bluuebunny/crossref_metadata_2025 huggingface dataset:
Urinary tract infection
Authors: Tomson Charles , Sheerin Neil
Published: February 2020

Urinary tract infection (UTI) is a common condition, accounting for 1 to 3% of all primary care consultations in the United Kingdom. It affects patients of both sexes and all ages. The commonest organism causing uncomplicated community-acquired bacterial UTI is Escherichia coli. The occurrence and course of a UTI is influenced by the integrity of the host defence and by bacterial virulence factors. Disruption of the highly specialized transitional cell epithelium which lines the urinary tract, incomplete bladder emptying, anatomical abnormalities, and the presence of a foreign body, such as a urinary catheter, can all contribute to disruption of the host defence and increase the likelihood of infection. Sexual intercourse and use of spermicides increase the risk, and genetic factors influence the susceptibility of some people. Diagnosis—acute uncomplicated UTI can often be diagnosed on symptoms alone, with urinalysis increasing diagnostic accuracy. Submission of a sample for microbiological testing is unnecessary in most cases. Differential diagnoses (‘culture-negative syndromes’) include chlamydial infection, urethral syndrome, and painful bladder syndrome (interstitial cystitis). Investigation—beyond microbiological testing, further investigation of women with uncomplicated UTI is seldom justified. In men, and those women with features indicating complicated infection, investigation for an underlying cause should be considered. Management: antibiotics—trimethoprim and nitrofurantoin remain the first choice for community-acquired UTI in the United Kingdom. Complicated UTI is caused by a wider spectrum of organisms, and recommendations for treatment differ. This chapter discusses the prevention of recurrent uncomplicated UTI and management of complicated UTIs due to urethral catheterization, urinary tract stones, anatomically abnormal kidneys, and pregnancy, and other causes such as fungal infections, tuberculosis, and schistosomiasis.
Urinary tract obstruction
Authors: Yaqoob Muhammad M. , McCafferty Kieran
Published: February 2020

Obstructive nephropathy can manifest as either a sudden or an insidious decline in renal function, which can be halted or even reversed by relief of obstruction. Obstruction can be due to anatomical or functional abnormalities of the urethra, bladder, ureter, or renal pelvis, which may be congenital or acquired, and it can also occur as a consequence of diseases extrinsic to the urinary tract. Although dilatation of the outflow system proximal to the site of obstruction is a characteristic finding, widening of the ureter and/or pelvicalyceal system does not necessarily indicate the presence of obstruction, and flow may be obstructed without such dilatation. Aetiology—calculi and pelviureteric junctional obstruction are common causes of unilateral obstruction, while prostatic enlargement, stone disease, and bladder and pelvic tumours account for about 75% of cases of bilateral obstruction in developed countries. To the clinician, the first and most important question is whether urinary tract obstruction is of recent onset (acute obstruction) or long-standing (chronic obstruction). The pathophysiological changes, clinical features, approach to investigation, and management differ in important respects in these two circumstances, which are discussed separately in this chapter under the headings of acute upper urinary tract obstruction, acute lower urinary tract obstruction, chronic upper urinary tract obstruction, and chronic lower urinary tract obstruction. Retroperitoneal fibrosis, a rare condition, is also discussed.
Introduction to haematology
Authors: Hatton Chris
Published: February 2020

Haematology is the study of the composition, function, and diseases of the blood. The approach to a patient suspected of having a haematological disorder begins with taking a history (particularly noting fatigue, weight loss, fever, and history of bleeding) and performing a clinical examination (looking for signs of anaemia, infection, bleeding, and signs of cellular infiltration causing splenomegaly and/or lymphadenopathy). Key investigations include a full blood count, a blood film, and (in selected cases) examination of the bone marrow. Further diagnostic tests now routinely performed on blood and marrow samples include immunophenotyping and cytogenetic and molecular analysis. Mutational signatures may be diagnostically useful and potentially define treatment, keeping haematology in the vanguard of advances in modern medicine.
Myelodysplastic syndromes
Authors: Brierley Charlotte K. , Steensma David P.
Published: February 2020

The myelodysplastic syndromes (MDS) are marrow failure syndromes characterized by cytopenias, blood cell dysmorphology, acquired clonal cytogenetic and molecular genetic mutations, and a risk of development of acute myeloid leukaemia. MDS may evolve in patients previously treated with cytotoxic chemotherapy or radiotherapy for a solid tumour, but most commonly arise de novo in patients over 60 years old. Most patients present with features of chronic anaemia or manifestations related to thrombocytopenia or infection. The diagnosis may be suggested by the presence of normocytic or macrocytic anaemia, with the peripheral blood smear showing dysplastic changes in red blood cells or neutrophils. Bone marrow aspirate and biopsy permits detailed cytogenetic study, which is critical for diagnostic classification and prognosis. Increasingly, molecular genetic assays (next-generation sequencing panels) aid in diagnosis and prognosis.

The World Health Organization (WHO) classification recognizes various MDS subtypes based on the morphological appearance of the peripheral blood and bone marrow. These include MDS with excess blasts, MDS with deletion of the long arm of chromosome 5, and MDS with ring sideroblasts.

