEP (kappa, lambda), IgG (kappa) and IgA (lambda) in urine. An autopsy showed massive infiltration of myeloma cells which were positive for lambda light chain in bone marrow, suggesting a development of myeloma from a diclonal gammopathy in about 3 years. Non-IgM SMM Non-IgM SMM (also termed IgG and IgA SMM because of the rarity of IgD and IgE SMM) is diagnosed in asymptomatic individuals based on criteria identical to those listed above for Non-IgM MGUS except that: their intact IgG or IgA myeloma protein levels are equal to or greater than 30 grams/liter rather than 15 grams/liter; their bone marrow shows plasma cells comprise between 10% and <60% rather than <10% of nucleated cells; and/or their 24-hour urine contains 0.5 gram or greater levels of Bence Jones, i.e. light chain myeloma, proteins. individuals must also lack evidence of more recently established multiple myeloma-defining criteria viz., CRAB features, amyloidosis, more than one solitary plasmacytoma, and/or serum or urine free light chain κ to λ or λ to κ ratios of 100 or greater. Individuals diagnosed with light chain MGUS typically do not express detectable levels of an IgG, IgA, IgD, IgE, or IgM intact myeloma protein in their blood. Rather, they overexpress a monoclonal, aberrant free κ (i.e. kappa) or λ (i.e., lambda) immunoglobulin light chain. For diagnosis, the κ and λ free light chains are quantified by immunological methods and the ratio of κ to λ light chains is used to detect unbalanced light chain synthesis that is indicative of a monoclonal light chain plasma cell dyscrasia. Light chain MGUS is defined as a disorder in which a serum κ to λ free light chain ratio falls outside the normal range of 0.26–1.65 (mean =0.9) provided that it is not associated with: a) any of the CRAB criteria, b) a bone marrow plasma cell count of 10 or a higher percentage of nucleated cells, c) evidence of amyloid deposition (see Light chain deposition disease), and d) an accumulation of 0.5 or more grams of the monoclonal light chain in the urine over a 24-hour period. Light chain SMM Light chain smoldering multiple myeloma (light chain SMM) was previously termed idiopathic Bence Jones proteinuria. The condition is currently diagnosed in asymptomatic individuals who have a 24-hour urinary Bence Jones, i.e. light chain myeloma protein level, that is >0.5 grams and/or bone marrow plasma cells that are 10% to <60% of nucleated cells. These individuals must also; lack detectable IgG, IgA, IgD, IgE, or IgM myeloma proteins in sera; have a free κ/λ or λ/κ light chain ratio outside of 0.26 to 1.65 range but less than 100; and/or have no evidence for the presence of any one of the CRAB criteria, amyloidosis, or end organ damage attributable to the myeloma proteins or plasma cells. Renal amyloidosis is an uncommon cause of nephrotic syndrome. The clinical conditions in Chinese people remain obscure. This is a retrospective review of the clinicopathological spectrum of 12 cases diagnosed in Taichung Veterans General Hospital from October 1982 to November 1993. Charts and renal pathological slides were reviewed retrospectively. A scoring system was set to evaluate the degree of amyloid deposition in the renal tissue. The clinical profile, immunological data, pathological picture and final outcomes are presented and discussed, with literature review. There were 12 cases of primary amyloidosis including 1 case of multiple myeloma. All were confirmed by renal biopsy. The cases were all male with mean age of onset as 53.3 +/- 11.3 (range: 32 to 65 years). The mean follow-up duration was 22.9 +/- 32.8 months. The initial average creatinine clearance was 66.7 +/- 42.7 ml/min; mean daily urine protein was 7.0 +/- 4.1 grams. Nephrotic syndrome was the main clinical manifestation, present in all 12 cases. Other presenting symptoms and signs included: malaise in 7 cases; hypertension and anorexia in 4 cases; limb numbness in 3 cases; low back pain, dizziness and microhematuria in 2 cases each; anemia, headache, stroke, restrictive cardiomyopathy, hepatomegaly, syncope, body weight loss, dysphagia and skin itching in one case individually. Amyloid cardiomyopathy was present in 4 of the 8 patients who received echocardiography. The mean serum albumin level was 1.9 +/- 0.7 mg/dl, globulin level 3.1 +/- 1.1 mg/dl. Urinary Bence-Jones protein examination was performed in 8 cases; none revealed positive response. The mean immunoglobulin (Ig) level for the patients included: IgG 1018 +/- 901 mg/dl, IgA 262.0 +/- 313.8 mg/dl, IgM 104.8 +/- 84.2 mg/dl. There were at least 4 cases with high levels of one Ig but depressed levels in the others. M-component was shown by immunoelectrophoresis (IEP) in 90% of the cases. IEP impression in 10 cases revealed 2 cases of IgA lambda, 2 cases IgA kappa, 3 cases IgG lambda and 1 case IgG kappa monogammopathy, 1 case free lambda myeloma and 1 case negative. The ratio of kappa to lambda chain was 3:6. Bone marrow biopsy performed in 8 cases found only 1 case with multiple myeloma, one with amyloidosis; the other 6 cases were unremarkable. Mesangium was the site of heaviest amyloid deposition, followed by tubular basement membrane, artery and interstitium. The median survival time for those whose total score was lower than 3 points was 97.5 months; 3 to 5 points, 14 months; 6 points or more, 18.5 months. The median survival time was 21.6 months and 3-year-survival rate was 32.7%. The 2 cases with long-term survival were of 111 months and 84 months. The possible reason included: 1) Organ-limited renal amyloidosis; 2) Light amyloid deposition; 3) Younger age; 4) Other undetected favorable factors. 1) Renal amyloidosis is not a frequent diagnosis of nephrotic syndrome in Taiwan, but it should be suspected in every patient over 50 years old with a recent onset of proteinuria. 2) Renal amyloidosis can be diagnosed only by renal biopsy. 3) Primary renal amyloidosis is a disease of poor prognosis. Immunoglobulin D (IgD) myeloma is a rare disease, about 2% of all myelomas, even rarer when accompanied with another multiple myeloma in biclonal gammopathy. We presented a case of biclonal gammopathy-as-sociated manifestation of IgD myeloma and light chain disease in a patient who initially had renal failure. 37-year-old male approximately one month before hospitalization began to feel malaise and fatigue along with decreased urination. Laboratory analysis revealed azotemia. A dialysis catheter was placed and hemodialysis started. The patient was then admitted to our hospital for further tests and during admission, objective examination revealed pronounced paleness with hepatosplenomegaly and hypertension (170/95 mmHg). Laboratory analysis showed erythrocyte sedimentation rate 122 mm/h, expressed anemic syndrome (Hb 71 g/L) and renal failure dialysis rank: creatinine 1,408 micromol/L, urea 31.7 mmol/L. There was two M components in serum protein electrophoresis: IgD lambda and free light chain lambda. Proteinuria was nephrotic rank (5.4 g/24 h), whose electrophoresis revealed 2 M components--massive in alpha 2 fraction of 71%; 7% in the discrete beta fraction, beta 2M / serum 110 mg / L, in urine 1.8 mg/L--extremely high; IgL kappa I lambda index 1:13 (reference value ratio 2:1). The findings pointed to double myeloma disease: IgD myeloma and Bence Jones lambda myeloma. Bone biopsy confirmed IgD myeloma lambda 100% infiltration medulla predominantly plasmablasts. The treatment continued with hemodialysis 3 times per week with chemotherapy protocol bortezomib, doxorubicin, dexamethasone. After 4 cycles of chemotherapy, there was a decrease of IgD, lamda-light chains, reduction in proteinuria (1.03 g/24 h), so hemodialysis was reduced to once per week. Six months after treatment initiation the patient underwent autologous bone marrow transplantation. In a 2-year follow-up period double myeloma disease showed complete remission. The presented rare form of double myeloma disease with initial renal insufficiency underscores the importance of careful observation and teamwork that can alter the course of this serious disease. Light chain deposition disease (LCDD) is characterized by the deposition of monoclonal immunoglobulin light chains in the kidney, which can cause end-stage kidney disease if not treated. While kidney biopsy is required for definitive diagnosis, choosing an appropriate biopsy method may be problematic when examining patients with atrophic kidneys. A 66-year-old Japanese man was referred to our institution with a three-month history of leg edema. Clinical investigations revealed proteinuria levels of 7.5 g/day. CT-guided percutaneous kidney biopsy was selected as the biopsy method because atrophic kidneys were poorly visualized on ultrasonography. Kidney biopsy revealed nodular glomerulosclerosis, exclusive deposition of the κ chain, and powdery electron-dense deposits, all of which were indicative of LCDD. Bence-Jones protein was detected in the urine. The patient also had an abnormal serum-free light chain ratio. Bone marrow biopsy revealed multiple myeloma; therefore, the patient was diagnosed to have LCDD with multiple myeloma. The patient was treated with daratumumab, bortezomib, cyclophosphamide, and dexamethasone. After a one-year follow-up, the patient had hematological and renal responses without any treatment-related adverse effects. Our case demonstrates the effectiveness of daratumumab as a treatment for LCDD with nephrotic-range proteinuria. Additionally, we suggest that CT-guided kidney biopsy should be considered as a diagnostic test in patients with kidney atrophy when making a definitive diagnosis. A 64-year-old African American male presented to the emergency department with subacute low back pain for two weeks and decreased urine output. He was found to have a potassium level of 9.2 mmol/L and was uremic with a creatinine level of 28.5 mg/dL and blood urea nitrogen (BUN) level of 201 mg/dL. He also tested positive for COVID-19. He was then started on continuous renal replacement therapy (CRRT). His urinalysis showed more than 500 mg/dL of protein. A workup for multiple myeloma was also conducted, and urine protein electrophoresis test was positive for free lambda light chains with a level of 17,700 mg/L and free kappa light chains with a level of 88.30 mg/L with a kappa:lambda free light chain ratio of 0.005. Additionally, serum Bence Jones protein level was elevated at 240 mg/dL, and serum beta-2 microglobulin level was elevated at 31.41 mg/L. An immunoglobulin (Ig) panel also showed low levels of IgG, IgA, and IgM. Kidney biopsy for this patient showed definite cast nephropathy and minimal chronic changes, with only one of over 20 glomeruli sclerosed and minimal interstitial deposits. The patient was started on chemotherapy with cyclophosphamide, bortezomib, and dexamethasone (CyBorD). A 76-year-old man was admitted to Kisen hospital because of lumbago and chest pain. Laboratory examinations revealed a chronic renal failure with marked elevation of the serum BUN (48.8 mg/dl) and creatinine levels (8.2 mg/dl). The serum electrophoresis demonstrated a hypergammaglobulinemia with M peaks. An immunoelectrophoresis demonstrated monoclonal IgD-lambda and IgG-kappa proteins in the serum, and lambda-type Bence Jones protein in the urine (0.4 g/day). Bone marrow smears revealed an abnormal proliferation of atypical plasma cells (43%). A systemic X-ray examination of the skeletal system showed systemic osteoporosis without punched out lesion. The patient was diagnosed as having IgD-lambda type multiple myeloma and IgG-kappa type benign monoclonal gammopathy by quantifying concentration of two M proteins (1,160 mg/dl in IgD, 1,179 mg/dl in IgG, respectively). A combination chemotherapy with melphalan and prednisolone was administered monthly for multiple myeloma, and hemodialysis for the renal failure was performed 3 times a week. A marked improvement of his laboratory findings including a diminution of the serum IgD-lambda M-protein was obtained. On the other hand, IgG-kappa M-protein level was unchanged. Two M-protein levels showed a different behavior after the combination chemotherapy. Although the patient died of congestive heart failure, the partial remission of multiple myeloma has been maintained for 16 months with chemotherapy. A 32-year-old Japanese woman presented with hypertension, nephrotic syndrome, microhematuria, and severe hypocomplementemia. Her serum creatinine concentration increased from 1.46 mg/dL (129.0 μmol/L) to 3.46 mg/dL (305.8 μmol/L) over 1 month. Renal biopsy revealed Congo red-negative nodular glomerulosclerosis accompanied by mesangial proliferation. There was extensive staining of immunoglobulin (Ig) G in the glomerular and tubular basement membranes and expanded mesangial regions. Staining was negative for IgA, IgM, and kappa and lambda light chains and positive for the gamma 1 IgG subclass. Staining for constant domains of the gamma heavy chains showed a deletion of the first constant domain (CH1). Electron microscopy revealed electron-dense deposits in the glomerular and tubular basement membranes and mesangium. These findings indicated gamma 1-heavy chain deposition disease (HCDD). Serum and urine immunoelectrophoresis revealed an IgG kappa monoclonal band, whereas bone marrow biopsy revealed monoclonal plasmacytosis with positive staining for kappa chains. HCDD associated with kappa light chain is extremely rare. We report the first case of HCDD with IgG kappa detected in the serum, urine, and bone marrow. The serum M component will be IgG in 53% of patients, IgA in 25%, and IgD in 1%; 20% of patients will have only light chains in serum and urine. Dipsticks for detecting proteinuria are not reliable at identifying light chains, and the heat test for detecting Bence Jones protein is falsely negative in ~50% of patients with light chain myeloma. Fewer than 1% of patients have no identifiable M component; these patients usually have light chain myeloma in which renal catabolism has made the light chains undetectable in the urine. In most of these patients, light chains can now be detected by serum free light chain assay. IgD myeloma may also present with light chain disease. About two-thirds of patients with serum M components also have urinary light chains. The light chain isotype may have an impact on survival. Patients secreting lambda light chains have a significantly shorter overall survival than those secreting kappa light chains. Whether this is due to some genetically important A 73-year-old male was admitted to the renal division of our hospital because of hypertension, proteinuria and bilateral pretibial edema. Eight years previously, he was diagnosed as being afflicted with interstitial pneumonia on the basis of a chest X-ray examination. Laboratory tests conducted during the current admission showed normocytic normochromic anemia, renal dysfunction and mild proteinuria. Total IgG was normal, but a high proportion of IgG2 was observed. M-protein in the serum was positive for both IgG lambda and Bence Jones protein (lambda type). A bone marrow biopsy showed the proportion of plasma cells to be 10.6%, but atypical cells were not found. We diagnosed the patient's condition as plasma cell dyscrasia. Light microscopy examination of a renal biopsy specimen showed moderate mesangial proliferation with a deposition of PAS-positive and Congo red negative materials in the mesangial area: nodular gomerulonephritis was seen in some glomeruli. Immunofluorescence revealed IgG and lambda light chains, strong linear staining along the glomerular basement membrane and tubular basement membrane and positivity in the mesangial area. Results of staining for IgA, IgM, fibrinogen and C3 were weakly positive in the mesangium area, while those for C4, Clq and free kappa were negative. Positive staining of IgG2 was seen by immunoperoxidase study, but the tissue was negative for IgG1, IgG3, IgG4. Electron microscopy demonstrated a dense granular deposition in the mesangial, subendothelial and peritubular area and a microfibrillar structure in the mesangial area. The diameter of the microfibrillar structure was 14 nm on the average.(ABSTRACT TRUNCATED AT 250 WORDS) We report here a case of a 58-year-old man who had nephrotic syndrome and immunoglobulin light chain (AL) amyloidosis. This patient underwent a renal biopsy to confirm the diagnosis. Treatment with permanganate before Congo red staining showed systemic secondary amyloidosis (AA) fibrils, which were sensitive to permanganate oxidation. Although this patient was initially diagnosed as having AA amyloidosis, he did not have any chronic inflammatory disease and/or malignancy. The level of amyloid A protein (7.9 microg/mL) in sera was within the normal range (0-8.0 microg/mL). Therefore, we performed an immunostaining of the precursor protein (amino terminus of constant region: kappa and lambda light chains, and AA protein) using duodenal biopsy specimens for a precise diagnosis. Immunostaining was positive for the amino terminus of constant region of the lambda light chain, and negative for the amino terminus of constant region of the kappa light chain and AA protein. No plasma cell proliferation in the bone marrow was observed. We finally diagnosed this patient as having primary AL amyloidosis. It appears that a pathological diagnosis must be performed by immunostaining the precursor proteins with the permanganate digestion technique in tissue of patients with amyloidosis. There were no abnormalities in serum and urine immunoelectrophoresis at the time of renal biopsy in this patient. During the follow-up period, after discharge, Bence Jones protein appeared in the urine, but not in the serum. It is necessary to observe patients with primary AL amyloidosis carefully to determine if they their condition will progress to multiple myeloma. Multiple myeloma Multiple myeloma is diagnosed in patients that (except for non-secretory multiple myeloma patients) have a clonal IgG, IgA, IgD, or IgE myeloma protein in their serum and/or a clonal κ or λ light chain in their serum or urine plus either one of two sets of criteria. In the first criteria set, patients must have ≥10% bone marrow clonal plasma cells plus ≥1 of the CRAB criteria; in the second criteria set, patients must have ≥10 bone marrow clonal plasma cells plus ≥1 of the following findings, ≥60% bone marrow clonal plasma cells, a free κ/λ or λ/κ light chain ratio in serum of ≥100 (the involved clonal light chain concentration must be ≥100 milligrams/liter), and/or >1 focal bone lesion on magnetic resonance imaging. The 5 year medium survival of patients with multiple myeloma treated with currently used treatment regiments is 48.5%. Light chain multiple myeloma In theory, multiple myeloma can produce all classes of immunoglobulin, but IgG paraproteins are most common, followed by IgA and IgM. IgD and IgE myeloma are very rare. In addition, light and or heavy chains (the building blocks of antibodies) may be secreted in isolation: κ- or λ-light chains or any of the five types of heavy chains (α-, γ-, δ-, ε- or μ-heavy chains). People without evidence of a monoclonal protein may have \"nonsecretory\" myeloma (not producing immunoglobulins); this represents about 3% of all people with multiple myeloma. Additional findings may include a raised calcium level (when osteoclasts are breaking down bone, releasing it into the bloodstream), raised serum creatinine level due to reduced kidney function, which is mainly due to casts of paraprotein deposition in the kidney, although the cast may also contain complete immunoglobulins, Tamm-Horsfall protein and albumin. A 79-year-old woman was admitted to our hospital because of leg edema due to a nephrotic syndrome. Urinary and serum immunoelectrophoresis showed positive for the lambda type of Bence Jones protein. A bone marrow aspiration test revealed mild plasmacytosis (6.4% of the total cells). These findings confirmed her diagnosis of monoclonal gammopathy of undetermined significance (MGUS). Her renal biopsy specimen revealed mild mesangial cell proliferation and an increase in the mesangial matrix. Immunofluorescence studies showed positive staining for IgG, IgA, C3, and kappa and lambda light chains in the capillary wall and mesangium area. Electron microscopy showed that the electron deposits in the thickened basement membrane were formed by randomly arranged 16- to 18-nm nonbranching fibrils. A Congo red stain for amyloid was negative. These findings corresponded with the diagnosis of fibrillary glomerulonephritis. Therefore, this case showed a rare combination of fibrillary glomerulonephritis and MGUS. Monoclonal gammopathy of undetermined significance (MGUS), is defined as the presence in the blood or urine of a monoclonal antibody, antibody heavy chain, or antibody light chain in a person lacking symptoms or signs of a more serious plasma cell dyscrasia. The condition is typically discovered as an incidental finding when serum protein electrophoresis is done for various reasons unrelated to plasma cell dyscrasias. Protein electrophoresis generally detects one of the following patterns of monoclonal myeloma protein spikes representing: a) intact IgG, IgA, IgE, IgE, or IgM; b) intact IgG, IgA, IgE, IgD, or IgM plus high concentrations of a free (i.e. not bound to a heavy chain) κ or λ light chain; c) a free κ chain in great excess of a λ chain or a free λ chain in great excess of a κ chain; and d) free γ, δ, or μ heavy chains unbound to a light chain (free α and ε heavy chain myeloma protein spikes have not been reported). Among MGUS cases expressing an intact antibody, 70%, 15%, Non-IgM MGUS, commonly termed MGUS, is diagnosed in individuals who exhibit a serum IgG, IgD, IgA, or IgE monoclonal protein with or without increased levels of blood and/or urine free κ or λ light chains. These patients typically also show small increases in bone marrow plasma cells. Further requirements for the diagnosis of non-IgM MGUS are: a) bone marrow clonal plasma cells <10% of total nucleated cells; b) absence of any of the four CRAB criteria (CRAB criteria are C = Calcium serum levels >1 milligram/deciliter above normal values and/or a serum level >11 milligram/deciliter; R = Renal insufficiency as defined by a glomerular filtration rate <40 milliliter/minute and/or a serum creatinine >2 gram/deciliter due to myeloma protein-induced kidney damaged; A = Anemia, as defined by a blood hemoglobin level >2 gram/deciliter below normal and/or <10 gram/deciliter due to the plasma cell dyscrasia rather than e.g. iron deficiency or blood loss; B = Bone lesions, i.e. ≥1 lytic (i.e. The proteins are immunoglobulin light chains (paraproteins) and are produced by neoplastic plasma cells. They can be kappa (most of the time) or lambda. The light chains can be immunoglobulin fragments or single homogeneous immunoglobulins. They are found in urine as a result of decreased kidney filtration capabilities due to kidney failure, sometimes induced by hypercalcemia from the calcium released as the bones are destroyed ,dehydration due to polyurea, amyloidosis or from the light chains themselves. The light chains have historically been detected by heating a urine specimen (which causes the protein to precipitate) and now by electrophoresis of concentrated urine. More recently, serum free light chain assays have been utilised in a number of published studies which have indicated superiority over the urine tests, particularly for patients producing low levels of monoclonal free light chains, as seen in nonsecretory multiple myeloma and AL amyloidosis. History PROTEINURIA ON URINE DIPSTICK Quantify by 24-h urinary excretion of protein and albumin or first morning spot albumin-to-creatinine ratio RBCs or RBC casts on urinalysis In addition to disorders listed under microalbuminuria consider Myeloma-associated kidney disease (check UPEP) Intermittent proteinuria Postural proteinuria Congestive heart failure Fever Exercise Go to Fig. 61-2 Macroalbuminuria 300-3500 mg/d or 300-3500 mg/g Microalbuminuria 30-300 mg/d or 30-300 mg/g Nephrotic range > 3500 mg/d or > 3500 mg/g + Consider Early diabetes Essential hypertension Early stages of glomerulonephritis (especially with RBCs, RBC casts)Consider Early diabetes Essential hypertension Early stages of glomerulonephritis (especially with RBCs, RBC casts) Nephrotic syndrome Diabetes Amyloidosis Minimal change disease FSGS Membranous glomerulopathy IgA nephropathy Reports on 102 patients suffering from IgD-myeloma are reviewed and analyzed. Patients with IgD-myeloma are younger than patients with myeloma producing IgG or IgA myeloma proteins.  Males are affected by this disease 3 times as often as females and 11 times as often as female patients in the group producing kappa light chain type of IgD myeloma protein. Hyperproteinaemia and extreme spikes of the monoclonal immunoglobulin occur less often. Approximately 90% of the patients have a lambda light chain myeloma protein and almost all patients excrete Bence-Jones protein. Renal insufficiency, amyloidosis, and plasma-cell leukemia are found more frequently than in other types of multiple myeloma. IgD-multiple myeloma carries a poorer prognosis, possibly related to the frequent finding of renal insufficiency.\nHere is the question:\nNEPHROLOGY: A 68-year-old patient consults for edema and asthenia. Laboratory tests showed creatinine 5 mg/dL, hemoglobin 10 g/dL and marked hypogammaglobulinemia in serum at the expense of IgG, IgA and IgM. A urinalysis reveals the presence of kappa light chains. What is your diagnostic suspicion?\nHere are the potential choices:\n1. Kappa light chain deposition disease.\n2. Nephrotic syndrome.\n3. Amyloidosis.\n4. IgA myeloma with Bence-Jones proteinuria.\n5. Light chain myeloma.\nThe correct answer is: ",