Treatment is symptomatic in most cases. The only potentially curative treatment is allogeneic bone marrow transplantation, which is often precluded due to patients’ advanced age or comorbidity. Higher-risk patients may experience a survival benefit from treatment with the DNA hypomethylating agent azacitidine, and decitabine delays disease progression to acute myeloid leukaemia. Some patients with lower-risk disease may show a response to immunosuppression with antithymocyte globulin and ciclosporin. Patients with isolated chromosome 5q deletions and lower-risk disease may respond dramatically to lenalidomide, an immunomodulatory drug.
Chronic myeloid leukaemia
Authors: Copland Mhairi , Holyoake Tessa L.
Published: February 2020

Chronic myeloid leukaemia (CML) has a worldwide incidence of 1 to 2 per 100 000 of the population. Most cases are caused by translocation of the distal end of chromosome 9 on to chromosome 22 which leads to the creation of a fusion protein expressed from the fusion gene formed by juxtaposition of parts of the BCR and ABL1 genes. The resulting oncoprotein is a constitutive tyrosine kinase and appears to operate as an initiator for the development of the leukaemia. Clinical features—many patients are asymptomatic at diagnosis, which is made following a routine blood test. Others present with signs and symptoms including fatigue, sweats, fever, weight loss, haemorrhagic manifestations, and abdominal discomfort (due to splenomegaly). Diagnosis—this is typically made by the examination of a peripheral blood film and the demonstration of the Ph chromosome by conventional cytogenetics in a bone marrow aspirate or peripheral blood sample. Polymerase chain reaction analysis of peripheral blood confirms the presence of a BCR-ABL1 transcript and characterizes the BCR-ABL1 junction. Treatment—the original TKI, imatinib, has had a very significant impact on the first-line management of patients with CML. It induces durable complete cytogenetic responses in the majority of patients and prolongs overall survival substantially. Second- and third-generation TKIs show enhanced potency against BCR-ABL1 activity and are licensed within Europe for first-line (dasatinib, nilotinib) or second-line or subsequent (dasatinib, nilotinib, bosutinib, ponatinib) use in CML. Patients with suboptimal responses to first-line treatment can be offered a different second-line TKI; or a third-line TKI, such as ponatinib; or allogeneic stem cell transplantation—for patients less than 65 years of age and with a suitable donor.
The polycythaemias
Authors: Aruch Daniel , Hoffman Ronald
Published: February 2020

Polycythaemia or erythrocytosis is characterized by an abnormal increase in the numbers of red blood cells, leading to an elevation in the haemoglobin concentration and haematocrit (>49% in men and >48% in women). The cause may be either (1) primary—due to an intrinsic defect of haematopoietic stem cells; or (2) secondary—due to extrinsic stimulation of progenitor erythroid cells by circulating growth factors; and the condition needs to be distinguished from (3) pseudopolycythaemia—in which haematocrit is raised because the plasma volume is decreased. Secondary polycythaemias: associated with appropriate erythropoietin secretion—conditions that are ultimately the result of tissue hypoxia and subsequent excessive erythropoietin production include (1) living at high altitude, (2) chronic lung disease, (3) cyanotic congenital heart disease with right-to-left shunting, (4) carbon monoxide intoxication—as occurs in heavy smokers, (5) haemoglobin variants with increased oxygen affinity, and (6) mutations in genes involved in the oxygen sensing pathway. Associated with inappropriate erythropoietin secretion—in the absence of tissue hypoxia, inappropriate erythropoietin production commonly originates from the kidney and many renal disorders are associated with erythrocytosis. Tumour-associated polycythaemia may also result from cerebellar haemangioblastoma, hepatocellular carcinoma, phaeochromocytoma, and other adrenal tumours. Primary polycythaemia: polycythaemia vera—is a clonal, chronic progressive haematological malignancy characterized by excessive proliferation of erythroid, myeloid, and megakaryocytic elements in the bone marrow. Aetiology—up to 95% of cases are caused by somatic mutations in the pluripotent haemopoietic stem cells leading to replacement of a key valine residue by phenylalanine at position 617 of the JAK2 kinase (V617F), which releases it from autoinhibition. Less common mutations have been described recently, primarily JAK2 exon 12 and LNK mutations.
Histiocytosis
Authors: Hatton Chris
Published: February 2020