        "gold_answer": "1 Kappa light chain deposition disease.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 43-year-old man was admitted to our hospital because of legs edema and periorbital edema in Dec. 1983. Laboratory findings showed massive proteinuria (3.7 g/day), Bence Jones protein (BJP) in urine, and hypoproteinemia. Peripheral blood examinations were normal and a bone marrow aspiration showed hypocellularity with slight increase of monocytes and plasma cells. Serum immunoelectrophoresis showed two M-components (IgG kappa, IgA lambda). Serum IgG was 1,690 mg/dl, IgA 379 mg/dl and IgM 160 mg/dl. No remarkable findings were obtained in bone survey, Ga-scintigraphy and rectal biopsy, and a diagnosis of diclonal gammopathy with nephrotic syndrome was made. In Aug. 1986, serum IgA started to increase rapidly with concomitant decrease IgG. He died of pneumonia due to pancytopenia in Dec. 1986, when serum IgG was 450 mg/dl, IgA 1,014 mg/dl, and IgM less than 39 mg/dl. Immunoelectrophoresis showed two M-components (IgG kappa, IgA lambda) in serum and BEP (kappa, lambda), IgG (kappa) and IgA (lambda) in urine. An autopsy showed massive infiltration of myeloma cells which were positive for lambda light chain in bone marrow, suggesting a development of myeloma from a diclonal gammopathy in about 3 years. Non-IgM SMM Non-IgM SMM (also termed IgG and IgA SMM because of the rarity of IgD and IgE SMM) is diagnosed in asymptomatic individuals based on criteria identical to those listed above for Non-IgM MGUS except that: their intact IgG or IgA myeloma protein levels are equal to or greater than 30 grams/liter rather than 15 grams/liter; their bone marrow shows plasma cells comprise between 10% and <60% rather than <10% of nucleated cells; and/or their 24-hour urine contains 0.5 gram or greater levels of Bence Jones, i.e. light chain myeloma, proteins. individuals must also lack evidence of more recently established multiple myeloma-defining criteria viz., CRAB features, amyloidosis, more than one solitary plasmacytoma, and/or serum or urine free light chain κ to λ or λ to κ ratios of 100 or greater. Individuals diagnosed with light chain MGUS typically do not express detectable levels of an IgG, IgA, IgD, IgE, or IgM intact myeloma protein in their blood. Rather, they overexpress a monoclonal, aberrant free κ (i.e. kappa) or λ (i.e., lambda) immunoglobulin light chain. For diagnosis, the κ and λ free light chains are quantified by immunological methods and the ratio of κ to λ light chains is used to detect unbalanced light chain synthesis that is indicative of a monoclonal light chain plasma cell dyscrasia. Light chain MGUS is defined as a disorder in which a serum κ to λ free light chain ratio falls outside the normal range of 0.26–1.65 (mean =0.9) provided that it is not associated with: a) any of the CRAB criteria, b) a bone marrow plasma cell count of 10 or a higher percentage of nucleated cells, c) evidence of amyloid deposition (see Light chain deposition disease), and d) an accumulation of 0.5 or more grams of the monoclonal light chain in the urine over a 24-hour period. Light chain SMM Light chain smoldering multiple myeloma (light chain SMM) was previously termed idiopathic Bence Jones proteinuria. The condition is currently diagnosed in asymptomatic individuals who have a 24-hour urinary Bence Jones, i.e. light chain myeloma protein level, that is >0.5 grams and/or bone marrow plasma cells that are 10% to <60% of nucleated cells. These individuals must also; lack detectable IgG, IgA, IgD, IgE, or IgM myeloma proteins in sera; have a free κ/λ or λ/κ light chain ratio outside of 0.26 to 1.65 range but less than 100; and/or have no evidence for the presence of any one of the CRAB criteria, amyloidosis, or end organ damage attributable to the myeloma proteins or plasma cells. Renal amyloidosis is an uncommon cause of nephrotic syndrome. The clinical conditions in Chinese people remain obscure. This is a retrospective review of the clinicopathological spectrum of 12 cases diagnosed in Taichung Veterans General Hospital from October 1982 to November 1993. Charts and renal pathological slides were reviewed retrospectively. A scoring system was set to evaluate the degree of amyloid deposition in the renal tissue. The clinical profile, immunological data, pathological picture and final outcomes are presented and discussed, with literature review. There were 12 cases of primary amyloidosis including 1 case of multiple myeloma. All were confirmed by renal biopsy. The cases were all male with mean age of onset as 53.3 +/- 11.3 (range: 32 to 65 years). The mean follow-up duration was 22.9 +/- 32.8 months. The initial average creatinine clearance was 66.7 +/- 42.7 ml/min; mean daily urine protein was 7.0 +/- 4.1 grams. Nephrotic syndrome was the main clinical manifestation, present in all 12 cases. Other presenting symptoms and signs included: malaise in 7 cases; hypertension and anorexia in 4 cases; limb numbness in 3 cases; low back pain, dizziness and microhematuria in 2 cases each; anemia, headache, stroke, restrictive cardiomyopathy, hepatomegaly, syncope, body weight loss, dysphagia and skin itching in one case individually. Amyloid cardiomyopathy was present in 4 of the 8 patients who received echocardiography. The mean serum albumin level was 1.9 +/- 0.7 mg/dl, globulin level 3.1 +/- 1.1 mg/dl. Urinary Bence-Jones protein examination was performed in 8 cases; none revealed positive response. The mean immunoglobulin (Ig) level for the patients included: IgG 1018 +/- 901 mg/dl, IgA 262.0 +/- 313.8 mg/dl, IgM 104.8 +/- 84.2 mg/dl. There were at least 4 cases with high levels of one Ig but depressed levels in the others. M-component was shown by immunoelectrophoresis (IEP) in 90% of the cases. IEP impression in 10 cases revealed 2 cases of IgA lambda, 2 cases IgA kappa, 3 cases IgG lambda and 1 case IgG kappa monogammopathy, 1 case free lambda myeloma and 1 case negative. The ratio of kappa to lambda chain was 3:6. Bone marrow biopsy performed in 8 cases found only 1 case with multiple myeloma, one with amyloidosis; the other 6 cases were unremarkable. Mesangium was the site of heaviest amyloid deposition, followed by tubular basement membrane, artery and interstitium. The median survival time for those whose total score was lower than 3 points was 97.5 months; 3 to 5 points, 14 months; 6 points or more, 18.5 months. The median survival time was 21.6 months and 3-year-survival rate was 32.7%. The 2 cases with long-term survival were of 111 months and 84 months. The possible reason included: 1) Organ-limited renal amyloidosis; 2) Light amyloid deposition; 3) Younger age; 4) Other undetected favorable factors. 1) Renal amyloidosis is not a frequent diagnosis of nephrotic syndrome in Taiwan, but it should be suspected in every patient over 50 years old with a recent onset of proteinuria. 2) Renal amyloidosis can be diagnosed only by renal biopsy. 3) Primary renal amyloidosis is a disease of poor prognosis. Immunoglobulin D (IgD) myeloma is a rare disease, about 2% of all myelomas, even rarer when accompanied with another multiple myeloma in biclonal gammopathy. We presented a case of biclonal gammopathy-as-sociated manifestation of IgD myeloma and light chain disease in a patient who initially had renal failure. 37-year-old male approximately one month before hospitalization began to feel malaise and fatigue along with decreased urination. Laboratory analysis revealed azotemia. A dialysis catheter was placed and hemodialysis started. The patient was then admitted to our hospital for further tests and during admission, objective examination revealed pronounced paleness with hepatosplenomegaly and hypertension (170/95 mmHg). Laboratory analysis showed erythrocyte sedimentation rate 122 mm/h, expressed anemic syndrome (Hb 71 g/L) and renal failure dialysis rank: creatinine 1,408 micromol/L, urea 31.7 mmol/L. There was two M components in serum protein electrophoresis: IgD lambda and free light chain lambda. Proteinuria was nephrotic rank (5.4 g/24 h), whose electrophoresis revealed 2 M components--massive in alpha 2 fraction of 71%; 7% in the discrete beta fraction, beta 2M / serum 110 mg / L, in urine 1.8 mg/L--extremely high; IgL kappa I lambda index 1:13 (reference value ratio 2:1). The findings pointed to double myeloma disease: IgD myeloma and Bence Jones lambda myeloma. Bone biopsy confirmed IgD myeloma lambda 100% infiltration medulla predominantly plasmablasts. The treatment continued with hemodialysis 3 times per week with chemotherapy protocol bortezomib, doxorubicin, dexamethasone. After 4 cycles of chemotherapy, there was a decrease of IgD, lamda-light chains, reduction in proteinuria (1.03 g/24 h), so hemodialysis was reduced to once per week. Six months after treatment initiation the patient underwent autologous bone marrow transplantation. In a 2-year follow-up period double myeloma disease showed complete remission. The presented rare form of double myeloma disease with initial renal insufficiency underscores the importance of careful observation and teamwork that can alter the course of this serious disease. Light chain deposition disease (LCDD) is characterized by the deposition of monoclonal immunoglobulin light chains in the kidney, which can cause end-stage kidney disease if not treated. While kidney biopsy is required for definitive diagnosis, choosing an appropriate biopsy method may be problematic when examining patients with atrophic kidneys. A 66-year-old Japanese man was referred to our institution with a three-month history of leg edema. Clinical investigations revealed proteinuria levels of 7.5 g/day. CT-guided percutaneous kidney biopsy was selected as the biopsy method because atrophic kidneys were poorly visualized on ultrasonography. Kidney biopsy revealed nodular glomerulosclerosis, exclusive deposition of the κ chain, and powdery electron-dense deposits, all of which were indicative of LCDD. Bence-Jones protein was detected in the urine. The patient also had an abnormal serum-free light chain ratio. Bone marrow biopsy revealed multiple myeloma; therefore, the patient was diagnosed to have LCDD with multiple myeloma. The patient was treated with daratumumab, bortezomib, cyclophosphamide, and dexamethasone. After a one-year follow-up, the patient had hematological and renal responses without any treatment-related adverse effects. Our case demonstrates the effectiveness of daratumumab as a treatment for LCDD with nephrotic-range proteinuria. Additionally, we suggest that CT-guided kidney biopsy should be considered as a diagnostic test in patients with kidney atrophy when making a definitive diagnosis. A 64-year-old African American male presented to the emergency department with subacute low back pain for two weeks and decreased urine output. He was found to have a potassium level of 9.2 mmol/L and was uremic with a creatinine level of 28.5 mg/dL and blood urea nitrogen (BUN) level of 201 mg/dL. He also tested positive for COVID-19. He was then started on continuous renal replacement therapy (CRRT). His urinalysis showed more than 500 mg/dL of protein. A workup for multiple myeloma was also conducted, and urine protein electrophoresis test was positive for free lambda light chains with a level of 17,700 mg/L and free kappa light chains with a level of 88.30 mg/L with a kappa:lambda free light chain ratio of 0.005. Additionally, serum Bence Jones protein level was elevated at 240 mg/dL, and serum beta-2 microglobulin level was elevated at 31.41 mg/L. An immunoglobulin (Ig) panel also showed low levels of IgG, IgA, and IgM. Kidney biopsy for this patient showed definite cast nephropathy and minimal chronic changes, with only one of over 20 glomeruli sclerosed and minimal interstitial deposits. The patient was started on chemotherapy with cyclophosphamide, bortezomib, and dexamethasone (CyBorD). A 76-year-old man was admitted to Kisen hospital because of lumbago and chest pain. Laboratory examinations revealed a chronic renal failure with marked elevation of the serum BUN (48.8 mg/dl) and creatinine levels (8.2 mg/dl). The serum electrophoresis demonstrated a hypergammaglobulinemia with M peaks. An immunoelectrophoresis demonstrated monoclonal IgD-lambda and IgG-kappa proteins in the serum, and lambda-type Bence Jones protein in the urine (0.4 g/day). Bone marrow smears revealed an abnormal proliferation of atypical plasma cells (43%). A systemic X-ray examination of the skeletal system showed systemic osteoporosis without punched out lesion. The patient was diagnosed as having IgD-lambda type multiple myeloma and IgG-kappa type benign monoclonal gammopathy by quantifying concentration of two M proteins (1,160 mg/dl in IgD, 1,179 mg/dl in IgG, respectively). A combination chemotherapy with melphalan and prednisolone was administered monthly for multiple myeloma, and hemodialysis for the renal failure was performed 3 times a week. A marked improvement of his laboratory findings including a diminution of the serum IgD-lambda M-protein was obtained. On the other hand, IgG-kappa M-protein level was unchanged. Two M-protein levels showed a different behavior after the combination chemotherapy. Although the patient died of congestive heart failure, the partial remission of multiple myeloma has been maintained for 16 months with chemotherapy. A 32-year-old Japanese woman presented with hypertension, nephrotic syndrome, microhematuria, and severe hypocomplementemia. Her serum creatinine concentration increased from 1.46 mg/dL (129.0 μmol/L) to 3.46 mg/dL (305.8 μmol/L) over 1 month. Renal biopsy revealed Congo red-negative nodular glomerulosclerosis accompanied by mesangial proliferation. There was extensive staining of immunoglobulin (Ig) G in the glomerular and tubular basement membranes and expanded mesangial regions. Staining was negative for IgA, IgM, and kappa and lambda light chains and positive for the gamma 1 IgG subclass. Staining for constant domains of the gamma heavy chains showed a deletion of the first constant domain (CH1). Electron microscopy revealed electron-dense deposits in the glomerular and tubular basement membranes and mesangium. These findings indicated gamma 1-heavy chain deposition disease (HCDD). Serum and urine immunoelectrophoresis revealed an IgG kappa monoclonal band, whereas bone marrow biopsy revealed monoclonal plasmacytosis with positive staining for kappa chains. HCDD associated with kappa light chain is extremely rare. We report the first case of HCDD with IgG kappa detected in the serum, urine, and bone marrow. The serum M component will be IgG in 53% of patients, IgA in 25%, and IgD in 1%; 20% of patients will have only light chains in serum and urine. Dipsticks for detecting proteinuria are not reliable at identifying light chains, and the heat test for detecting Bence Jones protein is falsely negative in ~50% of patients with light chain myeloma. Fewer than 1% of patients have no identifiable M component; these patients usually have light chain myeloma in which renal catabolism has made the light chains undetectable in the urine. In most of these patients, light chains can now be detected by serum free light chain assay. IgD myeloma may also present with light chain disease. About two-thirds of patients with serum M components also have urinary light chains. The light chain isotype may have an impact on survival. Patients secreting lambda light chains have a significantly shorter overall survival than those secreting kappa light chains. Whether this is due to some genetically important A 73-year-old male was admitted to the renal division of our hospital because of hypertension, proteinuria and bilateral pretibial edema. Eight years previously, he was diagnosed as being afflicted with interstitial pneumonia on the basis of a chest X-ray examination. Laboratory tests conducted during the current admission showed normocytic normochromic anemia, renal dysfunction and mild proteinuria. Total IgG was normal, but a high proportion of IgG2 was observed. M-protein in the serum was positive for both IgG lambda and Bence Jones protein (lambda type). A bone marrow biopsy showed the proportion of plasma cells to be 10.6%, but atypical cells were not found. We diagnosed the patient's condition as plasma cell dyscrasia. Light microscopy examination of a renal biopsy specimen showed moderate mesangial proliferation with a deposition of PAS-positive and Congo red negative materials in the mesangial area: nodular gomerulonephritis was seen in some glomeruli. Immunofluorescence revealed IgG and lambda light chains, strong linear staining along the glomerular basement membrane and tubular basement membrane and positivity in the mesangial area. Results of staining for IgA, IgM, fibrinogen and C3 were weakly positive in the mesangium area, while those for C4, Clq and free kappa were negative. Positive staining of IgG2 was seen by immunoperoxidase study, but the tissue was negative for IgG1, IgG3, IgG4. Electron microscopy demonstrated a dense granular deposition in the mesangial, subendothelial and peritubular area and a microfibrillar structure in the mesangial area. The diameter of the microfibrillar structure was 14 nm on the average.(ABSTRACT TRUNCATED AT 250 WORDS) We report here a case of a 58-year-old man who had nephrotic syndrome and immunoglobulin light chain (AL) amyloidosis. This patient underwent a renal biopsy to confirm the diagnosis. Treatment with permanganate before Congo red staining showed systemic secondary amyloidosis (AA) fibrils, which were sensitive to permanganate oxidation. Although this patient was initially diagnosed as having AA amyloidosis, he did not have any chronic inflammatory disease and/or malignancy. The level of amyloid A protein (7.9 microg/mL) in sera was within the normal range (0-8.0 microg/mL). Therefore, we performed an immunostaining of the precursor protein (amino terminus of constant region: kappa and lambda light chains, and AA protein) using duodenal biopsy specimens for a precise diagnosis. Immunostaining was positive for the amino terminus of constant region of the lambda light chain, and negative for the amino terminus of constant region of the kappa light chain and AA protein. No plasma cell proliferation in the bone marrow was observed. We finally diagnosed this patient as having primary AL amyloidosis. It appears that a pathological diagnosis must be performed by immunostaining the precursor proteins with the permanganate digestion technique in tissue of patients with amyloidosis. There were no abnormalities in serum and urine immunoelectrophoresis at the time of renal biopsy in this patient. During the follow-up period, after discharge, Bence Jones protein appeared in the urine, but not in the serum. It is necessary to observe patients with primary AL amyloidosis carefully to determine if they their condition will progress to multiple myeloma. Multiple myeloma Multiple myeloma is diagnosed in patients that (except for non-secretory multiple myeloma patients) have a clonal IgG, IgA, IgD, or IgE myeloma protein in their serum and/or a clonal κ or λ light chain in their serum or urine plus either one of two sets of criteria. In the first criteria set, patients must have ≥10% bone marrow clonal plasma cells plus ≥1 of the CRAB criteria; in the second criteria set, patients must have ≥10 bone marrow clonal plasma cells plus ≥1 of the following findings, ≥60% bone marrow clonal plasma cells, a free κ/λ or λ/κ light chain ratio in serum of ≥100 (the involved clonal light chain concentration must be ≥100 milligrams/liter), and/or >1 focal bone lesion on magnetic resonance imaging. The 5 year medium survival of patients with multiple myeloma treated with currently used treatment regiments is 48.5%. Light chain multiple myeloma In theory, multiple myeloma can produce all classes of immunoglobulin, but IgG paraproteins are most common, followed by IgA and IgM. IgD and IgE myeloma are very rare. In addition, light and or heavy chains (the building blocks of antibodies) may be secreted in isolation: κ- or λ-light chains or any of the five types of heavy chains (α-, γ-, δ-, ε- or μ-heavy chains). People without evidence of a monoclonal protein may have \"nonsecretory\" myeloma (not producing immunoglobulins); this represents about 3% of all people with multiple myeloma. Additional findings may include a raised calcium level (when osteoclasts are breaking down bone, releasing it into the bloodstream), raised serum creatinine level due to reduced kidney function, which is mainly due to casts of paraprotein deposition in the kidney, although the cast may also contain complete immunoglobulins, Tamm-Horsfall protein and albumin. A 79-year-old woman was admitted to our hospital because of leg edema due to a nephrotic syndrome. Urinary and serum immunoelectrophoresis showed positive for the lambda type of Bence Jones protein. A bone marrow aspiration test revealed mild plasmacytosis (6.4% of the total cells). These findings confirmed her diagnosis of monoclonal gammopathy of undetermined significance (MGUS). Her renal biopsy specimen revealed mild mesangial cell proliferation and an increase in the mesangial matrix. Immunofluorescence studies showed positive staining for IgG, IgA, C3, and kappa and lambda light chains in the capillary wall and mesangium area. Electron microscopy showed that the electron deposits in the thickened basement membrane were formed by randomly arranged 16- to 18-nm nonbranching fibrils. A Congo red stain for amyloid was negative. These findings corresponded with the diagnosis of fibrillary glomerulonephritis. Therefore, this case showed a rare combination of fibrillary glomerulonephritis and MGUS. Monoclonal gammopathy of undetermined significance (MGUS), is defined as the presence in the blood or urine of a monoclonal antibody, antibody heavy chain, or antibody light chain in a person lacking symptoms or signs of a more serious plasma cell dyscrasia. The condition is typically discovered as an incidental finding when serum protein electrophoresis is done for various reasons unrelated to plasma cell dyscrasias. Protein electrophoresis generally detects one of the following patterns of monoclonal myeloma protein spikes representing: a) intact IgG, IgA, IgE, IgE, or IgM; b) intact IgG, IgA, IgE, IgD, or IgM plus high concentrations of a free (i.e. not bound to a heavy chain) κ or λ light chain; c) a free κ chain in great excess of a λ chain or a free λ chain in great excess of a κ chain; and d) free γ, δ, or μ heavy chains unbound to a light chain (free α and ε heavy chain myeloma protein spikes have not been reported). Among MGUS cases expressing an intact antibody, 70%, 15%, Non-IgM MGUS, commonly termed MGUS, is diagnosed in individuals who exhibit a serum IgG, IgD, IgA, or IgE monoclonal protein with or without increased levels of blood and/or urine free κ or λ light chains. These patients typically also show small increases in bone marrow plasma cells. Further requirements for the diagnosis of non-IgM MGUS are: a) bone marrow clonal plasma cells <10% of total nucleated cells; b) absence of any of the four CRAB criteria (CRAB criteria are C = Calcium serum levels >1 milligram/deciliter above normal values and/or a serum level >11 milligram/deciliter; R = Renal insufficiency as defined by a glomerular filtration rate <40 milliliter/minute and/or a serum creatinine >2 gram/deciliter due to myeloma protein-induced kidney damaged; A = Anemia, as defined by a blood hemoglobin level >2 gram/deciliter below normal and/or <10 gram/deciliter due to the plasma cell dyscrasia rather than e.g. iron deficiency or blood loss; B = Bone lesions, i.e. ≥1 lytic (i.e. The proteins are immunoglobulin light chains (paraproteins) and are produced by neoplastic plasma cells. They can be kappa (most of the time) or lambda. The light chains can be immunoglobulin fragments or single homogeneous immunoglobulins. They are found in urine as a result of decreased kidney filtration capabilities due to kidney failure, sometimes induced by hypercalcemia from the calcium released as the bones are destroyed ,dehydration due to polyurea, amyloidosis or from the light chains themselves. The light chains have historically been detected by heating a urine specimen (which causes the protein to precipitate) and now by electrophoresis of concentrated urine. More recently, serum free light chain assays have been utilised in a number of published studies which have indicated superiority over the urine tests, particularly for patients producing low levels of monoclonal free light chains, as seen in nonsecretory multiple myeloma and AL amyloidosis. History PROTEINURIA ON URINE DIPSTICK Quantify by 24-h urinary excretion of protein and albumin or first morning spot albumin-to-creatinine ratio RBCs or RBC casts on urinalysis In addition to disorders listed under microalbuminuria consider Myeloma-associated kidney disease (check UPEP) Intermittent proteinuria Postural proteinuria Congestive heart failure Fever Exercise Go to Fig. 61-2 Macroalbuminuria 300-3500 mg/d or 300-3500 mg/g Microalbuminuria 30-300 mg/d or 30-300 mg/g Nephrotic range > 3500 mg/d or > 3500 mg/g + Consider Early diabetes Essential hypertension Early stages of glomerulonephritis (especially with RBCs, RBC casts)Consider Early diabetes Essential hypertension Early stages of glomerulonephritis (especially with RBCs, RBC casts) Nephrotic syndrome Diabetes Amyloidosis Minimal change disease FSGS Membranous glomerulopathy IgA nephropathy Reports on 102 patients suffering from IgD-myeloma are reviewed and analyzed. Patients with IgD-myeloma are younger than patients with myeloma producing IgG or IgA myeloma proteins.  Males are affected by this disease 3 times as often as females and 11 times as often as female patients in the group producing kappa light chain type of IgD myeloma protein. Hyperproteinaemia and extreme spikes of the monoclonal immunoglobulin occur less often. Approximately 90% of the patients have a lambda light chain myeloma protein and almost all patients excrete Bence-Jones protein. Renal insufficiency, amyloidosis, and plasma-cell leukemia are found more frequently than in other types of multiple myeloma. IgD-multiple myeloma carries a poorer prognosis, possibly related to the frequent finding of renal insufficiency.\nHere is the question:\nNEPHROLOGY: A 68-year-old patient consults for edema and asthenia. Laboratory tests showed creatinine 5 mg/dL, hemoglobin 10 g/dL and marked hypogammaglobulinemia in serum at the expense of IgG, IgA and IgM. A urinalysis reveals the presence of kappa light chains. What is your diagnostic suspicion?\nHere are the potential choices:\n1. Kappa light chain deposition disease.\n2. Nephrotic syndrome.\n3. Amyloidosis.\n4. IgA myeloma with Bence-Jones proteinuria.\n5. Light chain myeloma.\nThe correct answer is: 1. Kappa light chain deposition disease."