The histiocytoses are disorders derived from the dendritic cell and monocyte/macrophage lineages, with the classification of this group of disorders relating to the underlying cell of origin. Dendritic cell disorders—there has been much debate about the nature of these conditions, and their status as neoplastic or primary inflammatory diseases; for Langerhans’ cell histiocytosis in particular, there is increasing evidence of their clonal nature, as manifest by recurrent BRAF mutations. Clinical features and diagnosis—these are highly variable and dependent on the sites affected by histiocytic infiltration. Symptoms and signs may include rashes, bony pain, lymphadenopathy, hepatomegaly and splenomegaly, cough and dyspnoea, features of marrow failure, and endocrine presentations (classically diabetes insipidus). Diagnosis typically follows imaging and biopsy, with the demonstration of a histiocytic infiltrate confirmed by immunostaining. Treatment and prognosis—the rarity and heterogeneity of these diseases has made it difficult to achieve a consensus on treatment. For localized disease, curettage, steroid injections, or targeted radiotherapy may be helpful. For more systemic disease, combination chemotherapy is typically used. Treatment schedules differ between adults and children. Prognosis is dependent mainly on the site(s) of involvement. Our expanding appreciation of the molecular basis of these conditions also provides some justification for the use of BRAF inhibitors and other targeted small molecule therapies. Macrophage-related disorders—these include haemophagocytic lymphohistiocytosis, a collection of macrophage-activating syndromes which may be either reactive to underlying inflammatory, infective, or neoplastic disease, or consequent upon a primary genetic lesion affecting cytotoxic T-cell killing function. Rosai–Dorfman disease is a separate macrophage proliferation syndrome, thought to be non-neoplastic, which causes massive cervical lymphadenopathy, usually in children.
Hodgkin lymphoma
Authors: Bhatt Vijaya Raj , Armitage James O.
Published: February 2020

Hodgkin’s lymphoma is derived from a profoundly defective B cell, with the pathobiology, histology, and clinical features being both characteristic and distinct from non-Hodgkin’s lymphomas. Its cause is unknown. Incidence is about 3 per 100 000 per year in Western countries with a bimodal age distribution meaning that it is one of the commoner lymphomas of young people. Most cases are highly responsive to combination chemotherapy, with many patients being cured of their disease. Patients with Hodgkin’s lymphoma may present with lymphadenopathy, a mediastinal (or other) mass, and systemic symptoms including weight loss, fever, and night sweats (B-symptoms). Workup requires staging with positron emission tomography (PET)-CT imaging, and biopsy. Classical Hodgkin’s lymphoma is defined by the presence of the binucleate Reed–Sternberg cell in an appropriate inflammatory histological context. These cells have a characteristic immunohistochemical phenotype, showing CD15 and CD30 positivity, but being immunonegative for classical B-cell markers such as CD20. Additional histological subtypes have been defined, with the most clinically significant being lymphocyte-predominant Hodgkin’s lymphoma. Patients with localized disease may be treated with chemotherapy with or without radiotherapy. Those with more advanced-stage disease require combination chemotherapy, with radiotherapy to sites of initial bulk disease. While relapse is uncommon in patients with early-stage disease, some 20% of patients with advanced-stage disease may need ‘salvage’ chemotherapy regimens for relapsed disease, when the aim is to attain PET negativity before embarking on high-dose therapy with stem cell rescue. Since many patients have a good outcome, it is essential to minimize the long-term sequelae of treatment. Risk stratification is a major focus of clinical trials in this area to determine optimal treatment strategies.
Acquired aplastic anaemia and pure red cell aplasia
Authors: Marsh Judith C.W. , Gandhi Shreyans , Mufti Ghulam J.
Published: February 2020

Aplastic anaemia (AA) is a rare bone marrow failure (BMF) disorder characterized by pancytopenia and a hypocellular bone marrow. AA is commonly acquired, immune mediated, and idiopathic in nature. Activated autoreactive, cytotoxic CD8+ T cells are present but recent work has shown that CD4+ T cells appear to be more important in the pathogenesis of acquired AA. The immune nature of acquired AA provides the rationale for one of the treatment options, namely immunosuppressive therapy. First-line treatment of acquired AA is either immunosuppressive therapy with antithymocyte globulin and ciclosporin or allogeneic haematopoietic stem cell transplantation (HSCT). Both modalities offer excellent survival. Patients treated with immunosuppressive therapy are at later risk of relapse and clonal evolution to myelodysplastic syndrome and acute myeloid leukaemia, so require long-term follow-up. HSCT, if successful, is curative, but risks include graft rejection, infections, and graft-versus-host disease (GVHD); recent changes to the transplant conditioning regimen have reduced the GVHD risk. The inherited forms of AA include Fanconi’s anaemia, a disorder of DNA repair, dyskeratosis congenita, a disorder of telomere maintenance, and Shwachman–Diamond syndrome, one of the so-called ribosomopathies characterized by defective ribosomal biogenesis. Pure red cell aplasia (PRCA) is a form of BMF characterized by severe anaemia with reticulocytopenia and reduced erythroid progenitors in the bone marrow. PRCA most commonly is an acquired disorder and immune mediated, and often occurs in association with a wide range of conditions. Diamond–Blackfan anaemia, an inherited form of PRCA, is another example of a ribosomopathy, and is caused by mutations in one of many ribosomal protein genes, resulting in haploinsufficiency.
Paroxysmal nocturnal haemoglobinuria
Authors: Luzzatto Lucio
Published: February 2020

Paroxysmal nocturnal haemoglobinuria (PNH) is a unique disorder in which many of the patient’s red cells have an abnormal susceptibility to activated complement. This results from the presence of a clone that originates from a haematopoietic stem cell bearing an acquired somatic mutation in the X-linked gene PIGA, required for the biosynthesis of the glycosylphosphatidylinositol molecule which anchors many proteins to the cell membrane, including the complement regulators CD59 and CD55. The ‘classical’ presentation is with ‘passing blood instead of urine’ (haemoglobinuria). Sometimes the patient presents with the full triad of (1) haemolytic anaemia, (2) pancytopenia, and (3) thrombosis—most commonly of intra-abdominal veins. An element of bone marrow failure is always present; and sometimes the disease may be preceded by or may evolve to bone marrow aplasia indistinguishable from acquired aplastic anaemia. Definitive diagnosis is based on demonstrating the presence of a discrete population of ‘PNH red blood cells’ by flow cytometry using anti-CD59. In most cases, especially when the patient is transfusion dependent and/or has severe signs and symptoms, there is an indication for long-term treatment with the complement inhibitor eculizumab.
Iron metabolism and its disorders
Authors: Cox Timothy M. , Porter John B.
Published: February 2020

Iron deficiency and iron storage disease—the latter principally due to inherited and acquired anaemias such as thalassemia—are disorders of massive clinical significance across the globe. Iron deficiency is the commonest cause of anaemia, affecting about 1 billion people, and about 0.75 million people have thalassaemia. Largely neglected by health services in rich and resource-poor countries alike, disorders of iron metabolism, whether inherited, nutritional, or otherwise, represent a long-standing public health challenge. Improved screening methods for detection, diagnosis, and appropriate supplementation—as well as genetic counselling—can offer a great deal to relieve the burden in stricken communities. Advances in chelation therapy have improved the survival of patients with iron-loading anaemias and transfusion-related haemochromatosis, and better understanding of the molecular pathophysiology of iron homeostasis now offers the prospect of definitive therapies to control pathological erythropoiesis and the inappropriate drive to acquire lethal quantities of toxic iron.
Disorders of the synthesis or function of haemoglobin
Authors: Hay Deborah , Weatherall David J.
Published: February 2020

The inherited disorders of haemoglobin are the commonest single-gene disorders in the world. Disorders of haemoglobin can be genetic or acquired and due to disordered production of one or more globin chains or structural change in the globin chain. The most important disorders are the genetic conditions thalassaemia and sickle cell disease. Thalassaemia—a heterogeneous group of genetic disorders, all resulting from a reduced rate of production of one or more of the globin chains of haemoglobin and inherited in a simple Mendelian fashion. They are clinically classified according to their severity into major (a severe transfusion-dependent disorder), intermediate (characterized by anaemia and splenomegaly), and minor (a symptomless carrier state) forms. The β thalassaemias are the most important types of thalassaemia because they are very common and produce severe anaemia in their homozygous and compound heterozygous states. Most countries in which the disease is common are putting a major effort into programmes for its prevention (population screening and prenatal diagnosis). Symptomatic management of severe disease requires regular blood transfusion, judicious use of splenectomy if hypersplenism develops, and chelating agents to reduce iron overload. Sickle cell disease—haemoglobin S differs from haemoglobin A by the substitution of valine for glutamic acid at position 6 in the β globin chain, and homozygosity for haemoglobin S produces the state of sickle cell disease. This occurs very frequently in African populations and, sporadically, throughout the Mediterranean region and the Middle East, with extensive pockets in India. Management of both acute and chronic complications remains largely supportive, with hydroxycarbamide being the only clinically proven effective treatment to date.
Acquired haemolytic anaemia
Authors: Powers Amy , Silberstein Leslie
Published: February 2020

Premature destruction of red cells occurs through two primary mechanisms: (1) decreased erythrocyte deformability that leads to red cell sequestration and extravascular haemolysis in the spleen and other components of the reticuloendothelial system—may be caused by membrane defects, metabolic abnormalities, exogenous oxidizing agents, or pathological antibodies; and (2) red cell membrane damage and intravascular haemolysis—may be caused by exposure to pathological antibodies, activated complement, mechanical forces, chemicals, and infectious agents. Congenital haemolytic anaemias—congenital disorders resulting in a haemolytic anaemia include (1) disorders of the red cell membrane such as hereditary spherocytosis and hereditary elliptocytosis; (2) disorders of red cell enzymes such as glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency; and (3) disorders of globin structure. Acquired immune haemolytic anaemias—immune haemolysis may occur when IgG, IgM, or IgA antibodies and/or complement bind to the erythrocyte surface. Autoimmune haemolytic anaemias—these are best classified according to the temperature at which the antibody optimally binds to the erythrocyte: warm autoimmune haemolytic anaemia, cold agglutinin-mediated autoimmune haemolytic anaemia, paroxysmal cold haemoglobinuria, and mixed type autoimmune haemolytic anaemia. Drug-induced haemolytic anaemia—haemolysis can be caused by drugs that induce a positive DAT. Drug-induced antibodies may be drug dependent or drug independent depending on whether the presence of the drug is required for their detection. Alloimmune haemolytic anaemias—these include acute haemolytic transfusion reactions and other conditions such as delayed haemolytic transfusion reactions, passenger lymphocyte haemolysis, and haemolytic disease of the newborn. Acquired nonimmune haemolytic anaemias and microangiopathic haemolytic anaemia are also discussed in this chapter.
Acquired coagulation disorders
Authors: Warkentin T.E.
Published: February 2020