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Respiratory alkalosis (Pa CO2 < 35 mmHg) occurs when there is too little carbon dioxide in the blood. This may be due to hyperventilation or else excessive breaths given via a mechanical ventilator in a critical care setting. The action to be taken is to calm the person and try to reduce the number of breaths being taken to normalize the pH. The respiratory pathway tries to compensate for the change in pH in a matter of 2–4 hours. If this is not enough, the metabolic pathway takes place. Under normal conditions, the Henderson–Hasselbalch equation will give the blood pH where: 6.1 is the acid dissociation constant (pKa) of carbonic acid () at normal body temperature [] is the concentration of bicarbonate in the blood in mEq/L PaCO2 is the partial pressure of carbon dioxide in the arterial blood in mmHg Blood gas analysis plays an important role in both diagnosis and subsequent treatment of critically ill patients in the emergency department and the ICU. Historically, arterial blood is predominantly used for blood gas analysis. The puncture is painful and complications may occur. The purpose of the present study was to evaluate the agreement between arterial and venous blood gas analysis and whether the sole use of venous blood gas analysis would have changed therapy. Adult patients who were intubated in the field and received an arterial and venous blood gas analysis within 15 mins after admission to the ED were eligible for inclusion. The values for pH, pCO<sub2</sub, HCO<sub3</sub-, base excess and lactate levels were collected retrospectively. Mean differences were calculated by subtracting venous from arterial values. The agreement between venous and arterial measurements was assessed using the method of Bland and Altman. Blood gases were assessed by two independent physicians using a standardized questionnaire to determine whether the use of venous blood gases would have led to a different interpretation of the situation (other diagnostic path) or a change of therapy (eg. respirator adjustment). Acceptable limits were defined before the collection of data started. Fifty patients (62% male, median age 63years) who were treated at the Emergency Department between June 1, 2014 and December 31, 2014 were included in the study. Following average differences and limits of agreement (LOA) were documented: pH 0.02312 with LOA from -0.048 to 0.094; pCO<sub2</sub -3.612 mmHg with LOA from -15 to 8.1 mmHg; BE -0.154 mmol/l with LOA from -3.7 to 3.4 mmol/l; HCO<sub3</sub-0.338 mmol/l with LOA from -2.27 to 2.9 mmol/l; Lactate -0.124 mg/dl with LOA from -2.28 to 2.03 mg/dl. Using venous blood gas results 100% of the patients with metabolic alkalosis were correctly diagnosed. Metabolic acidosis was detected with a high sensitivity (80.64%), specificity (89.47%) and positive predictive value (92.59%). The answers to lactate and acidosis due to AKI showed a specificity and positive predictive value of 100%. The respiratory adjustment showed a high sensitivity (91.89%) but a low specificity (38.46%). For pH, bicarbonate, BE and lactate venous blood gases can be used as surrogates for arterial measurements. Venous pCO<sub2</sub can be used for screening of hypercapnia and trending. Respirator adjustments may be done too often if the venous blood gas is used. Diagnosis Diagnoses can be done by doing an ABG (Arterial Blood Gas) laboratory study, with a pH <7.35 and a PaCO2 >45 mmHg in an acute setting. Patients with COPD and other Chronic respiratory diseases will sometimes display higher numbers of PaCO2 with HCO3- >30 and normal pH. Terminology Acidosis refers to disorders that lower cell/tissue pH to < 7.35. Acidemia refers to an arterial pH < 7.36. See also Acidosis Alkalosis Arterial blood gas Chemical equilibrium pCO2 pH pKa Metabolic acidosis Metabolic alkalosis Respiratory alkalosis References External links Acid–base disturbances Interpretation Base excess beyond the reference range indicates metabolic alkalosis if too high (more than +2 mEq/L) metabolic acidosis if too low (less than −2 mEq/L) Blood pH is determined by both a metabolic component, measured by base excess, and a respiratory component, measured by PaCO2 (partial pressure of carbon dioxide). Often a disturbance in one triggers a partial compensation in the other. A secondary (compensatory) process can be readily identified because it opposes the observed deviation in blood pH. For example, inadequate ventilation, a respiratory problem, causes a buildup of CO2, hence respiratory acidosis; the kidneys then attempt to compensate for the low pH by raising blood bicarbonate. The kidneys only partially compensate, so the patient may still have a low blood pH, i.e. acidosis. In summary, the kidneys partially compensate for respiratory acidosis by raising blood bicarbonate. In general, it is much easier to correct acute pH derangement by adjusting respiration. Metabolic compensations take place at a much later stage. However, in a critical setting, a person with a normal pH, a high CO2, and a high bicarbonate means that, although there is a high carbon dioxide level, there is metabolic compensation. As a result, one must be careful as to not artificially adjust breaths to lower the carbon dioxide. In such case, lowering the carbon dioxide abruptly means that the bicarbonate will be in excess and will cause a metabolic alkalosis. In such a case, carbon dioxide levels should be slowly diminished. See also Anion gap Radial artery puncture Chemical equilibrium Hemoximetry Arteriovenous oxygen difference References External links Online arterial blood gas calculator Diagnostic intensive care medicine Respiratory physiology Blood tests Respiratory therapy Medicine In medicine, the partial pressure of carbon dioxide in arterial blood is called or PaCO2. Measurement of in the systemic circulation indicates the effectiveness of ventilation at the lungs' alveoli, given the diffusing capacity of the gas. It is a good indicator of respiratory function and the closely related factor of acid–base homeostasis, reflecting the amount of acid in the blood (without lactic acid). Normal values for humans are in the range 35–45 mmHg. Values less than this may indicate hyperventilation and (if blood pH is greater than 7.45) respiratory alkalosis. Values greater than 45 mmHg may indicate hypoventilation, and (if blood pH is less than 7.35) respiratory acidosis. Aquatic Sciences Example 1 [28] : ABG: pH = 7.39, PaCO 2 = 51 mm Hg, PaO 2 = 59 mm Hg, HCO 3 = 30 mEq/L and SaO 2 = 90%, on room air. pH is in the normal range, so use 7.40 as a cutoff point, in which case it is < 7.40, and acidosis is present. The elevated PaCO 2 indicates respiratory acidosis, and the elevated HCO 3 indicates a metabolic alkalosis. The value consistent with the pH is PaCO 2 . Therefore, this is a primary respiratory acidosis. The acid-base that is inconsistent with the pH is the elevated HCO3, indicating a metabolic alkalosis, so there is compensation signifying a non-acute primary disorder because it takes days for metabolic compensation to be effective. Last, the decreased PaO 2 indicates an abnormality with oxygenation. However, a history and physical will help delineate the severity and urgency of required interventions, if any. Example 2 [28] : ABG: pH = 7.45, PaCO 2 = 32 mm Hg, PaO 2 = 138 mm Hg, HCO 3 = 23 mEq/L, the base deficit = 1 mEq/L, and SaO 2 is 92%, on room air. The patient presented with a mixed acid-base disorder, with a significant metabolic alkalosis and a bicarbonate concentration of 44 meq/L. A venous blood gas was drawn soon after his presentation; venous and arterial blood gases demonstrate a high level of agreement in hemodynamically stable patients, allowing for the interpretation of acid-base disorders with venous blood gas results. In response to his metabolic alkalosis, the Pco2 should have increased by 0.75 mmHg for each 1-meq/L increase in bicarbonate; the expected Pco2 should have been ~55 mmHg. Given the Pco2 of 62 mmHg, he had an additional respiratory acidosis, likely caused by respiratory muscle weakness from his acute hypokalemia and subacute hypercortisolism. The role of venous blood gases as an alternative to arterial blood gases in patients with severe acute heart failure has not been established. To assess the correlation between arterial and peripheral venous blood gases together with pulse-oximetry (SpO2), as well as to estimate arterial values from venous samples in the first hours upon admission of patients with acute cardiogenic pulmonary oedema. Simultaneous venous and arterial blood samples were extracted on admission and over the next 1, 2, 3, 4, and 10 hours. SpO2 was also registered at the same intervals. A total of 178 pairs of samples were obtained from 34 consecutive patients with acute cardiogenic pulmonary oedema. Arterial and venous blood gases followed a parallel course in the first hours, showing high correlation rates at all time intervals. Venous samples underestimated pH (mean difference -0.028) and overestimated CO2 (+5.1 mmHg) and bicarbonate (+1 mEq/l). Conversely, SpO2 tended to underestimate SaO2 (mean±SD: 93.1±9.1 vs. 94.2±8.4). Applying simple mathematical formulae based on these differences, arterial values were empirically calculated from venous samples, showing acceptable agreement in the Bland-Altman test. Likewise, a venous pH &lt;7.32, pCO2 &gt;51.3 mmHg, and bicarbonate &lt;22.8 mEq/l could fairly identify arterial acidosis, either respiratory or metabolic, with a test accuracy of 92, 68, and 91%, respectively. In patients with cardiogenic pulmonary oedema, arterial blood gas disturbances may be estimated from peripheral venous samples. By monitoring SpO2 simultaneously, arterial punctures could often be avoided. Guidelines A 1 mmHg change in PaCO2 above or below 40 mmHg results in 0.008 unit change in pH in the opposite direction. The PaCO2 will decrease by about 1 mmHg for every 1 mEq/L reduction in [] below 24 mEq/L A change in [] of 10 mEq/L will result in a change in pH of approximately 0.15 pH units in the same direction. Assess relation of pCO2 with pH: If pCO2 & pH are moving in opposite directions i.e., pCO2 ↑ when pH is <7.4 or pCO2 ↓ when pH > 7.4, it is a primary respiratory disorder. If pCO2 & pH are moving in same direction i.e., pCO2 ↑when pH is >7.4 or pCO2 ↓ when pH < 7.4, it is a primary metabolic disorder. Parameters and reference ranges These are typical reference ranges, although various analysers and laboratories may employ different ranges. The normal range for pH is 7.35–7.45. As the pH decreases (< 7.35), it implies acidosis, while if the pH increases (> 7.45) it implies alkalosis. In the context of arterial blood gases, the most common occurrence will be that of respiratory acidosis. Carbon dioxide is dissolved in the blood as carbonic acid, a weak acid; however, in large concentrations, it can affect the pH drastically. Whenever there is poor pulmonary ventilation, the carbon dioxide levels in the blood are expected to rise. This leads to a rise of carbonic acid, leading to a decrease in pH. The first buffer of pH will be the plasma proteins, since these can accept some H+ ions to try to maintain acid-base homeostasis. As carbon dioxide concentrations continue to increase (PaCO2 > 45 mmHg), a condition known as respiratory acidosis occurs. The body tries to maintain homeostasis by increasing the respiratory rate, a condition known as tachypnea. This allows much more carbon dioxide to escape the body through the There are differences in the acute and chronic stages of respiratory acidosis or alkalosis. Acute respiratory acidosis from increased PCO2 will result in immediate changes to serum bicarbonate levels due to the bicarbonate buffer system; however, this is limited in its ability to achieve homeostasis. The kidney will gradually increase the serum bicarbonate levels in chronic cases. Chronic respiratory acidosis is when the acidemia exists for 3 to 5 days, which is approximately how long it will take the kidney to buffer the acidemia. In acute respiratory acidosis, normally, the serum bicarbonate will increase by 1 mEq/L for every 10 mmHg increase in PCO2. For chronic respiratory acidosis, the serum bicarbonate will increase by 4 to 5 mEq/L for every 10 mmHg rise in PCO2. [6] [5] The result typically causes a mild chronic acidosis or low-normal pH near 7.35. [6] In regards to respiratory alkalosis, the same timeframe applies to acute versus chronic. In acute respiratory alkalosis, for every decrease in PCO2 by 10 mmHg, the serum bicarbonate will also decrease by 2 mEq/L. In chronic respiratory alkalosis, or alkalosis lasting 3 to 5 days, for every 10mmHg drop in PCO2, it is expected that serum bicarbonate will decrease by 4 to 5 mEq/L. [5] [6] A blood gas test or blood gas analysis tests blood to measure blood gas tension values, it also measures blood pH, and the level and base excess of bicarbonate. The source of the blood is reflected in the name of each test; arterial blood gases come from arteries, venous blood gases come from veins and capillary blood gases come from capillaries. The blood gas tension levels of partial pressures can be used as indicators of ventilation, respiration and oxygenation. Analysis of paired arterial and venous specimens can give insights into the aetiology of acidosis in the newborn. Values measured Blood gas tests also measure the levels of bicarbonate and of standard bicarbonate, of base excess, of oxygen saturation, and of pH. An arterial blood gas test is more often used. Clinical significance Blood gas tests can be used in the diagnosis of a number of acidosis conditions such as lactic, metabolic, and respiratory acidosis, diabetic ketoacidosis, and also of respiratory alkalosis. Particularly, umbilical cord blood gas analysis can give an indication of preceding fetal hypoxic stress. In combination with other clinical information, normal paired arterial and venous cord blood gas results can usually provide a robust defence against a suggestion that an infant had an intrapartum hypoxic‐ischaemic event. Acute respiratory acidosis: HCO3− increases 1 mEq/L for each 10 mm Hg rise in PaCO2. Chronic respiratory acidosis: HCO3− rises 3.5 mEq/L for each 10 mm Hg rise in PaCO2. The expected change in pH with respiratory acidosis can be estimated with the following equations: Acute respiratory acidosis: Change in pH = 0.08 X ((40 − PaCO2)/10) Chronic respiratory acidosis: Change in pH = 0.03 X ((40 − PaCO2)/10) Respiratory acidosis does not have a great effect on electrolyte levels. Some small effects occur on calcium and potassium levels. Acidosis decreases binding of calcium to albumin and tends to increase serum ionized calcium levels. In addition, acidemia causes an extracellular shift of potassium, but respiratory acidosis rarely causes clinically significant hyperkalemia. Diagnosis The regulation of PCO2 is also involved in metabolic acidosis and alkalosis, as well. In metabolic acidosis, for every 1 mEq/L drop of bicarbonate, there will be a decrease in PCO2 by 1.2 mmHg. [5] For sudden drops in bicarbonate, it will take approximately 12 to 24 hours to reach full compensation; however, this process will start in as early as 30 minutes by chemoreceptor and CSF pH changes. [7] Another way to determine the expected PCO2 and compare the value obtained on blood gas analysis with metabolic acidosis is to utilize Winter’s equation. [8] If the measured PCO2 is higher or lower than the Winter’s equation PCO2, there may be a secondary respiratory acidosis or alkalosis, respectively. This situation may be the case in underlying lung pathology or neuromuscular pathology, such as an anoxic injury-causing minute ventilation control to become reduced. Also, in the presence of very severe metabolic acidosis, there is a limit to respiratory compensation with minute ventilation. The PCO2 typically cannot fall below 8 to 12 mmHg, and the sustained increase in minute ventilation to achieve this low PCO2 will usually cause rapid respiratory fatigue. In the case of metabolic alkalosis, the expected compensation of PCO2 is to increase by 0.7 mmHg for every 1 mEq/L increase in serum bicarbonate. [5] Gasometry is the measurement of dissolved gases in the blood, by measuring pH, carbon dioxide pressure (pCO(2)), serum bicarbonate (HCO(3-)), and lactate and serum electrolytes: sodium, potassium and chlorine you can make a diagnosis, etiology and treatment in the critically ill patient. The aim is to provide five steps for the interpretation of blood gases by: 1. The definition of acidemia or acidosis, or alkalemia or alkalosis. 2. Defining the metabolic component or respiratory. 3. To determine the anion gap; levels above 15 ± 2 determine other likely causes of excess anions (methanol, uremia, diabetic ketoacidosis, paraldehyde, ionized, lactic acidosis, ethylene glycol and salicylates. 4. Compensation, using the Winter formula. 5. The delta gap, with the formula for determining intrinsic and metabolic alkalosis. When anion gap is normal, is calculated urinary anion gap; the value is negative if the loss is extrarenal, contrary to the positive result is renal etiology. In many people a high causes a feeling of shortness of breath, but the lack of this symptom is no guarantee that the other effects are not occurring. A significant percentage of rebreather deaths have been associated with CO2 retention. The effects of high can take several minutes to hours to resolve once the cause has been removed. Diagnosis Blood gas tests may be performed, typically by radial artery puncture, in the setting of acute breathing problems or other acute medical illness. Hypercapnia is generally defined as an arterial blood carbon dioxide level over 45 mmHg (6 kPa). Since carbon dioxide is in equilibrium with carbonic acid in the blood, hypercapnia drives serum pH down, resulting in respiratory acidosis. Clinically, the effect of hypercapnia on pH is estimated using the ratio of the arterial pressure of carbon dioxide to the concentration of bicarbonate ion, . Tolerance The alveolar pO2 is not routinely measured but is calculated from blood gas measurements by the alveolar gas equation. Partial pressure of carbon dioxide Pathology The partial pressure of carbon dioxide, along with the pH, can be used to differentiate between metabolic acidosis, metabolic alkalosis, respiratory acidosis, and respiratory alkalosis. Hypoventilation exists when the ratio of carbon dioxide production to alveolar ventilation increases above normal values – greater than 45mmHg. If pH is also less than 7.35 this is respiratory acidosis. Hyperventilation exists when the same ratio decreases – less than 35mmHg. If the pH is also greater than 7.45 this is respiratory alkalosis. See also Alveolar-arterial gradient Diffusing capacity Pulmonary alveolus References Respiratory physiology To calculate the expected pCO2 in the setting of metabolic alkalosis, the following equations are used: pCO2 = 0.7 [HCO3] + 20 mmHg ± 5 pCO2 = 0.7 [HCO3] + 21 mmHg Treatment To effectively treat metabolic alkalosis, the underlying cause(s) must be corrected. A trial of intravenous chloride-rich fluid is warranted if there is a high index of suspicion for chloride-responsive metabolic alkalosis caused by loss of gastrointestinal fluid (e.g., due to vomiting). Terminology Alkalosis refers to a process by which the pH is increased. Alkalemia refers to a pH which is higher than normal, specifically in the blood. See also Hypokalemia Metabolic acidosis Respiratory acidosis Respiratory alkalosis References External links Acid–base disturbances Diagnostic approach and causes Metabolic Acidosis is defined as a reduced serum pH, and an abnormal serum bicarbonate concentration of <22 mEq/L, below the normal range of 22 to 29 mEq/L. However, if a patient has other coexisting acid-base disorders, the pH level may be low, normal or high in the setting of metabolic acidosis. In the absence of chronic respiratory alkalosis, metabolic acidosis can be clinically diagnosed by measuring serum bicarbonate levels in the blood, which is generally a standard component of blood panels. Imperatively, when weighing a metabolic acidosis diagnosis, the change in serum bicarbonate levels over time should be considered; if baseline bicarbonate results are unknown, a single set of values may be misinterpreted. Causes Generally, metabolic acidosis occurs when the body produces too much acid (e.g., lactic acidosis, see below section), there is a loss of bicarbonate from the blood, or when the kidneys are not removing enough acid from the body. Types Respiratory acidosis can be acute or chronic. In acute respiratory acidosis, the PaCO2 is elevated above the upper limit of the reference range (over 6.3 kPa or 45 mm Hg) with an accompanying acidemia (pH <7.36). In chronic respiratory acidosis, the PaCO2 is elevated above the upper limit of the reference range, with a normal blood pH (7.35 to 7.45) or near-normal pH secondary to renal compensation and an elevated serum bicarbonate (HCO3− >30 mEq/L). Causes Acute Acute respiratory acidosis occurs when an abrupt failure of ventilation occurs. This failure in ventilation may be caused by depression of the central respiratory center by cerebral disease or drugs, inability to ventilate adequately due to neuromuscular disease (e.g., myasthenia gravis, amyotrophic lateral sclerosis, Guillain–Barré syndrome, muscular dystrophy), or airway obstruction related to asthma or chronic obstructive pulmonary disease (COPD) exacerbation. Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise in arterial carbon dioxide levels is called hypercapnia. Respiratory failure is classified as either Type 1 or Type 2, based on whether there is a high carbon dioxide level, and can be acute or chronic. In clinical trials, the definition of respiratory failure usually includes increased respiratory rate, abnormal blood gases (hypoxemia, hypercapnia, or both), and evidence of increased work of breathing. Respiratory failure causes an altered mental status due to ischemia in the brain. The typical partial pressure reference values are oxygen Pa O2 more than 80 mmHg (11 kPa) and carbon dioxide Pa CO2 less than 45 mmHg (6.0 kPa). Cause More specific definitions of end-organ dysfunction exist for SIRS in pediatrics. Cardiovascular dysfunction (after fluid resuscitation with at least 40 ml/kg of crystalloid) hypotension with blood pressure < 5th percentile for age or systolic blood pressure < 2 standard deviations below normal for age, or vasopressor requirement, or two of the following criteria: unexplained metabolic acidosis with base deficit > 5 mEq/l lactic acidosis: serum lactate 2 times the upper limit of normal oliguria (urine output ) prolonged capillary refill > 5 seconds core to peripheral temperature difference Respiratory dysfunction (in the absence of a cyanotic heart defect or a known chronic respiratory disease) the ratio of the arterial partial-pressure of oxygen to the fraction of oxygen in the gases inspired (PaO2/FiO2) < 300 (the definition of acute lung injury), or Diagnosis The diagnosis of respiratory alkalosis is done via test that measure the oxygen and carbon dioxide levels (in the blood), chest x-ray and a pulmonary function test of the individual. The Davenport diagram allows clinicians or investigators to outline blood bicarbonate concentrations (and blood pH) after a respiratory or metabolic acid-base disturbance Classification There are two types of respiratory alkalosis: chronic and acute as a result of the 3–5 day delay in kidney compensation of the abnormality. Acute respiratory alkalosis occurs rapidly, have a high pH because the response of the kidneys is slow. Chronic respiratory alkalosis is a more long-standing condition, here one finds the kidneys have time to decrease the bicarbonate level. pH Alkalosis refers to the process due to which there is elevation of blood pH. Alkalemia refers to an arterial blood pH of greater than 7.45. Mutations to the V-ATPase 'a4' or 'B1' isoforms result in distal renal tubular acidosis, a condition that leads to metabolic acidosis, in some cases with sensorineural deafness. Arterial blood gases will indicate low pH, low blood HCO3, and normal or low PaCO2. In addition to arterial blood gas, an anion gap can also differentiate between possible causes. The Henderson-Hasselbalch equation is useful for calculating blood pH, because blood is a buffer solution. In the clinical setting, this equation is usually used to calculate HCO3 from measurements of pH and PaCO2 in arterial blood gases. The amount of metabolic acid accumulating can also be quantitated by using buffer base deviation, a derivative estimate of the metabolic as opposed to the respiratory component. In hypovolemic shock for example, approximately 50% of the metabolic acid accumulation is lactic acid, which disappears as blood flow and oxygen debt are corrected. Treatment Base excess (or deficit) is one of several values typically reported with arterial blood gas analysis that is derived from other measured data. The term and concept of base excess were first introduced by Poul Astrup and Ole Siggaard-Andersen in 1958. Estimation Base excess can be estimated from the bicarbonate concentration ([HCO3−]) and pH by the equation: with units of mEq/L. The same can be alternatively expressed as Calculations are based on the Henderson-Hasselbalch equation: Ultimately the end result is: Interpretation Base excess beyond the reference range indicates metabolic alkalosis if too high (more than +2 mEq/L) metabolic acidosis if too low (less than −2 mEq/L) Winters' formula, named for Dr. R.W. Winters, is a formula used to evaluate respiratory compensation when analyzing acid–base disorders and a metabolic acidosis is present. It can be given as , where HCO3− is given in units of mEq/L and pCO2 will be in units of mmHg. Winters' formula gives an expected value for the patient's PCO2; the patient's actual (measured) PCO2 is then compared to this: If the two values correspond, respiratory compensation is considered to be adequate. If the measured PCO2 is higher than the calculated value, there is also a secondary respiratory acidosis or mixed acid base disorder. If the measured PCO2 is lower than the calculated value, there is also a secondary respiratory alkalosis or mixed acid base disorder. References Respiratory therapy Mathematics in medicine pH Alkalosis refers to the process due to which there is elevation of blood pH. Alkalemia refers to an arterial blood pH of greater than 7.45. Treatment Respiratory alkalosis is very rarely life-threatening, though pH level should not be 7.5 or greater. The aim in treatment is to detect the underlying cause. When PaCO2 is adjusted rapidly in individuals with chronic respiratory alkalosis, metabolic acidosis may occur. If the individual is on a mechanical ventilator then preventing hyperventilation is done via monitoring ABG levels. In popular culture In The Andromeda Strain, one of the characters is exposed to contamination, but saves himself by increasing his respiratory rate to induce alkalosis. See also References Further reading External links Acid–base disturbances\nHere is the question:\nPNEUMOLOGY: A 24-year-old woman is found lying in the street by passers-by. On arrival of the emergency team she was found with an oxygen saturation of 88% breathing room air and on examination with pinpoint pupils. She was transferred to the emergency room of the nearest hospital, where the baseline arterial blood gases showed: pH 7.25, PaC02 60 mmHg, Pa02 58 mmHg, bicarbonate 26 mEq/1 and base excess of -1. In blood sodium was 137 mEq/1 and chloride 100 mEq/1:\nHere are the potential choices:\n1. Partial respiratory failure.\n2. Metabolic acidosis.\n3. Pure respiratory acidosis.\n4. Respiratory alkalosis due to lack of chloride.\n5. Blood gases can only be venous blood.\nThe correct answer is: ",