Acquired disorders of coagulation may be the consequence of many underlying conditions, and although they may share abnormality of a coagulation test, for example, a prolonged prothrombin time, their clinical effects are diverse and often opposing. General clinical approach: diagnosis—most acquired disorders of coagulation can be identified by screening haemostasis tests, including (1) prothrombin time; (2) activated partial thromboplastin time; (3) thrombin clotting time; (4) fibrinogen degradation products, including (5) the cross-linked fibrin assay (D-dimer); and (6) complete blood count with examination of a blood film. Few bleeding disorders give normal results in all these tests, but disorders predisposed to thrombosis as a result of deficiency of natural anticoagulants (e.g. antithrombin, protein C, and protein S) or certain mutations (e.g. factor V Leiden) must be specifically sought. Treatment—patients with coagulopathies who are bleeding or who require surgery are usually treated with blood products such as platelets and frozen plasma. Other treatments used in particular circumstances include (1) vitamin K—required for the post-translational modification of factors II, VII, IX, and X as well as the anticoagulant factors, protein C, and protein S; (2) cryoprecipitate—used principally for the treatment of hypofibrinogenaemia; (3) concentrates of specific factors—used in isolated deficiencies (e.g. of factors VIII, IX, XI, VIIa, or fibrinogen); (4) antifibrinolytic agents (e.g. ε-aminocaproic acid and tranexamic acid); (5) desmopressin (1-deamino-8-d-arginine vasopressin)—increases factor VIII and von Willebrand factor.
Blood transfusion
Authors: Giovanniello D.S. , Snyder E.L.
Published: February 2020

Transfusion of blood components is a life-saving treatment for patients with severe haemorrhage and can also be used to replace coagulation factors and to ameliorate the effects of severe anaemia, thrombocytopenia, and impaired platelet function. With greater understanding of red cell, platelet, and leucocyte antigen structure and function, transfusion therapy has improved. In addition, understanding current and emerging infectious agents has ensured patient safety. Transfusion medicine has expanded over recent decades to include multiple disciplines, such as therapeutic apheresis, cellular therapy, and tissue banking. One of the most important technological improvements in transfusion therapy was the development of sterile, disposable, and flexible plastic containers that allow separation of whole blood into cellular (e.g. red cells, platelets) and noncellular (e.g. plasma, cryoprecipitate) components, known as apheresis. This technology allows the blood of a donor or patient to pass through an apparatus that separates out one particular constituent and returns the remainder to the circulation. Anticoagulants and additives currently used to collect blood allow storage of liquid suspensions of concentrated red cells for 35 to 42 days. These advances have essentially eliminated the use of whole blood. Blood transfusion is used to treat patients with severe anaemia, haemorrhage, thrombocytopenia, and coagulation disorders. Although the hazards of blood replacement are relatively small, the expected benefit of a transfusion must outweigh the risk to the patient. Therefore, a thorough understanding of the indications of blood transfusion is required to minimize unnecessary blood replacement and to prevent wastage of limited blood resources. Clinicians who prescribe blood transfusion must also be familiar with the risks and be able to recognize and treat transfusion reactions.
Structure and function of skin
Authors: McGrath John A.
Published: February 2020

Skin provides a mechanical barrier against the external environment, but has further roles in thermoregulation, metabolism, and the regulation of fluid balance, as well as being socially important in contributing to physical and chemical attraction between individuals.

There are more than 1,000 different skin diseases, although relatively few are commonly encountered in general medical practice. However, several skin conditions can reflect a general medical problem such as a systemic infection, or a cutaneous manifestation of internal disease (e.g. patients with underlying malignancy, endocrine disorders, or chronic inflammatory diseases). An understanding of skin structure and function is also important in dealing with the common clinical scenario of ‘skin failure’ resulting from adverse drug reactions, burns, or extensive trauma.
Papulosquamous disease
Authors: Griffiths Christopher E.M.
Published: February 2020

Papulosquamous diseases are characterized by well-demarcated areas of papules and scale, typically on an erythematous background. The differential diagnosis includes psoriasis, lichen planus, mycosis fungoides, discoid lupus erythematosus, eczema/dermatitis, drug eruptions, tinea, pityriasis versicolor, secondary syphilis, and pityriasis rosea. The presence of significant pruritus is a useful marker to help with the differential diagnosis: lichen planus and discoid eczema are typically pruritic, whereas others, such as psoriasis, are less so. The distribution is also key to diagnosis, with psoriasis often showing characteristic symmetrical involvement of the extensor surfaces, scalp, and nails. Histology can be essential to reach a diagnosis and plan an appropriate approach to management.
Dermatitis/eczema
Authors: Friedmann Peter S. , Arden-Jones Michael J. , Hay Roderick J.
Published: February 2020

Eczema is a characteristic pattern of skin inflammation that has many subtypes, with some induced by external factors such as irritants or skin sensitizers. Atopic eczema is due partly to a genetic susceptibility, which programmes altered immune responses and skin physiology, together with reactions to exogenous allergens and microbes, but several eczema patterns do not appear to have external causes. Management requires identification and avoidance of provoking factors. The inflammation is treated with topical steroids of different potencies, supplemented with moisturizers. Newer therapies include topical calcineurin antagonists, with a range of systemic therapies being used to control the most severe types of disease.
Infections of the skin
Authors: Hay Roderick J.
Published: February 2020

A huge variety of different organisms exist on healthy skin, the normal microbiome. Under certain circumstances, microbes can actively infect the skin as a primary or secondary event in cutaneous or systemic disease. The most common causes of bacterial infection of the skin are Staphylococcus aureus or β-haemolytic streptococci. There are increasing reports of both hospital- and community-acquired infection by methicillin-resistant S. aureus. Mycobacterium tuberculosis remains a common skin infection in many tropical areas, and syphilis, leprosy, and leishmaniasis are important skin infections in some parts of the world. Dermatophytosis, or ringworm, is caused by mould fungi that can digest keratin (keratinophilic). The diagnosis can be confirmed in the laboratory by examining scrapings or clippings of skin, hair, or nails mounted in potassium hydroxide. Occasionally, in the immunocompromized patient these and other herpes virus infections can disseminate, both to other parts of the skin as well as internally.
Sebaceous and sweat gland disorders
Authors: Layton Alison M.
Published: February 2020

Cutaneous glands in humans include holocrine or sebaceous glands and merocrine or sweat glands. Merocrine glands are subdivided into apocrine, eccrine, and apoeccrine glands. Disorders of each of these cutaneous glands have been associated with disease. Apocrine glands in adults are found predominantly in the axillae and anogenital regions, with a few located in the ear canal (ceruminous glands) and eyelids (Moll’s glands). Disorders associated with apocrine glands include hidradenitis suppurativa, Fox–Fordyce disease, bromhidrosis, trimethylaminuria, and chromhidrosis. Eccrine glands are the sweat-producing glands of the skin. Many drugs and systemic diseases can influence the degree of sweating, such as thyroid disease, infection, carcinoid, and cholinergic drugs. In cystic fibrosis, the concentration of sodium chloride in sweat is increased. Meanwhile, acne is a common inflammatory skin disease often associated with significant psychosocial morbidity.
Cutaneous reactions to drugs
Authors: Walsh Sarah , Creamer Daniel , Lee Haur Yueh
Published: February 2020

Adverse reactions to medications are common and important cause of iatrogenic illness. Severe cutaneous adverse drug reactions include toxic epidermal necrolysis, Stevens–Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis, which together constitute 2% of all adverse drug reactions and may be life-threatening. Less severe drug-induced skin reactions such as exanthems, urticaria, lichenoid drug rashes, and fixed drug eruptions are more common, sometimes termed benign cutaneous adverse reactions, and generally resolve without sequelae. Drugs may also cause adverse events due to alteration of the normal function of the skin or its appendages. This may take the form of photosensitivity, abnormal pigmentation, or disrupted growth of hair or nails.
Alzheimer’s disease and other dementias
Authors: Schott Jonathan M.
Published: February 2020

Dementia is defined as a syndrome consisting of progressive impairment in memory and other cognitive deficits (aphasia, apraxia, agnosia, or disturbance in executive function) in the absence of another explanatory central nervous system disorder, depression, or delirium, sufficient to interfere with activities of daily living. In recent years there has been a move to consider and classify patients with less severe forms of cognitive impairment—so-called mild cognitive impairment—and non-memory presentations, with the latest DSM-V criteria identifying individuals with major or minor neurocognitive syndromes. Ongoing research using biomarkers suggest that there is a long presymptomatic phase for many causes of dementia.
Epilepsy in later childhood and adulthood
Authors: Sen Arjune , Johnson M.R.
Published: February 2020

Epilepsy is a common, serious neurological disease, with prevalence of 1% and a cumulative lifetime risk of 5%. An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive, synchronous neuronal activity. Epilepsy is defined as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition. Traditionally epilepsy was diagnosed after a patient had two or more unprovoked seizures. However, a more modern definition of epilepsy would also include patients who have had an isolated seizure and have evidence for an enduring alteration in the brain that increases the likelihood of future seizures such as an ‘epileptiform’ electroencephalogram abnormality or an appropriate lesion on structural brain imaging (CT or MRI). Epilepsy cannot, though, be diagnosed unless there has been at least one clinical event compatible with an unprovoked seizure.
Narcolepsy
Authors: Walker Matthew C.
Published: February 2020

Narcolepsy with cataplexy is a specific syndrome of daytime sleepiness, disrupted nocturnal sleep, and episodes of sudden loss of muscle tone—provoked by the anticipation of emotions (in particular laughter)—leading to a tendency to fall, mouth opening, dysarthria or mutism, and facial muscle jerking. It is associated with loss of hypocretin (orexin) neurons in the hypothalamus, hypocretin concentrations in the cerebrospinal fluid below 110 pg/ml, and the HLA genotype DQ B1*0602. A less common form of narcolepsy without cataplexy probably has a different, as yet unknown, pathogenesis. Once established, narcolepsy is lifelong; spontaneous recovery does not occur. Symptomatic treatment—which is essential for school performance, work, driving ability, and quality of life—is with stimulant (e.g. amphetamine) and anticataplectic (e.g. clomipramine) drugs. More recently, sodium oxybate, an anaesthetic, has been used to induce deep sleep overnight, resulting in improvements in all symptoms.
Sleep disorders
Authors: Reading Paul J.
Published: February 2020