        "gold_answer": "3 Pure respiratory acidosis.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n Respiratory alkalosis (Pa CO2 < 35 mmHg) occurs when there is too little carbon dioxide in the blood. This may be due to hyperventilation or else excessive breaths given via a mechanical ventilator in a critical care setting. The action to be taken is to calm the person and try to reduce the number of breaths being taken to normalize the pH. The respiratory pathway tries to compensate for the change in pH in a matter of 2–4 hours. If this is not enough, the metabolic pathway takes place. Under normal conditions, the Henderson–Hasselbalch equation will give the blood pH where: 6.1 is the acid dissociation constant (pKa) of carbonic acid () at normal body temperature [] is the concentration of bicarbonate in the blood in mEq/L PaCO2 is the partial pressure of carbon dioxide in the arterial blood in mmHg Blood gas analysis plays an important role in both diagnosis and subsequent treatment of critically ill patients in the emergency department and the ICU. Historically, arterial blood is predominantly used for blood gas analysis. The puncture is painful and complications may occur. The purpose of the present study was to evaluate the agreement between arterial and venous blood gas analysis and whether the sole use of venous blood gas analysis would have changed therapy. Adult patients who were intubated in the field and received an arterial and venous blood gas analysis within 15 mins after admission to the ED were eligible for inclusion. The values for pH, pCO<sub2</sub, HCO<sub3</sub-, base excess and lactate levels were collected retrospectively. Mean differences were calculated by subtracting venous from arterial values. The agreement between venous and arterial measurements was assessed using the method of Bland and Altman. Blood gases were assessed by two independent physicians using a standardized questionnaire to determine whether the use of venous blood gases would have led to a different interpretation of the situation (other diagnostic path) or a change of therapy (eg. respirator adjustment). Acceptable limits were defined before the collection of data started. Fifty patients (62% male, median age 63years) who were treated at the Emergency Department between June 1, 2014 and December 31, 2014 were included in the study. Following average differences and limits of agreement (LOA) were documented: pH 0.02312 with LOA from -0.048 to 0.094; pCO<sub2</sub -3.612 mmHg with LOA from -15 to 8.1 mmHg; BE -0.154 mmol/l with LOA from -3.7 to 3.4 mmol/l; HCO<sub3</sub-0.338 mmol/l with LOA from -2.27 to 2.9 mmol/l; Lactate -0.124 mg/dl with LOA from -2.28 to 2.03 mg/dl. Using venous blood gas results 100% of the patients with metabolic alkalosis were correctly diagnosed. Metabolic acidosis was detected with a high sensitivity (80.64%), specificity (89.47%) and positive predictive value (92.59%). The answers to lactate and acidosis due to AKI showed a specificity and positive predictive value of 100%. The respiratory adjustment showed a high sensitivity (91.89%) but a low specificity (38.46%). For pH, bicarbonate, BE and lactate venous blood gases can be used as surrogates for arterial measurements. Venous pCO<sub2</sub can be used for screening of hypercapnia and trending. Respirator adjustments may be done too often if the venous blood gas is used. Diagnosis Diagnoses can be done by doing an ABG (Arterial Blood Gas) laboratory study, with a pH <7.35 and a PaCO2 >45 mmHg in an acute setting. Patients with COPD and other Chronic respiratory diseases will sometimes display higher numbers of PaCO2 with HCO3- >30 and normal pH. Terminology Acidosis refers to disorders that lower cell/tissue pH to < 7.35. Acidemia refers to an arterial pH < 7.36. See also Acidosis Alkalosis Arterial blood gas Chemical equilibrium pCO2 pH pKa Metabolic acidosis Metabolic alkalosis Respiratory alkalosis References External links Acid–base disturbances Interpretation Base excess beyond the reference range indicates metabolic alkalosis if too high (more than +2 mEq/L) metabolic acidosis if too low (less than −2 mEq/L) Blood pH is determined by both a metabolic component, measured by base excess, and a respiratory component, measured by PaCO2 (partial pressure of carbon dioxide). Often a disturbance in one triggers a partial compensation in the other. A secondary (compensatory) process can be readily identified because it opposes the observed deviation in blood pH. For example, inadequate ventilation, a respiratory problem, causes a buildup of CO2, hence respiratory acidosis; the kidneys then attempt to compensate for the low pH by raising blood bicarbonate. The kidneys only partially compensate, so the patient may still have a low blood pH, i.e. acidosis. In summary, the kidneys partially compensate for respiratory acidosis by raising blood bicarbonate. In general, it is much easier to correct acute pH derangement by adjusting respiration. Metabolic compensations take place at a much later stage. However, in a critical setting, a person with a normal pH, a high CO2, and a high bicarbonate means that, although there is a high carbon dioxide level, there is metabolic compensation. As a result, one must be careful as to not artificially adjust breaths to lower the carbon dioxide. In such case, lowering the carbon dioxide abruptly means that the bicarbonate will be in excess and will cause a metabolic alkalosis. In such a case, carbon dioxide levels should be slowly diminished. See also Anion gap Radial artery puncture Chemical equilibrium Hemoximetry Arteriovenous oxygen difference References External links Online arterial blood gas calculator Diagnostic intensive care medicine Respiratory physiology Blood tests Respiratory therapy Medicine In medicine, the partial pressure of carbon dioxide in arterial blood is called or PaCO2. Measurement of in the systemic circulation indicates the effectiveness of ventilation at the lungs' alveoli, given the diffusing capacity of the gas. It is a good indicator of respiratory function and the closely related factor of acid–base homeostasis, reflecting the amount of acid in the blood (without lactic acid). Normal values for humans are in the range 35–45 mmHg. Values less than this may indicate hyperventilation and (if blood pH is greater than 7.45) respiratory alkalosis. Values greater than 45 mmHg may indicate hypoventilation, and (if blood pH is less than 7.35) respiratory acidosis. Aquatic Sciences Example 1 [28] : ABG: pH = 7.39, PaCO 2 = 51 mm Hg, PaO 2 = 59 mm Hg, HCO 3 = 30 mEq/L and SaO 2 = 90%, on room air. pH is in the normal range, so use 7.40 as a cutoff point, in which case it is < 7.40, and acidosis is present. The elevated PaCO 2 indicates respiratory acidosis, and the elevated HCO 3 indicates a metabolic alkalosis. The value consistent with the pH is PaCO 2 . Therefore, this is a primary respiratory acidosis. The acid-base that is inconsistent with the pH is the elevated HCO3, indicating a metabolic alkalosis, so there is compensation signifying a non-acute primary disorder because it takes days for metabolic compensation to be effective. Last, the decreased PaO 2 indicates an abnormality with oxygenation. However, a history and physical will help delineate the severity and urgency of required interventions, if any. Example 2 [28] : ABG: pH = 7.45, PaCO 2 = 32 mm Hg, PaO 2 = 138 mm Hg, HCO 3 = 23 mEq/L, the base deficit = 1 mEq/L, and SaO 2 is 92%, on room air. The patient presented with a mixed acid-base disorder, with a significant metabolic alkalosis and a bicarbonate concentration of 44 meq/L. A venous blood gas was drawn soon after his presentation; venous and arterial blood gases demonstrate a high level of agreement in hemodynamically stable patients, allowing for the interpretation of acid-base disorders with venous blood gas results. In response to his metabolic alkalosis, the Pco2 should have increased by 0.75 mmHg for each 1-meq/L increase in bicarbonate; the expected Pco2 should have been ~55 mmHg. Given the Pco2 of 62 mmHg, he had an additional respiratory acidosis, likely caused by respiratory muscle weakness from his acute hypokalemia and subacute hypercortisolism. The role of venous blood gases as an alternative to arterial blood gases in patients with severe acute heart failure has not been established. To assess the correlation between arterial and peripheral venous blood gases together with pulse-oximetry (SpO2), as well as to estimate arterial values from venous samples in the first hours upon admission of patients with acute cardiogenic pulmonary oedema. Simultaneous venous and arterial blood samples were extracted on admission and over the next 1, 2, 3, 4, and 10 hours. SpO2 was also registered at the same intervals. A total of 178 pairs of samples were obtained from 34 consecutive patients with acute cardiogenic pulmonary oedema. Arterial and venous blood gases followed a parallel course in the first hours, showing high correlation rates at all time intervals. Venous samples underestimated pH (mean difference -0.028) and overestimated CO2 (+5.1 mmHg) and bicarbonate (+1 mEq/l). Conversely, SpO2 tended to underestimate SaO2 (mean±SD: 93.1±9.1 vs. 94.2±8.4). Applying simple mathematical formulae based on these differences, arterial values were empirically calculated from venous samples, showing acceptable agreement in the Bland-Altman test. Likewise, a venous pH &lt;7.32, pCO2 &gt;51.3 mmHg, and bicarbonate &lt;22.8 mEq/l could fairly identify arterial acidosis, either respiratory or metabolic, with a test accuracy of 92, 68, and 91%, respectively. In patients with cardiogenic pulmonary oedema, arterial blood gas disturbances may be estimated from peripheral venous samples. By monitoring SpO2 simultaneously, arterial punctures could often be avoided. Guidelines A 1 mmHg change in PaCO2 above or below 40 mmHg results in 0.008 unit change in pH in the opposite direction. The PaCO2 will decrease by about 1 mmHg for every 1 mEq/L reduction in [] below 24 mEq/L A change in [] of 10 mEq/L will result in a change in pH of approximately 0.15 pH units in the same direction. Assess relation of pCO2 with pH: If pCO2 & pH are moving in opposite directions i.e., pCO2 ↑ when pH is <7.4 or pCO2 ↓ when pH > 7.4, it is a primary respiratory disorder. If pCO2 & pH are moving in same direction i.e., pCO2 ↑when pH is >7.4 or pCO2 ↓ when pH < 7.4, it is a primary metabolic disorder. Parameters and reference ranges These are typical reference ranges, although various analysers and laboratories may employ different ranges. The normal range for pH is 7.35–7.45. As the pH decreases (< 7.35), it implies acidosis, while if the pH increases (> 7.45) it implies alkalosis. In the context of arterial blood gases, the most common occurrence will be that of respiratory acidosis. Carbon dioxide is dissolved in the blood as carbonic acid, a weak acid; however, in large concentrations, it can affect the pH drastically. Whenever there is poor pulmonary ventilation, the carbon dioxide levels in the blood are expected to rise. This leads to a rise of carbonic acid, leading to a decrease in pH. The first buffer of pH will be the plasma proteins, since these can accept some H+ ions to try to maintain acid-base homeostasis. As carbon dioxide concentrations continue to increase (PaCO2 > 45 mmHg), a condition known as respiratory acidosis occurs. The body tries to maintain homeostasis by increasing the respiratory rate, a condition known as tachypnea. This allows much more carbon dioxide to escape the body through the There are differences in the acute and chronic stages of respiratory acidosis or alkalosis. Acute respiratory acidosis from increased PCO2 will result in immediate changes to serum bicarbonate levels due to the bicarbonate buffer system; however, this is limited in its ability to achieve homeostasis. The kidney will gradually increase the serum bicarbonate levels in chronic cases. Chronic respiratory acidosis is when the acidemia exists for 3 to 5 days, which is approximately how long it will take the kidney to buffer the acidemia. In acute respiratory acidosis, normally, the serum bicarbonate will increase by 1 mEq/L for every 10 mmHg increase in PCO2. For chronic respiratory acidosis, the serum bicarbonate will increase by 4 to 5 mEq/L for every 10 mmHg rise in PCO2. [6] [5] The result typically causes a mild chronic acidosis or low-normal pH near 7.35. [6] In regards to respiratory alkalosis, the same timeframe applies to acute versus chronic. In acute respiratory alkalosis, for every decrease in PCO2 by 10 mmHg, the serum bicarbonate will also decrease by 2 mEq/L. In chronic respiratory alkalosis, or alkalosis lasting 3 to 5 days, for every 10mmHg drop in PCO2, it is expected that serum bicarbonate will decrease by 4 to 5 mEq/L. [5] [6] A blood gas test or blood gas analysis tests blood to measure blood gas tension values, it also measures blood pH, and the level and base excess of bicarbonate. The source of the blood is reflected in the name of each test; arterial blood gases come from arteries, venous blood gases come from veins and capillary blood gases come from capillaries. The blood gas tension levels of partial pressures can be used as indicators of ventilation, respiration and oxygenation. Analysis of paired arterial and venous specimens can give insights into the aetiology of acidosis in the newborn. Values measured Blood gas tests also measure the levels of bicarbonate and of standard bicarbonate, of base excess, of oxygen saturation, and of pH. An arterial blood gas test is more often used. Clinical significance Blood gas tests can be used in the diagnosis of a number of acidosis conditions such as lactic, metabolic, and respiratory acidosis, diabetic ketoacidosis, and also of respiratory alkalosis. Particularly, umbilical cord blood gas analysis can give an indication of preceding fetal hypoxic stress. In combination with other clinical information, normal paired arterial and venous cord blood gas results can usually provide a robust defence against a suggestion that an infant had an intrapartum hypoxic‐ischaemic event. Acute respiratory acidosis: HCO3− increases 1 mEq/L for each 10 mm Hg rise in PaCO2. Chronic respiratory acidosis: HCO3− rises 3.5 mEq/L for each 10 mm Hg rise in PaCO2. The expected change in pH with respiratory acidosis can be estimated with the following equations: Acute respiratory acidosis: Change in pH = 0.08 X ((40 − PaCO2)/10) Chronic respiratory acidosis: Change in pH = 0.03 X ((40 − PaCO2)/10) Respiratory acidosis does not have a great effect on electrolyte levels. Some small effects occur on calcium and potassium levels. Acidosis decreases binding of calcium to albumin and tends to increase serum ionized calcium levels. In addition, acidemia causes an extracellular shift of potassium, but respiratory acidosis rarely causes clinically significant hyperkalemia. Diagnosis The regulation of PCO2 is also involved in metabolic acidosis and alkalosis, as well. In metabolic acidosis, for every 1 mEq/L drop of bicarbonate, there will be a decrease in PCO2 by 1.2 mmHg. [5] For sudden drops in bicarbonate, it will take approximately 12 to 24 hours to reach full compensation; however, this process will start in as early as 30 minutes by chemoreceptor and CSF pH changes. [7] Another way to determine the expected PCO2 and compare the value obtained on blood gas analysis with metabolic acidosis is to utilize Winter’s equation. [8] If the measured PCO2 is higher or lower than the Winter’s equation PCO2, there may be a secondary respiratory acidosis or alkalosis, respectively. This situation may be the case in underlying lung pathology or neuromuscular pathology, such as an anoxic injury-causing minute ventilation control to become reduced. Also, in the presence of very severe metabolic acidosis, there is a limit to respiratory compensation with minute ventilation. The PCO2 typically cannot fall below 8 to 12 mmHg, and the sustained increase in minute ventilation to achieve this low PCO2 will usually cause rapid respiratory fatigue. In the case of metabolic alkalosis, the expected compensation of PCO2 is to increase by 0.7 mmHg for every 1 mEq/L increase in serum bicarbonate. [5] Gasometry is the measurement of dissolved gases in the blood, by measuring pH, carbon dioxide pressure (pCO(2)), serum bicarbonate (HCO(3-)), and lactate and serum electrolytes: sodium, potassium and chlorine you can make a diagnosis, etiology and treatment in the critically ill patient. The aim is to provide five steps for the interpretation of blood gases by: 1. The definition of acidemia or acidosis, or alkalemia or alkalosis. 2. Defining the metabolic component or respiratory. 3. To determine the anion gap; levels above 15 ± 2 determine other likely causes of excess anions (methanol, uremia, diabetic ketoacidosis, paraldehyde, ionized, lactic acidosis, ethylene glycol and salicylates. 4. Compensation, using the Winter formula. 5. The delta gap, with the formula for determining intrinsic and metabolic alkalosis. When anion gap is normal, is calculated urinary anion gap; the value is negative if the loss is extrarenal, contrary to the positive result is renal etiology. In many people a high causes a feeling of shortness of breath, but the lack of this symptom is no guarantee that the other effects are not occurring. A significant percentage of rebreather deaths have been associated with CO2 retention. The effects of high can take several minutes to hours to resolve once the cause has been removed. Diagnosis Blood gas tests may be performed, typically by radial artery puncture, in the setting of acute breathing problems or other acute medical illness. Hypercapnia is generally defined as an arterial blood carbon dioxide level over 45 mmHg (6 kPa). Since carbon dioxide is in equilibrium with carbonic acid in the blood, hypercapnia drives serum pH down, resulting in respiratory acidosis. Clinically, the effect of hypercapnia on pH is estimated using the ratio of the arterial pressure of carbon dioxide to the concentration of bicarbonate ion, . Tolerance The alveolar pO2 is not routinely measured but is calculated from blood gas measurements by the alveolar gas equation. Partial pressure of carbon dioxide Pathology The partial pressure of carbon dioxide, along with the pH, can be used to differentiate between metabolic acidosis, metabolic alkalosis, respiratory acidosis, and respiratory alkalosis. Hypoventilation exists when the ratio of carbon dioxide production to alveolar ventilation increases above normal values – greater than 45mmHg. If pH is also less than 7.35 this is respiratory acidosis. Hyperventilation exists when the same ratio decreases – less than 35mmHg. If the pH is also greater than 7.45 this is respiratory alkalosis. See also Alveolar-arterial gradient Diffusing capacity Pulmonary alveolus References Respiratory physiology To calculate the expected pCO2 in the setting of metabolic alkalosis, the following equations are used: pCO2 = 0.7 [HCO3] + 20 mmHg ± 5 pCO2 = 0.7 [HCO3] + 21 mmHg Treatment To effectively treat metabolic alkalosis, the underlying cause(s) must be corrected. A trial of intravenous chloride-rich fluid is warranted if there is a high index of suspicion for chloride-responsive metabolic alkalosis caused by loss of gastrointestinal fluid (e.g., due to vomiting). Terminology Alkalosis refers to a process by which the pH is increased. Alkalemia refers to a pH which is higher than normal, specifically in the blood. See also Hypokalemia Metabolic acidosis Respiratory acidosis Respiratory alkalosis References External links Acid–base disturbances Diagnostic approach and causes Metabolic Acidosis is defined as a reduced serum pH, and an abnormal serum bicarbonate concentration of <22 mEq/L, below the normal range of 22 to 29 mEq/L. However, if a patient has other coexisting acid-base disorders, the pH level may be low, normal or high in the setting of metabolic acidosis. In the absence of chronic respiratory alkalosis, metabolic acidosis can be clinically diagnosed by measuring serum bicarbonate levels in the blood, which is generally a standard component of blood panels. Imperatively, when weighing a metabolic acidosis diagnosis, the change in serum bicarbonate levels over time should be considered; if baseline bicarbonate results are unknown, a single set of values may be misinterpreted. Causes Generally, metabolic acidosis occurs when the body produces too much acid (e.g., lactic acidosis, see below section), there is a loss of bicarbonate from the blood, or when the kidneys are not removing enough acid from the body. Types Respiratory acidosis can be acute or chronic. In acute respiratory acidosis, the PaCO2 is elevated above the upper limit of the reference range (over 6.3 kPa or 45 mm Hg) with an accompanying acidemia (pH <7.36). In chronic respiratory acidosis, the PaCO2 is elevated above the upper limit of the reference range, with a normal blood pH (7.35 to 7.45) or near-normal pH secondary to renal compensation and an elevated serum bicarbonate (HCO3− >30 mEq/L). Causes Acute Acute respiratory acidosis occurs when an abrupt failure of ventilation occurs. This failure in ventilation may be caused by depression of the central respiratory center by cerebral disease or drugs, inability to ventilate adequately due to neuromuscular disease (e.g., myasthenia gravis, amyotrophic lateral sclerosis, Guillain–Barré syndrome, muscular dystrophy), or airway obstruction related to asthma or chronic obstructive pulmonary disease (COPD) exacerbation. Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise in arterial carbon dioxide levels is called hypercapnia. Respiratory failure is classified as either Type 1 or Type 2, based on whether there is a high carbon dioxide level, and can be acute or chronic. In clinical trials, the definition of respiratory failure usually includes increased respiratory rate, abnormal blood gases (hypoxemia, hypercapnia, or both), and evidence of increased work of breathing. Respiratory failure causes an altered mental status due to ischemia in the brain. The typical partial pressure reference values are oxygen Pa O2 more than 80 mmHg (11 kPa) and carbon dioxide Pa CO2 less than 45 mmHg (6.0 kPa). Cause More specific definitions of end-organ dysfunction exist for SIRS in pediatrics. Cardiovascular dysfunction (after fluid resuscitation with at least 40 ml/kg of crystalloid) hypotension with blood pressure < 5th percentile for age or systolic blood pressure < 2 standard deviations below normal for age, or vasopressor requirement, or two of the following criteria: unexplained metabolic acidosis with base deficit > 5 mEq/l lactic acidosis: serum lactate 2 times the upper limit of normal oliguria (urine output ) prolonged capillary refill > 5 seconds core to peripheral temperature difference Respiratory dysfunction (in the absence of a cyanotic heart defect or a known chronic respiratory disease) the ratio of the arterial partial-pressure of oxygen to the fraction of oxygen in the gases inspired (PaO2/FiO2) < 300 (the definition of acute lung injury), or Diagnosis The diagnosis of respiratory alkalosis is done via test that measure the oxygen and carbon dioxide levels (in the blood), chest x-ray and a pulmonary function test of the individual. The Davenport diagram allows clinicians or investigators to outline blood bicarbonate concentrations (and blood pH) after a respiratory or metabolic acid-base disturbance Classification There are two types of respiratory alkalosis: chronic and acute as a result of the 3–5 day delay in kidney compensation of the abnormality. Acute respiratory alkalosis occurs rapidly, have a high pH because the response of the kidneys is slow. Chronic respiratory alkalosis is a more long-standing condition, here one finds the kidneys have time to decrease the bicarbonate level. pH Alkalosis refers to the process due to which there is elevation of blood pH. Alkalemia refers to an arterial blood pH of greater than 7.45. Mutations to the V-ATPase 'a4' or 'B1' isoforms result in distal renal tubular acidosis, a condition that leads to metabolic acidosis, in some cases with sensorineural deafness. Arterial blood gases will indicate low pH, low blood HCO3, and normal or low PaCO2. In addition to arterial blood gas, an anion gap can also differentiate between possible causes. The Henderson-Hasselbalch equation is useful for calculating blood pH, because blood is a buffer solution. In the clinical setting, this equation is usually used to calculate HCO3 from measurements of pH and PaCO2 in arterial blood gases. The amount of metabolic acid accumulating can also be quantitated by using buffer base deviation, a derivative estimate of the metabolic as opposed to the respiratory component. In hypovolemic shock for example, approximately 50% of the metabolic acid accumulation is lactic acid, which disappears as blood flow and oxygen debt are corrected. Treatment Base excess (or deficit) is one of several values typically reported with arterial blood gas analysis that is derived from other measured data. The term and concept of base excess were first introduced by Poul Astrup and Ole Siggaard-Andersen in 1958. Estimation Base excess can be estimated from the bicarbonate concentration ([HCO3−]) and pH by the equation: with units of mEq/L. The same can be alternatively expressed as Calculations are based on the Henderson-Hasselbalch equation: Ultimately the end result is: Interpretation Base excess beyond the reference range indicates metabolic alkalosis if too high (more than +2 mEq/L) metabolic acidosis if too low (less than −2 mEq/L) Winters' formula, named for Dr. R.W. Winters, is a formula used to evaluate respiratory compensation when analyzing acid–base disorders and a metabolic acidosis is present. It can be given as , where HCO3− is given in units of mEq/L and pCO2 will be in units of mmHg. Winters' formula gives an expected value for the patient's PCO2; the patient's actual (measured) PCO2 is then compared to this: If the two values correspond, respiratory compensation is considered to be adequate. If the measured PCO2 is higher than the calculated value, there is also a secondary respiratory acidosis or mixed acid base disorder. If the measured PCO2 is lower than the calculated value, there is also a secondary respiratory alkalosis or mixed acid base disorder. References Respiratory therapy Mathematics in medicine pH Alkalosis refers to the process due to which there is elevation of blood pH. Alkalemia refers to an arterial blood pH of greater than 7.45. Treatment Respiratory alkalosis is very rarely life-threatening, though pH level should not be 7.5 or greater. The aim in treatment is to detect the underlying cause. When PaCO2 is adjusted rapidly in individuals with chronic respiratory alkalosis, metabolic acidosis may occur. If the individual is on a mechanical ventilator then preventing hyperventilation is done via monitoring ABG levels. In popular culture In The Andromeda Strain, one of the characters is exposed to contamination, but saves himself by increasing his respiratory rate to induce alkalosis. See also References Further reading External links Acid–base disturbances\nHere is the question:\nPNEUMOLOGY: A 24-year-old woman is found lying in the street by passers-by. On arrival of the emergency team she was found with an oxygen saturation of 88% breathing room air and on examination with pinpoint pupils. She was transferred to the emergency room of the nearest hospital, where the baseline arterial blood gases showed: pH 7.25, PaC02 60 mmHg, Pa02 58 mmHg, bicarbonate 26 mEq/1 and base excess of -1. In blood sodium was 137 mEq/1 and chloride 100 mEq/1:\nHere are the potential choices:\n1. Partial respiratory failure.\n2. Metabolic acidosis.\n3. Pure respiratory acidosis.\n4. Respiratory alkalosis due to lack of chloride.\n5. Blood gases can only be venous blood.\nThe correct answer is: 2. Metabolic acidosis."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The therapeutic role of bronchodilators in bronchiolitis remains controversial. The aim of this study is to evaluate the safety and the clinical response to nebulized salbutamol in infants with mild acute bronchiolitis. Thirty-three infants, aged 1 month to 5 months and 22 days (mean: 92.4 days) were included in the study. Patients received either nebulized salbutamol (0.15 mg/kg per dose: 16 infants) or a placebo (normal saline aerosol: 17 infants), delivered by an oxygen propellent, three times at intervals of 1 hour, as part of a double-blind randomized trial. Effect of treatment was evaluated by measuring respiratory and heart rate, clinical scores based on the degree of retraction and wheezing, and oxygen saturation. Clinical assessment was repeated 30 minutes after each nebulization. A nasopharyngeal swab was obtained for detection of respiratory syncytial virus (VRS) antigens by immunofluorescence assay in all patients. Patients in the salbutamol group exhibited significantly greater improvement in respiratory rate (P = 0.01), accessory muscle score (P &lt; 0.001) and wheezing score (P &lt; 0.001). There was no significant difference in oxygen saturation between both groups. Infants treated with salbutamol exhibited a non-significant increase in heart rate after the three sprays; no other adverse effects were noted. VRS was identified in 78% of the children tested. Salbutamol is safe and effective in relieving the respiratory distress of young infants with acute bronchiolitis. Our study confirms previous observations that infants younger than six months of age respond as well as older children when given three doses of nebulized salbutamol. Responders could not be differentiated from non responders by personal or family histories of atopy and VRS isolation. A longitudinal study could establish a correlation between response to bronchodilator therapy and later development of asthma. Bronchiolitis is a common lower respiratory tract infection in infants and young children, and respiratory syncytial virus (RSV) is the most common cause of this infection. RSV is transmitted through contact with respiratory droplets either directly from an infected person or self-inoculation by contaminated secretions on surfaces. Patients with RSV bronchiolitis usually present with two to four days of upper respiratory tract symptoms such as fever, rhinorrhea, and congestion, followed by lower respiratory tract symptoms such as increasing cough, wheezing, and increased respiratory effort. In 2014, the American Academy of Pediatrics updated its clinical practice guideline for diagnosis and management of RSV bronchiolitis to minimize unnecessary diagnostic testing and interventions. Bronchiolitis remains a clinical diagnosis, and diagnostic testing is not routinely recommended. Treatment of RSV infection is mainly supportive, and modalities such as bronchodilators, epinephrine, corticosteroids, hypertonic saline, and antibiotics are generally not useful. Evidence supports using supplemental oxygen to maintain adequate oxygen saturation; however, continuous pulse oximetry is no longer required. The other mainstay of therapy is intravenous or nasogastric administration of fluids for infants who cannot maintain their hydration status with oral fluid intake. Educating parents on reducing the risk of infection is one of the most important things a physician can do to help prevent RSV infection, especially early in life. Children at risk of severe lower respiratory tract infection should receive immunoprophylaxis with palivizumab, a humanized monoclonal antibody, in up to five monthly doses. Prophylaxis guidelines are restricted to infants born before 29 weeks' gestation, infants with chronic lung disease of prematurity, and infants and children with hemodynamically significant heart disease. Bronchiolitis, a lower respiratory tract infection, commonly affects infants and children younger than 2 years. Respiratory syncytial virus is the most common cause. Nasal congestion, rhinorrhea, and mild fever occur in the first 1 to 3 days. Symptoms worsen for several days to include wheezing and other lower respiratory tract signs, and then resolve over days to weeks. However, some children develop hypoxemia and/or respiratory distress and require hospitalization. The diagnosis is clinical, based on the history and physical examination findings. Routine chest x-rays and blood tests are not recommended. Management is supportive, including nasal suctioning, oxygen (in cases of hypoxemia), and hydration. Use of bronchodilators (ie, albuterol, epinephrine) and systemic corticosteroids is not recommended in infants and children ages 1 to 23 months. Pneumonia, another common infection in infants and children, typically is caused by viruses or bacteria. The diagnosis is clinical, and chest x-rays and blood cultures are not required for patients well enough to be treated as outpatients. Antibiotics are not routinely required for preschool-aged children (ie, younger than 5 years) with pneumonia because most have viral infections. For immunized school-aged children with mild to moderate pneumonia suspected to be of bacterial origin, amoxicillin is recommended. In school-aged children, if atypical pathogens (eg, Mycoplasma) are suspected, a macrolide antibiotic should be prescribed. In the wake of a community outbreak of bronchiolitis in northern Israel from December 1993 to March 1994, we conducted a retrospective study of 108 infants aged 2 weeks to 14 months with proven respiratory syncytial virus (RSV) infection (diagnosed by a rapid RSV antigen test in nasopharyngeal secretions). 