Dysfunctional sleep is an important cause of morbidity and is associated with numerous long-term health problems. Sleep-related symptoms can loosely be divided into insomnias, disorders causing excessive daytime sleepiness, and parasomnias, with some conditions having elements of all three categories. The need to sleep is imperative, reflecting the fact that sleepiness, similar to hunger and thirst, is a true drive state. Although its function remains largely elusive, disordered sleep can be associated with profound adverse effects on cognition, mental health, and physical well-being. Moreover, sleep-related symptoms are very common, with 25% of people reporting problems that significantly and regularly impact on daily activities.
Syncope
Authors: Larner Andrew J.
Published: February 2020

Syncope is the most common identified cause of transient loss of consciousness, being ten times more frequent than epilepsy. It is a consequence of cerebral hypoperfusion due to reduced cardiac output, often related to reduced venous return due to decreased peripheral vascular resistance with pooling of blood volume in dependent body parts. Diagnosis is clinical, based on history of the circumstances of the event obtained from the patient and reliable eyewitness(es). In most patients, particularly under 45 years of age, the condition is benign and self-limiting, with an excellent prognosis, requiring little investigation beyond physical examination and electrocardiogram to exclude heart disease. Cardiac causes of syncope may require specific treatment.
Brainstem death and prolonged disorders of consciousness
Authors: Ercole Ari , Hutchinson Peter J. , Pickard John D.
Published: February 2020

Advances in resuscitation and the advent of modern intensive care techniques to support the circulation challenge the simple definition of death in terms of loss of spontaneous circulation (‘cardiac death’). Instead, death is now better regarded as an irreversible loss of the capacity for consciousness combined with irreversible loss of the capacity to breathe. Since the brainstem is required for both consciousness and spontaneous breathing, irreversible loss of brainstem function (e.g. after trauma, haemorrhage, or hypoxia/ischaemia) defines the state of ‘brainstem death’. Clinical criteria for the diagnosis of brainstem death have been published, but practice varies around the world. Brainstem death lies at the extreme end of this spectrum and is, by definition, permanent. Unlike those with brainstem death, patients with prolonged disorders of consciousness may survive for many years without physiological support. The care of such patients has huge social, societal, ethical, and economic implications.
Visual pathways
Authors: Ajina Sara , Kennard Christopher
Published: February 2020

This chapter investigates visual disturbances, which may be caused by diseases of the optic disc, optic nerve, optic chiasm, optic tract, lateral geniculate nucleus, optic radiations, and occipital lobe of the brain, as well as other brain areas involved in complex visual processing. Diagnosis of disturbances of the visual pathways requires both knowledge of their anatomy and physiology, and the ability to carry out a thorough neuro-ophthalmological examination which should enable (1) documentation of the character and extent of the visual disturbance, and (2) topographic localization of the lesion, so that the relevant investigative techniques, such as radiological imaging, can be appropriately requested.
Eye movements and balance
Authors: Strupp Michael , Brandt Thomas
Published: February 2020

The disorders underlying vertigo and dizziness are often combined with disturbances of eye movements; reciprocal effects occur because of the anatomical and functional overlap of the vestibular and ocular motor systems. Therefore, both systems must always be tested in patients complaining of vertigo and dizziness. Using a systematic approach it is possible to make a correct diagnosis in more than 90% of patients. The history is of special importance and one should already have an idea, from the symptoms reported by the patient, what the underlying cause of the vertigo is in order to differentiate the different forms of peripheral, central and functional vestibular vertigo/dizziness and non-vestibular forms.
Traumatic brain injury
Authors: Lawrence Tim , Watkins Laurence
Published: February 2020

Traumatic brain injury is one of the leading causes of death and disability worldwide. It is an extremely heterogenous condition with respect to mechanism, pathophysiology, injury pattern, and investigation findings, with highly variable outcomes, posing a significant challenge to clinicians treating it.

Essential to the management of traumatic brain injury is an integrated, multidisciplinary approach from rapid resuscitation and early intervention through to rehabilitation. The pathophysiology can be divided into primary and secondary injury, where primary represents the injury at the point of trauma and secondary the progression of injury due to a cascade of downstream events occurring as a consequence of the primary injury and subsequent physiological insults.
Viral infections
Authors: McGill Fiona , Farrar Jeremy , Wills Bridget , De Jong Menno , Warrell David A. , Solomon Tom
Published: February 2020

This chapter looks at how enteroviruses are responsible for most cases of viral meningitis where a pathogen is identified; many other viruses can also cause meningitis with considerable geographical and seasonal variation. Their typical presentation is with sudden onset of fever, headache, neck stiffness, and photophobia. There is no change in conscious level. Prognosis is generally good, though recent data suggest not always. Viruses invade and damage the central nervous system in two ways: directly, by infecting the leptomeninges, brain, and spinal cord; and, indirectly, by inducing an immunological reaction resulting in para and postinfectious diseases. In both cases, the terms ‘meningitis’, ‘encephalitis’, and ‘myelitis’ are used alone or in combination.
Intracranial abscesses
Authors: Lawrence Tim , Kerr Richard S.C.
Published: February 2020