47% of the infants were less than 8 weeks old. Mean hospital stay was 6.6 days (range 1-60). The characteristic clinical findings were: cough in all patients, dyspnea in 96%, rhinitis in 95% and fever in 55%. In those younger than 8 weeks, or in those with underlying diseases, hospitalization was longer, the disease was more serious and complications more frequent (p &lt; 0.002). 4 children (3%) died, 3 of whom had severe congenital heart defects. All children were treated with oxygen and beta-agonist inhalations. The 33% who also received corticosteroids were older and most had a history of pulmonary diseases, such as asthma or bronchopulmonary dysplasia. There was no difference between those who did or did not receive corticosteroids with regard to severity of disease or rate of complications. Ribavirin was used to treat 19 (17.5%), most of whom had underlying lung disease. The others were otherwise healthy infants younger than 8 weeks. 13 were cared for in the intensive care unit, 11 of whom required mechanical ventilation. A rapid test for detection of RSV infection enabled prompt isolation of infected patients so that the risk of nosocomial infection was reduced and Ribavirin therapy could be started early, if required. The benefit of beta-adrenergic agonists in the treatment of acutely wheezing infants and young children has not been well documented in the outpatient setting. To determine the efficacy of nebulized metaproterenol sulfate, 74 children aged 36 months or younger with acute wheezing participated in a double-masked, randomized, placebo-controlled clinical trial. Children received nebulized metaproterenol, either as an initial treatment or after a control treatment with normal saline solution. At baseline and 20 minutes after each treatment, an assessment was made that included measurements of heart rate, respiratory rate, oxygen saturation, and clinical variables related to respiratory compromise with the use of a standardized respiratory distress index (RDI). Children who received saline solution as initial therapy had no significant differences from baseline in any of the assessment measures. After metaproterenol therapy, children demonstrated an increase in heart rate ([mean +/- SD] 147 +/- 14 beats per minute vs 153 +/- 16 beats per minute), a decrease in respirations (50/min +/- 5/min vs 45/min +/- 7/min), improvement (lower scores) on the RDI (24 +/- 4 vs 15 +/- 2), and an increase in oxygen saturation (94.1% +/- 2.7% vs 95.3% +/- 3.0%). Patients aged 12 months or younger (n = 37) benefited from metaproterenol treatment (improvement in respiratory rate and RDI) but not to the same degree as children aged 24 months or older (n = 23) (improvement in respiratory rate, RDI, and oxygen saturation). Compared with assessments made before metaproterenol treatment, patients with respiratory syncytial virus infection (n = 21) had improvement in respirations (52/min +/- 7/min vs 45/min +/- 6/min) and RDI scores (22 +/- 4 vs 14 +/- 3). Based on a priori criteria (reduction in a premedication respiratory rate of 20% and an RDI score of 50%), responders to metaproterenol therapy included 45% of the entire sample and, respectively, 40% of those aged 12 months or younger, 52% of those aged 24 months or older, and 48% of patients who tested positive for respiratory syncytial virus. Although there appears to be an age-dependent degree of response, metaproterenol is effective in relieving the respiratory distress of young acutely wheezing children, including those with documented respiratory syncytial virus bronchiolitis. Bronchiolitis, a lower respiratory tract illness most often caused by respiratory syncytial virus, generally affects children under two years of age, commonly during the winter months. Necrosis of epithelial cells in the small airways leads to inflammation and airway obstruction, causing decreased oxygen saturation, with cough and wheezing. Hospital admission should be considered for children with pulse oximetry levels less than 95 percent at rest. Treatment consists of humidified oxygen, intravenous hydration and administration of nebulized albuterol. Infants with mild disease who are identified early in the course of illness should be reevaluated in 24 hours. Infants with congenital heart disease, bronchopulmonary dysplasia or a history of prematurity, who are at high risk for severe disease, should be treated with ribavirin. The responsiveness to bronchodilator is variable in infants with wheezing associated respiratory illness (WARI). Factors for prediction of the response will lead to more rational use of the bronchodilator in these infants. We examined the possible predictive factors in 44 children under 2 years of age who had their first episode of WARI. All of them were treated with 0.15 mg/kg of nebulized salbutamol. Thirty patients (68%) with decreasing clinical score &gt; or = 3 after treatment were considered as the responders while the remainder (14 infants) were non responders. By using Chi-square test, Fisher exact test and Mann-Whitney U test to compare the data of the 2 groups, the significant factors for the responders were older than 6 months and history of previous LRI (p &lt; 0.01). The significant factors for the non-responders included concurrent diarrhea, patchy pulmonary infiltration and positive RSV in the nasopharyngeal secretion (p &lt; 0.01). These results suggested effective bronchodilator therapy in infants older than 6 months or having a history of previous LRI. Those who had acute RSV infection or patchy infiltration in chest X-ray and associated diarrhea were less likely to respond. Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease in infants and young children. Most infections due to RSV are mild and do not require hospitalization. RSV causes both upper respiratory tract infections as well as lower respiratory tract infections. Infants with underlying disease states like bronchopulmonary dyslasia, congenital heart disease and prematurity appear more prone to develop severe infection and have a higher incidence of hospitalization. The exact pathogenesis of RSV is not well understood. The mortality associated with primary RSV infection in healthy children is estimated to be between .005% to .02%. In hospitalized children the mortality rate is estimated to be from 1% to 3%. Several treatment modalities in the form of bronchodilators, corticosteroids, ribavirin, intravenous immune gammaglobulin and antibiotics are available. Studies have failed to show the true beneficial effect of any of the above treatment modalities. Supportive care is only needed. The best treatment is the supportive care in the form of oxygen and fluids and close monitoring of the vital signs including oxygen saturation. Corticosteroids continue to be used by many physicians to treat infants with bronchiolitis. The aim of this study was to examine the short-term and long-term efficacy of oral corticosteroid therapy when added to beta2-agonists in infants with mild to moderate bronchiolitis (defined as the first episode of wheezing associated with low grade fever, rhinitis, tachypnea, and increased respiratory effort in a previously healthy infant during the winter months). Infants with mild to moderate bronchiolitis, were randomly assigned to receive either oral prednisone (2 mg/kg/day) or placebo for 3 days. All patients received nebulized albuterol q.i.d. during this period. Upon admission and after 3 days of therapy, a clinical score was assigned based on respiratory rate, use of accessory muscle, and the presence of wheeze. Oxygen saturation (SaO2) was also measured. On day 7, we inquired as to the well-being of each child. Two years later, the development of chronic respiratory symptoms was assessed. Thirty-eight infants were enrolled in the study; 20 received prednisone and 18 received placebo. Both groups were similar in terms of age, duration of illness prior to enrollment, pretrial medication use, clinical severity of bronchiolitis, history of atopy, and family history of atopy. After 3 and 7 days of treatment, both groups showed similar clinical improvement and there were no statistically significant differences between the two groups in the clinical score or in the SaO2. No major side effects were observed. Two years later, 32% of the infants continued to suffer from chronic respiratory symptoms, with a similar prevalence in both groups. We conclude that a 3-day course of oral corticosteroids is of no benefit to infants with mild to moderate bronchiolitis who are also treated with an inhaled beta2-agonist. In this review, we describe the history, epidemiology and clinical manifestations of infections attributed to respiratory syncytial virus (RSV) in children. At present, no cure exists for RSV infection but commonly employed palliative treatments include oxygen and inhaled beta(2)-adrenoceptor agonists, such as salbutamol, to relieve the wheezing and increased bronchiolar smooth muscle constriction. Adrenaline (epinephrine) has been found to be superior to the selective beta(2)-adrenoceptor agonists. Oral or inhaled corticosteroids should counteract the inflammatory response to RSV infection but their effectiveness is controversial. Inhaled ribavirin is the only licensed antiviral product approved for the treatment of RSV lower respiratory-tract infection in hospitalized children, although its use is now restricted to high-risk infants. Other treatments considered are nasopharyngeal suctioning, surfactant therapy, recombinant human deoxyribonuclease I, heliox (helium:oxygen) and inhaled nitric oxide. Prevention of infection by RSV antibodies is another strategy and, currently, palivizumab is the only safe, effective and convenient preventative treatment for RSV disease in high-risk populations of infants and young children. Its cost-effectiveness, however, has been questioned. Both live attenuated and subunit vaccines against RSV infection have been developed but so far there is no safe and effective vaccine available. Finding effective treatments and prophylactic measures remains a major challenge for the future. The role of systemic corticosteroids in the treatment of early childhood wheezing in children is not clear. We sought to determine whether prednisolone is effective in rhinovirus-induced early wheezing. We conducted a controlled trial comparing oral prednisolone (2 mg/kg per day in three divided doses for 3 days) with placebo in 78 hospitalized children (mean age, 1.1 year; standard deviation, 0.7) experiencing their first or second episode of wheezing induced by rhinovirus or respiratory syncytial virus. Mixed viral infections were excluded. Our primary end point was the time until the patient was ready for discharge; secondary end points included oxygen saturation during hospitalization, duration of symptoms, occurrence of relapses during the next 2 months and blood eosinophil counts at discharge and 2 weeks later. In multivariate regression analysis, prednisolone did not influence the time until ready for discharge, but it decreased relapses during the subsequent 2-month period in rhinovirus-affected children (prednisolone versus placebo, 22% versus 56%; odds ratio, 19.06; 95% confidence interval, 2.52-144.03; P = 0.004) and in children with blood eosinophils &gt; or = 0.2 x 10/L (respectively, 24% versus 71%; odds ratio, 10.57; 95% confidence interval, 1.99-56.22; P = 0.006). Rhinovirus-affected children had more blood eosinophils on admission (mean, 0.44 versus 0.086 x 10/L), had a higher prevalence of atopy (44% versus 8%) and were older (mean, 1.4 versus 0.9 years, P &lt; 0.001 for all) than respiratory syncytial virus-infected children. Prednisolone reduced relapses during a 2-month period after first episodes of wheezing associated with rhinovirus infection or blood eosinophils &gt; or = 0.2 x 10/L. Treatment for severe illness is primarily supportive, including oxygen therapy and more advanced breathing support with CPAP or nasal high flow oxygen, as required. In cases of severe respiratory failure, intubation and mechanical ventilation may be required. Ribavirin is the only antiviral medication currently licensed for the treatment of RSV in children, although its use remains controversial. Signs and symptoms RSV infection can present with a wide variety of signs and symptoms that range from mild upper respiratory tract infections (URTI) to severe and potentially life-threatening lower respiratory tract infections (LRTI) requiring hospitalization and mechanical ventilation. While RSV can cause respiratory tract infections in people of all ages and is among the most common childhood infections, its presentation often varies between age groups and immune status. Reinfection is common throughout life, but infants and the elderly remain at highest risk for symptomatic infection. Bronchiolitis is a common lower respiratory tract infection characterized by inflammation and obstruction of the small airways in the lungs. While several viruses can cause bronchiolitis, RSV is responsible for about 70% of cases. It usually presents with 2 to 4 days of runny nose and congestion followed by worsening cough, noisy breathing, tachypnea (fast breathing), and wheezing. As infants work harder to breathe, they can also show signs of respiratory distress, such as subcostal retractions (when the belly pulls under the ribcage), intercostal retractions (when the muscles between the ribs pull inward), grunting, and nasal flaring. If the child has not been able to feed adequately, signs of dehydration may also be present. Fever may be present, but high-grade fever is uncommon. Crackles and wheezing can often be heard on auscultation, and oxygen saturation levels may be decreased. Adults Reinfection with RSV remains common throughout life. Reinfection in adulthood often produces only mild to moderate symptoms indistinguishable from the common cold or sinus infection. Infection may also be asymptomatic. If present, symptoms are generally isolated to the upper respiratory tract: runny nose, sore throat, fever, and malaise. In the vast majority of cases, nasal congestion precedes the development of cough. In contrast to other upper respiratory infections, RSV is also more likely to cause new onset wheeze in adults. Only about 25% of infected adults will progress to significant lower respiratory tract infection, such as bronchitis or tracheobronchitis. Treatment Supportive care Treatment for RSV infection is focused primarily on supportive care. This may include monitoring a patient's breathing or using suction to remove secretions from the upper airway. Supplemental oxygen may also be delivered though a nasal cannula or face mask in order to improve airflow. In severe cases of respiratory failure, intubation and mechanical ventilation may be required to support breathing. If signs of dehydration are present, fluids may also be given orally or through an IV. Management of respiratory syncytial virus lower respiratory tract infection in infants is predominantly supportive and symptomatic. Outpatient management requires close attention to feeding, oral hydration, and monitoring of fever, behavior, and respiratory effort. In the small proportion of patients who need hospitalization, clinicians are concerned primarily with oxygenation and the possibility of oxygen desaturation. Appropriate interventions depend on the level of oxygenation as indicated by pulse oximetry or arterial blood gases. Hydration and symptomatic treatment with alpha- or ss(2 )-adrenergic agonist bronchodilators may lessen the work of breathing. The role of these agents remains controversial, however, and anticholinergic bronchodilators are considered ineffective. Current antiviral therapy is limited to aerosolized ribavirin. Immunotherapy with respiratory syncytial virus immune globulin or a monoclonal antibody has not been rewarding in terms of clinical outcome, although the antiviral effect of these agents has been impressive. There is concern about long-term pulmonary sequelae after respiratory syncytial virus lower respiratory tract infection early in life. Several recent studies, including new data reported here, suggest that ribavirin may have a beneficial effect on some of these sequelae, whereas other studies have failed to demonstrate any benefit. Future studies may help resolve this question. We report 7 cases of respiratory syncytial virus (RSV) infections among elderly patients hospitalized for acute lower tract infection during the winter months. The median age was 95 years (range: 79-106 years). 6 patients were living in nursing homes. All patients had chronic cardiopulmonary conditions. Clinical symptoms included upper respiratory tract symptoms for 3 of them and lower respiratory tract symptoms for all of them. Three patients developed a severe infection with acute respiratory failure. The chest X ray showed an interstitial infiltrate in 3 cases, a consolidation in one case. All patients received oxygen, respiratory physical therapy, nebulized B-agonists and antibiotics. Corticosteroids were used for 4 patients. Progress was favorable for all patients and none died. Diagnosis was obtained in a few hours by direct antigen detection by enzyme immunoassays (EIA) in sputum. Respiratory syncytial virus infection is a common cause of respiratory tract infection in the elderly, during the winter months. Clinical manifestations are similar to influenza infections. Detection of RSV antigens from sputum specimens may be a useful and rapid diagnostic method and merits further evaluation in the elderly. Early diagnosis of respiratory syncytial virus infection should be encouraged to allow the implementation of effective infection control procedures and avoid inadequate therapies. To establish current practice for hospital-based treatment of uncomplicated respiratory syncytial virus (RSV) infection in the Republic of Ireland. A questionnaire was sent to all consultant general paediatricians in the Republic of Ireland. The questionnaire described a clinical scenario and this was followed by a list of management questions. The scenario was of a 3-month-old infant with uncomplicated but moderately severe RSV infection requiring hospitalization. Seventy-three questionnaires were sent. 63/73 (86%) of the questionnaires were returned. With respect to management of this case almost all (61/63) the paediatricians felt that oxygen therapy was necessary (oxygen saturation described in the case was 90%). With respect to bronchodilator therapy, ipratropium bromide (38/63--60%) was chosen much more frequently than salbutamol (15/63--24%). Chest physiotherapy would have been prescribed by 8/63--13% of paediatricians. Oral steroids were infrequently chosen (1/63--2%) but nebulised steroids were selected in 7/63 (11%) cases. The routine use of RSV monoclonal antibody, palivizumab, for RSV prophylaxis was reported by 49% (31/63) of paediatricians. Prematurity with bronchopulmonary dysplasia was considered an indication for its administration by all of these but only 23% considered prematurity alone to be an indication. The management of infants with RSV bronchiolitis varies greatly among consultant paediatricians in Ireland. Evidence based guidelines may be of value in establishing a more uniform national treatment approach. Additional supportive treatments have been investigated specifically in infants hospitalized with RSV bronchiolitis. These include the following: Nebulized hypertonic saline has been shown to reduce length of hospitalization and reduce clinical severity in infants with viral bronchiolitis. It is thought that this treatment may help by reducing airway edema and mucus plugging to decrease airway obstruction. Heliox, a mixture of oxygen with helium, may improve respiratory distress within the first hour after starting treatment. It works by reducing airway resistance and decreasing the work of breathing. However, it has not been shown to impact overall illness outcomes. Chest physiotherapy has not been found to reduce disease severity and is not routinely recommended. Inhaled recombinant human deoxyribonuclease (rhDNase), an enzyme that digests the DNA that contributes to mucus plugging and airway obstruction, has not been shown to improve clinical outcomes in this group. Treatment is primarily supportive; treat mild disease with outpatient management using fluids and nebulizers if needed. Hospitalize in the setting of marked respiratory distress, O2 saturation of < 92%, toxic appearance, dehydration/poor oral feeding, a history of prematurity (< 34 weeks), age < 3 months, underlying cardiopulmonary disease, or unreliable parents. Treat inpatients with contact isolation, hydration, and O2. A trial of aerosolized albuterol may be attempted; continue albuterol therapy only if effective. RSV is the most common cause of bronchiolitis. Ribavirin is an antiviral drug that has a controversial role in bronchiolitis treatment. It is sometimes used in high-risk infants with underlying heart, lung, or immune disease. RSV prophylaxis with injectable polyor monoclonal antibodies (RespiGam or Synagis) is recommended in winter for high-risk patients ≤ 2 years of age (e.g., those with a history of prematurity, chronic lung disease, or congenital heart disease). Humidified Oxygen to alleviate hypoxia if saturations fall below 92%. Corticosteroid by mouth are recommended with five days of prednisone being the same 2 days of dexamethasone. One review recommended a seven-day course of steroids. Magnesium sulfate intravenous treatment increases bronchodilation when used in addition to other treatment in moderate severe acute asthma attacks. In adults intravenous treatment results in a reduction of hospital admissions. Low levels of evidence suggest that inhaled (nebulised) magnesium sulfate may have a small benefit for treating acute asthma in adults. Overall, high quality evidence do not indicate a large benefit for combining magnesium sulfate with standard inhaled treatments for adults with asthma. Heliox, a mixture of helium and oxygen, may also be considered in severe unresponsive cases. Intravenous salbutamol is not supported by available evidence and is thus used only in extreme cases. Respiratory syncytial virus (RSV) bronchiolitis in infancy can lead to bronchial hyper-reactivity or recurrent obstructive bronchitis. The aim of the present study was to determine whether the type of treatment has an influence on respiratory status after RSV bronchiolitis. The study involved 117 infants (mean age 2.6 months), who needed hospital treatment because of RSV bronchiolitis. The patients were divided randomly into three groups. All received the same symptomatic treatment. Group I children received symptomatic treatment only, group II children were treated for 7 days with inhaled budesonide, 500 microg three times per day, administered via a nebulizer. Group III children received nebulized budesonide, 500 microg twice per day for two months. Follow-up consisted of out-patient check-ups 2 and 6 months after the infection, and telephone contact two years after the infection. Statistically significant differences were seen between the groups. In group I 37% of the children had asthma, in group II 18%, and in group III 12%. According to the present study it seems that inhaled corticosteroid treatment during and after the acute phase of infant RSV bronchiolitis may have a beneficial effect on subsequent bronchial wheezing tendency.\nHere is the question:\nPEDIATRICS: A 2-month-old infant with an upper respiratory tract cold of 3 days of evolution, who begins with moderate respiratory distress and pulmonary auscultation with expiratory wheezing. Oxygen saturation is 89 %. Respiratory syncytial virus is isolated in the nasopharyngeal exudate. Which of the following treatments do you consider more indicated for this condition?\nHere are the potential choices:\n1. Oral rivabirin.\n2. Nebulized salbutamol.\n3. Supplemental oxygen.\n4. Intravenous corticosteroids.\nThe correct answer is: ",
        "gold_answer": "3 Supplemental oxygen.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n The therapeutic role of bronchodilators in bronchiolitis remains controversial. The aim of this study is to evaluate the safety and the clinical response to nebulized salbutamol in infants with mild acute bronchiolitis. Thirty-three infants, aged 1 month to 5 months and 22 days (mean: 92.4 days) were included in the study. Patients received either nebulized salbutamol (0.15 mg/kg per dose: 16 infants) or a placebo (normal saline aerosol: 17 infants), delivered by an oxygen propellent, three times at intervals of 1 hour, as part of a double-blind randomized trial. Effect of treatment was evaluated by measuring respiratory and heart rate, clinical scores based on the degree of retraction and wheezing, and oxygen saturation. Clinical assessment was repeated 30 minutes after each nebulization. A nasopharyngeal swab was obtained for detection of respiratory syncytial virus (VRS) antigens by immunofluorescence assay in all patients. Patients in the salbutamol group exhibited significantly greater improvement in respiratory rate (P = 0.01), accessory muscle score (P &lt; 0.001) and wheezing score (P &lt; 0.001). There was no significant difference in oxygen saturation between both groups. Infants treated with salbutamol exhibited a non-significant increase in heart rate after the three sprays; no other adverse effects were noted. VRS was identified in 78% of the children tested. Salbutamol is safe and effective in relieving the respiratory distress of young infants with acute bronchiolitis. Our study confirms previous observations that infants younger than six months of age respond as well as older children when given three doses of nebulized salbutamol. Responders could not be differentiated from non responders by personal or family histories of atopy and VRS isolation. A longitudinal study could establish a correlation between response to bronchodilator therapy and later development of asthma. Bronchiolitis is a common lower respiratory tract infection in infants and young children, and respiratory syncytial virus (RSV) is the most common cause of this infection. RSV is transmitted through contact with respiratory droplets either directly from an infected person or self-inoculation by contaminated secretions on surfaces. Patients with RSV bronchiolitis usually present with two to four days of upper respiratory tract symptoms such as fever, rhinorrhea, and congestion, followed by lower respiratory tract symptoms such as increasing cough, wheezing, and increased respiratory effort. In 2014, the American Academy of Pediatrics updated its clinical practice guideline for diagnosis and management of RSV bronchiolitis to minimize unnecessary diagnostic testing and interventions. Bronchiolitis remains a clinical diagnosis, and diagnostic testing is not routinely recommended. Treatment of RSV infection is mainly supportive, and modalities such as bronchodilators, epinephrine, corticosteroids, hypertonic saline, and antibiotics are generally not useful. Evidence supports using supplemental oxygen to maintain adequate oxygen saturation; however, continuous pulse oximetry is no longer required. The other mainstay of therapy is intravenous or nasogastric administration of fluids for infants who cannot maintain their hydration status with oral fluid intake. Educating parents on reducing the risk of infection is one of the most important things a physician can do to help prevent RSV infection, especially early in life. Children at risk of severe lower respiratory tract infection should receive immunoprophylaxis with palivizumab, a humanized monoclonal antibody, in up to five monthly doses. Prophylaxis guidelines are restricted to infants born before 29 weeks' gestation, infants with chronic lung disease of prematurity, and infants and children with hemodynamically significant heart disease. Bronchiolitis, a lower respiratory tract infection, commonly affects infants and children younger than 2 years. Respiratory syncytial virus is the most common cause. Nasal congestion, rhinorrhea, and mild fever occur in the first 1 to 3 days. Symptoms worsen for several days to include wheezing and other lower respiratory tract signs, and then resolve over days to weeks. However, some children develop hypoxemia and/or respiratory distress and require hospitalization. The diagnosis is clinical, based on the history and physical examination findings. Routine chest x-rays and blood tests are not recommended. Management is supportive, including nasal suctioning, oxygen (in cases of hypoxemia), and hydration. Use of bronchodilators (ie, albuterol, epinephrine) and systemic corticosteroids is not recommended in infants and children ages 1 to 23 months. Pneumonia, another common infection in infants and children, typically is caused by viruses or bacteria. The diagnosis is clinical, and chest x-rays and blood cultures are not required for patients well enough to be treated as outpatients. Antibiotics are not routinely required for preschool-aged children (ie, younger than 5 years) with pneumonia because most have viral infections. For immunized school-aged children with mild to moderate pneumonia suspected to be of bacterial origin, amoxicillin is recommended. In school-aged children, if atypical pathogens (eg, Mycoplasma) are suspected, a macrolide antibiotic should be prescribed. In the wake of a community outbreak of bronchiolitis in northern Israel from December 1993 to March 1994, we conducted a retrospective study of 108 infants aged 2 weeks to 14 months with proven respiratory syncytial virus (RSV) infection (diagnosed by a rapid RSV antigen test in nasopharyngeal secretions). 47% of the infants were less than 8 weeks old. Mean hospital stay was 6.6 days (range 1-60). The characteristic clinical findings were: cough in all patients, dyspnea in 96%, rhinitis in 95% and fever in 55%. In those younger than 8 weeks, or in those with underlying diseases, hospitalization was longer, the disease was more serious and complications more frequent (p &lt; 0.002). 4 children (3%) died, 3 of whom had severe congenital heart defects. All children were treated with oxygen and beta-agonist inhalations. The 33% who also received corticosteroids were older and most had a history of pulmonary diseases, such as asthma or bronchopulmonary dysplasia. There was no difference between those who did or did not receive corticosteroids with regard to severity of disease or rate of complications. Ribavirin was used to treat 19 (17.5%), most of whom had underlying lung disease. The others were otherwise healthy infants younger than 8 weeks. 13 were cared for in the intensive care unit, 11 of whom required mechanical ventilation. A rapid test for detection of RSV infection enabled prompt isolation of infected patients so that the risk of nosocomial infection was reduced and Ribavirin therapy could be started early, if required. The benefit of beta-adrenergic agonists in the treatment of acutely wheezing infants and young children has not been well documented in the outpatient setting. To determine the efficacy of nebulized metaproterenol sulfate, 74 children aged 36 months or younger with acute wheezing participated in a double-masked, randomized, placebo-controlled clinical trial. Children received nebulized metaproterenol, either as an initial treatment or after a control treatment with normal saline solution. At baseline and 20 minutes after each treatment, an assessment was made that included measurements of heart rate, respiratory rate, oxygen saturation, and clinical variables related to respiratory compromise with the use of a standardized respiratory distress index (RDI). Children who received saline solution as initial therapy had no significant differences from baseline in any of the assessment measures. After metaproterenol therapy, children demonstrated an increase in heart rate ([mean +/- SD] 147 +/- 14 beats per minute vs 153 +/- 16 beats per minute), a decrease in respirations (50/min +/- 5/min vs 45/min +/- 7/min), improvement (lower scores) on the RDI (24 +/- 4 vs 15 +/- 2), and an increase in oxygen saturation (94.1% +/- 2.7% vs 95.3% +/- 3.0%). Patients aged 12 months or younger (n = 37) benefited from metaproterenol treatment (improvement in respiratory rate and RDI) but not to the same degree as children aged 24 months or older (n = 23) (improvement in respiratory rate, RDI, and oxygen saturation). Compared with assessments made before metaproterenol treatment, patients with respiratory syncytial virus infection (n = 21) had improvement in respirations (52/min +/- 7/min vs 45/min +/- 6/min) and RDI scores (22 +/- 4 vs 14 +/- 3). Based on a priori criteria (reduction in a premedication respiratory rate of 20% and an RDI score of 50%), responders to metaproterenol therapy included 45% of the entire sample and, respectively, 40% of those aged 12 months or younger, 52% of those aged 24 months or older, and 48% of patients who tested positive for respiratory syncytial virus. Although there appears to be an age-dependent degree of response, metaproterenol is effective in relieving the respiratory distress of young acutely wheezing children, including those with documented respiratory syncytial virus bronchiolitis. Bronchiolitis, a lower respiratory tract illness most often caused by respiratory syncytial virus, generally affects children under two years of age, commonly during the winter months. Necrosis of epithelial cells in the small airways leads to inflammation and airway obstruction, causing decreased oxygen saturation, with cough and wheezing. Hospital admission should be considered for children with pulse oximetry levels less than 95 percent at rest. Treatment consists of humidified oxygen, intravenous hydration and administration of nebulized albuterol. Infants with mild disease who are identified early in the course of illness should be reevaluated in 24 hours. Infants with congenital heart disease, bronchopulmonary dysplasia or a history of prematurity, who are at high risk for severe disease, should be treated with ribavirin. The responsiveness to bronchodilator is variable in infants with wheezing associated respiratory illness (WARI). Factors for prediction of the response will lead to more rational use of the bronchodilator in these infants. We examined the possible predictive factors in 44 children under 2 years of age who had their first episode of WARI. All of them were treated with 0.15 mg/kg of nebulized salbutamol. Thirty patients (68%) with decreasing clinical score &gt; or = 3 after treatment were considered as the responders while the remainder (14 infants) were non responders. By using Chi-square test, Fisher exact test and Mann-Whitney U test to compare the data of the 2 groups, the significant factors for the responders were older than 6 months and history of previous LRI (p &lt; 0.01). The significant factors for the non-responders included concurrent diarrhea, patchy pulmonary infiltration and positive RSV in the nasopharyngeal secretion (p &lt; 0.01). These results suggested effective bronchodilator therapy in infants older than 6 months or having a history of previous LRI. Those who had acute RSV infection or patchy infiltration in chest X-ray and associated diarrhea were less likely to respond. Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease in infants and young children. Most infections due to RSV are mild and do not require hospitalization. RSV causes both upper respiratory tract infections as well as lower respiratory tract infections. Infants with underlying disease states like bronchopulmonary dyslasia, congenital heart disease and prematurity appear more prone to develop severe infection and have a higher incidence of hospitalization. The exact pathogenesis of RSV is not well understood. The mortality associated with primary RSV infection in healthy children is estimated to be between .005% to .02%. In hospitalized children the mortality rate is estimated to be from 1% to 3%. Several treatment modalities in the form of bronchodilators, corticosteroids, ribavirin, intravenous immune gammaglobulin and antibiotics are available. Studies have failed to show the true beneficial effect of any of the above treatment modalities. Supportive care is only needed. The best treatment is the supportive care in the form of oxygen and fluids and close monitoring of the vital signs including oxygen saturation. Corticosteroids continue to be used by many physicians to treat infants with bronchiolitis. The aim of this study was to examine the short-term and long-term efficacy of oral corticosteroid therapy when added to beta2-agonists in infants with mild to moderate bronchiolitis (defined as the first episode of wheezing associated with low grade fever, rhinitis, tachypnea, and increased respiratory effort in a previously healthy infant during the winter months). Infants with mild to moderate bronchiolitis, were randomly assigned to receive either oral prednisone (2 mg/kg/day) or placebo for 3 days. All patients received nebulized albuterol q.i.d. during this period. Upon admission and after 3 days of therapy, a clinical score was assigned based on respiratory rate, use of accessory muscle, and the presence of wheeze. Oxygen saturation (SaO2) was also measured. On day 7, we inquired as to the well-being of each child. Two years later, the development of chronic respiratory symptoms was assessed. Thirty-eight infants were enrolled in the study; 20 received prednisone and 18 received placebo. Both groups were similar in terms of age, duration of illness prior to enrollment, pretrial medication use, clinical severity of bronchiolitis, history of atopy, and family history of atopy. After 3 and 7 days of treatment, both groups showed similar clinical improvement and there were no statistically significant differences between the two groups in the clinical score or in the SaO2. No major side effects were observed. Two years later, 32% of the infants continued to suffer from chronic respiratory symptoms, with a similar prevalence in both groups. We conclude that a 3-day course of oral corticosteroids is of no benefit to infants with mild to moderate bronchiolitis who are also treated with an inhaled beta2-agonist. In this review, we describe the history, epidemiology and clinical manifestations of infections attributed to respiratory syncytial virus (RSV) in children. At present, no cure exists for RSV infection but commonly employed palliative treatments include oxygen and inhaled beta(2)-adrenoceptor agonists, such as salbutamol, to relieve the wheezing and increased bronchiolar smooth muscle constriction. Adrenaline (epinephrine) has been found to be superior to the selective beta(2)-adrenoceptor agonists. Oral or inhaled corticosteroids should counteract the inflammatory response to RSV infection but their effectiveness is controversial. Inhaled ribavirin is the only licensed antiviral product approved for the treatment of RSV lower respiratory-tract infection in hospitalized children, although its use is now restricted to high-risk infants. Other treatments considered are nasopharyngeal suctioning, surfactant therapy, recombinant human deoxyribonuclease I, heliox (helium:oxygen) and inhaled nitric oxide. Prevention of infection by RSV antibodies is another strategy and, currently, palivizumab is the only safe, effective and convenient preventative treatment for RSV disease in high-risk populations of infants and young children. Its cost-effectiveness, however, has been questioned. Both live attenuated and subunit vaccines against RSV infection have been developed but so far there is no safe and effective vaccine available. Finding effective treatments and prophylactic measures remains a major challenge for the future. The role of systemic corticosteroids in the treatment of early childhood wheezing in children is not clear. We sought to determine whether prednisolone is effective in rhinovirus-induced early wheezing. We conducted a controlled trial comparing oral prednisolone (2 mg/kg per day in three divided doses for 3 days) with placebo in 78 hospitalized children (mean age, 1.1 year; standard deviation, 0.7) experiencing their first or second episode of wheezing induced by rhinovirus or respiratory syncytial virus. Mixed viral infections were excluded. Our primary end point was the time until the patient was ready for discharge; secondary end points included oxygen saturation during hospitalization, duration of symptoms, occurrence of relapses during the next 2 months and blood eosinophil counts at discharge and 2 weeks later. In multivariate regression analysis, prednisolone did not influence the time until ready for discharge, but it decreased relapses during the subsequent 2-month period in rhinovirus-affected children (prednisolone versus placebo, 22% versus 56%; odds ratio, 19.06; 95% confidence interval, 2.52-144.03; P = 0.004) and in children with blood eosinophils &gt; or = 0.2 x 10/L (respectively, 24% versus 71%; odds ratio, 10.57; 95% confidence interval, 1.99-56.22; P = 0.006). Rhinovirus-affected children had more blood eosinophils on admission (mean, 0.44 versus 0.086 x 10/L), had a higher prevalence of atopy (44% versus 8%) and were older (mean, 1.4 versus 0.9 years, P &lt; 0.001 for all) than respiratory syncytial virus-infected children. Prednisolone reduced relapses during a 2-month period after first episodes of wheezing associated with rhinovirus infection or blood eosinophils &gt; or = 0.2 x 10/L. Treatment for severe illness is primarily supportive, including oxygen therapy and more advanced breathing support with CPAP or nasal high flow oxygen, as required. In cases of severe respiratory failure, intubation and mechanical ventilation may be required. Ribavirin is the only antiviral medication currently licensed for the treatment of RSV in children, although its use remains controversial. Signs and symptoms RSV infection can present with a wide variety of signs and symptoms that range from mild upper respiratory tract infections (URTI) to severe and potentially life-threatening lower respiratory tract infections (LRTI) requiring hospitalization and mechanical ventilation. While RSV can cause respiratory tract infections in people of all ages and is among the most common childhood infections, its presentation often varies between age groups and immune status. Reinfection is common throughout life, but infants and the elderly remain at highest risk for symptomatic infection. Bronchiolitis is a common lower respiratory tract infection characterized by inflammation and obstruction of the small airways in the lungs. While several viruses can cause bronchiolitis, RSV is responsible for about 70% of cases. It usually presents with 2 to 4 days of runny nose and congestion followed by worsening cough, noisy breathing, tachypnea (fast breathing), and wheezing. As infants work harder to breathe, they can also show signs of respiratory distress, such as subcostal retractions (when the belly pulls under the ribcage), intercostal retractions (when the muscles between the ribs pull inward), grunting, and nasal flaring. If the child has not been able to feed adequately, signs of dehydration may also be present. Fever may be present, but high-grade fever is uncommon. Crackles and wheezing can often be heard on auscultation, and oxygen saturation levels may be decreased. Adults Reinfection with RSV remains common throughout life. Reinfection in adulthood often produces only mild to moderate symptoms indistinguishable from the common cold or sinus infection. Infection may also be asymptomatic. If present, symptoms are generally isolated to the upper respiratory tract: runny nose, sore throat, fever, and malaise. In the vast majority of cases, nasal congestion precedes the development of cough. In contrast to other upper respiratory infections, RSV is also more likely to cause new onset wheeze in adults. Only about 25% of infected adults will progress to significant lower respiratory tract infection, such as bronchitis or tracheobronchitis. Treatment Supportive care Treatment for RSV infection is focused primarily on supportive care. This may include monitoring a patient's breathing or using suction to remove secretions from the upper airway. Supplemental oxygen may also be delivered though a nasal cannula or face mask in order to improve airflow. In severe cases of respiratory failure, intubation and mechanical ventilation may be required to support breathing. If signs of dehydration are present, fluids may also be given orally or through an IV. Management of respiratory syncytial virus lower respiratory tract infection in infants is predominantly supportive and symptomatic. Outpatient management requires close attention to feeding, oral hydration, and monitoring of fever, behavior, and respiratory effort. In the small proportion of patients who need hospitalization, clinicians are concerned primarily with oxygenation and the possibility of oxygen desaturation. Appropriate interventions depend on the level of oxygenation as indicated by pulse oximetry or arterial blood gases. Hydration and symptomatic treatment with alpha- or ss(2 )-adrenergic agonist bronchodilators may lessen the work of breathing. The role of these agents remains controversial, however, and anticholinergic bronchodilators are considered ineffective. Current antiviral therapy is limited to aerosolized ribavirin. Immunotherapy with respiratory syncytial virus immune globulin or a monoclonal antibody has not been rewarding in terms of clinical outcome, although the antiviral effect of these agents has been impressive. There is concern about long-term pulmonary sequelae after respiratory syncytial virus lower respiratory tract infection early in life. Several recent studies, including new data reported here, suggest that ribavirin may have a beneficial effect on some of these sequelae, whereas other studies have failed to demonstrate any benefit. Future studies may help resolve this question. We report 7 cases of respiratory syncytial virus (RSV) infections among elderly patients hospitalized for acute lower tract infection during the winter months. The median age was 95 years (range: 79-106 years). 6 patients were living in nursing homes. All patients had chronic cardiopulmonary conditions. Clinical symptoms included upper respiratory tract symptoms for 3 of them and lower respiratory tract symptoms for all of them. Three patients developed a severe infection with acute respiratory failure. The chest X ray showed an interstitial infiltrate in 3 cases, a consolidation in one case. All patients received oxygen, respiratory physical therapy, nebulized B-agonists and antibiotics. Corticosteroids were used for 4 patients. Progress was favorable for all patients and none died. Diagnosis was obtained in a few hours by direct antigen detection by enzyme immunoassays (EIA) in sputum. Respiratory syncytial virus infection is a common cause of respiratory tract infection in the elderly, during the winter months. Clinical manifestations are similar to influenza infections. Detection of RSV antigens from sputum specimens may be a useful and rapid diagnostic method and merits further evaluation in the elderly. Early diagnosis of respiratory syncytial virus infection should be encouraged to allow the implementation of effective infection control procedures and avoid inadequate therapies. To establish current practice for hospital-based treatment of uncomplicated respiratory syncytial virus (RSV) infection in the Republic of Ireland. A questionnaire was sent to all consultant general paediatricians in the Republic of Ireland. The questionnaire described a clinical scenario and this was followed by a list of management questions. The scenario was of a 3-month-old infant with uncomplicated but moderately severe RSV infection requiring hospitalization. Seventy-three questionnaires were sent. 63/73 (86%) of the questionnaires were returned. With respect to management of this case almost all (61/63) the paediatricians felt that oxygen therapy was necessary (oxygen saturation described in the case was 90%). With respect to bronchodilator therapy, ipratropium bromide (38/63--60%) was chosen much more frequently than salbutamol (15/63--24%). Chest physiotherapy would have been prescribed by 8/63--13% of paediatricians. Oral steroids were infrequently chosen (1/63--2%) but nebulised steroids were selected in 7/63 (11%) cases. The routine use of RSV monoclonal antibody, palivizumab, for RSV prophylaxis was reported by 49% (31/63) of paediatricians. Prematurity with bronchopulmonary dysplasia was considered an indication for its administration by all of these but only 23% considered prematurity alone to be an indication. The management of infants with RSV bronchiolitis varies greatly among consultant paediatricians in Ireland. Evidence based guidelines may be of value in establishing a more uniform national treatment approach. Additional supportive treatments have been investigated specifically in infants hospitalized with RSV bronchiolitis. These include the following: Nebulized hypertonic saline has been shown to reduce length of hospitalization and reduce clinical severity in infants with viral bronchiolitis. It is thought that this treatment may help by reducing airway edema and mucus plugging to decrease airway obstruction. Heliox, a mixture of oxygen with helium, may improve respiratory distress within the first hour after starting treatment. It works by reducing airway resistance and decreasing the work of breathing. However, it has not been shown to impact overall illness outcomes. Chest physiotherapy has not been found to reduce disease severity and is not routinely recommended. Inhaled recombinant human deoxyribonuclease (rhDNase), an enzyme that digests the DNA that contributes to mucus plugging and airway obstruction, has not been shown to improve clinical outcomes in this group. Treatment is primarily supportive; treat mild disease with outpatient management using fluids and nebulizers if needed. Hospitalize in the setting of marked respiratory distress, O2 saturation of < 92%, toxic appearance, dehydration/poor oral feeding, a history of prematurity (< 34 weeks), age < 3 months, underlying cardiopulmonary disease, or unreliable parents. Treat inpatients with contact isolation, hydration, and O2. A trial of aerosolized albuterol may be attempted; continue albuterol therapy only if effective. RSV is the most common cause of bronchiolitis. Ribavirin is an antiviral drug that has a controversial role in bronchiolitis treatment. It is sometimes used in high-risk infants with underlying heart, lung, or immune disease. RSV prophylaxis with injectable polyor monoclonal antibodies (RespiGam or Synagis) is recommended in winter for high-risk patients ≤ 2 years of age (e.g., those with a history of prematurity, chronic lung disease, or congenital heart disease). Humidified Oxygen to alleviate hypoxia if saturations fall below 92%. Corticosteroid by mouth are recommended with five days of prednisone being the same 2 days of dexamethasone. One review recommended a seven-day course of steroids. Magnesium sulfate intravenous treatment increases bronchodilation when used in addition to other treatment in moderate severe acute asthma attacks. In adults intravenous treatment results in a reduction of hospital admissions. Low levels of evidence suggest that inhaled (nebulised) magnesium sulfate may have a small benefit for treating acute asthma in adults. Overall, high quality evidence do not indicate a large benefit for combining magnesium sulfate with standard inhaled treatments for adults with asthma. Heliox, a mixture of helium and oxygen, may also be considered in severe unresponsive cases. Intravenous salbutamol is not supported by available evidence and is thus used only in extreme cases. Respiratory syncytial virus (RSV) bronchiolitis in infancy can lead to bronchial hyper-reactivity or recurrent obstructive bronchitis. The aim of the present study was to determine whether the type of treatment has an influence on respiratory status after RSV bronchiolitis. The study involved 117 infants (mean age 2.6 months), who needed hospital treatment because of RSV bronchiolitis. The patients were divided randomly into three groups. All received the same symptomatic treatment. Group I children received symptomatic treatment only, group II children were treated for 7 days with inhaled budesonide, 500 microg three times per day, administered via a nebulizer. Group III children received nebulized budesonide, 500 microg twice per day for two months. Follow-up consisted of out-patient check-ups 2 and 6 months after the infection, and telephone contact two years after the infection. Statistically significant differences were seen between the groups. In group I 37% of the children had asthma, in group II 18%, and in group III 12%. According to the present study it seems that inhaled corticosteroid treatment during and after the acute phase of infant RSV bronchiolitis may have a beneficial effect on subsequent bronchial wheezing tendency.\nHere is the question:\nPEDIATRICS: A 2-month-old infant with an upper respiratory tract cold of 3 days of evolution, who begins with moderate respiratory distress and pulmonary auscultation with expiratory wheezing. Oxygen saturation is 89 %. Respiratory syncytial virus is isolated in the nasopharyngeal exudate. Which of the following treatments do you consider more indicated for this condition?\nHere are the potential choices:\n1. Oral rivabirin.\n2. Nebulized salbutamol.\n3. Supplemental oxygen.\n4. Intravenous corticosteroids.\nThe correct answer is: 2. Nebulized salbutamol."