An intracranial abscess is a life-threatening condition. Although the incidence is low in countries where antimicrobial treatment for infections is widespread, they remain frequent causes of space-occupying masses in developing countries and, therefore, an important cause of death and disability. Early diagnosis and intervention is vital in reducing potential subsequent sequelae. This chapter describes how they can be broadly defined into three categories based on their anatomical location: extradural, subdural, and intraparenchymal. Aside from supportive care and (where possible) identification and treatment of any underlying cause, treatment requires (1) abscess drainage by image-guided surgical aspiration or excision by craniotomy, and (2) long-term antimicrobial therapy. Early intervention offers the best chance of recovery. Without intervention, intracranial abscesses are fatal. With appropriate treatment overall mortality is between 6.6% and 12.7%, depending on the surgical method used (aspiration compared with craniotomy, respectively). Long-term complications from neurological deficit and epilepsy remain frequent in survivors.
Diseases of the autonomic nervous system
Authors: Mathias Christopher J. , Low David A.
Published: February 2020

The autonomic nervous system innervates all organs, producing predominantly involuntary and automatic actions that are mediated by two principal efferent pathways, the sympathetic and parasympathetic, which are neurochemically and anatomically distinct. Numerous synaptic relays and neurotransmitters allow the autonomic control of organ function at local and central levels to be integrated with the requirements of the whole body. The peripheral and central components of the autonomic nervous system are frequently affected by diseases, conditions, or toxins. Autonomic disorders are described as (1) primary—without defined cause, including multiple system atrophy and acute/subacute dysautonomias; or (2) secondary—with specific defects or as a consequence of other conditions, including diabetes mellitus, Riley–Day syndrome, amyloid neuropathy, dopamine β-hydroxylase deficiency, spinal cord injury, and many drugs.
The motor neuron diseases
Authors: Jenkins Tom , Brockington Alice , Shaw Pamela J.
Published: February 2020

The motor neuron diseases can be considered an extended family of conditions with pathology affecting the lower and/or upper motor neurons, leading to clinical features of limb and/or bulbar weakness. Accurate diagnosis is essential to guide management, in particular, treatment options, any genetic implications, and prognosis. Amyotrophic lateral sclerosis is the family prototype and is a diffuse neurodegenerative disorder characterized by both upper and lower motor neuron cell death, causing progressive paralysis of limb, bulbar (speech and swallowing) and respiratory muscles, and resulting in death from respiratory failure. The cardinal clinical feature of combined upper and lower motor neuron signs in various body regions (bulbar, arms, trunk, legs) forms the basis for diagnostic criteria. There is no cure and the disease progresses relentlessly, with few patients surviving beyond 5 years from symptom onset.
Inherited neurodegenerative diseases
Authors: Sathe Swati
Published: February 2020

Many disorders of the nervous system, especially the degenerative conditions, have a genetic basis, which is usually due to a mutated gene resulting in decreased production of a critical structural or regulatory protein. Inherited neurodegenerative disorders present an enormous challenge because of the complexity of the nervous system, the broad clinical and genetic heterogeneity characteristic of these diseases, and the progressive and generally irreversible nature of their neuropathology. This chapter reviews and provides a guideline for inherited neurodegenerative disease. It is organized in a manner that a good neurological examination would be organized (i.e. systemic disorders followed by neurological disorders), discussed in a top-down manner (i.e. from cortex to muscle). Discussion of individual disorders starts with the molecular genetics, followed by molecular pathology, histology, clinical features, investigational findings, and management.
Disorders of the neuromuscular junction
Authors: Hilton-Jones David , Palace Jacqueline
Published: February 2020

This chapter looks at how two fundamentally different pathological processes are associated with disease at the neuromuscular junction: acquired disorders in which autoantibodies are directed against nerve or muscle receptor or ion channels; rare inherited conditions in which the defect may be pre- or postsynaptic. The acquired neuromuscular junction disorders are associated with antibodies directed against one of the ion channels. The fact that there are three autoimmune disorders known to affect such a small region may be explained by the neuromuscular junction, unlike the peripheral nerve, not being contained within the blood–nerve barrier, which stops just short of the nerve terminal, and thus being potentially exposed to circulating humoral attack. The inherited disorders may affect presynaptic processes (acetylcholine resynthesis, packaging, or release), acetylcholinesterase binding, or postsynaptic function (acetylcholine receptor numbers or localization). Pathogenic mechanisms are considered in more detail when discussing individual disorders.
Developmental abnormalities of the central nervous system
Authors: Verity Christopher M. , Hurst Jane A. , Firth Helen V.
Published: February 2020

This chapter deals with abnormalities that may result from failures at particular stages of central nervous system development. The brain and spinal cord arise from a sheet of cells that undergo transformations into the final complex structure. Failure of closure of the neural tube may result in anencephaly or spina bifida and failure of regionalization may cause holoprosencephaly. Disorders of neural proliferation or migration cause abnormalities of the cerebral cortex. There are distinct malformations of the posterior fossa structures and there are complex malformations that cannot be ascribed to just one abnormal step in development. The clinical problems associated with developmental abnormalities of the central nervous system are discussed and the approach to obtaining a clinical molecular diagnosis and providing genetic advice to the family is outlined.