    },
    {
        "question": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 60-year-old man was admitted to our hospital because of fever, hemorrhagic tendency, anemia and neurological abnormality. A blood count revealed that the hemoglobin was 6.8 g/dl, the reticulocyte was 17.3 percent with 2 erythroblasts per 100 white cells, the white cell count was 7,100/microliters and the platelet count was 0.8 x 10(4)/microliters. Peripheral blood smear demonstrated marked fragmentation of red cells. Bone marrow examination disclosed the marked erythroid hyperplasia. Although the bleeding time was prolonged (14 minutes 30 seconds), the other hemostatic data were within normal limits. The serum bilirubin level was 1.57 mg/dl; LDH level, 1,437 U/l; creatinine level, 0.92 mg/dl; BUN level 14.7 mg/dl. Haptoglobin was below 10 mg/dl. Results of immunological tests were all negative except the result of PAIgG (576.6 ng/10(7) cells). The urinalysis showed proteinuria, microhematuria and trace granular and hyaline casts. A diagnosis of thrombotic thrombocytopenic purpura was made. The patient was initially treated with prednisolone (60 mg), aspirin (1,000 mg), dipyridamole (150 mg), gabexate mesilate (1.5 g), sodium oxagrel (80 mg) daily with little response. The thirty days after admission, infusion of gamma globulin (20 g, daily) was given for 3 days. The clinical state and laboratory findings became dramatically improved shortly after the administration of gamma globulin and the laboratory data came to be normalized after 1 month. After ten months of this treatment, the patient is remained asymptomatic and the hematological data are within normal range without using any drug. A trial seems justified to confirm the value of this mode of therapy. A 78-year-old woman was admitted to our hospital because of disorientation and fever on January 21, 1992. Two days before admission she experienced vomiting, anorexia and general malaise. Laboratory examinations on admission disclosed a hemoglobin level of 11.1 g/dl and a platelet count of 8,000/microliters. The peripheral blood smear revealed anisocytosis with numerous schistocytes and poikilocytes. Polychromatophilic and nucleated red blood cells were also seen, and the reticulocyte count was 38/1000. Her serum lactate dehydrogenase (LDH) value was 2,977 WU and the total serum bilirubin level was 3.5 mg/dl with 2.7 mg/dl indirect reacting fraction. Serum creatinine was 4.7 mg/dl. Her consciousness became semicomatose after a systemic seizure which lasted approximately 15 seconds and her hemoglobin level decreased to 8.5 g/dl on hospital day 2. Therefore, we diagnosed her as having thrombotic thrombocytopenic purpura (TTP) because of the presence of all 5 features, that is, thrombocytopenia, microangiopathic hemolytic anemia, fluctuating neurologic abnormalities, renal dysfunction and fever. A plasmapheresis with fresh frozen plasma (FFP) replacement was begun on that day. She was also treated with anti-platelet agents, 80 mg/day aspirin, and 300 mg/day dipyridamole. Moreover, packed red blood cells (PRC) were infused. While also receiving diphenylhydantoin and phenobarbital to prevent convulsions, status epilepticus developed on day 3. Because of inhibited spontaneous respiration which was an adverse effect derived from diazepam and sodium thiamylal administered intravenously to treat the status epilepticus, an artificial respiration was initiated.(ABSTRACT TRUNCATED AT 250 WORDS) Disseminated intravascular coagulopathy (DIC) is characterized as activation of the clotting system resulting in fibrin thrombi, gradually diminishing levels of clotting factors with increased risk of bleeding. Basically two types of DIC are distinguished: (1) chronic (compensated) - with alteration of laboratory values and (2) acute (non-compensated) - with severe clinical manifestations: bleeding, shock, acute renal failure (ARF), transient focal neurologic deficit, delirium or coma. Chronic DIC related to metastatic neoplasia is caused by pancreatic, gastric or prostatic carcinoma in most of the cases. Incidence rate of DIC is 13-30% in prostate cancer, among those only 0.4-1.65% of patients had clinical signs and symptoms of DIC. In other words, chronic DIC is developed in one of eight patients with prostate cancer. DIC is considered as a poor prognostic factor in prostatic carcinoma. The similar clinical and laboratory findings of TTP-HUS (thrombotic thrombocytopenic purpura - hemolytic uremic syndrome) and DIC makes it difficult to differentiate between them. A 71 years old male patient with known chronic obstructive pulmonary disease, benign prostatic hyperplasia, significant carotid artery stenosis, gastric ulcer and alcoholic liver disease was admitted to another hospital with melena. Gastroscopy revealed intact gastric mucosa and actually non-bleeding duodenal ulcer covered by clots. Laboratory results showed hyperkalemia, elevated kidney function tests, indirect hyperbilirubinemia, increased liver function tests, leukocytosis, anemia, thrombocytopenia and elevated international normalized ratio (INR). He was treated with saline infusions, four units of red blood cells and one unit of fresh frozen plasma transfusions. Four days later he was transported to our Institution with ARF. Physical examination revealed dyspnoe, petechiae, hemoptoe, oliguria, chest-wall pain and aggressive behavior. Thrombocytopenia, signs of MAHA (fragmentocytes and helmet cells in the peripheral blood), normal INR, elevated lactate dehydrogenase (LDH) and ARF suggested TTP-HUS. Hemodialysis and six plasmaferesis (PF) were carried out. After the fifth PF, skin manifestations of thrombotic microangiopathy occurred on the feet. Clotting analysis revealed elevated D-dimer (&gt;5 μg/mL), normal fibrinogen (3.2 g/L), a slightly raised INR (1.36) and activated partial prothrombin time (APTT) (45.8 sec), normal reticulocyte (57 G/L) and a slightly low platelet count (123 G/L), which proved to be chronic DIC. Therapeutic dose of low-molecular-weight heparin (LMWH) was started. Elevated prostate-specific antigen (PSA) (109.6 ng/mL) suggested prostatic carcinoma. Prostate biopsy revealed adenocarcinoma (Gleason: 4+4 for left lobe and 3+3 for right lobe). Elevated alkaline phosphatase suggested metastases in the bone, which were confirmed by bone scintigraphy. Combined androgen blockade (CAB) was started. After three months follow-up our patient's status is satisfactory. PSA is in the normal range (4.6 ng/mL). Thrombocytopenia of uncertain origin with normal or raised INR, APTT, elevated D-dimer, normal fibrinogen and reticulocyte count prove the diagnosis of chronic DIC. This process warrants searching for metastatic neoplasia. Due to the relatively low serum levels of circulating procoagulant factors (e.g. tissue factor), therapeutic dose of LMWH can be used with good efficiency in chronic DIC with low risk of bleeding. Severe DIC as a complication of metastatic prostate cancer can be treated by androgen deprivation therapy (ADT) or CAB in combination with ketokonazole and concomitant use of supportive treatment. Deme D, Ragán M, Kovács L, Kalmár K, Varga E, Varga T, Rakonczai E. Metastatic prostate cancer complicated with chronic disseminated intravascular coagulopathy causing acute renal failure mimicking thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: pathomechanism, differential diagnosis and therapy related to a case. Schistocytes are fragmented red blood cells due to the flow of blood through damaged capillaries and indicate endothelial injury. They are typical of microangiopathic hemolytic anemia seen in life threatening conditions like disseminated intravascular coagulation or thrombotic thrombocytopenic purpura/hemolytic uremic syndrome .We report a rare sub-acute presentation of pernicious anemia with hemolysis, thrombocytopenia and numerous schistocytes that was initially diagnosed as a more serious thrombotic thrombocytopenic purpura. A 31-year-old Caucasian woman presented with fatigue and paresthesia of both feet for 1 week. Past medical history included hypertension and gastro-esophageal reflux disease. Examination revealed scleral icterus and pallor. Examination of the abdomen did not show hepatosplenomegaly. Initial laboratory tests showed severe anemia, and low platelets. Indirect bilirubin and serum Lactate De Hydrogenase were elevated. Prothrombin time, partial thromboplastin time, serum fibrinogen, and serum fibrin degradation product levels were normal. Peripheral smear revealed numerous schistocytes, anisocytosis and macro-ovalocytes. Thrombotic thrombocytopenic purpura (TTP) was suspected due to the constellation of sub-acute onset of fatigue and paresthesia along with thrombocytopenia, schistocytes and an elevated LDH. Plasmapheresis was initiated for possible TTP. However, platelet count worsened despite plasmapheresis for 4 days. On re-evaluation, vitamin B(12) was found to be low. Treatment with intra-muscular vitamin B(12) led to symptomatic and hematologic improvement. Pernicious anemia was confirmed by the presence of anti-intrinsic factor antibodies, elevated serum gastrin level and atrophic gastritis. Clinicians must be aware of unusual clinical presentation of vitamin B(12) deficiency with schistocytes as the management is simple and effective. Accurate and prompt diagnoses of thrombotic microangiopathy (TMA) in the emergency room (ER) and intensive care unit (ICU) setting can be challenging since its presentation involve multiple organ systems, and comorbid diseases can be deceptive for an accurate diagnosis.  Here, we present the case of a patient, who upon arrival to the ER, reported severe chest pain radiating to his left shoulder, diaphoresis, headache, and nausea. Several numbers of small petechiae on the bilateral lower extremities were also found during physical examination. Laboratory data demonstrated elevated troponin levels, platelet count of 34, and hemoglobin of  8.7 g/l. Establishing a differential diagnosis between a microvascular occlusive disorder and acute coronary syndrome was imperative to reduce further clinical complications and mortality. A peripheral smear, which is an essential test in approaching the diagnosis of thrombotic thrombocytopenic purpura (TTP), was done and it identified an increased number of schistocytes. The laboratory findings narrowed the diagnosis to an immunological process, where the dysfunctional platelets caused coronary thrombosis and further intermittent coronary ischemia. In this case report, we discuss the atypical presentation of TTP, its differential diagnosis, and management in order to develop an effective treatment in the ER and ICU settings and to reduce the mortality rate. Schistocyte count A normal schistocyte count for a healthy individual is <0.5% although usual values are found to be <0.2%. A schistocyte count of >1% is most often found in thrombotic thrombocytopenic purpura, although they are more often seen within the range of 3–10% for this condition. A schistocyte count of <1% but greater than the normal value is suggestive of disseminated intravascular coagulation, but is not an absolute diagnosis. The standard for a schistocyte count is a microscopic examination of a peripheral blood smear. Assessment of peripheral blood counts and blood film analysis are frequently performed as diagnostic procedures in emergency medicine. Far fewer situations exist, however, in which these analyses are the main clue in establishing an emergency diagnosis. Artifacts can lead to wrong diagnosis, e.g. pseudo-thrombocytopenia, which is defined as a low platelet count resulting from a laboratory artifact. Severe neutropenia (agranulocytosis) and extreme hyperleukocytosis, as well as suspicion of acute leukemia, require a rapid diagnostic work-up. A newly detected anemia should not necessarily be treated by packed red cell transfusions. The decision whether an anemic patient ought to receive transfusions should be based on the speed with which the anemia has developed, as well as on clinical judgement. As a rule a chronic anemia patient with hemoglobin above 70 g/l does not need transfusions. An uncritical transfusion policy can even cause emergencies, e.g. in patients with megaloblastic anemia or in anemic multiple myeloma patients with a hyperviscosity syndrome. An elevated hematocrit requires prompt further investigations. This is of utmost importance if one considers the diagnosis of polycythemia vera rubra, a disease in which patients are particularly prone to thrombotic complications. Fragmented red cells (schistocytes) on peripheral blood smears constitute a cardinal diagnostic clue for the detection of microangiopathic hemolytic anemias (MAHA), in particular for the diagnosis of the life-threatening thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Malaria is another example for a chief role of blood smears examination in achieving a rapid diagnosis. If one encounters an unexpected severe thrombocytopenia, a marrow examination reveals whether it is due to rapid peripheral destruction, or due to a marrow failure. Furthermore, in any patients with an unanticipated thrombocytopenia, a disseminated intravascular coagulation and a MAHA should be ruled out. Heparin-induced thrombocytopenia is a rare, but possibly fatal complication of therapy with heparins. Diagnosis CBC and blood film: decreased platelets and schistocytes PT, aPTT, fibrinogen: normal markers of hemolysis: increased unconjugated bilirubin, increased LDH, decreased haptoglobin negative Coombs test. Creatinine, urea, to follow renal function ADAMSTS-13 gene, activity or inhibitor testing (TTP). Intravenous tissue plasminogen activator (IV tPA) was shown to be an effective treatment for acute ischemic stroke (AIS). According to stroke guidelines, there is no need to wait for the complete blood count (CBC) and coagulation test results before application of IV alteplase if there is no suspected coagulation disorder. In this study, a patient with AIS and thrombotic thrombocytopenic purpura (TTP) symptoms during thrombolytic treatment was presented. A 33-year-old male patient was admitted at the 2.5th hour of AIS symptoms onset with right hemiparesis and sensorimotor aphasia. Cranial computed tomography (CT) and diffusion magnetic resonance imaging did not reveal any abnormality. In his medical history, the patient did not have any contraindication for thrombolytic treatment. To avoid delays to thrombolytic therapy, blood samples were taken, and after that, IV bolus alteplase treatment was applied. During maintenance treatment, agitation and vomiting developed. The result of blood samples showed less than 26,000 mm<sup3</sup platelet count and maintenance therapy was stopped. In control cranial CT, there was no hemorrhage. In the laboratory examination; anemia, low platelet count; increased indirect bilirubin, lactate dehydrogenase (LDH) levels were found, and fever was 38.4°C. Schistocytes were observed in peripheral blood smear and the patient was diagnosed as TTP. Stroke guidelines recommend not to wait for the results of CBC and coagulation tests before IV tPA treatment in patients who do not have any history of coagulopathy disorder. If possible, before applying IV tPA we may wait for the results of coagulation and CBC tests, keeping in mind the diseaes with high mortality such as TTP. Thrombotic thrombocytopenic purpura (TTP) is a rare microvascular occlusive disorder characterized by systemic intravascular aggregation of platelets, thrombocytopenia, and mechanical injury to red blood cells. We report a rare case of pernicious anemia presenting as TTP in a Jehovah's Witness. A 46-year-old Jehovah's Witness female presented with epigastric pain, vomiting, and diarrhea for 2 days and fatigue and paresthesias for 4 weeks. Initial laboratory evaluation showed severe anemia and thrombocytopenia with elevated total bilirubin and lactate dehydrogenase. Peripheral blood smear showed schistocytes, macroovalocytes, and hypersegmented neutrophils. TTP was suspected and plasmapheresis was offered. The patient refused it due to her religious beliefs. Due to the presence of macroovalocytes and hypersegmented neutrophils, vitamin B12 level was checked and found to be extremely low. Anti-intrinsic factor antibodies and anti-parietal cell antibodies were also positive; hence a diagnosis of pernicious anemia was established. Treatment with intramuscular vitamin B12 was initiated, which resulted in dramatic neurologic and hematologic improvement. Vitamin B12 deficiency can lead to elevated levels of homocysteine in the blood. Homocysteine can cause endothelial dysfunction, which can lead to formation of microvascular thrombi. Due to this phenomenon, vitamin B12 deficiency can rarely present with schistocytes and thrombocytopenia, which combined with other stigmata of vitamin B12 deficiency, can be misdiagnosed as TTP. A 73-year-old female with past medical history of essential hypertension, hyperlipidemia, seasonal allergies, and chronic back pain presented to the hospital with complaints of headaches, fevers, fatigue, generalized body aches, shortness of breath, and diarrhea. Initial complete blood count was remarkable for leukopenia with an absolute lymph count of 0.60 K/µL and severe thrombocytopenia (platelet count &lt; 3 K/µL). She was tested for COVID-19 via nasopharyngeal swab polymerase chain reaction (PCR) testing and found positive. Additional labs showed an elevated D-dimer, C-reactive protein, fibrinogen, and lactate dehydrogenase. Vitamin B12 and folate levels were obtained and found to be normal. Peripheral smear showed no schistocytes or additional hematologic abnormalities apart from thrombocytopenia. The patient was transfused one unit of platelets with no improvement in platelet count. Fibrinogen count was obtained and found in normal range at 458 mg/dL. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) were all found to be normal. Immune thrombocytopenia purpura (ITP) was suspected and intravenous immunoglobulin (IVIG) was administered at a dose of 1 g/kg/day for two doses. By day 4, the patient had marked response to treatment with platelet recovery to 105 K/µL and subsequently discharged by day 5 with complete resolution of symptoms and platelet count of 146 K/µL. Twenty-eight days after discharge, she presented to hematology clinic with platelet count of 8 K/µL. Repeat nasopharyngeal swab PCR COVID testing was negative and she was treated with IVIG and pulse dexamethasone with prompt response, confirming suspicion of underlying, undiagnosed ITP prior to COVID infection. Thrombotic thrombocytopenic purpura (TTP) is typically characterized by the symptomatic pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, and renal failure. Atypical TTP is the diagnosis used to describe the subset of patients with TTP who present with symptoms that deviate from the classic pentad. We report a case an 86-year-old woman who presented to the emergency department complaining of chest pain for one day. She was reportedly on antibiotics for sinus infection. Physical examination revealed multiple bilateral superficial hematomas, predominantly on her extremities. On admission, her lab values were as follows: platelet count of 6,000/cubic millimeter, hemoglobin of 10.4 grams/deciliter, leukocyte count of 5100 cells/cubic millimeter, total bilirubin of 2.3 milligrams/deciliter, and troponin-I of 5.190 nanograms/milliliter. Peripheral blood smear was normal and did not reveal any schistocytes. The patient was admitted to the intensive care unit with a diagnosis of a non-ST-elevation myocardial infarction and a presumed diagnosis of immune thrombocytopenic purpura from antibiotic use. She was treated with intravenous solumedrol and a high-intensity statin. On the third day of her admission, the patient's mental functioning deteriorated and was intubated to protect her airway. A second peripheral smear revealed schistocytes, and subsequent laboratory studies supported the diagnosis of TTP. Plasma exchange therapy was planned. However, the patient succumbed to cardiac arrest before it could be initiated. The diagnosis was later confirmed with an ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) assay.  This case serves as an example of one of the many ways in which TTP can present, and emphasizes the importance of considering TTP as a differential diagnosis. Platelet count < 150,000/˜L Hemoglobin and white blood count Normal Abnormal Bone marrow examination Peripheral blood smear Platelets clumped: Redraw in sodium citrate or heparin Fragmented red blood cells Normal RBC morphology; platelets normal or increased in size Microangiopathic hemolytic anemias (e.g., DIC, TTP) Consider: Drug-induced thrombocytopenia Infection-induced thrombocytopenia Idiopathic immune thrombocytopenia Congenital thrombocytopenia first appear in areas of increased venous pressure, the ankles and feet in an ambulatory patient. Petechiae are pinpoint, nonblanching hemorrhages and are usually a sign of a decreased platelet number and not platelet dysfunction. Wet purpura, blood blisters that form on the oral mucosa, are thought to denote an increased risk of life-threatening hemorrhage in the thrombocytopenic patient. Excessive bruising is seen in disorders of both platelet number and function. Laboratory evaluation plays a critically important role in diagnosing TTP because signs and symptoms are variable, and end-organ damage can be delayed. For diagnosis, the laboratory data must show anemia and thrombocytopenia along with an indication of active hemolysis, such as the presence of schistocytes, increased unconjugated bilirubin, increased reticulocyte count and increased lactate dehydrogenase. [23] [24] [25] As with any hemolysis in general, the serum haptoglobin decreases as it combines with the free hemoglobin released from the destroyed erythrocytes. <bObjective:</b To investigate the clinical characteristics, treatment and prognosis of children with acquired thrombotic thrombocytopenic purpura (TTP). <bMethods:</b The clinical manifestations, laboratory examination, treatment and prognosis of 5 children with acquired TTP hospitalized in Beijing Children's Hospital, Capital Medical University from January 2016 to July 2019 were analyzed retrospectively. <bResults:</b There were 5 children with acquired TTP including 2 males and 3 females, with the onset age of 8.9(0.8-14.5) years, while 11 children with TTP in the same period. Thrombocytopenia and microangiopathic hemolytic anemia were found in all 5 patients. Only one patient had typical pentalogy of TTP, 3 patients had nervous system symptoms and 3 patients had fever, while renal impairment was relatively rare (1 case). Laboratory examination showed severe thrombocytopenia (7(4-14) ×10<sup9</sup/L) and low level of hemoglobin (70(58-100)g/L) in all 5 children. Blood biochemical examination showed that total bilirubin (mainly indirect bilirubin) increased in 3 patients, lactate dehydrogenase increased in 5 patients, and urea nitrogen increased in 1 patient. Bone marrow smear showed megakaryocyte did not decrease. Plasma ADAMTS13 activity was 0 in all 5 patients while ADAMTS13 inhibitor was positive in 4 patients and negative in 1 patient. All 5 children received glucocorticoid therapy, rituximab was added in the early stage of the disease, and 3 children received plasma exchange. The time of platelet recovery to normal was 19 (9-29) days. One child had TTP recurrence after 9 months of treatment. The condition was stable after being treated with glucocorticoid and rituximab again. This case was finally diagnosed as systemic lupus erythematosus after more than 3 years followed up. By December 1, 2020, the follow-up time was 24(16-57) months.The clinical symptoms of all patients disappeared and the platelet level was stable at 159(125-269) ×10<sup9</sup/L. <bConclusions:</b Childhood acquired TTP is relatively rare, which can occur in all age groups. The clinical manifestations are mainly thrombocytopenia and microangiopathic hemolytic anemia, the plasma ADAMTS 13 activity and inhibitor test are helpful for the diagnosis of acquired TTP. Plasma exchange and rituximab are effective treatment. This disease requires long-term follow-up. Reference methods for determining the ADAMTS-13 activity are complex, and the results are not always readily available in an emergency setting. Thus, initial management should be started based on clinical presentation. Blood testing will likely show profound thrombocytopenia (counts <30x10 9 /L), microangiopathic hemolysis (schistocytes >1% in a blood smear), decreased ADAMTS-13 activity, and the presence of autoantibodies to ADAMTS-13. The direct Coombs test should be negative (except in some cases of SLE), and the coagulation test should not be prolonged. Other lab abnormalities include decreased haptoglobin, increased reticulocytes, elevated LDH, and elevated indirect bilirubin. [19] [20] [21] [22] Diagnosis A diagnosis of TTP is based on the clinical symptoms with the concomitant presence of thrombocytopenia (platelet count below 100×109/L) and microangiopathic hemolytic anemia with schistocytes on the blood smear, a negative direct antiglobulin test (Coombs test), elevated levels of hemolysis markers (such as total bilirubin, LDH, free hemoglobin, and an unmeasurable haptoglobin), after exclusion of any other apparent cause. USS can present similar to the following diseases, which have to be excluded: fulminant infections, disseminated intravascular coagulation, autoimmune hemolytic anemia, Evans syndrome, the typical and atypical form of hemolytic uremic syndrome, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, pre-eclampsia, heparin-induced thrombocytopenia, cancer that is often accompanied with metastasis, kidney injury, antiphospholipid antibody syndrome, and side effects from hematopoietic stem cell transplantation. Thrombotic thrombocytopenic purpura (TTP) is a rare disease due to deficiency of ADAMTS13 which can present with anemia and thrombocytopenia. The study highlights the role of PLASMIC score in diagnosis and rituximab in the treatment of this condition. Herein, we report a case of 38 years old female who had presented with fever, irritability, and altered sensorium. On investigations, she had hemolytic anemia, and thrombocytopenia with peripheral blood smear showing occasional schistocytes and managed with steroids and plasma exchange. As her platelet, LDH, and a few other lab parameters failed to normalize and met the criteria of refractory TTP, hence she was started on 5 cycles of rituximab and her condition improved. Thrombotic thrombocytopenic purpura can be presumed based upon PLASMIC score where if the score is 5 or more while ADAMTS13 assay is required for confirmation. It is a life-threatening condition where treatment options include therapeutic plasma exchange (PEX), glucocorticoids, Rituximab, and caplacizumab. Rituximab is considered particularly in refractory cases. Thrombotic thrombocytopenic purpura can lead to complications due to low platelet counts. Hence, early diagnosis and intervention are crucial to prevent such complications.\nHere is the question:\nHEMATOLOGY: A 67-year-old female patient on ticlopidine treatment comes to the emergency department with headache, asthenia and petechiae in the lower extremities. Laboratory tests showed hemoglobin 8.2 g/dL, MCV 100 fl, platelets 25000/ul and leukocytes 7500/ul with normal formula. The reticulocyte count was elevated and the blood smear showed numerous schistocytes. Coagulation studies (APTT, PT and fibrinogen) are normal. The biochemistry shows LDH 2700 IU/l and bilirubin 2.6 mg/dl. What is the most likely diagnosis?\nHere are the potential choices:\n1. Autoimmune thrombocytopenic purpura.\n2. Thrombotic thrombocytopenic purpura.\n3. Bone marrow aplasia.\n4. Drug-induced thrombopenia.\n5. Disseminated intravascular coagulation.\nThe correct answer is: ",
        "gold_answer": "2 Thrombotic thrombocytopenic purpura.",
        "prediction": "You are a helpful medical expert, and your task is to answer a multi-choice medical question using the relevant documents. Please choose the answer from the provided options. Your responses will be used for research purposes only, so please have a definite answer.\nHere are the relevant documents:\n A 60-year-old man was admitted to our hospital because of fever, hemorrhagic tendency, anemia and neurological abnormality. A blood count revealed that the hemoglobin was 6.8 g/dl, the reticulocyte was 17.3 percent with 2 erythroblasts per 100 white cells, the white cell count was 7,100/microliters and the platelet count was 0.8 x 10(4)/microliters. Peripheral blood smear demonstrated marked fragmentation of red cells. Bone marrow examination disclosed the marked erythroid hyperplasia. Although the bleeding time was prolonged (14 minutes 30 seconds), the other hemostatic data were within normal limits. The serum bilirubin level was 1.57 mg/dl; LDH level, 1,437 U/l; creatinine level, 0.92 mg/dl; BUN level 14.7 mg/dl. Haptoglobin was below 10 mg/dl. Results of immunological tests were all negative except the result of PAIgG (576.6 ng/10(7) cells). The urinalysis showed proteinuria, microhematuria and trace granular and hyaline casts. A diagnosis of thrombotic thrombocytopenic purpura was made. The patient was initially treated with prednisolone (60 mg), aspirin (1,000 mg), dipyridamole (150 mg), gabexate mesilate (1.5 g), sodium oxagrel (80 mg) daily with little response. The thirty days after admission, infusion of gamma globulin (20 g, daily) was given for 3 days. The clinical state and laboratory findings became dramatically improved shortly after the administration of gamma globulin and the laboratory data came to be normalized after 1 month. After ten months of this treatment, the patient is remained asymptomatic and the hematological data are within normal range without using any drug. A trial seems justified to confirm the value of this mode of therapy. A 78-year-old woman was admitted to our hospital because of disorientation and fever on January 21, 1992. Two days before admission she experienced vomiting, anorexia and general malaise. Laboratory examinations on admission disclosed a hemoglobin level of 11.1 g/dl and a platelet count of 8,000/microliters. The peripheral blood smear revealed anisocytosis with numerous schistocytes and poikilocytes. Polychromatophilic and nucleated red blood cells were also seen, and the reticulocyte count was 38/1000. Her serum lactate dehydrogenase (LDH) value was 2,977 WU and the total serum bilirubin level was 3.5 mg/dl with 2.7 mg/dl indirect reacting fraction. Serum creatinine was 4.7 mg/dl. Her consciousness became semicomatose after a systemic seizure which lasted approximately 15 seconds and her hemoglobin level decreased to 8.5 g/dl on hospital day 2. Therefore, we diagnosed her as having thrombotic thrombocytopenic purpura (TTP) because of the presence of all 5 features, that is, thrombocytopenia, microangiopathic hemolytic anemia, fluctuating neurologic abnormalities, renal dysfunction and fever. A plasmapheresis with fresh frozen plasma (FFP) replacement was begun on that day. She was also treated with anti-platelet agents, 80 mg/day aspirin, and 300 mg/day dipyridamole. Moreover, packed red blood cells (PRC) were infused. While also receiving diphenylhydantoin and phenobarbital to prevent convulsions, status epilepticus developed on day 3. Because of inhibited spontaneous respiration which was an adverse effect derived from diazepam and sodium thiamylal administered intravenously to treat the status epilepticus, an artificial respiration was initiated.(ABSTRACT TRUNCATED AT 250 WORDS) Disseminated intravascular coagulopathy (DIC) is characterized as activation of the clotting system resulting in fibrin thrombi, gradually diminishing levels of clotting factors with increased risk of bleeding. Basically two types of DIC are distinguished: (1) chronic (compensated) - with alteration of laboratory values and (2) acute (non-compensated) - with severe clinical manifestations: bleeding, shock, acute renal failure (ARF), transient focal neurologic deficit, delirium or coma. Chronic DIC related to metastatic neoplasia is caused by pancreatic, gastric or prostatic carcinoma in most of the cases. Incidence rate of DIC is 13-30% in prostate cancer, among those only 0.4-1.65% of patients had clinical signs and symptoms of DIC. In other words, chronic DIC is developed in one of eight patients with prostate cancer. DIC is considered as a poor prognostic factor in prostatic carcinoma. The similar clinical and laboratory findings of TTP-HUS (thrombotic thrombocytopenic purpura - hemolytic uremic syndrome) and DIC makes it difficult to differentiate between them. A 71 years old male patient with known chronic obstructive pulmonary disease, benign prostatic hyperplasia, significant carotid artery stenosis, gastric ulcer and alcoholic liver disease was admitted to another hospital with melena. Gastroscopy revealed intact gastric mucosa and actually non-bleeding duodenal ulcer covered by clots. Laboratory results showed hyperkalemia, elevated kidney function tests, indirect hyperbilirubinemia, increased liver function tests, leukocytosis, anemia, thrombocytopenia and elevated international normalized ratio (INR). He was treated with saline infusions, four units of red blood cells and one unit of fresh frozen plasma transfusions. Four days later he was transported to our Institution with ARF. Physical examination revealed dyspnoe, petechiae, hemoptoe, oliguria, chest-wall pain and aggressive behavior. Thrombocytopenia, signs of MAHA (fragmentocytes and helmet cells in the peripheral blood), normal INR, elevated lactate dehydrogenase (LDH) and ARF suggested TTP-HUS. Hemodialysis and six plasmaferesis (PF) were carried out. After the fifth PF, skin manifestations of thrombotic microangiopathy occurred on the feet. Clotting analysis revealed elevated D-dimer (&gt;5 μg/mL), normal fibrinogen (3.2 g/L), a slightly raised INR (1.36) and activated partial prothrombin time (APTT) (45.8 sec), normal reticulocyte (57 G/L) and a slightly low platelet count (123 G/L), which proved to be chronic DIC. Therapeutic dose of low-molecular-weight heparin (LMWH) was started. Elevated prostate-specific antigen (PSA) (109.6 ng/mL) suggested prostatic carcinoma. Prostate biopsy revealed adenocarcinoma (Gleason: 4+4 for left lobe and 3+3 for right lobe). Elevated alkaline phosphatase suggested metastases in the bone, which were confirmed by bone scintigraphy. Combined androgen blockade (CAB) was started. After three months follow-up our patient's status is satisfactory. PSA is in the normal range (4.6 ng/mL). Thrombocytopenia of uncertain origin with normal or raised INR, APTT, elevated D-dimer, normal fibrinogen and reticulocyte count prove the diagnosis of chronic DIC. This process warrants searching for metastatic neoplasia. Due to the relatively low serum levels of circulating procoagulant factors (e.g. tissue factor), therapeutic dose of LMWH can be used with good efficiency in chronic DIC with low risk of bleeding. Severe DIC as a complication of metastatic prostate cancer can be treated by androgen deprivation therapy (ADT) or CAB in combination with ketokonazole and concomitant use of supportive treatment. Deme D, Ragán M, Kovács L, Kalmár K, Varga E, Varga T, Rakonczai E. Metastatic prostate cancer complicated with chronic disseminated intravascular coagulopathy causing acute renal failure mimicking thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: pathomechanism, differential diagnosis and therapy related to a case. Schistocytes are fragmented red blood cells due to the flow of blood through damaged capillaries and indicate endothelial injury. They are typical of microangiopathic hemolytic anemia seen in life threatening conditions like disseminated intravascular coagulation or thrombotic thrombocytopenic purpura/hemolytic uremic syndrome .We report a rare sub-acute presentation of pernicious anemia with hemolysis, thrombocytopenia and numerous schistocytes that was initially diagnosed as a more serious thrombotic thrombocytopenic purpura. A 31-year-old Caucasian woman presented with fatigue and paresthesia of both feet for 1 week. Past medical history included hypertension and gastro-esophageal reflux disease. Examination revealed scleral icterus and pallor. Examination of the abdomen did not show hepatosplenomegaly. Initial laboratory tests showed severe anemia, and low platelets. Indirect bilirubin and serum Lactate De Hydrogenase were elevated. Prothrombin time, partial thromboplastin time, serum fibrinogen, and serum fibrin degradation product levels were normal. Peripheral smear revealed numerous schistocytes, anisocytosis and macro-ovalocytes. Thrombotic thrombocytopenic purpura (TTP) was suspected due to the constellation of sub-acute onset of fatigue and paresthesia along with thrombocytopenia, schistocytes and an elevated LDH. Plasmapheresis was initiated for possible TTP. However, platelet count worsened despite plasmapheresis for 4 days. On re-evaluation, vitamin B(12) was found to be low. Treatment with intra-muscular vitamin B(12) led to symptomatic and hematologic improvement. Pernicious anemia was confirmed by the presence of anti-intrinsic factor antibodies, elevated serum gastrin level and atrophic gastritis. Clinicians must be aware of unusual clinical presentation of vitamin B(12) deficiency with schistocytes as the management is simple and effective. Accurate and prompt diagnoses of thrombotic microangiopathy (TMA) in the emergency room (ER) and intensive care unit (ICU) setting can be challenging since its presentation involve multiple organ systems, and comorbid diseases can be deceptive for an accurate diagnosis.  Here, we present the case of a patient, who upon arrival to the ER, reported severe chest pain radiating to his left shoulder, diaphoresis, headache, and nausea. Several numbers of small petechiae on the bilateral lower extremities were also found during physical examination. Laboratory data demonstrated elevated troponin levels, platelet count of 34, and hemoglobin of  8.7 g/l. Establishing a differential diagnosis between a microvascular occlusive disorder and acute coronary syndrome was imperative to reduce further clinical complications and mortality. A peripheral smear, which is an essential test in approaching the diagnosis of thrombotic thrombocytopenic purpura (TTP), was done and it identified an increased number of schistocytes. The laboratory findings narrowed the diagnosis to an immunological process, where the dysfunctional platelets caused coronary thrombosis and further intermittent coronary ischemia. In this case report, we discuss the atypical presentation of TTP, its differential diagnosis, and management in order to develop an effective treatment in the ER and ICU settings and to reduce the mortality rate. Schistocyte count A normal schistocyte count for a healthy individual is <0.5% although usual values are found to be <0.2%. A schistocyte count of >1% is most often found in thrombotic thrombocytopenic purpura, although they are more often seen within the range of 3–10% for this condition. A schistocyte count of <1% but greater than the normal value is suggestive of disseminated intravascular coagulation, but is not an absolute diagnosis. The standard for a schistocyte count is a microscopic examination of a peripheral blood smear. Assessment of peripheral blood counts and blood film analysis are frequently performed as diagnostic procedures in emergency medicine. Far fewer situations exist, however, in which these analyses are the main clue in establishing an emergency diagnosis. Artifacts can lead to wrong diagnosis, e.g. pseudo-thrombocytopenia, which is defined as a low platelet count resulting from a laboratory artifact. Severe neutropenia (agranulocytosis) and extreme hyperleukocytosis, as well as suspicion of acute leukemia, require a rapid diagnostic work-up. A newly detected anemia should not necessarily be treated by packed red cell transfusions. The decision whether an anemic patient ought to receive transfusions should be based on the speed with which the anemia has developed, as well as on clinical judgement. As a rule a chronic anemia patient with hemoglobin above 70 g/l does not need transfusions. An uncritical transfusion policy can even cause emergencies, e.g. in patients with megaloblastic anemia or in anemic multiple myeloma patients with a hyperviscosity syndrome. An elevated hematocrit requires prompt further investigations. This is of utmost importance if one considers the diagnosis of polycythemia vera rubra, a disease in which patients are particularly prone to thrombotic complications. Fragmented red cells (schistocytes) on peripheral blood smears constitute a cardinal diagnostic clue for the detection of microangiopathic hemolytic anemias (MAHA), in particular for the diagnosis of the life-threatening thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Malaria is another example for a chief role of blood smears examination in achieving a rapid diagnosis. If one encounters an unexpected severe thrombocytopenia, a marrow examination reveals whether it is due to rapid peripheral destruction, or due to a marrow failure. Furthermore, in any patients with an unanticipated thrombocytopenia, a disseminated intravascular coagulation and a MAHA should be ruled out. Heparin-induced thrombocytopenia is a rare, but possibly fatal complication of therapy with heparins. Diagnosis CBC and blood film: decreased platelets and schistocytes PT, aPTT, fibrinogen: normal markers of hemolysis: increased unconjugated bilirubin, increased LDH, decreased haptoglobin negative Coombs test. Creatinine, urea, to follow renal function ADAMSTS-13 gene, activity or inhibitor testing (TTP). Intravenous tissue plasminogen activator (IV tPA) was shown to be an effective treatment for acute ischemic stroke (AIS). According to stroke guidelines, there is no need to wait for the complete blood count (CBC) and coagulation test results before application of IV alteplase if there is no suspected coagulation disorder. In this study, a patient with AIS and thrombotic thrombocytopenic purpura (TTP) symptoms during thrombolytic treatment was presented. A 33-year-old male patient was admitted at the 2.5th hour of AIS symptoms onset with right hemiparesis and sensorimotor aphasia. Cranial computed tomography (CT) and diffusion magnetic resonance imaging did not reveal any abnormality. In his medical history, the patient did not have any contraindication for thrombolytic treatment. To avoid delays to thrombolytic therapy, blood samples were taken, and after that, IV bolus alteplase treatment was applied. During maintenance treatment, agitation and vomiting developed. The result of blood samples showed less than 26,000 mm<sup3</sup platelet count and maintenance therapy was stopped. In control cranial CT, there was no hemorrhage. In the laboratory examination; anemia, low platelet count; increased indirect bilirubin, lactate dehydrogenase (LDH) levels were found, and fever was 38.4°C. Schistocytes were observed in peripheral blood smear and the patient was diagnosed as TTP. Stroke guidelines recommend not to wait for the results of CBC and coagulation tests before IV tPA treatment in patients who do not have any history of coagulopathy disorder. If possible, before applying IV tPA we may wait for the results of coagulation and CBC tests, keeping in mind the diseaes with high mortality such as TTP. Thrombotic thrombocytopenic purpura (TTP) is a rare microvascular occlusive disorder characterized by systemic intravascular aggregation of platelets, thrombocytopenia, and mechanical injury to red blood cells. We report a rare case of pernicious anemia presenting as TTP in a Jehovah's Witness. A 46-year-old Jehovah's Witness female presented with epigastric pain, vomiting, and diarrhea for 2 days and fatigue and paresthesias for 4 weeks. Initial laboratory evaluation showed severe anemia and thrombocytopenia with elevated total bilirubin and lactate dehydrogenase. Peripheral blood smear showed schistocytes, macroovalocytes, and hypersegmented neutrophils. TTP was suspected and plasmapheresis was offered. The patient refused it due to her religious beliefs. Due to the presence of macroovalocytes and hypersegmented neutrophils, vitamin B12 level was checked and found to be extremely low. Anti-intrinsic factor antibodies and anti-parietal cell antibodies were also positive; hence a diagnosis of pernicious anemia was established. Treatment with intramuscular vitamin B12 was initiated, which resulted in dramatic neurologic and hematologic improvement. Vitamin B12 deficiency can lead to elevated levels of homocysteine in the blood. Homocysteine can cause endothelial dysfunction, which can lead to formation of microvascular thrombi. Due to this phenomenon, vitamin B12 deficiency can rarely present with schistocytes and thrombocytopenia, which combined with other stigmata of vitamin B12 deficiency, can be misdiagnosed as TTP. A 73-year-old female with past medical history of essential hypertension, hyperlipidemia, seasonal allergies, and chronic back pain presented to the hospital with complaints of headaches, fevers, fatigue, generalized body aches, shortness of breath, and diarrhea. Initial complete blood count was remarkable for leukopenia with an absolute lymph count of 0.60 K/µL and severe thrombocytopenia (platelet count &lt; 3 K/µL). She was tested for COVID-19 via nasopharyngeal swab polymerase chain reaction (PCR) testing and found positive. Additional labs showed an elevated D-dimer, C-reactive protein, fibrinogen, and lactate dehydrogenase. Vitamin B12 and folate levels were obtained and found to be normal. Peripheral smear showed no schistocytes or additional hematologic abnormalities apart from thrombocytopenia. The patient was transfused one unit of platelets with no improvement in platelet count. Fibrinogen count was obtained and found in normal range at 458 mg/dL. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) were all found to be normal. Immune thrombocytopenia purpura (ITP) was suspected and intravenous immunoglobulin (IVIG) was administered at a dose of 1 g/kg/day for two doses. By day 4, the patient had marked response to treatment with platelet recovery to 105 K/µL and subsequently discharged by day 5 with complete resolution of symptoms and platelet count of 146 K/µL. Twenty-eight days after discharge, she presented to hematology clinic with platelet count of 8 K/µL. Repeat nasopharyngeal swab PCR COVID testing was negative and she was treated with IVIG and pulse dexamethasone with prompt response, confirming suspicion of underlying, undiagnosed ITP prior to COVID infection. Thrombotic thrombocytopenic purpura (TTP) is typically characterized by the symptomatic pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, and renal failure. Atypical TTP is the diagnosis used to describe the subset of patients with TTP who present with symptoms that deviate from the classic pentad. We report a case an 86-year-old woman who presented to the emergency department complaining of chest pain for one day. She was reportedly on antibiotics for sinus infection. Physical examination revealed multiple bilateral superficial hematomas, predominantly on her extremities. On admission, her lab values were as follows: platelet count of 6,000/cubic millimeter, hemoglobin of 10.4 grams/deciliter, leukocyte count of 5100 cells/cubic millimeter, total bilirubin of 2.3 milligrams/deciliter, and troponin-I of 5.190 nanograms/milliliter. Peripheral blood smear was normal and did not reveal any schistocytes. The patient was admitted to the intensive care unit with a diagnosis of a non-ST-elevation myocardial infarction and a presumed diagnosis of immune thrombocytopenic purpura from antibiotic use. She was treated with intravenous solumedrol and a high-intensity statin. On the third day of her admission, the patient's mental functioning deteriorated and was intubated to protect her airway. A second peripheral smear revealed schistocytes, and subsequent laboratory studies supported the diagnosis of TTP. Plasma exchange therapy was planned. However, the patient succumbed to cardiac arrest before it could be initiated. The diagnosis was later confirmed with an ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) assay.  This case serves as an example of one of the many ways in which TTP can present, and emphasizes the importance of considering TTP as a differential diagnosis. Platelet count < 150,000/˜L Hemoglobin and white blood count Normal Abnormal Bone marrow examination Peripheral blood smear Platelets clumped: Redraw in sodium citrate or heparin Fragmented red blood cells Normal RBC morphology; platelets normal or increased in size Microangiopathic hemolytic anemias (e.g., DIC, TTP) Consider: Drug-induced thrombocytopenia Infection-induced thrombocytopenia Idiopathic immune thrombocytopenia Congenital thrombocytopenia first appear in areas of increased venous pressure, the ankles and feet in an ambulatory patient. Petechiae are pinpoint, nonblanching hemorrhages and are usually a sign of a decreased platelet number and not platelet dysfunction. Wet purpura, blood blisters that form on the oral mucosa, are thought to denote an increased risk of life-threatening hemorrhage in the thrombocytopenic patient. Excessive bruising is seen in disorders of both platelet number and function. Laboratory evaluation plays a critically important role in diagnosing TTP because signs and symptoms are variable, and end-organ damage can be delayed. For diagnosis, the laboratory data must show anemia and thrombocytopenia along with an indication of active hemolysis, such as the presence of schistocytes, increased unconjugated bilirubin, increased reticulocyte count and increased lactate dehydrogenase. [23] [24] [25] As with any hemolysis in general, the serum haptoglobin decreases as it combines with the free hemoglobin released from the destroyed erythrocytes. <bObjective:</b To investigate the clinical characteristics, treatment and prognosis of children with acquired thrombotic thrombocytopenic purpura (TTP). <bMethods:</b The clinical manifestations, laboratory examination, treatment and prognosis of 5 children with acquired TTP hospitalized in Beijing Children's Hospital, Capital Medical University from January 2016 to July 2019 were analyzed retrospectively. <bResults:</b There were 5 children with acquired TTP including 2 males and 3 females, with the onset age of 8.9(0.8-14.5) years, while 11 children with TTP in the same period. Thrombocytopenia and microangiopathic hemolytic anemia were found in all 5 patients. Only one patient had typical pentalogy of TTP, 3 patients had nervous system symptoms and 3 patients had fever, while renal impairment was relatively rare (1 case). Laboratory examination showed severe thrombocytopenia (7(4-14) ×10<sup9</sup/L) and low level of hemoglobin (70(58-100)g/L) in all 5 children. Blood biochemical examination showed that total bilirubin (mainly indirect bilirubin) increased in 3 patients, lactate dehydrogenase increased in 5 patients, and urea nitrogen increased in 1 patient. Bone marrow smear showed megakaryocyte did not decrease. Plasma ADAMTS13 activity was 0 in all 5 patients while ADAMTS13 inhibitor was positive in 4 patients and negative in 1 patient. All 5 children received glucocorticoid therapy, rituximab was added in the early stage of the disease, and 3 children received plasma exchange. The time of platelet recovery to normal was 19 (9-29) days. One child had TTP recurrence after 9 months of treatment. The condition was stable after being treated with glucocorticoid and rituximab again. This case was finally diagnosed as systemic lupus erythematosus after more than 3 years followed up. By December 1, 2020, the follow-up time was 24(16-57) months.The clinical symptoms of all patients disappeared and the platelet level was stable at 159(125-269) ×10<sup9</sup/L. <bConclusions:</b Childhood acquired TTP is relatively rare, which can occur in all age groups. The clinical manifestations are mainly thrombocytopenia and microangiopathic hemolytic anemia, the plasma ADAMTS 13 activity and inhibitor test are helpful for the diagnosis of acquired TTP. Plasma exchange and rituximab are effective treatment. This disease requires long-term follow-up. Reference methods for determining the ADAMTS-13 activity are complex, and the results are not always readily available in an emergency setting. Thus, initial management should be started based on clinical presentation. Blood testing will likely show profound thrombocytopenia (counts <30x10 9 /L), microangiopathic hemolysis (schistocytes >1% in a blood smear), decreased ADAMTS-13 activity, and the presence of autoantibodies to ADAMTS-13. The direct Coombs test should be negative (except in some cases of SLE), and the coagulation test should not be prolonged. Other lab abnormalities include decreased haptoglobin, increased reticulocytes, elevated LDH, and elevated indirect bilirubin. [19] [20] [21] [22] Diagnosis A diagnosis of TTP is based on the clinical symptoms with the concomitant presence of thrombocytopenia (platelet count below 100×109/L) and microangiopathic hemolytic anemia with schistocytes on the blood smear, a negative direct antiglobulin test (Coombs test), elevated levels of hemolysis markers (such as total bilirubin, LDH, free hemoglobin, and an unmeasurable haptoglobin), after exclusion of any other apparent cause. USS can present similar to the following diseases, which have to be excluded: fulminant infections, disseminated intravascular coagulation, autoimmune hemolytic anemia, Evans syndrome, the typical and atypical form of hemolytic uremic syndrome, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, pre-eclampsia, heparin-induced thrombocytopenia, cancer that is often accompanied with metastasis, kidney injury, antiphospholipid antibody syndrome, and side effects from hematopoietic stem cell transplantation. Thrombotic thrombocytopenic purpura (TTP) is a rare disease due to deficiency of ADAMTS13 which can present with anemia and thrombocytopenia. The study highlights the role of PLASMIC score in diagnosis and rituximab in the treatment of this condition. Herein, we report a case of 38 years old female who had presented with fever, irritability, and altered sensorium. On investigations, she had hemolytic anemia, and thrombocytopenia with peripheral blood smear showing occasional schistocytes and managed with steroids and plasma exchange. As her platelet, LDH, and a few other lab parameters failed to normalize and met the criteria of refractory TTP, hence she was started on 5 cycles of rituximab and her condition improved. Thrombotic thrombocytopenic purpura can be presumed based upon PLASMIC score where if the score is 5 or more while ADAMTS13 assay is required for confirmation. It is a life-threatening condition where treatment options include therapeutic plasma exchange (PEX), glucocorticoids, Rituximab, and caplacizumab. Rituximab is considered particularly in refractory cases. Thrombotic thrombocytopenic purpura can lead to complications due to low platelet counts. Hence, early diagnosis and intervention are crucial to prevent such complications.\nHere is the question:\nHEMATOLOGY: A 67-year-old female patient on ticlopidine treatment comes to the emergency department with headache, asthenia and petechiae in the lower extremities. Laboratory tests showed hemoglobin 8.2 g/dL, MCV 100 fl, platelets 25000/ul and leukocytes 7500/ul with normal formula. The reticulocyte count was elevated and the blood smear showed numerous schistocytes. Coagulation studies (APTT, PT and fibrinogen) are normal. The biochemistry shows LDH 2700 IU/l and bilirubin 2.6 mg/dl. What is the most likely diagnosis?\nHere are the potential choices:\n1. Autoimmune thrombocytopenic purpura.\n2. Thrombotic thrombocytopenic purpura.\n3. Bone marrow aplasia.\n4. Drug-induced thrombopenia.\n5. Disseminated intravascular coagulation.\nThe correct answer is: 2. Thrombotic thrombocytopenic purpura."
    }
]